General and Synthetic Methods Volume 11
A Specialist Periodical Report
General and Synthetic Methods Volume 11 A Review of the Literature Published in 1986 Senior Reporter G . Pattenden, Department of Chemistry, University of Nottingham Reporters K. Carr, University of Nottingham K. Cooper, Pfizer Central Research, Sandwich, Kent D.J. Coveney, University of Nottingham T. Gallagher, University of Bath L.M. Harwood, University of Oxford D.W. Knight, University of Nottingharn T.V. Lee, University of Bristol C.M. Marson, University of Sheffield K.E.B. Parkes, Roche Products Limited, Welwyn Garden City H erts. N. Simpkins, Queen Mary College, University of London S.E. Thomas, University of Warwick P.J. Whittle, Pfizer Central Research, Sandwich, Kent
SOClETY OF CHEMISTRY
ISBN 0-85 186-924-6 ISSN 0141-2140 Copyright 0 1989 The Royal Society of Chemistry All Ri
ritrenpermission from the Royal Society of Chemistry
Published by The Royal Society of Chemistry, Thomas Graham House, Cambridge, CB4 4WF Printed by J . W . Arrowsmith Ltd, Bristol, England.
Introduction
This report on General and Synthetic Methods covers the literature published between January and December 1 9 8 6 . The aim of the Reports has been to provide a summary and assessment of reactions and methods in organic chemistry which are new (or useful variants of existing ones) and appear sufficiently general to be useful in synthesis. Interconversions between all the major functional groups are covered in five chapters (Chapters 1-S), and the applications of organometallic compounds in synthesis are treated in Chapter 6 . Two further chapters deal with developments in the synthesis of saturated carbocycles (Chapter 7) and saturated heterocycles (Chapter 8 ) and the final chapter provides a summary of 'Highlights in Total Synthesis of Natural Products'. A list of reviews on General and Synthetic methods is collected at the end of the Report. January 1 9 8 9
G. Pattenden
Contents
Chapter 1
1
Saturated and Unsaturated Hydrocarbons
By N. S i r n p k i n s
Chapter 2
Saturated Hydrocarbons
1
Olefinic Hydrocarbons
1
Conjugated 1,3-Dienes
16
Non-conjugated Dienes
23
Allenes
25
Alkynes
28
Enynes and Diynes
31
Polynes
34
Reference
38
43
Aldehydes and Ketones
By K.E.B.
Parkes
1
Synthesis of Aldehydes and Ketones Oxidative Methods Reductive Methods Methods Involving Umpolung Other Methods Cyclic Ketones
43 43 46 49 53 56
2
Synthesis of Functionalised Aldehydes and Ketones Unsaturated Aldehydes and Ketones a-Substituted Aldehydes and Ketones Dicarbonyl Compounds
63 72
Protection and Deprotection of Aldehydes Ketones
75
3 4
63
67
and
Reactions of Aldehydes and Ketones Reactions of Enolates Aldol Reacti&s Conjugate Addition Reactions
76 76 78 80
References
83
vii
Contents
viii
Chapter 3
Carboxylic Acids and Derivatives
89
By D.W. K n i g h t Carboxylic Acids General Synthesis Diacids and Half-esters Hydroxy-acids Keto-acids Unsaturated Acids Aromatic Acids Arylacetic Acids and Esters Acid Anhydrides Carboxylic Acid Protection
89 89 94 96 101 101 103
2
Carboxylic Acid Esters Esterification General Synthesis Diesters Hydroxy-esters Keto-esters Unsaturated Esters Aromatic Esters Thioesters, Selenoesters, and Related Compounds
108 108 110 113 116 124 130 144 144
3
Lactones p-Lactones Butyrolactones a-Methylenebutyrolactones Butenolides Tetronic Acids Phthalides Valerolactones Macrolides
148 148 148 159 161 165 165 168 173
4
Carboxylic Acid Amides
175
5
Amino-acids a-Amino-acids p-Amino-acids y-Amino-acids Unsaturated Amino-acids Asymmetric Hydrogenation Amino-acid Protection
179 179 185 188 188 189
References
191
Alcohols, Halogeno Compounds, and Ethers
208
1
Chapter 4
By L . M .
1
105
107 107
189
Harwood
Alcohols Preparation by Additions to Alkenes Preparation by Reduction of Carbonyl Compounds Preparation by Nucleophilic Alkylation Miscellaneous Methods Protection and Deprotection Reactions of Alcohols
208 208 211 215 227 231 235
ix
Contents
Oxidat Lon Deoxygenation Miscellaneous Reactions
235 237 239
2
Halogeno-compounds Preparation from Alcohols Preparation by Addition to Unsaturated Substrates Interhalide Conversions Halogenation of a- to Carbonyl Groups Miscellaneous Methods Reactions Elimination and Dehalogenation Coupling Reactions Miscellaneous Reactions
239 239 239 241 242 242 244 244 246
3
Ethers Preparation Reactions
248 248 250
4
Thiols
252
5
Thioethers
252
References
254
Amines, Nitriles, and other Nitrogen-containing Functional Groups
262
Chapter 5
By C.M.
MarSOn
1
Amines Primary Amines Secondary Amines Tertiary Amines Diamines Polyamines
262 262 272 280 282 285
2
Enamines
288
3
Allylamines, Homoallylamines, and Alkynlamines
290
4
Amino-alcohols
295
5
Amino-carbonyl Compounds
299
6
Amides and Thioamides
313
7
Nitriles and Isocyanides
332
8
Nitro- and Nitroso-compounds
342
9
Hydrazines and Hydrazones
355
10
Hydroxylamines and Hydroxamic acids
358
11
Imines, Iminium Salts, and Related Compounds
361
12
Oximes
368
13
Carbodi-imides
369
Conrents
X
14
Azides and Diazo-compounds
369
15
Azo- and Azoxy-compounds
373
16
Isocyanates, Thiocyanates, and Isothiocyanates
375
17
Nitrones
377
18
Nitrates and Nitrites
378
References
378
Organometallics in Synthesis
393
Chapter 6
By S.E. Thomas and T. Gallagher PART I:
The Transition Elements
393
By S.E. Thomas 1
Introduction
393
2
Reduction
393
3
Oxidation
398
4
Isomerisations and Rearrangements
401
5
Carbon-carbon Bond-forming Reactions via Organometallic Electrophiles via Organometallic Nucleophiles via Coupling and Cycloaddition Reactions via Carbonylation Reactions
401 401 410 420 427
6
Miscellaneous Reactions
432
References
432
Main Group Elements
437
PART 11:
By T. Gallagher
1
Group I Selective Lithiation Dianions, Alkenyl, and Alkynyl Anions Sodium and Potassium Sulphur and Selenium Stabilised Anions.
437 437 446 453 455
2
Group I1 Beryllium, Magnesium, and Calcium Zinc and Mercury
465 465 467
3
Group I11 Boron Aluminium and Thallium
471 471 478
xi
Contents
4
Group IV Silicon Allyl, Propargyl, and Benzyl Silanes Vinyl, Alkynyl, and Allenylsilanes Other Silicon-containing Reagents Tin and Lead
480 480 480 485 490 493
5
Group V Phosphorus Antimony and Bismuth
497 497 501
6
Group VI Sulphur Selenium and Tellurium
501 501 507
References
508
Saturated Carbocyclic Ring Synthesis
518
Chapter 7
By T.V. Lee 1
Three-membered Rings General Methods
518 518
2
Four-membered Rings
518
3
Five-membered Rings General Methods Fused Five-membered Rings
523 523 528
4
Six-membered Rings Diels-Alder Reactions Other Syntheses of Six-membered Rings Polyene Cyclisation
535 535 538 541
5
Seven-membered, Medium, and Large Rings
541
6
Ring Expansion Methods and Spiro-ring Compounds
543
References
543
Saturated Heterocyclic Ring Synthesis
547
Chapter 8
By K. Cooper and P.J. Whittle
1
Oxygen-containing Heterocycles Three-membered Rings Five-membered Rings Tetrahydrofurans Dihydrofurans Five-membered Rings containing more than One Oxygen Six-membered Rings Tetrahydropyrans and Dihydropyrans Pyrans Polyether Ionophores Medium Rings
547 547 551 551 554 557 557 557 560 560 563
Contents
xii
2
Sulphur-containing Heterocycles
565
3
Heterocycles containing more than One Heteroatom Nitrogen- and Oxygen-containing Rings Nitrogen- and Sulphur-containing Rings Oxygen and Sulphur, and Oxygen-, Nitrogen-, and Sulphur-containing Rings
568 568 571
4
Chapter 9
571 571 571
Nitrogen-containing Heterocycles Three-membered Rings Five-membered Rings containing more than One Nitrogen Six-membered Rings Six-membered Rings containing more than One Nitrogen Seven-membered Rings p- Lactams
600 603
References
607
Highlights in Total Synthesis of Natural Products
612
588 588
600
By K. Carr, D.J. Coveney, and G. Pattenden 1
Terpenes
612
2
Steroids
624
3
Alkaloids
624
4
Prostaglandins
637
5
Spiroacetals
641
6
Ionophores and Macrolides
645
7
Other Natural Products
649
References
656
Reviews on General and Synthetic Methods
659
Compiled by K. Carr, D.J.
Coveney, and G. Pattenden
1
Esters and Lactones
659
2
Fluoroorganic Compounds
659
3
Ketenes
659
4
Nitrogen-containing Functional Groups
659
5
Organometallics
660
6
Carbocyclic Ring Synthesis
661
Xlll
Contents 7
Heterocycles
662
8
Natural Products
662
9
Asymmetric and Selective Synthesis
663
10
Enzymic Reactions
664
11
Reduction
664
12
Photochemistry, Electrochemistry, and Sonochemistry 664
13
Radical Chemistry
665
14
General
665
15
Miscellaneous
666
Author Index
668
A
Saturated and Unsaturated Hydrocarbons BY N. SlMPKlNS
1
Saturated Hydrocarbons
A new radical method for the deoxygenation of secondary alchols has
appeared.'
The method consists of first reacting the alcohol with 2,2'-dibenzothiazolydisulphide in the presence of Bu3P leading to
the corresponding sulphide derivative ( l ) , which is then reacted with Bu 3 SnH to give the hydrocarbon product in excellent yield (Scheme 1). A wide variety of aryl aldehydes and ketones can be deoxygenated by a mixture of Zn12 and NaCNBH3 in dichloroethane.2 The reagent also gives good results with benzyiic, allylic and tertiary alcohols, although attempted reduction of u,@-unsaturated ketones gave complex mixtures of products. Highly efficient conjugate reduction of a,@-unsaturated ketones and aldehydes is possible by use of a three component system comprising a palladium catalyst, a hydrosilane, and zinc chloride (Scheme 2) .3
The same task of conjugate reduction can be accomplished on unsaturated esters, usually in near quantitative yield, using magnesium in methanol. 2
Olefinic Hydrocarbons
The protonolysis of alkenyldialkylboranes to give 2-alkenes can be conducted, in most cases, under neutral conditions using methanol. More hindered alkenyldisiamylboranes react less well, unless a small amount of a carboxylic acid is added. A variety of Z-alkenyl pheromones was prepared using this method.6 The synthesis of trans-alkenes
and unsymmetrical ketones was also accomplished
using vinylic organoborane chemistry.' Cross-coupling reactions are now possible between aryl (or vinyl) halides and trialkylboranes by the use of catalytic palladium (Scheme 3 ) . 8 The reaction appears not to suffer from side reactions due to 6-hydride elimination which are normally observed in such processes. The reduction of allylic acetates to the 1
2
General and Synthetic Methods
Bu3 SnH, AlBN
R’
\
R S H 2
Scheme 1
U
C
H
O
Scheme 2
Y
@
____) 9BBN THF
[fi
AcO
“‘Y/ Pd’,
Scheme 3
NaOH
3
1: Saturated and UnsaturatedHydrocarbons
(2)
(3) i RCHO ii H ~ O +
t
C02Et
Scheme 4
Ar3p+r-
SiR,
+
RIACHO
R2
+RIA/ OSi R3
R
'
r
S
i
R
1
OSiR,
+
R2
R2 anti ( L ]
R* syn ( L )
(51
Scheme 5
'yo R'
Li
CICH21, MeL;
CL
Scheme 6
Li
-+
General and Synthetic Methoak
4
68 ' l o
CO2Si Et2Me
05 iEt2 Me 70 'lo Scheme 7
P
h
S
G
C
N
Bu'Li,
TMEDA
75"/0
P h S \ O / M .
56Ole Scheme 8
Scheme 9
5
I: Saturated and Unsaturated Hydrocarbons
corresponding alkenes has been reported using Sm12 with a Pd(0) catalyst. The reaction gave high yields of deoxygenated products: unfortunately, mixtures of regioisomers usually result. Brandsma has illustrated the use of a new and highly potent basic mixture comprising ButOK, BuLi and TMEDA, by efficient generation of vinylpotassium from ethene. l o Warren's examination of the Horner-Wittig reaction continues with two more papers detailing the stereoselective reduction of The phosphorane (2) is normally rather a - ~ ~ p- o ketones.'' unreactive: however addition of NaH produces the ylide anion (3) which reacts with aldehydes to give predominantly ?-products (Scheme 4) .I2 The homologation of esters via a DIBAL reduction and phosphonate extension sequence is a commonly desired transformation.
The DIBAL reduction to give an aldehyde suitable
for homologation is often plagued by over-reaction problems,so that a reduction-reoxidation procedure is often required.
These
problems can be overcome by the neat trick of carrying out the ester reduction in the presence of the phosphonate anion.13 The Seyferth-Wittig reagent often gives vinylated by-products ( 4 ) , as well as the usually desired allylsilanes (5) (Scheme 5). Efficient and stereoselective formation of the syn-vinylated product (4) can be promoted by choice of suitable groups on silicon.l4 Wittig-type olefination reactions can be carried out using tungsten alkylidene complexes,15 and by the use of & I situ generated chloromethyl lithium (Scheme 6) .l 6 Diiodo alkenes have been prepared __ via a Wittig-like reaction which requires no base.17 Me3SiC1 accelerates the reaction of both catalytic and stoichiometric copper reagents with unsaturated carbonyl compounds to give the desired silylenol ethers. l8 An extensive study of the C ~ ~ ( C O ) ~ - c a t a l y sreaction ed of acetates and lactones with CO and HSiEt2Me has appeared." This reaction constitutes a very general, mild and high-yielding synthesis of siloxymethylidene products (Scheme 7 ) . Vinyl sulphides are available by reaction of phenylthiocarbenes with nitrile anions.20 Yields on the whole are fair to good, and with some modification several intramolecular versions are possible (Scheme 8). Vinyl sulphides, vinyl selenides and ketene seleno(thi0) acetals are formed in high yield by reaction of an appropriate vinyl bromide or dibromide with PhSe- or PhS- in the presence of a Ni (11) catalyst. 21 6-Phenylthio-nitro-olefins have been prepared as mixtures of stereoisomers as shown in Scheme 9.22
6
General and Synthetic Methods
HR3, HR3 F
R’
6utLi
-120 R2
wR3
R’
PhSQN-BuL I
R’
OC
I
R2
Li
R2
F
71- 88% Scheme 10
H 66% Ref. 26 R’C=CR*+
MX e.g.X=F,Cl,I or SCN
hR1 RZ
Ref. 27
Ref. 28 Scheme 11
Ref. 29
7 3 *I. Scheme 12
Ref. 30
I: Saturated and Unsaturated Hydrocarbons
7
Me (PhMqSi)2 CuLi, THF
Me
Me
SiMe2Ph 96 *I*
-
Me Me>-,
Me
SiMe2Ph
99 Ye
Scheme 13
-RHHHH Bu3SnBEtjL i
RC=CH
R
+
THF, McOH, CuCN
SnBuJ
H
BusSn
H
(8 1 Scheme 14
L i-C=C
Et3B
-R1
Me3SnCI
Li+[Et3&CsC-R1]
D -
E128
SnMq
1
i. Bu"Li , CuBr SMeZ ii, R2 X
Et
?(%Me3
R1
Ref.35
- i , PriNMgBr
ii , TfZNPh
63 *I* Scheme 15
80% Ref. 36
8
General and Synthetic Methods
Oxidation of the sulphide ( 6 ) to either the corresponding SulPhOxide or sulphone was also possible, and the products were used in Diels-Alder reactions. Alkenyl fluorides are available by reaction of the corresponding lithio compound with N-tert-butyl-N-fiuoro-benzene sulphonamide (Scheme 10) .23 Two new reports extend the chemistry of fluorinated vinyl organometallics. In the first, trifluorovinyllithium is shown to be much more stable in Et20 (up to -30°C) than in THF.24 Remarkably, the other research paper by the same group reports that the corresponding zinc reagent F C=CF-ZnC1 is stable for several days
"
in THF at room temperature. These findinqs a1 lowed considerable extension to the synthetic repertoire of these reagents. A variety of fluorinated products, including perfluoroalkylated alkenyl iodides are available y&i a palladium-catalysed reaction between perfluoroakyl iodides (RfI) and alkynes.26 This method and two other routes to alkenyl iodides are outlined in Scheme 1 1 . The use of bis(pyridine)iodotetrafluoroborate (7) in conjunction with various metal salts gave good yields of the desired 1,2-iodofunctionalised olefins.27 Curran's notable contributions to radical chemistry continue with a novel reaction which isomerises hex-5-ynyl iodides to the product (iodomethylene)cyclo-pentanes.2 8 2,2-Disubstituted vinylsilanes have been prepared in reqio and stereoselective fashion by reaction of aryl iodides with This and alkynyl silanes in the presence of a palladium catalyst." another palladium-catalysed transformation leading to aryl vinysilanes3' are outlined in Scheme 12. The latter process, involving arylation of trimethylvinylsilane with aryl iodides takes place smoothly if silver salts are included in the mixture; otherwise styrenes are formed y & a presumed addition-desilylpalladation. The scope of the palladium mediated addition of silylstannanes to acetylenes highlighted last year has been further examined.31 Allenes react with bis(phenyldimethylsily1)cuprate to give either vinylsilanes or
allylsilanes depending on the structure of the allene (Scheme 1 3 ) .32 The intermediate ally1 or vinyl copper reagents could also be reacted efficiently with other electrophiles such as MeI, CH3COC1, etc. The addition of PhMe2SiBEt3Li or Bu3SnBEt3Li to acetylenes occurs cleanly using CuCN as catalyst (Scheme 14) .33 This stereospecific *-addition
also exhibits good
I: Saturated and Unsaturated Hydrocarbons
9
BU"
SiMe,
y'""
Pd(OAd2, BujSnOAc
Ph
+
( 9 ) 81%, 97% E Ref. 38
v0vo W h 3 ,
Ph
V
(11)
O
V
(101 74%
O
Ref. 39
Me3Si &OAc (11 1
Scheme 16
Scheme 17
Ref. 42
MeMg-N
Y
~
OMe
HO@:Tr
OMe 94%, Ref. 43 Scheme 18
10
General and Synthetic Methods
[ Rd] R'N=SePh
R
RNCS 'NH~
(14)
Scheme 19
Scheme 20 E
70%
Ref. 47
73%
Ref. 48
I: Saturated and Unsaturated Hydrocarbons
11
regioselectivity, especially if CoC12(PPh3)2 is employed in place of CuCN, in which case the terminal isomer (8) is the exclusive product. A related report from the same research group describes
another synthesis of vinyl silanes by reacting alkenyl halides with (R3Si)3MnMgMe.3 4 Two other notable entries to vinyl silanes have appeared and examples are shown in Scheme 15. The first sequence35 uses the known stereoselective boron to carbon migration of an alkyl group using Me3SnC1 as the electrophilic trap. The boron group is then selectively attacked using n-BuLi, CuBr-SMe2 to give the alkenyl copper which can then be coupled with either ally1 bromide or methyl iodide. In the other method36 enol triflates are coupled with distannanes in a similar fashion to the well-established reaction with organostannanes. A number of (1-cyclohexeny1)diphenylphosphine oxides were prepared by Diels-Alder reaction of 37 2 - ( d i p h e n y l p h o s p h i n y l ) - 1 , 3 - b u t a d i e n e with suitable partners. Allylically unsaturated cyclic ethers of the same general type have been prepared by the research groups of Overman3* and T r ~ s t . ~ ’ Thus suitably substituted vinyl silanes undergo Lewis acid mediated intramolecular attack on a methoxyethoxymethyl (MEM) ether to give cyclic products, e.g. (9) (Scheme 16). The preparation of (10) by use of the trimethylenernethane (TMM) reagent ( 1 1 ) (which will not normally react with carbonyl groups) was made possible by the addition of Bu SnOAc in catalytic quantities. 3 Allylic alcohols (12) are formed when a,fi-epoxy sulphides are treated with 3-5 equivalents of BuLi at - 7 0 ° C (Scheme 17) . 4 0 Interestingly, clean desulphurisation to give the epoxide product (13) was also possible by the use of less BuLi at - 1 0 0 ° C . Opening of vinylic epoxides by organomercurials, mediated by palladium also gives allylic alcohol^,^' as do two other new methods which use epoxides as starting materials (Scheme 18). Thus transformation of chloromethyl epoxides to 2-substituted allylic alcohols occurs on exposure to telluride ion.4 2 Methylmagnesium-N-cyclohexylisopylamide is a new, mild reagent for isomerisation of epoxides. 43 The scope of the synthesis of allylic amines and their protected derivatives via sigmatropic rearrangement of selenilimines ( 1 4 ) has been examined (Scheme 19) .44 The reaction works well unless very sterically conjested products are being formed, and has some advantages over the original Sharpless procedure which provided the products as sulphonamides. Allylic amines have also been prepared via palladium catalysed azidation of
General and Synthetic Methods
12
Scheme 22
OBn +
Ph
phkIy-*
PhMezSi
OLi
PhMezSi
MeCHO
--+
P h Me2Si Ph$
Me
(16)
(15) Scheme 23
-
SiMe,
-
90O l O -~iMe,
95 %
Scheme 24
AryAr NaCHZ?, THF
OAc
Pd, Ligand
*‘cA z
e.9. Z=coMe or C02Me Scheme 25
I: Saturated and Unsaturated Hydrocarbons
13 Ph
PhYNvco2Me i , LDA
Ph
(17)
Scheme 2 6
99 'Ie d .e. , 96% e.e. Ref. 61
(20)
I
OH
bH Ref. 60
Scheme 27
Bu3SnH, AlBN
85 'Ie
Scheme 28
14
General and Synthetic Methods
allylic acetatesI4’ and by an elegant nitrone route described by DeShong (Scheme 2 0 ) .46 Thus, reaction of nitrones with vinyl silanes followed by reduction provides Peterson - type or Eintermediates which can then be eliminated to either
z-
products. Homoallylic amines were also prepared using allylsilane in the initial cycloaddition. Substitution reactions of allylic nitro compounds have received considerable attention and some examples are outlined in Scheme 21. In each case, examination of the regiochemistry of the reaction was of paramount concern, the results using palladium being superior to the SnC14 mediated process. Allylic sulphides constitute yet another group of products accessible by palladium mediated allylation.50 Excellent yields of allylstannanes are obtained in a new ultrasound-promoted preparation, (Scheme 22) .” The method is highly attractive in its simplicity, and gives isomerically pure compounds in some cases. Fleming has described further work on the synthesis of allylsilanes. 52 Thus stereoselective aldol condensation of a @-silylenolate, e.g. ( 1 5 ) , with an aldehyde was followed by a decarboxylative elimination to provide the allylsilane stereoselectively (Scheme 23). The corresponding trans-allylsilane could also be prepared from (16) using an alternative elimination via the 6-lactone. Stereocomplementary sequences were also possible using the Z-enolate corresponding to (15). A survey of transition metal catalysts, and ligands identified [Ir-(COD) (PPh3)2] PF6 as the most efficient for the isomerisation of alkenyl silanes to allylsilanes (Scheme 2 4 ) .53 By-products of the reaction include vinyl silane and saturated silanes. A new electrochemical oxidative cleavage of allylsilanes and benzylsilanes produces allyl or benzyl ethers.5 4 Asymmetric modifications of the palladium-catalysed allylic alkylation reaction have appeared from several laboratories. Very good results were obtained in the reaction of racemic allylic acetates with soft carbon nucleophiles in the presence of optically active ferrocenylphosphine ligands (Scheme 25) .55 The products could be obtained in up to E. 90% ee and in high yield. Kinetic resolution of racemic allylic acetates was also found to be possible.56 A similar asymmetric process combines an allyl acetate with a prochiral nucleophile to give the chiral allylated product (Scheme 26) . 5 7 Using the Schiff base (17) derived from glycine, the allylated amino ester (18) was prepared in up to 5 7 % ee. Asymmetric preparations of homoallylic alcohols have also appeared, most notably by reaction of allylic tin complexes with aldehydes.58
I : Saturated and Unsaturated Hydrocarbons
- RT -MgBr, 0
RCECCH20H
Cur
H
w I
9 i,CI2ZnCpz, 2 k L i
H
p q o -
-
ii,CO
SiMe3
SiMe3
Scheme 29
87 Y o
4
B(OPr ' l2
Ph
59 ' l o
76 '10
Scheme 30
t
Scheme 31
other isomers
Ph
General and Synthetic Methods
16
Metallic zinc or iron in the presence of BiC13 can be used to mediate the reaction between allylic halides and aldehydes to give homoallylic alcohols. 59
The method displays notable chemoselectivity betweeen aldehydes and ketones, and alcohol or
phenol groups can be incorporated in the substrates without protection. Both Roush6O and Brown61 have published studies of the stereoselective synthesis of homoallylic alcohols using various allylboron reagents (Scheme 27).
Thus Brown made use of
5- or
E-crotyl diisopinocamphenylborones, e.9. (19) prepared in situ, to
-
give any of the four possible isomeric 6-methylhomoallyl alcohol products in excellent de and ee.
Scheme 27 also highlights Roush's
results using tartrate-modified crotylboronates such as (20) with chiral aldehydes.
A number of cyclic homoallyl alcohols were
obtained using radical cyclisation of vinyl radicals onto trimethylsilylenol ethers (Scheme 28).
62
The problem of stereoselective construction of exocyclic alkenes has been addressed by two methods, both-starting with alkynes. Thus stereoselective allylmetallation of propargyl alcohols yielded intermediates capable of further elaboration by zirconium
-
promoted bicyclisation - carbonylation (Scheme 29) .63
The other approach used the stereospecific conversion of an alkynyl trialkylborate to a trisubstituted olefin,
the migration of an
alkyl group from boron to carbon.64 3
Conjugated 1,3-Dienes
Hydrodimerisation of terminal alkynes to give symmetrical trans, trans
-
1,3-dienes can be carried out straightforwardly by use of a A wide
CoC12/NaBH4/PPh3 system65: internal alkynes are unaffected.
variety of conjugated dienyl products are available by employing the palladium
-
catalysed coupling of alkenyl boronates with Both mono- and
various ary1,vinyl or ally1 halides (Scheme 30) . 6 6
disubstituted alkenyl boronates can be employed in this sequence, thus allowing for a high degree of flexibility.
The same group of
research workers has also published some closely related work
(z,?)
enabling stereoselective synthesis of -l-bromo-l13-dienes.67 Various dienyl alcohols and lactones were amongst the products prepared by reaction of allylic acetates with carbonyl compounds (Scheme 31) . 6 8 The method suffers from a lack of selectivity, both stereo - and regio-isomers being formed in most cases.
A
variety
of l-nitro-lI3-dienes were prepared by treatment of the corresponding dienes with trifluoroacetyl nitrate (prepared
&
1: Saturated and Unsaturated Hydrocarbons
17
Scheme 33
LiAIH4, THF
*
R
t
G
4
R*
R3
H
(21)
Ref. 72
-
Me3Si
SBBN
Me3Si
->‘iBD
me351
Me3Si (22)
or isomer Ref.
73
Scheme 34 0
SiMej Scheme 35
0
General and Synthetic Methods
18
SiMe3 I
NMe,
(24)
(26)
Ref. 78 OAc
Me0
rCo /
\
Piperovatine
Scheme 37
Ref. 79
19
I: Saturated and Unsaturated Hydrocarbons
Rsk
RS
X = CL or F
Scheme 38
(27)
-p;
Scheme 39
-qp@cp
OCOzMe
Ph
74Ole Scheme 40
20
General and Synthetic Methods
e )followed , by
an elimination step using KOAc (Scheme 32) .69 The dienyl products are sensitive to both acid and base but can be purified by distillation or by flash chromatography on silica gel impregnated with sodium carbonate. A new short route to dienyl-tin products proceeds via hydrozirconation of conjugated enynes, followed by transmetallation using Bu3SnCl . 7 0 Vinyl triflates can be coupled efficiently to various organotin compounds. Further details of this chemistry have now appeared including efficient preparations of trimethylsilyldienes (Scheme 33) .71 Two other routes to silyldienes are outlined in Scheme 34. Reduction of allenic alcohols ( 2 1 ) gave moderate yields of the dienyl products, although the stereoselectivity of the process leaves much to be desired. The second method, involving hydroboration of the allene ( 2 2 ) is much more stereoselective and enables either isomer of the final product to be obtained depending on the elimination conditions used. A key application for such dienes is in Diels-Alder reactions, where the products have vinylsilane functionality for further modification. This type of chemistry has now been explored with 2,3-bis(trimethylsilyl)buta-l, 3-dieneI itself readily available by dimerisation of organolithium ( 2 3 ) (Scheme 35) . 74 Diels-Alder chemistry of the silyl-substituted diene (24)7 5 and of 2-tributylstanny1-1,3-butadiene (25)7 6 , has also been reported (Scheme 3 6 ) . Reaction of (24) with a suitable dienophile gives an intermediate, e.g. (26) which, after elimination, undergoes a second cycloaddition. The scope of the sequence is quite broad, enabling heterocycloadditions and (3+4) cycloadditions to be incorporated. The vinylstannanes resulting from cycloadditions with ( 2 5 ) are rather versatile, as was demonstrated by conversion to an a,B-unsaturated acid. Double elimination reactions of B-substituted sulphones provides access to both unfunctionalised d i e n e ~and ~ ~ to dienamides.78 The method is shown in Scheme 37 along with another dienamide preparation which utilises M O ( C O ) ~in a key elimination step.79 Other syntheses of such unsaturated carbonyls include the acylation reaction of bisalky1thio-lI3-alkadienes, and the use of 3-phenylselenobutanal as a crotonaldehyde equivalent in phosphonate reactions (Scheme 38) The latter sequence proved superior to that using crotonaldehyde which gave poor yields of difficult-to-purify material. A number of a-methlene lactams unexpectedly furnished novel
1: Saturated and UnsaturatedHydrocarbons
21
SO2Ph
I
-+p+) R‘
Scheme 41
Scheme 42
RXZnBr
R<
H
H
CuCN
I
i,,-dN ii, -Br
SnMej
ZnBr
Scheme 43
R
22
General and Synthetic Methoak
a
Ref. 89
0
-@ 150 "C, 36 h
Ref. 90
(30)81%
H
Ref. 91
Scheme 44
+ Scheme 45
66 % OCO2 Me
W15'
///
lu-
Tc4cozM c7 H15
0 5 *I. Scheme 46
23
1: Saturated and Unsaturated Hydrocarbons
dienes ( 2 7 ) on treatment with lithiated acetonitrile;92 these products proved useful in the synthesis of benzofurans (Scheme 39). Pyrrolidine dienes are available by cyclisation of appropriate amino-enynes.83 The method is particularly attractive for the construction of bicyclic systems relevant to natural products such as alkaloids (Scheme 40).
Depending on the substituents present in
the enyne substrate and the catalyst used, 1,4-dienes can also be produced. Finally, the regiochemical outcome of palladium catalysed alkylations of dienyl acetates and epoxides has been studied.84 Clean attack of soft nucleophiles at the terminus of dienyl epoxides was observed in the absence of overriding steric factors. 4
Non-Conjugated Dienes
The vinyl sulphones (28) and (29) act as versatile coupling agents, for example with unsaturated organocuprates (Scheme 41) . 8 5 Nucleophiles such as enolates can also be used, and the resulting products are readily desulphonated. The palladium mediated coupling of Grignard reagents with vinyl bromides is a well established procedure; since the E - vinyl bromides react faster than the ?-isomers, Z/E mixtures of these compounds can be used to provide E-coupled products of high purity. 8 6 By employing Grignard reagents with remote unsaturation, a number of non-conjugated dienes were synthesised using this method. Homocoupling of allylic halides or acetates can be carried out electrochemically to give aromatic 1,5-dienes, (Scheme 42) .87
The reaction simply converts
half of the starting material to the corresponding allyltin reagent; the current is then disconnected and the allylic partners allowed to react overnight. The mixed gem - dimetallic species described by Knochel and Normant allow attractive one-pot syntheses of a wide variety of unsaturated products, including dienes (Scheme 43) .88 The dimetallic species are initially generated by addition of an allylic zinc bromide to a vinyl metal. These species can then be reacted directly with various electrophiles, although carbon alkylation requires addition of CuCN. Scheme 44 outlines three new cycloaddition
-
type processes
which lead to cyclic non-conjugated dienes. The synthesis of methylene cyclopentenes by direct reaction of a TMM with an acetylene proved unsuccessful. Masking the acetylene by reaction with cyclopentadiene allowed efficient TMM reaction, the final
24
General and Synthetic Methods
F
Ph
68 % Scheme 47
-m
= J J J I
I
COzEt
COz Et Scheme 48
Me
Br
Et
H
Me B U M, ~
catalyst
Et Scheme 50
NaNOZ , a q . AcOH
Scheme 51
30 - 98'1e
25
I: Saturated and Unsaturated Hydrocarbons
product being released after flash vacuum thermolysis (FVT).
The
tricyclic product (30) is one of two main structural types available by new tropone-olefin cycloadditions. Both this chemistry, and Wender's [4+4I approachg1 offer stereoselective entries to polycyclic products suitable for natural products synthesis. 5
Allenes
Regioselective isomerisation of various hydroxyl - substituted acetylenes to hydroxyallenes has been possible by treatment with butyllithium followed by protonation with phosphoric acid (Scheme 45) . 9 2 The formation of (31) was favoured in most reactions tried, presumably due to the directing influence of the hydroxyl group present as the lithium anion. Palladium catalysis finds yet another fruitful application in the conversion of acetylenic carbonates to allenic products. The allenylpalladium complexes thought to be intermediates in this reaction can either be reduced to give simple allenesg3 or carbonylated to give allenic esters In some cases acetylenic or dienyl products were (Scheme 46) . 9 4 obtained, but these reactions appear to be generally very clean and high-yielding. A very similar transformation of propargylic acetates to allenes has also been reported, again using palladium, but this time in combination with Sm12,95 ref . 9 ) . Reactions of such palladium species with various carbon nucleophiles has also been examined, furnishing a wide range of allenic compounds including polyunsaturated products (Scheme 47) .9 6
(cf.
A new indole synthesis involves the intramolecular [4+2] cycloaddition of a suitable allene dienamide such as ( 3 2 ) (Scheme 48) . 9 7 Conversion of the initial cycloadducts through to the desired indoles was achieved using DDQ or activated Mn02. Whilst the eight-membered ring allene 1,2-cyclo-octadiene dimerises at ambient temperature, the compound with a t-butyi group at the allene terminus is stable indefinitely, but isomerises on treatment with acid or base.98 Previous work on intramolecular Sakurai reactions using allylsilanes has now been extended to include propargyl silanes.99 Using this method a number of bicyclic allene products were prepared in stereoselective fashion (Scheme 49). Chiral allenic products are obtained either by reaction of propargylic derivatives with Grignard reagents under copper catalysis'" or by reaction of organometal lics with
26
General and Synthetic Methods
R3B
+
LiCzCR'
I
__j
Li+[R3B-C=
C-R']
-
I
2 , R -CC=C-R'
Tic14
R e f . 105
86%
"t
99% e.e. Ref. 106
CO2 R
CCHO &-Br
Pd,Bu4N5r, TMSCI, DMF)
OH 83% Scheme 5 3
Ref. 107
27
I : Saturated and Unsaturated Hydrocarbons
Scheme 5 4
or
OR
SEt
Scheme 55
0
(36)
Scheme 56
(34)
28
General and Synthetic Methods
bromoallenes.lol In the second case, the stereochemical outcome of the reactions catalysed by nickel or palladium (highlighted last year) has been revised due to revision of the product stereochemistry, (Scheme 50). 6
Alkynes
The alkylation of terminal acetylenes using DMSO as solvent has been further examined. The reaction is effective only for acetylides with an "inductively stabilising group"; in other cases the alkylation of DMSO becomes the predominant pathway. Another established reaction which has been evaluated further in some detail is the remarkable conversion of isopropylidene olefins to alkynes under standard nitrosation conditions (Scheme 51). 103 A wide range of terpenoid and non-terpenoid olefins will react, providing the (CH3 ) 2C=CHCH2- subunit is present. A flood of full details concerning recent developments in organoboron chemistry is emanating from the laboratories of H.C. Brown. Of particular relevance here is the detailed description of alkyne synthesis reaction of alkynyl organoborates with iodine (Scheme 52) . I o 4 This chemistry provides excellent access to a wide variety of simple and functionalised alkynes, the products here being suitable for pheromone synthesis. Homopropargylic alcohols are available by reaction of carbonyl compounds with allenyl silanes.lo5 Full details of this chemistry include preparations of variously substituted allenysilanes together with methods for their reaction using TiC14. The same compounds are available in optically active form by use of chiral allenylboronic esters. l o 6 This method is rather similar to the chemistry outlined in Scheme 27 for the preparation of homoallylic alcohols. A third method for the preparation of homoallylic alcohols involves the lead-promoted Barbier - type reaction of propargyl bromide with aldehydes. l o 7 An example of each of these methods is shown in Scheme 53. High Cram selectivity was observed in the reaction of stannylacetylenes with a steroidal aldehyde to give the corresponding propargyl alcohol. lo' A four-step procedure for the asymmetric reduction of acetylenic ketones to the corresponding propargylic alcohols involves cleavage of intermediate chiral acetals (33) (Scheme 5 4 ) . I o 9 The method, although effective, has the disadvantage of involving destructive removal of the chiral pentanediol.
I: Saturated and Unsaturated Hydrocarbons
29
M = Li or MgBr Scheme 57
x R-CEC-OTS
\
Bu3Sn\
BU-JSnCl
)cc=o
R
Scheme 58
EtZAl
-e - C 5 H l l
AIC13, EtZO, Cl-
CI
SO2Ph
iii I %"ll
Scheme 59 R RwBr
Si Me3
R -C
C -Z n CI [W(PP$,4 1
Scheme 60
30
General and Synthetic Methods
SiMe3
I
Ill
R
-+
+-Scheme 61
Si Me3
MeSSi
\
OH
OSi Ph2
(Z) Scheme 62
\SiMe,
31
I: Saturated and Unsaturated Hydrocarbons
More highly functionalised chiral propargyl alcohols are available by the chiral pool approach. For example, both fragments (34) and (35) were prepared from D-xylose, as intemediates for the synthesis of LTB4 (Scheme 55) .ll' A final propargylic alcohol preparation involves reaction of a fluorinated vinyl phosphonate with aldehydes, mediated by a mixture The reaction occurs of TBAF and (Me3Si)2O (Scheme 56) .ll' elimination of FP(0) (OEt) from (36) to form the correspondinq acetylene, which can then condense with the aldehyde after deprotonation by Me3SiO-. Acetylenic ketones are produced from the reaction of vanadium acetylides with aldehydes (Scheme 57) . l I 2 The reaction is thought to involve addition of the dichlorovanadium acetylide to the aldehyde followed by oxidation of the vanadium alkoxide intermediate. Another new acetylide reaction uses the aluminium derivatives which open propiolactones to give 13-alkynyl propionic acids. Two papers describe some new chemistry of alkynolates. In the first,l14 these species are generated by treatment of alkynyl tosylates with MeLi. Trapping on carbon or oxygen is then possible, depending on the electrophile used (Scheme 58). The other report also prepares alkynol silyl ethers, although via a different route.'" Interestingly, using TMSC1, the kinetically formed alkynol ether was found to isomerise on warming to the silylated ketene. 7
Enynes and Diynes
Trost has disclosed some new chemistry of allylic sulphones which allows for highly selective substitution of the sulphone group by certain organo-metallics.l16 Amongst the products which can be synthesised are non-conjugated enynes, e.g. Scheme 59. The palladium - catalysed coupling of organometallics, e.g. Grignards, with vinyl halides (cf. ref.86) has been extended to include alkynylzinc chloride reagents (Scheme 60). Both silylated E enyne~''~ and diynenes118 were prepared in high isomeric purity and in very good yields. Again, since the E-vinyl halides react faster, mixtures of geometric isomers can be used to obtain pure g-products. A very elegant stereoselective preparation of conjugated dienynes utilises a [ 2 , 3 ] Wittig rearrangment - Peterson As can be seen, both the olefination sequence (Scheme 61) .I1'
3-2
32
General and Synthetic Methoa3
OH C02Me
R
Scheme 63
/
/
(39)
S c h e m e 64
1: Saturated and Unsaturated Hydrocarbons
33
R
(40)
''
Scheme 65
R-C-C-StR'
-
Zn TMSa I
QC,
CI
ZnCI Zn, TMSCl
Scheme 67
General and Synthetic Methoak
34
and 3-E products are available using either of the stereocomplementary elimination conditions for the Peterson reaction. Another Wittig rearranement, this time with the silicon substituent 0- to the ether linkage, ultimately provides a non-conjugated 2-enyne, (Scheme 62) .120 Here the trimethylsilyl group is vital in controlling the resulting olefin geometry, which contrasts to that obtained in Scheme 61, and in related rearrangements without the silicon group. This chemistry is just one of many recent approaches to leukotrienes or fragments thereof. In another approach, conjugated dienynes were constructed by coupling protected propargyl alcohols with dienyl chlorides (Scheme 6 3 ) .12'
Thus a dihydro L T B 4 methyl ester (37) as well as other stereoisomers of this system were available, potentially in chiral form using the chiral fragments ( 3 4 ) and (35) mentioned earlier. Dienyl triflates can also be used in such couplings to give the same type of products.'22 In syntheses of the naturally occurring enynes cis- and trans laurediol, (38) and (39), the key coupling step involved reaction of a protected propargylic Grignard reagent with a propargylic bromide (Scheme 64) The asymmetric centres in these products were set up using the Sharpless asymmetric epoxidation procedure. A number of unusual ynenol lactones have been synthesised by an
iodolactonisation - palladium coupling sequence (Scheme 65). 1 2 4 The Z-isomers of the final products were also prepared y & the Z-iodolactones (2-40) which were in turn available by isomerisation of the E-isomers with iodine. Finally, dimerisation of acetylenes to symmetrical diynes is now possible by oxidation of acetylenic selenides (Scheme 66) reaction proceeds only if R is aromatic or vinylic.
8
The
Polynes
Conjugated trienes are amongst the products accessible via the Zn/TMSCl mediated dimerisation of carbonyl substrates, including a, @-unsaturated ketones. 126 The reaction is thought to proceed via the formation of an organozinc carbenoid which combines with a second equivalent of carbonyl substrate to produce an intermediate epoxide, which then undergoes deoxygenation, (Scheme 67). McMurry has detailed further chemistry of the unusual cyclic triene ( 4 1 ) and its X-ray analysis.12' A variety of polyene natural products have again attracted synthetic interest. The polyprenol bacterialprenol ( 4 2 ) has been
1: Saturated and Unsaturated Hydrocarbons
35
Hmm o H N i.(44)
So, TOI
OH
(45)
(43)
I I I
9
H
CI
r
i t -
0-Ph
1
36
General and Synthetic Methodr
OH
I: Saturated and Unsaturated Hydrocarbons
37
(48)
(49)
HO (50) Scheme 70
38
General and Synthetic Methods
prepared by coupling of fragments using sulphone alkylation,
.
(Scheme 68) 128 Thus (E,E)-farnesyl-p-tolylsulphone (43) was coupled with chloride (44) to give, after deprotection/ desulphonylation, the alcohol (45). This in turn was converted to the corresponding sulphone and again coupled with the chloride (44), giving the natural product following reduction.
The absolute configuration of (-)-botyococcene (46) has been established, following matching of fragments obtained by oxidative degradation with ones prepared by unambiguous synthetic routes. 129 A further synthesis of (2)-fecapentaene (47) has appeared which delivers the product in the pure all-trans,crystalline form, S cheme 69) .I3' Further syntheses of the lipoxins have appeared, for example of lipoxin B (48),131 and of epoxide (49), a possible biosynthetic precursor to lipoxins A and B . 1 3 2 The sesterterpene ircinianin (50) has been synthesised a a biogenetic pathway involving IMDA reaction of the triene tetronic The triene unit was constructed using a acid (51) (Scheme 70) Julia reaction, whilst the tetronic acid portion was attached using an aldol-type reaction of methyl-2-methyltetronate. Finally more chemistry aimed at the synthesis of the polyene macrolide Amphoterocin B has appeared. 1 3 4
References 1.
Y-Watanabe, T.Araki, Y.Ueno, and T.Endo, Tetrahedron Lett.,
2.
C.K.LaE C.Dufresne, P.C.Belanger, S.Pietre, and J.Scheigetz,
1986, 27, 5385. 3. 4. 5. 6. 7. 8. 9.
H.C.Brown and G.A.Molander, J. Org. Chem., 1986, 51, 4512. H.C.Brown and K.K.Wang, J. Org. Chem., 1986, 51, 4514. H.C.Brown, D.Basavaiah, S.U.Kulkarni, H.D.Lee,E.Negishi, and J-J.Katz, J. Org. Chem., 1986, 51, 5270. N-Miyaura, T-Ishiyama, M.Ishikawa, and A.Suzuki, Tetrahedron Lett., 1986, 27, 6369. m b u c h i , J.Eanaga, and M.Yamaguchi, Tetrahedron Lett., 1986 27, 601; J.Tsuji, I.Minami, and I.Shimizu, Synthesis, 1 9 8 6 , 623.
10.
11. 12.
13. 14.
L.Brandsma, H.D.Verkruijsse, C.Schade, and P. von Rague Schleyer, J. Chem. SOC., Chem. Commun., 1986, 260. J.Elliott and S. Warren, Tetrahedron Lett., 1986, 27, 645; N.Greeves and S.Warren, P259. K.M.Pietrusiewicz and J.Monkiewicz, Tetrahedron Lett., 1986,
w.,
27, 739. -
J.M.Takacs, M.A.Helle, and F.L.Seely, Tetrahedron Lett., 1986,
27, 1257. -
M.Tsukamoto, H.Iio, and T.Tokoroyama, J. Chem. SOC., Chem. Commun., 1986, 880.
39
I: Saturated and Unsaturated Hydrocarbons
15. 16.
A.Aguero, J.Kress, and J.A.Osborn, J. Chem. Soc., Chem. Commun., 1986, 531. J-Barluenqa, J.L.Fernandez-Simon, J.M.Concellon, and M.Yus, J.Chem. SOC., Chem.Commun., 1986, 1665. F-Gavina, S.V.Luis, P.Ferrer, A.M.Costero, and J.A.Marco, J. Chem. Research ( S ) , 1986, 330. Y.Horiguchi, S.Matsuzawa, E.Nakamura, and I.Kuwa]ima, Tetrahedron Lett., 1986, 27, 4025, E.Nakamura, S.Matsuzawa, Y.Horiguchi, and I.KuwajiG, P4029. N.Chatani, S.Fujii, Y.Yamasaki, S.Murai, and N.Sonoda, J. Am. Chem. SOC., 1986, 108, 7361. T.Harada, A-Karasawa, and A.Oku, J . Org. Chem., 1986, 51, 842. J. H.J.Christau, B.Chabaud, R-Labaudiniere, and H. Christ=, Org. Chem., 1986, 11, 875. N.Ono, A.Kamimura, and A-Kaji, J. Org. Chem., 1986, 51, 2139. S.H.Lee and J.Schwartz, J. Am. Chem. Soc., 1986, 108,2445. J.P.Gillet, R.Sauvetre, and J.F.Normant, Synthesis., 1986, 355. J.P. Gillet, R.Sauvetre, and J.F.Normant, Synthesis, 1986, 538. T.Ishihara, M.Kuroboshi, and Y.Okada, Chem. Lett., 1986, 1895. J.Barluenga, M.A.Rodriguez, J.M.Gonzalez, P.J.Campos, and G. Asensio, Tetrahedron Lett., 1986, 27, 3303. D.P.Curran, M-H.Chen, and D.Kim, J T A m . Chem. SOC., 1986, 108, 2489. A.Arcadi, S.Cacchi, and F.Marinelli, Tetrahedron Lett., 1986, 27, 6397. .K-Karabelas and A-Hallberg, J. Org. Chem., 1986, 51, 5286. B.L.Chenard and C.M.Van Zyl, ________ J. Org. Chem., 1 9 8 6 , ~ 1 - ,3561. 1.Fleming and F.J.Pulido, J. Chem.=., Chem. Commun., 1986, 1010. K.Nozaki, K.Wakamatsu, T.Nonaka, W.Tuckmante1, K.Oshima, and K.Utimoto, Tetrahedron Lett., 1986, 27, 2007. K.Fugami, K.Oshima, K.Utimoto, and H-ozaki, Tetrahedron Lett., 1986, 27, 2161. K-H. Chu and K.K.Wanq, J. Org. Chem., 1986, 51, 767. W.D.Wulff, G.A.Peterson-, W.E.Bauta, K-S. Chan, K.L.Faron, S.R.Gilbertson, R.W.Kaesler, D.C.Yang, and C.K.Murray, J . Org. Chem., 1986, 51, 277. T.Minami, T.Chikugo, and T.Hanamoto, J. Orq. Chern., 1986, 51, 2210. L.E.Overman, A.Castaneda, and T.A.Blumenkopf, J. Am. Chem. SOC., 1986, 1303. B.M.Trost and S.A.King, Tetrahedron Lett., 1986, 27, 5971. T.Satoh, Y.Kaneko, and K.Yamakawa, Tetrahedron Lett., 1986, 27, 2379. R.C.Larock and S.J.Ilkka, Tetrahedron Lett., 1986, 27, 2211. G-Polson and D.C.Dittmer, Tetrahedron Lett., 1986, 27, 5579. P.Mosset, S.Manna, J.Viala, and J.R.Falck, Tetrahedron L e s . , 1986, 27, 299. A.Spaltenstein, P.A.Carpino, and P.B.Hopkins, Tetrahedron Lett., 1986, 3, 147; R.G.Shea, J.N.Fitzner, J.E.Fankhauser, A.Spaltenstein, P.A.Carpino, R.M.Peevey, D.V.Pratt, B.J.Tenge, and P.B.Hopkins, J . Org. Chem., 1986, 5243. S-1-Murahashi, Y.Tanigawa, Y.Imada, and Y.Tanaguchi, Tetrahedron Lett., 1986, 27, 227. P.DeShong, J.M.Leginus, and S.W.Lander, Jr., J. Org. Chem., 1986, 51, 574. R.Tamura, Y.Kai, M-Kakihana, K-Hayashi, M.TsuJi, T.Nakamura, and D.Oda, J. Org. Chem., 1986, 51, 4375. N.Ono, I.Hamamoto, A.Kamimura, and A.Kaji, J. Org. Chem., 1986, 51, 3734. H.Miyake and K.Yamamura, Tetrahedron Lett., 1986, 27, 3025. B.M.Trost and T.S.Scanlan, Tetrahedron Lett., 1986,c, 4141. .______
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.
w.,
s.,
~
z,
45. 46 47. 48. 49. 50.
General and Synthetic Methods
40
51. 52. 53. 54. 55. 56. 57. 58.
-
59 60. 61.
Y.Naruta, Y.Nishigaichi, and K.Maruyama, Chem. Lett., 1986, 1857. 1-Fleming and A.K.Sarkar, J. Chem. S O C . , Chem. Commun., 1986, 1199. I.Matsuda, T.Kato, S.Sato, and Y.Izumi, Tetrahedron Lett., 1986, 27, 5747. J - Y o s h x a , T.Murata and S.Isoe, Tetrahedron Lett., 1986, 27, 3373. T.Hayashi, A.Yamamoto, T.Hagihara, and Y.Ito, Tetrahedron Lett., 1986, 27, 191. Z y a s h i , A.Emamoto, and Y.Ito, J. Chem. SOC., Chem. Commun., 1986, 1090. J.P.Genet, D.Ferroud, S.Juge, and J.R.Montes, Tetrahedron Lett., 1986, 27, 4573. T.Mukaiyama, N.Minowa, T.Oriyama, and K.Narasaka, E. Lett., 1986, 97; G.P.Boldrini, E.Tagliavini, C.Trombini, and A.Umani-Ronchi, J. Chem. S O C . , Chem. Commun., 1986, 685. M.Wada, H.Ohki, and K.Akiba, Tetrahedron Lett., 1986, 27, 4771. W.R.Roush, M.A.Adam, A.E.Walts, and D.J.Harris, J. Am.Chem. S O C . , 1986, 108, 3422. H.C.Brown and K.S.Bhat, J. Am. Chem. S O C . , 1986, 108, 5919; ibid., P293. H.Urabe and Isao Kuwajima, Tetrahedron Lett., 1986, 27, 1355. E-Negishi, Y.Zhang, F.E.Cederbaum, and M.B.Webb, J. Org. Chem., 1986, 51, 4080. E.J.Corey and W.L.Seibe1, Tetrahedron Lett., 1986, 27, 905. N.Satyanarayana and M-Periasamy, Tetrahedron Lett., 1986, 27, 6253. N.Miyaura, M.Satoh, and A.Suzuki, Tetrahedron Lett., 1986, 27, 3745; M.Satoh, N.Miyaura, and A.Suzuki, Chem. Lett., 1986, 1329. S.Hyuga, S.Takinami, S.Hara, and A.Suzuki, Tetrahedron Lett., 1986, 27, 977; S.Hyuga, S.Takinami, S.Hara, and A.Suzuki, Chem. Lett., 1986, 459. T.Tabuchi, J.Inanaga, and M.Yamaguchi, Tetrahedron Lett., 1986, 27, 1195. A.J.Bloom and J.M.Mellor, Tetrahedron Lett., 1986, 27, 873. M.D.Fryzuk, G.S.Bates, and C.Stone, Tetrahedron Lett., 1986, 27, 1537. TJ.Scott and J.K.Stille, J. Am. Chem. SOC., 1986, 108, 3033. K.K.Wang, S.S.Nikam, and M.M.Marcano, Tetrahedron Lett., 1986, 27, 1123. C.Liu and K.K.Wang, J. Org. Chem., 1986, 51, 4733. P.J.Garratt and A.Tsotinis, Tetrahedron Lett., 1986, 27, 2761. A.Hosomi, K.Otaka, and H.Sakurai, Tetrahedron Lett., 1986, 27_, 2881. M.Taddei and A.Mann, Tetrahedron Lett., 1986, 27, 2913. J.Otera, H.Misawa, and K.Sugimoto, J. O r g . C h e E , 1986, 51, 3830. T.Mandai, T.Moriyama, K.Tsujimoto, M.Kawada, and J.Otera, Tetrahedron Lett., 1986, 27, 603. R.J.Blade and J.E.RobinsoC Tetrahedron Lett., 1986, 27, 3209. M.Hojo, R.Masuda, and E.Okada, Tetrahedron Lett., 27, 353. S.Hanessian, P.J.Hodges, S.P.Sahoo, and P.J.Roy, ______ Tetrahedron Lett., 1986, 27, 2949. A.W.Murray, N.D.Murray, and R.G.Reid, J. Chem. S O C . , Chem. Commun., 1986, 1230. B.M.Trost and S-F.Chen, J. Am. Chem. S o c . , 1986, 108, 6053. B.M.Trost, C.J.Urch, and M-H.Hung, Tetrahedron Lett., 1986, 27, 4949. P.Auvray, P.Knoche1, and J.F.Normant, Tetrahedron Lett., 1986, 27, 5095. ~
62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85.
I : Saturated and Unsaturated Hydrocarbons 86. 87. 88. 89.
R.Rossi and A.Carpita, Tetrahedron Lett., 1 9 8 6 , 2 7 , 2 5 2 9 . J.Yoshida, H.Funahashi, H.Iwasaki, and N.KawabatZ Tetrahedron Lett., 1 9 8 6 , 27, 4 4 6 9 . P.Knoche1 and J.F.Normant, Tetrahedron Lett., 1 9 8 6 , 27, 4 4 2 7 ; ibid, P 4 4 3 1 . B.M.TrOSt, J.M. Balkovec, and S.R.Angle, Tetrahedron Lett., 1986,
90. 91. 92.
94.
27, 1 4 4 5 .
fun funk and ~ . ~ . ~ o l t oJ.n ,m. Chem. Soc., 1 9 8 6 ,
108, 4 6 5 5 .
P.A.Wender and N.C.Ihle, J. Am. Chem. SOC., 1 9 8 6 , 108, 4 6 7 8 . M.Enomoto, T-Katsuki, and M.Yamaguchi, Tetrahedron Lett., 1 9 8 6 , 27,
93.
41
4599.
T T s u j i , T.Sugiura, M.Yuhara, and I.Minami, J. Chem. SOC., Chem. Commun., 1 9 8 6 , 9 2 2 . J.Tsuji, T.Sugiura, and I.Minami, Tetrahedron Lett., 1 9 8 6 ,
27,
731. 95. 96. 97 -
T.Tabuchi, J.Inanaga, and M.Yamaguchi, Tetrahedron Lett., 1 9 8 6 , 27, -
5237.
E.Keinan and E.Bosch, J. Org. Chem., 1 9 8 6 , 51, 4 0 0 6 . K.Hayakawa, T.Yasukouchi, and K.Kanematsu, Tetrahedron Lett., 1986,
27, 1 8 3 7 .
J.D.Price and R.P.Johnson, Tetrahedron Lett., 1 9 8 6 , 27, 4 6 7 9 . D.Schinzer, J.Stef€en, and S.Solyom, J. Chem. S O C . , Chem. Commun., 1 9 8 6 , 8 2 9 . 1 0 0 . I.Marek, P.Mangeney, A.Alexakis, and J.F.Normant, Tetrahedron
98. 99.
=.,
1 9 8 6 , 27, 5 4 9 9 . 1 0 1 . A.M.Caporusso, L-Lardicci, and F.Da Settimo, Tetrahedron Lett., 1 9 8 6 , 27, 1 0 6 7 . 1 0 2 . J.M.Chong and S.Wong, Tetrahedron Lett., 1 9 8 6 , 2 7 , 5 4 4 5 . 1 0 3 . S.L.Abidi, Tetrahedron Lett., 1 9 8 6 , 2 7 , 2 6 7 . 1 0 4 . H.C.Brown, D.Basavaiah, and N.G.Bhat, J. Org. Chem., 1 9 8 6 , 5.1, 4518; J.A.Sikorski, N.G.Bhat, T.E.Cole, K.K.Wang, and H.C.Brown, ibid., P 4 5 2 1 ; A.Suzuki, N.Miyaura, S.Abiko, M.Itoh, M.M.Midland,A.Sinclair, and H.C.Brown, ibid., P 4 5 0 7 ; C.A.Brown, M.C.Desai, and P.K.Jadhav, i b i d . , 2 1 6 2 . 1 0 5 . R.L.Danheiser, D.J.Carini, and C.A.Kwasigroch, J . Org. Chem., 1986, 3870. 1 0 6 . N.Ikeda, I.Arai, and H-Yamamoto, J. A m . Chem. SOC., 1 9 8 6 , 108, 483. 1 0 7 . H.Tanaka, T.Hamatani, S.Yamashita, and S.Torii, Chem. Lett., 1986, 1461. 1 0 8 . Y.Yamamoto, S-Nishii, and K.Maruyama, J. Chem. SOC., Chem. Commun., 1 9 8 6 , 1 0 2 . 1 0 9 . A.Mori, K.Ishihara, and H.Yamamoto, Tetrahedron Lett., 1 9 8 6 , 2 7 , 9 8 7 ; K.Ishihara, A.Mori, I.Arai, and H.Yamamoto, Tetrahedron Lett., 1 9 8 6 , 2 7 , 9 8 3 . 1 1 0 . m a n e t t i , Pxollin, and J.R.Pougny, Tetrahedron Lett., 1 9 8 6 , 27, 5853. 111. T-Ishihara, T.Maekawa, and T.Ando, Tetrahedron Lett., 1 9 8 6 , 357 * 1 1 2 . T.Hirao, D-Misu, and T.Agawa, Tetrahedron Lett., 1 9 8 6 , 933. 1 1 3 . M.Shinoda, K.Iseki, T-Oguri, Y-Hayasi, S.Yamada, and M.Shibasaki, Tetrahedron Lett., 1 9 8 6 , 2 7 , 87. 1 1 4 . P.J.Stang and K.A.Roberts, J. Am. ChemTSoc., 1 9 8 6 , 7125. 1 1 5 . C.J.Kowalski, G.S.La1, and M.S.Haque, J. Am. Chem. SOC., 1 9 8 6 , 27, 7127. J. Am. Chem. SOC., 1 9 8 6 , 1098. 1 1 6 . B.M.Trost and M.R.Ghadiri, _________ 1 1 7 . B.P.Andreini, A.Carpita, and R.Rossi, Tetrahedron Lett., 1 9 8 6 , 27, 5533. 118. A-Carpita and R.Rossi, Tetrahedron Lett., 1 9 8 6 , 27, 4 3 5 1 . 1 1 9 . K-Mikami, T.Maeda, and T.Nakai, Tetrahedron Lett., 1 9 8 6 , 21, 4189.
x,
27,
27,
108, 108,
General and Synthetic Methods
42
120. A.D.Kaye, G.Pattenden, and S.M.Roberts, Tetrahedron Lett., 1986, 27, 2033. Tetrahedron _ _ _ _ _ _ Lett., ~ 1986, 27, 121. D.GuilErm and G.Linstrumelle, _ 5857 122. S-Cacchi, E-Morera, and G.Ortar, Synthesis, 1986, 320; for another preparation of dienynes from enol triflates see: L. Castedo, A.Mourino, and L.A.Sarandeses, Tetrahedron Lett., 1986, 27, 1523. 123. B.Anorbe, V.S.Martin, J.M.Palazon, and J.M.Trujill0, Tetrahedron Lett., 1986, 27, 4991. 124. R.W.Spencer, T.F.Tam, E.Thomas, V.J.Robinson, and Allen Krantz, J. Am. Chem. SOC., 1986, 108, 5589. 125. J.V.Comasseto, V.Catani, J.T.B.Ferreira, and A.L.Braqa, JChem. SOC., ______ Chem. Commun., 1986, 1067. 126. A.K.Banerjee, M.C.Sulbaran de Carrasco, C.S.V.Frydrych-Houge, and W.B.Motherwel1, J.Chem. S O C . , Chem. Commun., 1986, 1803. 127. J.E.McMurry, G.J.Haley, J.R.Matz, J.C.Clardy, G.Van Duyne, R.Gleiter, W.Schafer, and D.H.White, J. Am. Chem. SOC., 1986, 108, 2932. 128. sate, O.Miyamoto, S.Inoue, Y.Matsuhashi, S.Koyama, and T.Kaneko, J. Chem. SOC., Chem. Commun., 1986, 1761. 129. J.D.White, T.C.Somers, and G.Nagabushana Reddy, J. Am. Chem. SOC., 1986, 108, 5352. 130. s . P f a e n d l e r , F.K.Maier, and S.Klar, J. Am. Chem. S O C . , 1986, 108, 1338. __ 131. K.C.Nicolaou and S.E.Webber, Synthesis, 1986, 453. Tetrahedron Lett., 1986, 5173; 132. E.J.Corey and M.M.Mehrotra, _________ K.C.Nicolaou and S.E.Webber, J. Chem. S s . , Chem. Commun., 1986, 1816. 133. K.Takeda, M.Sato, and E.Yoshii, Tetrahedron Lett., 1986, 17, 3903. 134. B.M.Trost, P.Metz, and J.T.Hane, Tetrahedron Lett., 1986, 27, P5695; K.C.Nicolaou, T.K.Chakraborty, R.A.Daines, 5691; and N.S.Simpkins, J. Chem. SOC., Chem. Commun., 1986, 413.
z-,
m.,
2 Aldehydes and Ketones BY K.E.B. PARKES 1
Synthesis of Aldehydes and Ketones
Oxidative Methods. - Several new chromium based oxidants have been described. These include a variety of polymer supported complex chromates', the imidazolium dichromate (1) which is selective for allylic and benzylic alcohols,' zinc dichromate which oxidises primary and secondary alcohols while leaving allylic alcohols ~ n a f f e c t e d , ~the bis-phosphonium dichromate (2), and a variety of amine and ether complexes of chromium peroxide (CrO7 ) which if not over-selective have the attractive advantage of operating under
condition^.^
A rather neglected group of high valence neutral transition metal oxidants is the ferrates, and reports of several studies of these reagents have now appeared.
Thus, the oxidation
chemistry of barium ferrate monohydrate has been compared with that of barium manqanate and of manganese dioxide and found to be most similar to the former.6 Silver ferrate7 and a mixture of potassium ferrate, alumina, and copper sulphate8 have also been found to be useful oxidants. A method of oxidising secondary alcohols to ketones with catalytic ruthenium tetraoxide in a two phase system with electrochemical regeneration of the oxidant'
has also been
described. The low cost and ready availability of both hydrogen peroxide and tert-butyl hydroperoxide (TBHP) continues to promote interest in catalysts which would allow the wider use of these oxidants. Japanese workers have now found that TBHP in the presence of molybdenum hexacarbonyl and cetylpyridinium chloride" or alternatively the phosphomolybdate ammonium salt (3)l 1 will selectively oxidise secondary alcohols in the presence of primary alcohols and also cleave vicinal dio1s.A similar oxidation using hydrogen peroxide cataylsed with either molybdenum ( V I ) or tungsten
(VI) salts and performed under phase transfer conditions has also been reported, although lower selectivity in the oxidation of secondary alcohols was observed.l2 Several interesting variants on the Kornblum oxidation have been published this year.
These include a modification of the
original conditions by the inclusion of sodium hydrogen carbonate 43
General and Synthetic Methods
44
+
R----vcI,
R'CHO
____)
(3)
R/+
52 "10
\
H H
agXh 1
I
Me ( 5 a ) X=H
I 5 b l X=D
C02 Et
Me
2: Aldehydes and Ketones
45
and sodium iodide in the reaction mixture to allow the ready oxidation of less reactive and more delicately functionalised halides [equation ( 1 ) ]13, the extension of the reaction to alkyl nitrite substrates14, and the introduction of two new oxidants for the transformation, tetrabutylammonium periodate,l5 and for allylic halides, N-ethylpiperidine-N-oxide [equation (2)] . l6 Amongst other oxidants reported are bis(quinuclidine)bromine(I) tetraf luoroborate (3) in the presence of silver tetraf luoroborate, l7 Raney nickel for the selective oxidation of secondary alcohols in the presence of primary alcohols,l8 bis (cyclopentadienyl) zirconium hydride as catalyst of the Openhauer-type oxidation of primary alcohols,19'20 the use of a ruthenium instead of the more usual palladium catalyst in the oxidation of secondary and allylic alcohols with ally1 methyl carbonate,21 and horse liver alcohol dehydrogenase immobilised on glass beads and used in organic media.22 Two research groups have reported that oxidation of benzylic methylene may be achieved in quite respectable yields with excess pyridinium chlorochromate in ref luxing d i ~ h l o r o m e t h a n eor ~~ benzene.24 The same transformation can also be achieved with tert-butyl hydroperoxide catalysed by the cyclic chromium ester (4), a method which has the considerable advantages of avoiding the toxicity and disposal problems associated with the use of stoichiometric chromium reagents. 25 The oxidative hydration of alkenes to aldehydes or ketones is most often achieved on the laboratory scale in two steps by hydroboration followed by oxidation of the intermediate alcohol. H.C.Brown and co-workers now report that it is possible to oxidise the first formed alkyl borane with pyridinium chlorochromate26 or aqueous chromic acid27 to give moderate to good yields of the corresponding aldehydes or ketones in a one pot process. Similar direct oxidation of alkenyl boronates is also possible. 2 8 Last year the exciting development from Hirao's group of alkylvanadium reagents which add oxidativity to aldehydes to give good yields of ketones was reported. They have now reported an extension of the method to include alkynylvanadium dichlorides permitting the preparation of u,B-acetylenic ketones [equation ( 3 )I .29
Finally in this section a catalytic bismuth system for the cleavage of vicinal diols with triphenylbismuth and N-bromosuccinimide in buffered aqueous acetonitrile has been described.30 In some cases the procedure compares well with
General and Synthetic Methods
46
existing methodologies for glycol cleavage [equation ( 4 1 1 . Reductive Methods. - Detailed procedures for the conjugate reduction of a,@- unsaturated ketones with sodium dithionite under phase transfer conditions,3 1 or with diphenylsilane catalysed by palladium (0) in the presence of zinc chloride32 have been published. Another method for the conjugate reduction of unsaturated ketones but not aldehydes, uses
1,3-dimethyl-2-phenylbenzimidazoline (5) in the presence of aluminium chloride.
The reaction also allows the specific
introduction of deuterium to either the 6-position of the enone by using the deuterated reagent (5b), or to the a-position by using deuterium oxide in the work up.33
The same reagent, without the
Lewis acid catalyst, may also be used €or the reduction of ahalocarbonyl compounds to aldehydes and ketones or of acid halides to aldehydes.
Specific introduction of deuterium with (5b) is
again possible. 3 4 Reductive dehalogenation of a-haloketones may also be achieved in the presence of a metal salt in refluxing tetrahydrofuran by either sodium iodide35 or sodium hydrogen telluride: 36 salts used include iron (II), aluminium iron (111), tin (11) and chromium (111) chlorides. Samarium diiodide rapidly reduces a very wide range of a-heterosubstituted ketones to ketones in methanolic tetrahydrofuran at -78°C.
Substrates used included a-halo,
-acetoxy, -silyloxy, -tosyloxy, -phenlthio and -phenylsuphonyl ketones, although compounds with sterically crowded a-centres were reduced less cleanly giving complex mixtures, and only low yields were obtained in the reduction of a-hydroxy ketones. 37
Lithium
diphenylphosphide has been introduced as a reagent for the dehydroxylation of acyloins.38 In view of the increasing use of a-phenylsulphonyl ketones in synthesis, a new method for the reductive removal of the activating functionality by irradiation of the sulphone in the presence of RuC12(bipy)3 and the Hantzsch ester
(6) should prove useful.39
The reaction appears to be selective
for a-sulphonyl ketones; a-sulphonyl esters and nitriles are not cleaved and ester, nitrile and olefinic functionality is tolerated. At -5OOC in the presence of catalytic methylcopper and HMPA, diisobutylaluminium hydride will selectively reduce enones, including 6,O-disubstituted enones, in a 1,4- sense to give good yields of saturated ketones.
Unfortunately HMPA apears to be
essential to the success of the reaction and it could not be replaced by other dipolar aprotic solvents. The method may also be
47
2: Aldehydes and Ketones
~1
+
PhVCI2
7 2 'lo
Br
Br
L
Reagents
i.
CH2=CHCH2MgBr,
ii, H 2 0
Scheme 1
Reagents: i, K ~ C O J ,P r i O H ; ii, NaBHk, E t O H ; i i i , N a H , M e l , DMF, iv, H C I , a q . MeOH
Scheme 2
General and Synthetic Metho&
48
iii
Reagents: i, NaH , ( M e S ) 2 , DMSO; ii. NaH then
Me0
DzO;iii, 130-170°C, 1 Torr
Scheme 3
Reagents: i, Bu'Li;
ii, cyclohexonone, iii, H 2 0 ; iv, ( C O Z H ) 2 . H 2 0 , E t 2 0
Scheme 4
Reagents: i, xylene,
A;
ii, T F A , 2 0
OC;
iii, ( C 0 2 H ) 2
Scheme 5
2: Aldehydes and Ketones
49
used to reduce dienones in a 1,6- sense to give enones.40 The preparation of ketones by the reaction of organometallic compounds with carboxylic acid derivatives, although conceptually attractive is often difficult to achieve in practice. However it is now reported that in the presence of an excess of chlorotrimethylsilane in THF at -110°C primary alkyllithiums will react cleanly with methyl or ethyl esters, including formates, to give good yields of ketones or aldehydes after hydrolytic work up of the intermediate silyloxy compounds, with very little of the tertiary alcohol being formed.4 1 Organovanadium reagents, which may be generated in dichloromethane from equimolar amounts of vanadium trichloride and Grignard reagents, undergo highly chemoselective coupling with acid chlorides to give ketones in modest to good yields. A wide range of other functionality including nitriles, esters, ketones and halides are tolerated in this reaction [equation (5)] .4 2 (E)-Phenyl-2-pyridyl ketone-0-acyloximes, which are prepared by acylation of the oxime with an acid chloride, have been found to react with Grignard reagents to give, after work-up, good yields of ketones (Scheme 1 ) .43 The electroreduction of allylic or benzylic halides in the presence of an excess of an acid anhyride has also been reported to lead to ketones although the yields are very variable. 4 4 Methods Involving Umpolung. - The use of the methylthiomethylsulphone formyl anion synthon for the preparation of alkyl arylmethyl ketones (Scheme 2 ) 4 5 and of deuterated benzaldehyde derivatives (Scheme 3)46 has been described. Baldwin et al. have now published the full details of their studies on tbutylhydrazones as acyl anion equivalents.4 7 The hydrazones, which are easily prepared from t-butylhydrazine hydrochloride in a conventional manner, may be deprotonated with either LDA or an alkyllithium in THF at 0°C. The alkylation of the resulting ambident anion often seems to be problematical with small electrophiles such as methyl iodide favouring N-alkylation ( 8 7 : 1 3 ) and more sterically demanding electrophiles like isopropyl iodide failing to react. Reaction with carbonyl electrophiles was found to be rather more general, providing a route to acyloins (Scheme 4). Although the anions could be trapped with some Michael acceptors, the same products were more conveniently prepared by means of a thermal ene reaction (Scheme 5) . 4 8 3-Stannyl-1-silyloxycyclohex-1-ene (7) has been reported as a synthon for the a,B-dianions of cyclohexanone.
Thus trans-
General and Synthetic Methodr
50
TBDMSO
OTBDMS I , II
SnBu3 Ph
(7)
25
lii
1
:
we- % OTBDMS
OMe
Ph
Ph
Reagents
I,
BuLi
,
TMEDA.
11,
PhCHO.
NaH, M e I .
111,
IV,
CH2=CHCH2BrI
Scheme 6
go ‘
Ph*CN
+
/
+id
do
& ‘ Reagents
TASF
0
‘
0
‘
0
1
0
i, K2CO3, MeCN, ii, A g N 0 3 , a q T H F
Scheme 7
1
-
1
0
2: Aldehydes and Ketones
51
(6)
85
:
15 ii
I
R-C=C-OLi
RC02Et
R
T
o H
Reagents
-
R
RwoA
R -0SiMe3 \
I,
LiTMP, BULI , CH2Br2 ; i t , cyclohexadiene, THF,
v,
H ~ O +or BU,N+F-
-0Li \
h
,
111,
Ac20,
I-. ,
Me3SiCI,
Scheme 8
Reagents: i , MeC(OEt)3, EtCOZH(trace), 200°C; ii, 0 3 , CH2C12, MeOH,-78OC; i i i . M e z S , O°C
Scheme 9
52
General and Synthetic Methodr
,Ic;c. \\\
HO
Ag+
* (11)
Ph Li
(--so)(
]
(9)
0 I1
RL Reagents
O I,
-I- RCHO
1
, 111
H
BunLi ,
11.
Jones reagent,
111,
Si02, hexane. EtOAc
S c h e m e 10
T H F ; ii , CNCOPh
Reagents : i , Tr-No.’,
;
iii, H 2 0
S c h e m e 11
CONMe2 Ph
HoYoNMez +
Ye
Ph&O
“CONMe,
ve P
‘CONMe,
h
b
/,
iii
Ph d O\’ C O N M e 2
1
5.7 > 9 5 % e.e.
o
Reagents: i , M e 3 A I
;
HO
i i , 03,MeOH, - 7 8
OC ;
iii, M e 2 S
S c h e m e 12
CONMe,
2: Aldehydes and Ketones
53
metallation of ( 7 ) with butyllithium in the presence of TMEDA gave an allylic anion, which could be trapped with aromatic aldehydes to give a mixture of y and a hydroxyalkylated products in a ratio varying from 25:l to 2:l depending on the substitution of the aromatic ring. The resulting silylenol ether, after protection of the free hydroxyl, could be alkylated with either allyl bromide or piperonal in the presence of tris(dimethy1amino)sulphur (trimethylsi1y)difluoride (TASF) thereby forming an a , @ 49
disubstituted cyclohexanone (Scheme 6). The phenylcyanocarbamoyl chloride (8) has been used as a benzoyl anion equivalent in an intramolecular process to effect the replacement of the hydroxyl group of phenols and enols by the benzoyl group (Scheme 7) . 5 0 Other Methods. - In toluene or tetrahydrofuran at 50°C a variety of aryl, vinyl, benzyl and allyl halides can be formylated, in good yields, by treatment with tributyltin hydride under 1-3 atmospheres pressure of carbon monoxide in the presence of catalytic palladium(0). The reaction conditions were compatible with a wide range of other functionality [equation (6)I , and in the case of allylic and vinylic halides the starting material double bond Allylic halides were geometry is largely retained [equation ( 7 ) I . formylated at their less substituted end.51 A one carbon homologative synthesis of aldehydes may be achieved by the reduction of lithium ynolates, prepared by treating esters with bromomethyllithium, with cyclohexadiene (Scheme 8 ) . 5 2 Tsuda et al. have continued their studies on the palladium(0) catalysed decarboxylative allylation of B-keto esters and B-keto acids. They now report that both allylic acetates [equation and 1,3- diene monoepoxides [equation ( 9 ) I 5 4 may be used to allylate a variety of B-keto acids, or, in the former case, their lithium salts. A beneficial effect of h e x a d e c y l t r i m e t h y l a m o n i u m bromide on the alkaline decarboethoxylation of 13-keto esters has been reported.55 The power of pericyclic reactions for forming new carbon-carbon bonds is nicely illustrated by the use of the Claisen orthoester rearrangement to prepare y-ketoesters with a quaternary centre next to the ketone (Scheme 9 ) . 5 6 The use of silver salts to catalyse the acetylenic oxy- Cope rearrangement for the preparation of a , B - 6 , ~ unsaturated ketones has also been reported [equation (10)] .5 7 A pinacol-type rearrangement of epoxy silyl ethers has been
used to prepare 8-hydroxy ketones, the migratory aptitudes observed
General and Synthetic Methods
54
n = 5 , 6 , 7 or 8
*
SiMe3
R
R
Et
(10)
vi R e a g e n t s : i , Et30'BFL
BF4'
iii, i v
1 , ii, EtSH , NaOMe, M e O H ;
iii, N a I 0 4 , M e O H ; i v , C a C 0 3 , P h H ,
v , H3PO,,+ , H C 0 2 H , v i , HCI, BunOH
Scheme 13
A
,
2: Aldehydes and Ketones
b
n 0
6
.. ... i
55
'
O! 2T0L
d b v Reagents. i . 4steps.71'1.;
ii,K2CO3,MepCO
or
J
QR NaH, DMF. i i i , R X ; i v , N a H , K H , O M S O ;
v , pyridinium tosylate , aqueous acetone
Scheme 14
Me
. , I1 .I
I
(12)
Rmgmts : i , K , NH3, But
reagent
-
O H ,THF, -78
OC
ii, LiBr, R X
;
;
kii-v
L
iii , 03, MeOH
;
iv, Zn , AcOH
v, Jones
Scheme 15
i - iii
R1-Z
-7
0 "
Reagents : i , R 2 M
J
Y
0
;
R3
ii, 12 ; in, brominatim
R3
R2;3I3 0
iv
;
iv , 2 equiv. But Li
Scheme
16
56
General and Synthetic Methods
seem to parallel those of the normal pinacol rearrangement [equation (11)I . 5 8 V-Hydroxy ketones were prepared in moderate to good yields by reaction of aldehydes with the v-propanol anion equivalent (9) followed by Jones oxidation and hydrolysis (Scheme 10) .” Y Amidoketones may be prepared by amidoethylation of ketones by treatment of their sodium enolates with N-benzoylaziridine. The reaction appears to be fairly general although bisamidoethylation was a problem with methyl ketones (Scheme 1 1 ) .60 Chiral a-substituted carbonyl compounds have been prepared in high optical purity (64-98%) by the use of organoaluminium chemistry. Thus treatment of an acetal derived from an a , B unsaturated aldehyde and _R,R- tartaric acid diamide with a trialkylalane gives largely the 1,4- addition product from which the desired ketone is derived by ozonolysis (Scheme 12) .61 p-Methoxybenzenetellurinic anhydride has been reported as a mild reagent for the hydration of terminal acetylenes, yields
are frequently very good [equation (12)1 .62 The preparations of 2-phenylcycioalkanones by the reaction of diphenylcopper lithium with a , a’ -dibromocycloalkanones [equation (13)1 ,63 and of trimethylsilyl cyclopropyl ketones by a carbene insertion reaction [equation (14)] ,64 have also been reported. Cyclic Ketones. - Several interesting papers have appeared directed at overcoming some of the drawbacks of the Nazarov cyclisation for cyclopentenone synthesis. These include studies by the Denmark group on the stereochemistry of the silicon directed Nazarov cyclisation in cyclohexenyl systems [equation (15)I ,65 the use of tin rather than silicon to direct the cyclisation,66 a preparation of B-silyl divinyl ketones from vinylsilanes and acid chlorides,67 and a preparation of divinylketones from 4-oxothianes (10) (Scheme 13) .6 8 Interestingly, a related 4-oxothiane derivative has been used in conjunction with the Ramberg-Backlund reaction for the preparation of 3-alkyl-3-cyclopentenones. 69 Thus the disulphone (11) could be alkylated with primary bromides and iodides in the presence of potassium carbonate or sodium hydride as base. Further treatment with excess sodium hydride containing a small amount of potassium hydride gave, by means of the Ramberg-B8cklund reaction, a protected 3-cyclopentenone. Deprotection with minimal conjugation of the double bond was achieved with pyridinium tosylate in moist acetone (Scheme 14). Two approaches to 2,3-disubstituted cyclopentenones have been reported.
The first
uses the Birch reductive alkylation of the indanone (12) to
57
2: Aldehydes and Ketones
0
II
i - iii
(13) Reagents
'
i, L D A , ii, 5'10
Pd(PPh314 T H F ; iii, KOH, H 2 0 , A I
S c h e m e 17
II
I I
(14)
H
/i
i 4
%O
"'
(15)
Reagents: i , - 7 8
O C ,
CHzC12 then
Ce(1V)
ii( Hg(I1). H30';
S c h e m e 16
iii, OH-
General and Synthetic Methods
58
J
iii
n = 2 , 3 , 5 or 6
Reagents : i
I
T M S C l , LDA , T H F , - 78 OC
TsOH.
ii , Me(CH2),
COCl, A I C l 3 , CHZCIz
A Scheme
19
(17)
(16)
0
, - 78
OC
;
iii, P h H ,
2: Aldehydes and Ketones
59
Reagents : i , acrolen , AIMe2CI ; ii , acrolem
Scheme
20
Me
Me
Ph
I
‘-Ph
0
Ph
Reagents: i . L D A , Met, - 7 B o C , T H F ; i i , LDA,HMPA, PhCHZBr; iii, RedAl, PhMe, -60 to 2 5 OC: i v , aq. EtOH ,(Bu4N)H2PO4
Scheme 21
General and Synthetic Methodr
60
introduce the 2-substituentI which needs to be derived from a reactive alkyl halide, followed by ozonolysis (Scheme 15) .70 The second uses the reaction of a l-iodo-3-bromopropene, available with a wide range of substitutions by alkyl metal addition, iodination and bromination of propargylic alcohols, with the lithium enolate of an N,N-dialkylcarboxamide. Cyclisation is achieved y & a vinyllithium prepared by lithium halogen exchange with tert-butyllithium (Scheme 16) 71 Cyclopentanone preparations have also been reported by a conjugate addition - intramolecular enolate trapping procedure [equation (16)172 and by a palladium(I1) catalysed diazo insertion reaction [equation (17)] 7 3 The annelation of cyclopentenone rings has also received some attention this year with the introduction of two new reagents for the purpose: the enol phosphate (13) (Scheme 1 7 ) , 7 4 and the cobalt stabilised propargylic cation (14) whose use is nicely exemplified by a synthesis of the natural product cyclocloorenone ( 1 5 ) (Scheme 18) . 7 5 A cyclopentenone annelation of an ally1 sulphide has also been reported (Scheme 19) .76 Despite its drawbacks, the Robinson annelation is still the most widely used cyclohexenone ring annelation. Variants on the reaction in which the ketone is activated by carboxylation so that the Michael addition is performed with a [3-keto acid,77 or in which the phosphonate reagent (16) is substituted for ethyl vinyl ketone allowing the ring-closure to take place by means of a Wadsworth-Emmons reaction,78 have been published. Convenient syntheses of ethyl vinyl ketone7' and the Stork silyl reagent (17)
.
.
for Robinson annelation8' have been described. A very different cyclohexenone annelation is provided by the reaction of 2-formyl-2-cyclohexenones with enamines [equation (18)] .81 Snider et al. have previously reported that the dimethylaluminium chloride catalysed sequential ene reactions of exocyclic olefins leads to cyclohexanols. They now find that in the presence of excess acrolein, the aluminium alkoxide intermediate will undergo an Oppenauer oxidation resulting in a one-pot cyclohexanone ring annelation (Scheme 20) .82 Meyers and his group have published an interesting asymmetric synthesis of chiral 4,4-disubstituted cyclohexenones which depends on the sequential alkylation of the chiral aldehydo-ketone equivalent (18). Because alkylation occurs preferentially from the less hindered, lower face, both enantiomers are available from this one intermediate by varying the order in which the alkylation steps are performed (Scheme 2 1 ) .83
61
2: Aldehydes and Ketones
i , ii
Reagents
i , MeMgBr , THF, 0 O C
;
+
ii .2 equiv
H$ - (
0
QoL'
Scheme 2 2
Me,Si /\/\/ \ (CH,),COCl
Tic14
(23) (CH21n
n = 3 , 4 or 5
GeneraI and Synthetic Methods
62
4
Reagents
I .
P t O z , H 2 , EtOH , ti, 200
”
OC
S c h e m e 23
Reagents. i , R X X , NaH, D M F , i i , S i 0 2 ; iii, C u C I z , MeOH, H 2 0
Scheme 24
2: Aldehydes and Ketones
63
Reaction of cyclopropanone ethyl hemiacetal with methylmagnesium bromide and two equivalents of cyclohexanone lithium enolate provides a very interesting and highly stereospecific synthesis of tricyclic cycloheptanones; a serendipitous reaction that gives products clearly of considerable interest in the field of natural product chemistry (Scheme 2 2 ) .84 A study of free radical rnacrocyclisation has been published, very respectable yields were obtained using tin hydride to form the radical and enones as radical acceptors. Interestingly neither high dilution nor syringe pump techniques were found to be necessary. Unsaturation in the carbon chain was tolerated and did not lead to the formation of bicyclic products [equation (19)] . 8 5 The yields of large ring ketones obtained by means of an oxy-Cope rearrangement [equation ( 2 0 1 1 are very heavily dependent on the particular batch of potassium hydride used. It is now reported that pretreatment of the potassium hydride with 10 mol % of iodine gives consistently high yields €or the reaction irrespective of the batch or source of the reagent.86 Krief and his group have reported on a cycloalkenone homologation using selenium chemistry [equation ( 2 1 ) I 87 , while sulphur chemistry provides the basis of a fairly general cycloalkanone synthesis in which an olefin cyclisation is initiated by a Pummerer intermediate formed by treating the starting material with trifluoroacetic anhydride [equation (22)] .88 Routes to a-cyclopropylketones [equation ( 2 3 ) ] ,89 to octalones by means of a Diels Alder reaction, and to some spiro-ketones by cyclisation of w-iodoestersgl have also been reported. 2
Synthesis of Functionalised Aldehydes and Ketones
Unsaturated Aldehydes and Ketones. - Trimethylsilylenol ethers derived from either aldehydes or ketones are oxidised, in good yields, to enals or enones respectively, by treatment with diallyl carbonate in the presence of catalytic palladium(0). Acetonitrile is the required solvent if allylation is to be avoided as a side reaction. In the additional presence of catalytic tributyltin methoxide enol acetates can also be oxidised.9 2 Further flexibility is given to the selenoxide elimination as a route to enones by a recent report from the Liotta group. They find that in THF-HMPA the sodium enolates of a-phenylselenoketones rearrange very readily to give good yields of the product with selenium in the less highly substituted a-position [equation ( 2 4 ) I . 93
64
General and Synthetic Methods
0
Reagents: i , LiOSOZF, ii, NaOH, H202
iii, Me2CHC02H ; iv, HCL
Scheme 25
"30
Me
p
h
q
Me
-
- phy - *% 0
TMSO
SnCL3
Me
OTBOMS
6
OTBDMS
&+
i
(26)
Me
ii. iii
PPh3
4
4
HO Reagents : i , But Me2SiOTf, PPh3, THF; ii, BunLi,
0
OC
;
v. Pr"CH0, TiC14, CHZC12, - 7 8
THF
;
OC
S c h e m e 26
iii , PriCHO; i v , Bu:
N+F-, T H F ,
65
2: Aldehydes and Ketones
Chromium (11) salts have been found to reduce a-acetylenic ketones with high stereoselectivity to trans-enones.9 4 Several protocols for the preparation of unsaturated ketones by the reaction of alkenyl- or alkynyl- metal derivatives with esters or with acid chlorides have been reported. Thus a,B-unsaturated ketones were prepared by the Pd(0) catalysed coupling of alkenyl cuprates with acid chloridesg5 or by the reaction of hindered esters with allylmagnesium bromide in the presence of LDA, a reaction which provides a convenient preparation of a-damascone [equation ( 2 5 ) 1 . 9 6 Alkynyl ketones may conveniently be prepared by the reaction of alkynyllithiums with esters in the presence of boron trifluoride etherate in tetrahydrofuran as solvent at - 7 8 ° C . 97 A procedure using enamines to prepare enones from acid chlorides has also been reported (Scheme 2 3 ) . 9 8 The silica gel catalysed rearrangement of allylic sulphones has been used very ingeniously as the basis of a flexible synthesis of aa-unsaturated ketones (Scheme 2 4 ) .” The reaction of an oxonium ion with an alkynyl boronate provides the key step in another approach to enones. The first formed acetal borane may either be worked up by protiodeboronation to give an a,B-disubstituted enone or alternatively a second alkyl migration may be induced with lithium fluorosulphonate to give 6,B-disubstituted products (Scheme 25) . l o o Treatment of siloxycyclopropanes, available from ketones by methylenation of their silyl enol ethers, with stannic chloride gives B-trichlorostannyl ketones. Although these compounds may be isolated, they undergo fairly ready dehydrostannation on warming, providing an alternative method for the methylenation of ketones [equation ( 2 6 ) 1 . lo’ A new approach to the B-functionalisation of enones involves treating the substrate with t-butyldimethylsilyl triflate (TBDMSOTf) in the presence of triphenylphosphine. This phosphoniosilylation reaction gives a silylenol ether-Wittig salt which, after ylid formation, may be condensed with an aldehyde to give a silyl dienol ether. These may either be protiodesilylated to give the B-functionalised enone or alternatively used in aldol type chemistry for the preparation of more complex molecules (Scheme 26) . I o 2 A conceptually related aproach to B-fuctionalisation uses silicon chemistry for the elaboration of the B-side chain. This requires the preparation of a 6-trimethylsilylmethyl enone by conjugate addition of trimethylsilylmethylmagnesium chloride and oxidation, to give the
key intermediate (19).
The B-substituent is then elaborated by
General and Synthetic Methocis
66
n
n
c Reagents
1,
TMSCHZMgCl, CuBr.Me2S, TMSCI;
Me0 Ill
11,
(CH2CHCH20)2C0, Pd(OAc)p,
OMe
o, , -
I
SnC14; i v ,
Reagents. i , H 2 , Raney
27
Ni , B(OH)3 , a q . MeOH ; i i , BF3.Et*OI C H ~ C I Z 0, OC
Scheme 2 8
Reagents
’
\
\O
Scheme
i , TMSCI, NEt3. DMF,
A,.
11,
HI04, MeOH
, TMSI
2: Aldehydes and Ketones
61
condensation of (19) either with acetals, catalysed by stannic chloride, or with aldehydes, catalysed by trimethylsilyl iodide (Scheme 27) . I o 3 A B-arylation of enones using thallium reagents has also been reported.lo4 The preparation of 6,y-unsaturated ketones requires particularly mild conditions if conjugation of the double bond is to be avoided. Nevertheless two useful approaches to these molecules have been reported. The first uses a Peterson elimination to form the double bond in a nitrile oxide derived 6-hydroxy ketone (Scheme 28).lo5 The other uses a Claisen rearrangement to prepare an a-hydroxy-y, 6-unsaturated aldehyde from which the desired 4 , Y-unsaturated ketone is formed by periodate cleavage (Scheme 29). 106 a-Substituted Aldehydes and Ketones. - Hoffman et al. have reported further details of their a-oxidation of ketone enol derivatives by treatment with p-ni trophenyl sulphony 1 peroxide , and have also published methods for the conversion of the a - p - n i t r o p h e n y l s u l p h o n o x y ketone products to a-hydroxy ketones, a-hydroxyacetals and a-aminoketones. lo* A related a-hydroxylation
of lithium enolates with dibenzyl peroxydicarbonate has also been p u b 1 i ~ h e d . l ~The ~ oxidation of some ketone sodium enolates with the chiral camphorsulphonyl oxaziridine (20) gave a-hydroxy ketones in optical purities of 65 - 9 5 % . Because both enantiomers of the oxidant are available both a-hydroxy ketones can be prepared. A convenient synthesis of L-(S)-glyceraldehyde acetonide, the less readily available enantiomer of this useful a-hydroxyaldehyde building block, from L-ascorbic acid, has been described. Several approaches to a-hydroxy ketones which involve carboncarbon bond formation have been reported. These include the reaction of Grignard reagents with the 0 - trimethylsilyl ethers of aldehyde cyanohydrins followed by the hydrolysis of the hydroxy-imine intermediate, and the reaction of the acyl anion equivalent (21) with aldehydes.l13 An approach to chiral acyloins uses the reaction of protected a-hydroxyesters with organolithium compounds in ether-pentane at -1OO"C, or alternatively after conversion to the dimethylamide, with a Grignard reagent in ether THF at 5"C.'14 Very little racemisation was seen in the reaction with product and starting material ee being closely similar. An alternative preparation of protected chiral a-hydroxy aldehydes uses Bakers yeast to enantiospecifically reduce the a-ketoaldehyde precursor (22) with >,95% ee, although the chemical yields were far
68
General and Syntheric Methods
TOIS-STOI
Me+sTol
1 1 1 ~
____) Ill
STol
STo1
Me
(22)
q,:h
1 iv
M
Meq
V
H Reagents
I,
BunLi,
11,
STol
MeC02Et
, 111.
Baker's y e a s t ,
IV,
NaH, PhCH2Br, DMF. v , HgO,
BFS aEt20
Scheme 3 0
Me
I
Me,
o i e - O E t
~
-
M ,e
Qzi-OEt
(26)
Me02x02Me OH
Meo2
F A
Me0
M e 0p
r
Br
Br ii/
I
Br Reagents
'
I,
Br2, CC14 , catalytic
HBr
; II
, MeS03H
, MeOH
Scheme 31
69
2: Aldehydes and Ketones
(27)
-
NHTs
(30) OMe
0
II
+
phs*
LOTHP
L
Ph
Reagents : i , Sn(0Tf l2 , E t N 2 ; ii ,
rn.3 N
I
Me
;
i i i , PhS-S02
General and Synthetic Methodr
70
.
lower (Scheme 30) Another route to a-hydroxyketones involves the two step oxidation of (alkenyl)alkoxysilanes, which are conveniently prepared by the hydrosilylation of acetylenes, with mcpba to give the epoxide and then with hydrogen peroxide in the presence of fluoride to give the a-hydroxyketone final product in At least one alkoxy group bound to high yield [equation (26)I . silicon appears to be required for the reaction to be successful.116 A procedure for the preparation of a-fluoroketones and fluoroaldehydes by the low temperature fluorination of silylenol ethers with 5% fluorine gas in nitrogen with freon 11 as solvent has been published. The yields were generally good, although some problems of over-fluorination were encountered with silyl enol ethers derived from methyl ketones. Protected a-bromoalkyl aryl ketones may be prepared by the asymmetric bromination of enantiomerically pure acetals. Both yields and optical purities were high, and little racemisation was seen in the one example hydrolysed to the parent a-bromoketone The rather unexpected bromination of some 3-keto (Scheme 31) steroids by treatment with benzeneselenyl bromide in ethyl acetate has been reported. a-Iodoketones have been relatively less studied than their chloro and bromo analogues, reflecting both their lower stability and less ready synthesis. However it has now been found that these compounds may easily be prepared in good yield by the treatment of ketones with iodine and mercuric chloride.120 The authors found that the more substituted ketone a-position was selectively iodinated, although, rather puzzlingly, the preparation fails for cyclic ketones which gave only the a-chloro product. Alternatively a-iodoketones may be prepared from alkenes by reaction with bis (sym-collidine)iodine (I) tetrafluoroborate [I' (collidine) BFq-] in dimethylsulphoxide [equation (27)I . 121 Although the reaction showed little regioselectivity specifically axial iodides were obtained from the reaction of conformationally biased alkenes. a-Chloro and a-bromo, but not a-iodo, a,@-unsaturated ketones may be prepared by treating diosphenol derived dimethylthiocarbamates with lithium chloride or bromide in hot acetonitrile-acetic acid [equation (28)1 . 122 Platinum sulphide on carbon has been reported as a chemoselective catalyst for the hydrogenation of nitro-ketones to aminoketone hydrochlorides.1 2 3 N,N-Dialkylaminomethyl ketones may be prepared in good yields by the reaction of (N, N-dialkylaminomethyl) tributyltin reagents with acid
71
2: Aldehydes and Ketones
(33)
n O
d
O
E
t
.+”’ 0
Si Ph2Me R
HO
0 Reagents : i , R1 MgX
;
ii, lo*/. aq. HCI ; iii. PCC, CHZC12
Scheme 33
;
i v , NaHC03
;
v . Jones reagent
72
General and Synrheric Methodr
chlorides. The reaction conditions are compatible with aromatic acetal, aldehyde and nitrile functionality [equation (29)] A rather interesting electrochemical preparation of protected a-amino aldehydes uses an anodic oxidation at platinum of a N-tosylamine in methanol containing potassium hydroxide and potassium bromide a s co-electrolyte [equation (30)] The reaction involves a 1,2migration of the protected amino group, postulated to occur via the intermediacy of an azirine, and proceeds in surprisingly high yields for such a complex transformation. Yamakawa et al. have continued their long string of communications describing the reactions of a,B-epoxysulphoxides with nucleophiles to give afunctionalised ketones and aldehydes. This year details of the reaction for the preparation of a-aminoketones [equation (31)] , 126 a-acetoxy ketones,12' and the application of the reaction using sulphur and selenium nucleophiles to the preparation of unsaturated ketones, have a1 1 been pub1 ished . Chiral a-phenylthio ketones may be prepared in good yields and high ee by the reaction of tin (11) enolates with thiosulphonates in the presence of chiral diamines (Scheme 32) .130 A procedure for the preparation of cyclic chiral a-sulphinyl ketones by the boron trifluoride etherate catalysed reaction of methyl toluenesulphinate with silyl enol ethers has been described [equation (32) I . 131 a-Silyl ketones and aldehydes may be prepared by a pinacol-type rearrangement of a,B-dihydroxy silanes in which the silicon group preferentially migrates [equation (33)1 . 132 Both (3-ketosilanes and (3-ketophosphonates can be prepared from a-bromoketones by successive treatment with lithium hexamethyldisilazide, t-butyllithium and chlorotrimethylsilane or diethyl chlorophosphate electrophiles as appropriate [equations (34) and (35)1 . 133 cyclic (3-ketophosphonatesmay also be prepared by the base induced [1,3] oxygen to carbon migration of phosphorus in an enol p h 0 ~ p h a t e . l ~ ~ Dicarbonyl Compounds. - The preparation of ketones by the reaction of Grignard reagents with a-diphenylmethylsilyl esters has, by using acetal protected ketoesters, been extended to the synthesis of a variety of mono-protected diketones [equation (36)] The same chemistry, using the a-diphenylmethylsilyl derivatives of a-butyrolactone and a-valerolactone, allows access to a variety of 1 ,4-diketonesI 4-ketoaldehydesI and 4-ketoacids (Scheme 33) lI2-Diketones have been prepared by oxidation of acetylenes with molybdenum pentoxide HMPA complex in dichloroethaneI 137 by the
73
2: Aldehydes and Ketones
X
my 0
+
CN_____)
Y&NMe2
(41)
0
0
General and Synthetic Methods
74
-
Ph
RC0,Me
R3-OC0,Et
+
Me3SnCHi
(48) Ph
R
A
(49)
2: Aldehydes and Ketones
75
Pd (0) catalysed rearrangement of a-nitroepoxides [equation (37)1 from acids by an application of the Wasserman singlet oxygen procedure for the cleavage of B-enaminoketones [equation (38)I , 139 and, in a protected form, by a [3,3]-sigmatropic rearrangement of the silyl ketene acetals of methyl a-allyloxyacetates [equation (39)I Synthesis of a cyclic 1,3- dicarbonyl compound from an acyclic 1,2-dicarbonyl compound may be achieved in two steps by a photochemical cyclisation followed by a cationic rearrangement in which the cyclobutanone acyl group migrates preferentially [equation (40)I 1 4 1 A detailed study has been published of the preparation of 1,4diketones by the Michael-Stetter reaction, in which particular attention was paid to the effect of substituent variation on this
.
rather unpredictable reaction. In general it was found that while the Michael component could tolerate both electron donating and electron withdrawing substitution, the aldehyde must only contain electron withdrawing or neutral substitution [equation (41)1 . 142 Symmetrical 1,s- diketones may be prepared by addition of a THF solution of a ketone lacking a’- hydrogens to a solution of potassium in DMF - THF; the central methylene appears to derive from the formal carbon of dimethylformamide [equation (42)] A more general preparation of 1,s- dicarbonyl compounds uses the boron trifluoride etherate catalysed reaction of silyl enol ethers with 3-methoxyallyl alcohols in nitromethane [equation (43)l. The reaction may also be performed with alkyl vinyl ethers in which case keto-acetal products are obtained [equation (44)1. 144 3
Protection and Deprotection of Aldehydes and Ketones
Although the acetal is probably the most widely used carbonyl protecting group, formation of dioxolanes from sterically hindered, or from conjugated, ketones, is often difficult and can require forcing conditions. It has now been found that high pressure (15 kbar) techniques can provide a solution to this problem, with either ethylene glycol and toluene sulphonic acid in the presence of triethyl orthoformate as dehydrating agent or with 1,2- bis [(trimethylsilyl) oxy] ethane and trimethylsilyl triflate being used as the reagents.14’ Aldehydes may be converted efficiently to their dimethyl or ethylene acetals in the presence of ketones by electrocatalysis [equation ( 4 5 ) 1 , 146 Deprotection of acetals can be achieved in aqueous diglyme or dioxane with 1,3-
General and Synthetic Methodr
76
diis0thiocyanato tetrabuty ldistannoxane ( 2 3 ) cata 1ysis147 or under virtually neutral, non-aqueous conditions with sodium iodide and 148 phenyl dichlorophosphate in refluxing benzene. Silica gel treated with thionyl chloride has been found to be an efficient thioacetalization catalyst for the preparation of both dithianes and dithiolanes. Ketones require considerably more vigorous conditions allowing the use of the system for the selective protection of aldehydes in the presence of ketones [equation (46)1 .I4’ In the presence of stoichiometric boron trifluoride etherate, 2,2-dimethyl-2-si1a-ll3-dithiane converts both aldehydes and their dimethylacetals to dithianes in a rapid and high yielding reaction [equation (47)I . Methyl triphenylphosphonium tribromide15’ and trityl methyl ether in the presence of trityl perchloratelS2 have been reported as efficient and mild dethioacetalisation reagents. The latter reagent was particularly interesting in that diethylthioacetals were found to be particularly reactive and could be deprotected selectively in the presence of dithianes and diphenylthioacetals [equation (4811. Deprotection of methyl and phenylselenoacetals may be achieved by treatment with iron (111) or copper (11) nitrates suported on K10 clay.153 Deoximation seems to have received a lot of attention this year with cetyltrimethylammonium permanganate,154 chromyl chloride supported on silica gel, iodosobenzene diacetate, and Raney sodium hypophosphite,157 all being reported as reagents nickel for the transformation.
”’
-
4
Reactions of Aldehydes and Ketones
Reactions of Enolates. - For the first time the structure of a bromomagnesium ketone enolate i .e (24) has been determined by X-ray crystallography. The enolates of methyl ketones may be generated regiospecifically from esters by reaction with two equivalents of trimethyl- or triphenyl-stannylmethyllithium [equation (49)l. The resulting enolates were then used in a variety of crossed aldol reactions.15’ The alkylation of a-hetero substituted aldehydes and ketones is often a far from simple process. However methods for both the a and a’ -alkylation of fluoroacetone by way of its lithium N-cyclohexyl enamide,160 and the alkylation of formamido ketones161 have been reported. The allylation of ketones has received a
2: Aldehydes and Ketones
R l q R 2
77
-
R3
OTf P h o - - P h
I
CI (26)
vRy7 3 R~<
R
’
L
S
E
t
R~CHO
E t S SnOTf
R’
R
SEt
E t SSiMe,
,
\i. (27)
OSnOTf
v
O
TR 2f
SEt
Scheme 34
78
General and Synthetic MethodF
surprisingly large amount of attention. Thus, with palladium (0) catalysis, a- nitro ketones react with allyl carbonates at the less hindered allylic terminus; the products are then denitrated with tributyl tin hydride to give 4,5- unsaturated ketones [equation (50)I . 162 Alternatively, allylation may be achieved via the ketone silyl enol ether by treatment with a secondary or tertiary allyl methyl ether in the presence of trityl perchlorate; an allyl cation is presumably the intermediate. 163 The reaction of enol silanes with both saturated and conjugated thionium ylids has been studied. In the former case the ylid is formed by protonation of a vinyl sulphide with a preformed complex of titanium tetrachloride with either methanol or t-butanol; reaction with the silyl ether then gives a 8-thio ketone in rather variable yields [equation (51)] .164 The conjugated thionium ylids are prepared by the Pummerer reaction of an allyl sulphoxide, with trimethylsilyl triflate in the presence of ethyl diisopropylamine, and give products of ketone allylation [equation ( 5 2 ) 1 The otherwise rather difficult carbon alkylation of cyclohexane 1,3-diones may be achieved photochemically although in rather variable yield, by irradiation through pyrex of a benzene solution of the dione and an enol ether, the alkyl portion of which is 166 transferred [equation (53)3 . The formation of chiral enol derivatives by the enantioselective deprotonation of symmetrically substituted ketones under kinetically controlled conditions has been studied. The best base for the purpose was found to be ( 2 5 ) , with eels of up to 7 4 % being observed [equation (54)3 . 167 The intramolecular palladium (0)
-
catalysed allylation of proline derived enamines has been shown to give allyl ketones of very high optical purity although the chemical yields are modest and the generality of the reaction has yet to be demonstrated [equation (55)1 . 168
-
Aldol Reactions. Seebach et al. have published a detailed study of the diasteroselective aldol reaction of boron enolates, generated from an ethyl ketone by treatment with boron trichloride or an alkoxydichloroborane in the presence of Hunig's base. The reaction was found to occur with 3 topicity in selectivities from 90-99% Two research groups have reported on the preparation of ds.16' optically active boron enolates from chiral boranes (26)170 or (27) topicity is again observed although the product enantiomeric excesses are not as high as the diastereoselectivities which are again 90%. The aldol reactions of boron enolates have
2: Aldehydes and Ketones
79
Reagents : i , ButMgBr. THF, E t Z O , - 7 8
O C i
ii, Al amalgam, THF, 0°C
Scheme 3 5
YHLi
iYPh O x 0
80
General and Synthetic Methods
been modelled using MNDO calculations, and remakably good agreement between calculated and experimental structure
-
selectivity data
were obtained.172 Aluminium montrnorill~nite'~~ and rhodium ~arbonyll'~have been reported as catalysts for the aldol reaction of enol silanes with aldehydes, but in neither case are the stereoselectives at all high. The reaction has also been found to occur without Lewis acid catalysis in water or in 1:l water : oxolane.
Although the yields
are not high, the method is of interest in that =-products found to predominate (3:l syn : %-selectivity
anti)
were
in contradistinction to the
found in the Lewis acid catalysed reaction.175
An
exemplary study of the diastereoselection in the Lewis acid catalysed reaction of enol silanes with aldehydes has been published by the Heathcock group.176 They found that in general the reactions of prochiral enol silanes with prochiral aldehydes showed little simple diastereoselection, although an exception was found in the enol silane of ethyl t-butyl ketone which gave useful antiselectivity.
z-
a-Alkoxy aldehydes were also an exception and reacted
in a chelation controlled manner with high diastereofacial selectivity.
The results were rationalised in terms of an open
transition state.
A syn-stereoselective aldol reaction which uses ~
catalytic tin (11) has also been reported (Scheme 34) A somewhat different type of approach to chiral aldol products uses a sulphinyl group as a removable chiral auxillary.
Although
the chemical yields were modest, the optical purities of the products (54 - 78%) must be regarded as impressive for the difficult case of chiral 6-hydroxy ketones with no a-alkyl substituent (Scheme 3 5 ) The diazabicyclooctane (DABCO) catalysed aldol type reaction of acrylic esters with aldehydes has now been extended to use methyl vinyl ketone as substrate.
Although the reaction is slow (up to 15
days), quite good yields may be obtained [equation (56)I .17' Similar products may be synthesised using allenolates prepared by the 1,4- addition of iodide to acetylenic ketones.
Several sources
of iodide could be used including tetrabutylammonium iodide/titanium tetrachloride which gave high Z-stereoselectivity at -78" and largely E-products at 0°C [equation ( 5 7 ) 1 Conjugate Addition Reactions.
-
Two protocols for achieving the
enantioselective conjugate addition of an alkyl group to an enone using a cuprate containing a chiral ligand have been reported.
In
one case the lithium amide (28) was used to prepare an amidocuprate
2: Aldehydes and Ketones
81
(58)
m= lor2 n = 0-3 R', R 2 = H or Me
8i
- IV
Reagents. i , L D A ; ii , CH*=CHCOEt; iii, Et36; IV CH2=CHFPh3ir
Scheme 36
OTBDMS
+
PhCHO
Tr+c'Oi*
9TBDMS ph*
Ph
(62)
82
General and Synthetic Methods
which gave chiral addition products in up to 50% Far better enantioselectivities (75 - 95% ee) could be obtained using the ephedrine derived tridentate alkoxide ligand (29), for which the transition state model (30) is proposed. The enantioselectivity of the reaction appears to be very sensitive to any alkoxide impurities present as contaminents of the alkyllithium reagents, and special measures need to be taken to remove them.182 The preparation and reactions of higher order cuprates containing the 2-thienyl ligand have been described. Although requiring the addition of a Lewis acid if a good yield of the conjugate addition product is to be obtained, they do have the advantage of being prepared from Grignard reagents rather than a lkyl1ithiums . 183 Lithium triorganozincates, which may be prepared from a l k y l i t h i ~ m s l or ~ ~ alkylmagnesium chlorides185 and zinc chloride add 1,4- to enones in good yield. The reagents have advantages over cuprates of better solubility and thermal stability and their chief drawback, that only one of the three ligands is transferred, can be avoided by using organozincates of the form RMe2ZnLi in which methyl is a non-transferred ligand. Another conjugate addition which may involve organo-zinc species is that of alkyl halides to enones in aqueous solvent mixtures in the presence of a zinc-copper couple; the efficiency of the reaction is greatest when the medium is sonicated.186 An extensive study of the preparation of BIB-disubstituted a,a-unsaturated ketones by the Michael addition elimination reaction of a variety of cuprates with a-alkylthioenones has been published. The conjugate addition chemistry of a number of formyl- and acyl- anion equivalents has been studied: these include the amino-nitrile (31),1 8 8 f 1 8 9 the protected cyanohydrin (32) and the sulphur stabilised anions (33) and (34). I g 1 The conjugate additions of lithium acylcyanocuprates themselves have been studied. These reagents, which are prepared by the carbonylation of lithium alkylcyanocuprates with carbon monoxide, were found to give very good yields of 1 ,4- diketones [equation ( 5 8 )] . Basic alumina, in the absence of solvents, has been found to catalyse the Michael addition of aliphatic nitro compounds to 193 a,B-unsaturated ketones [equation ( 5 9 1 1 . A study of the base-catalysed intramolecular Michael addition of cyclic B-ketoester - enoneslg4 and -ynoneslg5 has been reported [equation (60)l: the former reaction appears to be the more general and the effects of varying structure could be rationalised in terms
2: Aldehydes and Ketones
83
of stereoelectronic effects. A variety of sequential Michael additions have been developed by Posner et al. as a versatile means of cyclohexane annelation. One example, in which the first conjugate addition is to an enone and the ring is closed by a Wittig reaction is illustrated in Scheme 36. 196 Heathcock et al. have reported a study of the diastereoselectivity of the conjugate addition of preformed lithium enolates with a , a - unsaturated ketones.
They found a strong
correlation between enolate geometry and product stereochemistry with Z-enolates providing
addition products and E-enolates
usually giving the syn - product.lg7
The same research group has
also studied the diastereoselective preferences of the Mukaiyama Michael reaction where it was found that the major product derived from reaction with ul topicity.lg8 Trityl perchlorate has been found to be a convenient catalyst €or the reaction, the products of ul-selectivity again predominating. The reagent also catalyses the analagous reaction of ester derived silylenol ethers,2oo the double Michael reaction of siloxy-dienes with a0-unsaturated ketones [equation (61)I , 201 and the interesting three component coupling depicted in equation (62). 202 References 1. 2. 3. 4. 5.
6. 7. 8. 9.
10.
11. 12. 13. 14.
T.Brunelet, C.Jouitteau and G-Gelbard, J. Org. Chem., 1986, 51, 4016. S.Kim and D.C.Lhim, Bull. Chem. SOC. Jpn., 1986, 2,3297. H.Firouzabadi, A.R.Sardarian, H.Moosavipour and G.M.Afshari, Synthesis. 1986, 285. H-J.Cristau, E-Torreilles, P-Morand and H.Christo1, Tetrahedron Lett.. 1986, 27, 1775. H .Firouzabadi,N. Iranpoor, F.Kiaeezadeh and J.Toofan, Tetrahedron, 1986, 42, 719. H.Firouzabadi, D.Mohajer and M.Entezari-Moghaddam, Synth. Commun., 1986, 16, 723. H.Firouzabadi, D.Mahajer and M.Entezari-Moghaddam, Synth. Commun., 1986, 16, 211. K.S.Kim, Y.H.SoG, N.H.Lee and C.S.Hahn, Tetrahedron Lett., 1986, 27, 2875. S.Torii, T.Inokuchi and T.Sugiura, J. Org. Chem., 1986, 51, 155. K.Yamawaki, T.Yoshida, T.Suda, Y.Ishii and M.Ogawa, Synthesis, 1986, 59. K-Yamawaki, T.Yoshida, H.Nishihara, Y.1shi.i and M.Ogawa, Synth. Commun., 1986, 16, 537. O.Bortolini, V.=nte, F.Di Furia and G-Modena, J.Org. Chem., 1986. . 51, . 2661. P.Dave,H-S.Byun and R.Enge1, Synth. .Commun., 1986, 16, 1343. S.Carranza R.; C.Perez G. and S.Perez G., Tetrahedron, 1986 42, 4133. -
General and Synthetic Methods
84 15.
P.Ferraboschi, M.N.Azadani, E.Santaniello and S.Trave, Synth. Commun., 1986, 16, 43. S.Suzuki, T.Onishi, Y.Fujita, H.Misawa and J.Otera, Bull. Chem. SOC. Jpn., 1986, 59, 3287. 17. L.K.Blair, K.D.Parris, O.F.D.Lee, K.F.Jenkins, R.C.Feese, T.Belcher, D.Badqer, D.Morris and C.Kuhn, J. Orq. Chem., 1986, 51 , 5454. 5482. 18. M.E.Krafft and B.Zorc, J. Org. Chem., 1986, 19. Y.Ishii, T.Nakano, A.Inada, Y.Kishigami, K.Sakurai and M.Oqawa, J. Org. Chem., 1986, 51, 240. 20. T.Nakano, T.Terada, Y x s h i i and M.Oqawa, Synthesis., 1986, 774. 21. I.Minami, M.Yamada and J.Tsuji, Tetrahedron Lett., 1986, 1, 1805. 22. J.Grunwald, B.Wirz, M.P.Scollar and A.M.Klibanov, J. h e r . Chem. Soc., 1986, 27, 6732. 23. E.J.Parish, S.ChitEkorn and T.Wei, Synth. Commun., 1986, 16, 1371. 24. R.Rathore, N.Saxena and S.Chandrasekaran, Synth. Commun., 1986, 16, 1493. 3139. 25. J . M u z a Z , Tetrahedron Lett., 1986, 26. H.C.Brown, S.U.Kulkarni, C.G.Rao and V.D,.Patil, Tetrahedron, 1986, 42, 5515. 27. H . C . B r G n and C.P.Garg, Tetrahedron, 1986, 42, 5511. 28. H.C.Brown, D.Basavaiah, S.U.Kulkarni, H.D.Lee, E-i.Negishi and J.J.Katz, J. Orq. Chem., 1986, 5 1 , 5270. 933. 29. T.Hirao, D.Misu and T.Aqawa, TeGahedron Lett., 1986, 7, 30. D.H.R.Barton, J.Finet, W.B.Motherwel1 and C.Pichon. Tetrahedron, 1986, 42, 5627. 31. F.Camps, J.Col1 and J.Guitart, Tetrahedron, 1986, 42, 4603. 32. E.Keinan and N.Greenspoon, J. Amer. Chem. S O C . , 1986, 108, 7314. 33. H.Chikashita and K.Itoh, Bull. Chem. S O C . Jpn., 1986, 59, 1747. 34. H-Chikashita, H.Ide and K.Hoh, J. Org. Chem., 1986, x 7 5 4 0 0 . 35. A.Omo, E.Fujimoto and M.Ueno, ~Synthesis, 1986, 570. 36. A.Ono, E.Fujimoto and M.Ueno, Synth. Commun., 1986, 16, 653. 37. G.A.Molander and G.Hahn, J. Org. Chem., 1986, 51, 1135. 38. A.Leone-Bay, J. Orq. Chem., 1986, 51, 2378. 39. K.Nakamura, M.FuJii, H.Mekata, S.Oka and A.Ohno, Chemistry Letters, 1986, 87. 40. T.Tsuda, T-Hayashi, H-Satomi, T.Kawamoto and T.Saequsa, J. O r q . Chem., 1986, 51, 537. 951. 41. M.P.Cooke, J.Org.Chem., 1986, 42. T.Hirao, D.Misu, K.Yao and T.Agawa, Tetrahedron Lett., 1986, 27 , 929. 43. T.Miyasaka, H.Monobe and S.Noquchi, Chemistry Letters, 1986, 449. 44. E.d'Incan, S.Sibille, J.Perichon, M-0.Moinqeon and J.Chaussard, Tetrahedron Lett., 1986, 27, 4175. 45. K.Ogura, K-Ohtsuki, K.Takahashi and H-Iida, Chemistry Letters, 1986, 1597. 46. B-Wladislaw, L.Marzorati and R.B.UchGa, Synthesis, 1986, 964. 47. J.E.Baldwin, R.M.Adlington, J.C.Bottaro, J.N.Kolhe, M.W.D.Perry and A.U.Jain, Tetrahedron, 1986, 42, 4223. 48. J.E.Baldwin, R.M.Adlington, A.U.Jain, J.N.Kolhe and M.W.D.Perry, Tetrahedron, 1986, 42, 4247. 49. B.L.Chenard, Tetrahedron Lett., 1986, 27, 2805. 50. I.T.Kay and S.E.J.Glue, Tetrahedron Lett., 1986, 27, 113. 51. V.P.Baillarqeon and J.K.Stille, J. Amer. Chem. S O C . , 1986, 108, 452. 52. C.J.Kowalski and M.S.Haque, J. Amer. Chem. SOC., 1986, 108, 1325. 16.
z,
x!,
~
x,
2: AIdehydes and Ketones
53. 54. 55. 56. 57. 58. 59 60. 61. 62 63. 64. 65 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88.
89., 90.
85
T-Tsuda, M-Okada, S.Nishi and T.Saegusa, J. Org. Chem., 1986, 51, 421. -
T.Tsuda, M-Tokai, T.Ishida and T.Saegusa, J. Orq. Chem., 1986,
51, 5216. -
F.D.Mills, Synth. Commun., 1986, 2,905. L.Carman, L.D.Kwart and T-Hudlicky, Synth. Commun., 1986, 2, 169. N-Bluthe, J.Gore and M-Malacria, Tetrahedron, 1986, 42, 1333. K.Maruoka, M.Haseqawa and H.Yamamoto, J . Amer. Chem. S O C . , 1986, 108, 3827. K.Fuji, M.Node and Y.Usami, Chemistry Letters, 1986, 961. H.Stamm and R.Weiss, Synthesis, 1986, 392. K Maruoka, S.Nakai, M.Sakurai and H.Yamamoto, Synthesis, 1986, 130.
N.X.Hu, Y.ASO, T.Otsubo and F.Oqura, Tetrahedron Lett., 1986, 27 , 6099. X.Lei, C.Doubleday and N.J.Turro, Tetrahedron Lett., 1986, 27, 4671. O.Tsuge, S-Kanemasa, T.Suzuki and K.Matsuda, Bull. Chem. SOC. Jpn., 1986, 59, 2851. S.E.Denmark, K.L.Habermas, G.A.Hite and T.K.Jones, Tetrahedron, 1986, 42, 2821. M.R.PeZ and C.R.Johnson, Tetrahedron Lett., 1986, 27, 5947. B.L.Chenard, C.M.Van Zyl and D.R.Sanderson, Tetrahedron Lett., 1986, 27, 2801. H-MatsFama, Y.Takei and M.Kobayashi, Bull. Chem. SOC. Jpn., 1986, 59, 2657. H-Matsuyama, Y.Miyazawa and M.Kobayashi, Chemistry Lett., 1986, 433. C.J.Moody and J.Toczek, Tetrahedron Lett., 1986, 27, 5253. H.Sawada, M.Webb, A.T.Stol1 and E-i.Neqishi, Tetrahedron Lett., 1986, 27, 775. W.A.NuFnt and F.W.Hobbs, J. Orq. Chem., 1986, 3376. D.F.Taber, J.C.Amedio and R.G.Sherril1, J. Orq. Chem., 1986, 51, 3382. S.C.Welch, J-M.Assercq and J-P.Loh, Tetrahedron Lett., 1986, 27, 1115. K S a h a , S.Muchmore, D.van der Helm and K.M.Nicolas, J. Orq. Chem., 1986, 51, 1960. K.Hiroi, H.Sato and K.Kotsuji, Chemistry Lett., 1986, 743. R.S.Olsen, Z.A.Fataftah and M.W.Rathke, Synthetic Commun., 1986, 16, 1133. F.Kuo and P.L.Fuchs, Synthetic Commun., 1986, 16, 1745. B.Byrne and K.J.Wengenroth, Synthesis, 1986, 870. M.S.Baird and H.H.Hussain, Tetrahedron Lett., 1986, 27, 5143. W.L.Meyer, M.J.Brannon, A.Merritt and D.Seebach, Tetrahedron Lett., 1986, 27, 1449. B.B.Snider andB.E.Goldman. Tetrahedron, 1986. _ 42. 2951. ' A.I.Meyers, B.A.Lefker, K.T.Wanner and R.A.Aitken, J. Orq. Chem., 1986, 51, 1936. =Carey, C.=ors and P-Helquist, J. Amer. Chem. SOC., 1986, 108, 8313. N.A.Porter, D.R.Maqnin and B.T.Wriqht, J. Amer. Chem. SOC., 1986, 108, 2787. T.L.Macdonald, K.J.Natalie, G.Prasad and J.S.Sawyer, J. Orq. Chem., 1986, 51, 1124. X i e f and Jz.Laboureur, J.C.S. Chem. Commun., 1986, 702. H.Ishibashi, S.Harada, M.Okada, M.Ikeda, K.Ishiyama, H.Yamashita and T.Tamura, Synthesis, 1986, 847. Y.Hatanaka and I.Kuwajima, Tetrahedron Lett., 1986, 27, 719. R.Zschiesche, E.L.Grimm and H-U.Reissiq, Angew. Chemie. Int. Ed. Enql., 1986, 25, 1086.
z,
r
86
General and Synthetic Methods
91.
T.van der Does, G.W.Klumpp and M.Schake1, Tetrahedron Lett., 1986, 27, 519. 92. I-Minami, K-Takahashi, I.Shimizu, T.Kimura and J.Tsuji, Tetrahedron, 1986, 42, 2971. 93. D.Liotta, M-Saindane, R.Monahan, D.Brothers and A.Fivush, Synthetic Commun., 1986, 16, 1461. 94. A.B.Smith, P.A.Levenberg and J.Z.Suits, Synthesis, 1986, 184. 95. N.Jabri, A-Alexakis and J.F.Normant, Tetrahedron., 1986, 42, 1369. 96. C.Fehr and J.Galindo, Helvecica Chim. Acta, 1986, 69, 228. 97. M.Yamaguchi, K.Shibato, S.Fujiwara and I.Hirao, Syzhesis., 1986, 421. 98. P.Zhang and L.Li, Synthetic Commun., 1986, 16, 957. 99. K.Ogura, T.Iihama, S.Kiuchi, T.Kajiki, O.Koshikawa, K.Takahashi and H.Iida, J. Org. Chem., 1986, 51, 700. 100. A.Pelter and M.E.Colclough, Tetrahedron Lett., 1986, 27, 1935. 101. I.Ryu, S.Murai and N.Sonoda, J. Org. Chem., 1986, 51, 2389. 102. A.P.Kozikowski and S.H.Jung, J. Org. Chem., 1986, 51, 3400. 103. Y.Hatanka and I.Kuwajima, J. Org. Chem., 1986, X I 1932. 104. R.A.Kjonaas, J. Org. Chem., 1986, 51, 3708. 105. D.P.Curran and B.H.Kim, Synthesis., 1986, 312. 106. J.L.C.Kachinsky and R.G.Salomon, J. Org. Chem., 1986, 51, 1393. 107. R.V.Hoffman and C.S.Carr, Tetrahedron Lett., 1986, 27, 5811. 108. R.V.Hoffman, B.C.Jankowski, C.S.Carr and E.N.Duesler, J. Org. Chem., 1986, 2,130. 109. M.P.Gore and J.C.Vederas, J. O r g . Chem., 1986, 3700. 110. F.A.Davis and M.S.Haque, J. Org. Chem., 1986, 51, 4083. 111. C.Hubschwerlen, Synthesis., 1986, 962. 112. M.Gil1, M.J.Kiefe1 and D.A.Lally, Tetrahedron Lett., 1986, 27, 1933. 113. K.Ogura, T.Tsuruda, K.Takahashi and H.Iida, Tetrahedron Lett., 1986, 27, 3665. 114. M.Larcmveque and Y.Petit, Synthesis, 1986, 60. 115. G.Guanti, L.Banfi, A.Guaragna and E.Narisano, J.C.S. Chem. Commun., 1986, 138. 65. 116. K.Tamao and K.Maeda, Tetrahedron Lett., 1986, 7, 117. S.T.Purrinqton, N.V.Lazaridis and C.L.Bumgardner, -____ Tetrahedron Lett., 1986, 2 7 , 2715. 118. Z s t a l d i , STavicchioli, C.Giordano and F.Ugqeri, Anqew. Chem. Int. Ed. Engl., 1986, 25, 259. 119. Y.J.Abu1-Hajj, J. Org. Chem., 1986, 5 1 , 3380. 120. J.Barluenga, J.M.Martinez-Gallo, C.Ncera and M.Yus, Synthesis., 1986, 678. 121. R.D.Evans and J.H.Schauble, Synthesis, 1986, 727. 122. A.A.Ponaras and 0-Zaim, J. Org. Chem., 1986, 51, 4741. 123. R.Tamura, D.Oda and H-Kurokawa, Tetrahedron Lett., 1986, 27, 5759. 124. J-B.Verlhac and J-P-Quintard, Tetrahedron Lett., 1986, 27, 2361. 125. T.Shono, Y.Matsumura, S.Katoh, K.Inoue and Y.Matsumoto, Tetrahedron Lett., 1986, 27, 6083. 126. T.Satoh, Y.Kaneko, K.Sakata and K.Yamakawa, Bull. Chem. S O C . __ Jpn., 1986, 2,457. 127. T.Satoh, S.Motohashi and K.Yamakawa, Bull. Chem. SOC. Jpn., 1986, 59, 946. 128. T.Satoh, T.Kumagawa and K-Yamakawa, Tetrahedron Lett., 1986, 27, 2471. 129. T.Satoh, S-Motohashi and K.Yamakawa, Tetrahedron Lett., 1986, 27, 2889. 130. T.Yura, N.Iwasawa, R.Clark and T.Mukaiyama, Chemistry Lett., 1986, 1809. 131. K.Hiroi and N.Matsuyama, Chemistry Lett., 1986, 65. ~
z,
2: Aldehydes and Ketones
87
132. 133.
R.F.Cunico, Tetrahedron Lett., 1 9 8 6 , 27, P.Sampson, G.B.Hammond and D.F.Wiemer,J.
134.
G.B.Hammond, T.Caloqeropoulou and D.F.Wiemer, Tetrahedron Lett., 1 9 8 6 , 27, 4 2 6 5 . m n t i a g o , I.M.de Lopez-Cepero and G.L.Larson, Synthetic Commun., 1 9 8 6 , 16, 6 9 7 . R.M.Betancourt de Perez, L.M.Fuentes, G.L.Larson, C.L.Barnes and M.J.Heeq, J. Org. Chem., 1 9 9 6 , 51, 2 0 3 9 . F.P.Ballistreri, S.Failla, G.A.Toma&lli and R.Curci, Tetrahedron Lett., 1 9 8 6 , 27, 5 1 3 9 . Y.~.Vankar and S.P.Singh, Chemistry Lett., 1 9 8 6 , 1 9 3 9 . R.Conrow and P.S.Portoghese, J. Org. Chem., 1 9 8 6 , 5 1 , 9 3 8 . S.Raucher and L.M.Gustavson, Tetrahedron Lett., 1 9 8 6 , 27, 1 5 5 7 . N.K.Hamer, Tetrahedron Lett.,R.B.Phillip-nd A.J.Robichaud, Synthetic Commun.,
4269.
Orq. Chem., 1 9 8 6 ,
51,
4342. 135.
136. 137. 138. 139. 140. 141.
142.
1986,
16, 4 1 1 .
143.
S-i-Kiyooka, T.Yamashita, J-i.Tashiro, K.Takano and Y.Uchio, Tetrahedron Lett., 1 9 8 6 , 27, 5 6 2 9 . 1 4 4 . P.Duhame1, L.Hennequin, J.M.Poirier, G.Tave1 and C.Vottero, Tetrahedron, 1 9 8 6 , 42, 4 7 7 7 . 1 4 5 . W.G.Dauben, J.M.Gerdes and G.C.Look, J. Org. Chem., 1 9 8 6 , 4964. 1 4 6 . J.Gora, K-Smiqielski and J.Kula, Synthesis, 1 9 8 6 , 5 8 6 . 1 4 7 . J.Otera and H-Nozaki, Tetrahedron Lett., 1 9 8 6 , . 2 7 , 5 7 4 3 . 1 4 8 . H.Liu and S.Yu, Synthetic Commun., 1 9 8 6 , 16, 1 3 5 7 . 1 4 9 . Y-Kamitori, M.Hojo, R.Masuda, T.Kimura andT.Yoshida, J. Org. Chem., 1 9 8 6 , 5 1 , 1 4 2 7 . 1 5 0 . J.A.Soderquistand E.I.Miranda, Tetrahedron Lett., 1 9 8 6 , 6305. 1 5 1 . H-J.Cristau, A.Bazbouz, P.Morand and E.Torreilles, Tetrahedron Lett., 1 9 8 6 , 2 7 , 2 9 6 5 . 1 5 2 . M.Ohshima. M.=rakami and T.Mukaiyama, Chemistry Lett., 1 9 8 6 , 1593. 1 5 3 . P.Laszlo, P.Pennetreau and A.Krief, Tetrahedron Lett., 1 9 8 6 , 27, 3 1 5 3 . 1 5 4 . P:Vankar, R.Rathore and S.Chandrasekaran, J. Orq. Chem., 1 9 8 6 , 51, 3063. 1 5 5 . M.Salm/on, R.Miranda and E.Angeles, Synthetic Commun., 1 9 8 6 , 1827. 1 5 6 . R.A.Moriarty, 0.Prakash and P.R.Vavilikolanu, Synthetic Commun., 1986, 1247. 1 5 7 . D.Monti, P.Gramatica, G-Speranza, S.Tagliapietra and P.Manitto, Synthetic Commun., 1 9 8 6 , 803. 1 5 8 . P.G.Williard and J.M.Salvino, J.C.S. Chem. Commun., 1 9 8 6 , 1 5 3 . 1 5 9 . T.Sato, H.Matsuoka, T-Iqarashi and E.Murayama, Tetrahedron Lett., 1 9 8 6 , 2 7 , 4 3 3 9 . 1 6 0 . =Welch andK.W.Seper, J. Orq. Chem., 1 9 8 6 , 51, 1 1 9 . 1 6 1 . J.Ackrel1, J.M.Muchowski, E.Galeazzi and A.Guzman, J. Orq. Chem., 1 9 8 6 , 51, 3 3 7 4 . 1 6 2 . N.Ono, 1.Hamamoto and A.Kaji, J. Org. Chem., 1 9 8 6 , 5 1 , 2 8 3 2 . 1 6 3 . T.Mukaiyama, H.Nagaoka, M.Ohshima and M.Murakarni, Chemistry ___ Letts., 1 9 8 6 , 1 0 0 9 . 1 6 4 . T.Takeda, Y.Kaneko and T.Fujiwara, Tetrahedron Lett., 1 9 8 6 , 3029. 1 6 5 . R.Hunter and C.D.Simon, ___________ Tetrahedron Lett., 1 9 8 6 , 1385. 1 6 6 . N.M.Berry, M.C.P.Darey and L.M.Harwood, Tetrahedron Lett., 1986, 2319. 1 6 7 . N.S.Simpkins, J.C.S. Chem. Commun., 1 9 8 6 , 88. 1 6 8 . K.Hiroi, K.Suya and S.Sato, J.C.S. Chem. Commun., 1 9 8 6 , 4 6 9 . 604. 1 6 9 . H.Chow and D.Seebach, Helvetica Chim. Acta, 1 9 8 6 ,
27,
16,
16,
16,
27,
27,
27,
2,
88
General and Synthetic Methods
170. M.T.Reetz, F.Kunisch and P.Heitmann, Tetrahedron Lett., 1986, 27, 4721. 171. I.PaterSOn, M.A.Lister and C.K.McClure, Tetrahedron Lett., 1986, 27, 4787. 172. C.Gennari, R.Todeschini, M.G.Beretta, G.Favini and C.Scolastico, J. Orq. Chem., 1986, 51, 612. 173. M.Kawai, M.Onaka and Y.Izumi, Chemistry Lett., 1986, 1581. 174. S.Sato, 1.Matsuda and Y.Izumi, Tetrahedron Lett., 1986, 27, 5517. 175. A-Lubineau, J. Orq. Chem., L986, 51, 2142. 176. C.H.Heathcock, S.K.Davidsen, K.T.=g and L.A.Flippin, J. Orq. Chem., 1986, 51, 3027. 177. Z r a , N.Iwazwa and T.Mukaiyama, Chemistry Lett., 1986, 187. 178. F.Schneider and R.Simon, Synthesis, 1986, 582. 179. D.Basavaiah and V.V.L.Gowriswari, Tetrahedron Lett., 1986, 27, 2031. 180. M.Taniquchi, S.Kobayashi, M.Nakaqawa T.Hino and Y.Kishi, Tetrahedron Lett., 1986, 27, 4763. 181. S.H.Bertz, G.Dabbaqh and G.Sundararajan, J. Org. Chem., 1986, 4953. 182. E.J.Corey, R.Naef and F.J.Hannon, J. Amer. Chem. SOC., 1986, 108, 7114. 183. =.Lipshutz, D.A.Parker, S.L.Nguyen, K.E.McCarthy, J.C.Barton, S.E.Whitney and H.Kotsuki, Tetrahedron., 1986, 42, 2873. 184. R.A.Watson and R.A.Kjonaas, Tetrahedron Lett., 1986, 27, 1437. 185. R.A.Kjonaas and E.J.Vawter, J. Orq. Chem., 1986,. 51, 3993. Lett., 1986, 27, 186. C.Petrier, C.Dupuy and J . L . L u c h e , h e d r o n 3149. 187. R.K.Dieter and L.A.Silks, J. Org. Chem., 1986, 51, 4687. 188. M.Zervos, L.Wartski and J.Seyden-Penne, Tetrahedron., 1986, 42, 4963. 189. M.Zervos and L.Wartski, Tetrahedron Lett., 1986, 27, 2985. 190. D.J.Aqer and M.B.East, J. Orq. Chem., 1986, 51, 3983. 191. K.Ogura, N.Yahata, M.Minoguchi, K.Ohtsuki, Kyakahashi, and H.Iida, J. Org. Chem., 1986, 51, 508. 192. D.Seyferth and R.C.Hui, Tetrahedron Lett., 1986, 27, 1473. 193. G.Rosini, E.Marotta, R.Ballini, and M.Petrini, Synthesis, 1986, 237. 194. G.Berthiaume, J-F.Lavall6e and P.Deslongchamps, Tetrahedron Lett., 1986, 27, 5451. 195. J-D.Lavall6eIG.Berthiaume, P.Deslonqchamps and F.Grein, Tetrahedron Lett., 1986, 27, 5455. 196. G.H.Posner, S-B.Lu and E.Eirvatham, Tetrahedron Lett., 1986, 27, 659, and, G.H.Posner and E.Asirvatham, g , 1986, 27, 663. 197. D.A.Oare and C.H.Heathcock, Tetrahedron Lett., 1986, 27,6169. 198. C.H.Heathcock and D.E.Uehlinq, J. Org. Chem., 1986, 51, 279. 199. T.Mukaiyama, M.Tamura and S.Kobayashi, Chemistry Lett., 1986, 1017. 200 * T.Mukaiyama, M.Tamura and S.Kobayashi, Chemistry Lett., 1986, 1817. 201. T.Mukaiyama, Y.Sagawa and S.Kobayashi, Chemistry Lett., 1986, 1821. 202. S.Kobayashi and T. Mukaiyama, Chemistry Lett., 1986, 221.
3 Carboxylic Acids and Derivatives BY D.W. KNIGHT 1
Carboxylic Acids
General Synthesis.
-
Oxidations of alcohols and aldehydes to the
carboxylic acid level can often be problematical despite the plethora of reagents available and so new, mild methods for effecting such transformat,ons are always of interest.
A particularly attractive
development in this field is the use of potassium permanganate in a mixture of t-butanol and aqueous sodium dihydrogen phosphate at pH values between 4.4 and 7.0, for the conversion of aldehydes to Yields are generally excellent ( > 9 5 % ) , the carboxylic acids.' reactions are very rapid, often taking less than 10 minutes but most significantly, a variety of protecting groups including acetonides, TBDMS, ThP, MOM and benzyl ethers are unaffected by this reagent mixture.
A somewhat less mild method consists of treating an
aldehyde (RCHO) with t-butyl trimethylsilyl peroxide and a catalytic amount of trityl perchlorate resulting in the formation of a diperoxide species [RCH(02LBu)2] which is decomposed to the acid, RC02H, using either aqueous piperidine at 90°C or copper sulphate and
(L)-ascorbic acid at ambient temperature.
Yields are generally good;
isolated olefins and benzyl ethers at least are not affected.
This
method is clearly limited in scale whereas an alternative method for oxidising aldehydes to acids using sodium chlorite and 35% hydrogen peroxide does appear to have some potential for large scale work.3 Yields are especially high for oxidations of aromatic aldehydes, and for other conjugated aldehydes such as cinnamaldehydes, and saturated aliphatic aldehydes.
Isolated double bonds, amino groups and Bisulphite complexes of aldehydes are
sulphides are also attacked.
efficiently oxidised to carboxylic acids using a Moffatt-type oxidation with dimethyl sulphoxide and acetic a n h ~ d r i d e . ~Work up of the reaction mixture with methanolic methoxide or an amine gives the corresponding ester or amide. Both alcohols and aldehydes can be oxidised to carboxylic acids using ruthenium tetroxide;
an efficient, two-phase (CC14-aq.NaC1)
electro-oxidation method has been developed for the generation of Ru04 which could be especially useful f o r oxidations of carbohydrate derivatives, partly protected as acetonides. Zinc dichromate 89
General and Synthetic Metho&
90
R’ .‘CON
19 1
SiPh,Me
RAcop
Mez
(1 0 )
91
3: Carboxylic Acids and Derivatives
trihydrate is also capable of oxidising a variety of primary alcohols to the corresponding carboxylic acids. However, the acidic nature of the reagent makes it incompatible with ketals and probably many other acid-labile groups;
the reagent also oxidises aromatic systems and
can attack olefins and acetylenes. 1,2-Diols are efficiently cl?aved to the corresponding carboxylic acids, usually in excellent yields ( > g o % ) , simply by treatment with hydrogen peroxide (40% w/v) but in the presence of both tungstate (Na2W04.2H20) and phosphate (H3P04) catalysts at P H ~ .The ~ method could be especially useful for large scale preparations. A new method for obtaining chiral a-substituted carboxylic acids
consists of S,2' ring openings of the tartramide-derived acetals ( 1 ) by trialkylaluminum reagents followed by cleavage of the major products (2) using KMn04-Na104.8 Optical yields of the acids ( 3 ) are often essentially quantitative, but the method is clearly limited by the availability of the aluminum reagent and the wastage of two alkyl groups, as well as by the oxidative cleavage method which precludes, for example, the presence of other double bonds.
However, many useful
products can be obtained, and the ready availability of both enantiomers of the acetal ( 1 ) is an additional attraction. Rather more familiar ligands have also been used to direct asymmetric alkylations a- to carboxylic acid precursors. Thus the pyrrolidine (4) can be enolised and alkylated to provide the di-substituted cyano-acetic Such alkylations are acids (5) [80-90% eel after acidic hydrolysis.' often prevented by the bulky chiral ligand; in this case the small steric requirement. of the cyano group is presumably crucial to the success of the method.
During work towards a synthesis of the
ionophore antibiotic ionomycin, Evans has utilised his prolinol propionamide methodology to obtain acid ( 6 ) of very high optical purity . 10 Simple unsaturated acids [e.g. ( 7 ) l can be reduced in essentially quantitative optical yields to give butanoates (8) using an enoate reductase together with methyl viologen (paraquat) as an electron-transfer reagent, hydrogen and a modified Pd-C or Pt-C hydrogenation catalyst. The system looks particularly simple and will hopefully be effective with a variety of other substrates. The hindered cyclopropyl ester ( 9 ) , as well as the corresponding t-butyl ester, can be lithiated [using tBuLi in the case of ester ( 9 ) ] and homologated by reactive electrophiles such as allylic bromides and aldehydes : subsequent ester cleavage using KOtBu provides the
General and Synthetic Methods
92
R’
f ‘2 H
OC Ph3
(18)
0
\I
Ph..
H
122)
(211
Ph
I
Ph/ (251
(241
(23)
R3 A r y S S H
CO,H
R2+C0,
0
H
S R’
(27)
(26)
,CO,Me R 1 CO,H 4
‘CO, H H (301
(29) H
HO,C
OR
’r H
OH Co2Et
“;ii
CO,H
02E
93
3: Carboxylic Acids and Derivatives
cyclopropanecarboxylic acids ( 1 0 )
.IL
Further routes to some useful
a-substituted acids have been reported.
Phenoxides adsorbed on
Amberlite IRA 4 0 0 resin react smoothly with sodium chloroacetate to give aryloxyacetic acids (11) in good yields.13 In common with other bulky silyl chlorides, diphenylmethylsilyl chloride C-silylates carboxylic acid dianions to give acids (12) which can be re-enolised and alkylated at the a-position.14 Further developments in the preparation of chiral O-substituted carboxylic acids using ligands derived from camphor have been described by Oppolzer.
For example, the sultam-imides (13) can be
hydrogenated with > 90% diastereofacial selectivity to give acids ( 1 4 ) and recovered ligand in excellent yields after hydrolysis. l 5 Despite some obvious limitations, this methodology seems certain to find many applications.
The same starting material (13) also undergoes
asymmetric conjugate addition of hydride when treated with L-selectride; trapping of the resulting enolate with methyl iodide followed by hydrolysis has been used to obtain the acid (15) in a single operation and in excellent optical yield.16
As with the
foregoing protocol, this method could find many applications. Further examples of the elaboration of chiral B-substituted acids [e.g. ( 1 4 ) l using Michael additions to sterically screened alkenoates An alternative to also derived from camphor have been reported.” this is the addition of nucleophiles to proline derivatives (16); depending upon the precise way the reactions are carried out, either enantiomer of the final product (17) can be obtained with up to 60% Somewhat better in this latter respect are the related derivatives (18) which undergo efficient Michael additions of Grignard reagents using CuBr.Me2S leading to acids (19) with enantiomeric enrichments of 77-97%. l9 Asymmetric Michael additions have also been effected with the aid of various enzymes using
2-(trifluoromethyl)propenoic acid as the substrate: [(20),
the products
X=O, NH(R‘) and S ] were obtained using water, alcohols, amines
and thiols as nucleophiles in usually good yields with optical purities of 39-70%.20 A group of rather different Michael acceptors are the chiral vinyl sulphoximines (21) which undergo conjugate additions with a variety of organometallic species to give, after carboxylation [LDA, (MeO)2CO], desulphurisation (AlHg), and hydrolysis, acids (19) with > 9 0 % ee in the optimum cases discovered.21 Loss of the chiral auxiliary is a drawback although on the credit side, the method can also be used to prepare chiral
94
General and Synthetic Methods
hydrocarbons simply by desulphurisation of the initial Michael adduct, and presumably a range of other derivatives obtainable from the initial ionised sulphoxide. Removal of a chiral auxiliary can be a limiting factor in much of the foregoing methodology, especially where amide linkages are involved. In the special case of a-methylbenzylamine derivatives [e.g. (22)1, which are often usec for optical resolutions of acids RC02H, removal of the benzyl group can be efficiently performed with suitable substrates by reduction using the system Li-NH3-THF-H20.22 Racemisation a- to the carbonyl is reported not to occur under these conditions. The resulting primary amide can be hydrolysed to the acid (RC02H) using potassium hydroxide in hot ethylene glycol if no a-proton is present; with enolisable amides the best hydrolysis method found was that due to Olah, using nitrosonium tetraf luoroborate, NOBF4. A useful two-carbon homologation method involves alkylations of the carbanion (23) derived from the corresponding 2-methylimidazoline using n-butyl lithium, followed by acidic hydrolysis leading to acids (25) in generally good to excellent yields.23 The intermediates (24) could presumably also be useful as "protected" carboxylic acids. 6-Aroylthiopropionic acids (26) can be obtained by enantioselective hydrolyses of the corresponding racemic methyl esters using various microbial lipases.2 4 However, enantiomeric excesses of both the acids (26) and the recovered esters are variable (6-98%). An alternative route to racemic 4-alkylthiocarboxylic acids (27) in general consists of Michael additions to a,B-unsaturated acids by alkylthiolates, the novelty being that these are generated by hydrolysis of the corresponding z,z-dialkyl dithiocarbonates, (RS12C0, using a variety of aqueous basic conditions, thus avoiding the handling of an alkyl thiol at this stage; yields are generally excellent.25 Similar conjugate additions to acetylenic acids lead to the unsaturated acids (28), also in excellent yields. Epoxidations of a,B-unsaturated acids using potassium peroxymonosulphate [KHS05; oxonel in aqueous acetone are more conveniently conducted in the presence of excess sodium bicarbonate rather than continuously adding a base, to avoid low pH values, as originally reported. Yields of the epoxy-acids (29) are excellent on 26 small and large (multi-kilo) scales. Diacids and Half-esters. - A research group led by Gais has given full accounts of their work on the PLE-catalysed asymmetric
3: Carboxylic Acids and Derivatives
95
4M
HZSOL
KOH
acoO
n SPh
H 0,C
(421
(41)
Scheme 1
p:i
R'
i M e2 R
' 4 0 M e
CO,M e (L3)
96
General and Synthetic Methods
hydrolysis of E -d i e ~ t e r s . ~ ~ method will doubtless find many The applications since useful chiral starting materials such as half-ester (30), which contains three readily distinguished functional groups, can be easily and efficiently produced on a relatively large scale, e.g. 200 g.
Various improvements both in the rate of reaction and
in the optical yields resultinc from this type of hydrolysis have been reported. 28 Similar hydrolyses using PLE, or better lipase-MY, have been used to obtain the a-fluoro-esters (31) with up to 91% ee; this transformation is somewhat unusual in that halogenated substrates are often incompatible with such enzymic systems.29
The
initial products (31) can be used to obtain chiral a-fluoroalkanoates.
PLE-catalysed hydrolysis has also been used to prepare 30
the useful tartrate derivatives [(32); R=Me or PhCH2].
A new route to racemic 2-arylsuccinic acids consists of condensations between D-nitrostyrenes (33) and the enamine (34); subsequent acidic hydrolysis of the resulting adducts (conc. HC1, reflux) then gives the diacids (35) in good to excellent yields.31 A milder hydrolysis procedure would clearly extend the scope of this method.
Dye-sensitised photo-oxygenation in methanol can be used to
prepare half-esters (36) in good yield from the corresponding 1 ,2-cyclopentanediones. 32
When applied to cyclic 1 ,2-diolsI the
cleavage method using hydrogen peroxide discussed above7 represents a useful approach to many a,w-dicarboxylic acids. Hydroxy-acids. - Once again the emphasis in this area has been on the development of asymmetric routes to a- and O-hydroxy-acids. Whitesell and co-workers have assessed the suitability of a variety of auxiliaries for controlling asymmetric ene reactions of chiral glyoxalates (37) leading to a-hydroxy-acid precursors (38).33 Optimum inductions are observed when the substituent R1 contains a phenyl group, e.g. the 8-phenylmenthol derivatives, indicating that complexation between the aromatic substituent and the Lewis acid is important.
Essentially complete asymmetric induction can be achieved
under optimum conditions.
The related method whereby asymmetric
Grignard additions to glyoxalates (37) and the corresponding pyruvates are used to establish a chiral centre a - to the ester carbonyl group has been reported in full34 and used to prepare both enantiomers of the aggregation pheromone Frontalin, from esters of 8-phenylmenthol . 3 5 As with the ene reactions, chiral induction is essentially complete. Both enantiomers of an a-hydroxy-acid (40) can be obtained from a
97
3: Carboxylic Acids and Derivatives
single a-keto-amide (39), derived from
( 5 )- p r ~ l i n e . This ~~
preliminary study has only been applied to two examples [ ( 3 9 ) ; R=Ph i or Bu] but has revealed that, in the presence of lithium halides, reduction using LiBH4 gives (5)-(40) (up to 80% ee) whereas when i Bu 2 A 1 H is used, (5)-(40) is obtained with an ee of 59% when R=Ph. Chiral acids (40) can also be obtained with optical yields in the range 60-95% by alkylations of enolates derived from chiral amides of glycolic and lactic acids.37
Dibenzyl peroxydicarbonate
[(PhCH O C 0 2 ) 2 ] ,prepared from aqueous hydrogen peroxide and benzyl 2 chloroformate, is yet another hydroxyl cation equivalent capable of directly introducing an oxygen function (in this case, a benzylcarbonate) a- to a carbonyl group, by condensation with an enolate of the latter.38 When applied to chiral enolates derived from oxazolidinone carboximides of the type developed by Evans, a-hydroxyacids (40) are obtained with almost complete optical purity in excellent yields. variable.
However, yields with other enolates are rather
The electro-carboxylation of nXzhydes, RCHO,
previously
regarded as impossible, can be effected using a sacrifical aluminum anode, to give a-hydroxy-acids, RCH(OH)C02H, in variable yields: aromatic aldehydes work best and the method is also applicable to aromatic ketones, in which cases yields are much higher (62-85%).39 One example has been given of a potentially useful version of the benzil-benzilic acid rearrangement in which a-acetoxy-ketones ( 4 1 ) , obtained by Pummerer rearrangement of the corresponding a-thio-ketone, undergoes ring contraction to give the a-hydroxy-acid (42), a precursor of the corresponding cyclopentanone, upon treatment with aqueous potassium hydroxide. 4 0 The (2.3]-sigrnatropic (Wittig) rearrangement of a-allyloxy esters or acids has been highlighted recently as a general route to a-hydroxyacids and esters.41 One problem associated with this methodology is the possibility of competing I3.31-sigmatropic (Claisen) rearrangements especially when esters are used as substrates (Scheme 1 ) . In general the Wittig rearrangement occurs at lower temperatures; for example, C-silyl-esters (43) are converted into the a-hydroxy-esters (44) when treated with fluoride (TBAF) at -85"C, whereas the corresponding g-silyl derivatives (45) simply revert to the starting ester when treated with fluoride.
(Thermolysis of ester enolates
(45) results in the expected Claisen rearrangement).42
It t h u s
appears that the "free" enolate of keten acetal (45) is not formed
General and Synthetic Methods
98
& , gcozH & ?H
f"
OBn
(CO,H
-- 0
+
--0
+
H (53)
(52)
(57) 0
158)
99
3: Carboxylic Acids and Derivatives upon treatment with fluoride.
The pathway taken by ester enolates
(Scheme 1 ) depends remarkably on how these intermediates are generated; exclusiiJe [2.3]-Wittig rearrangements occur when the lithium enolate is generated using LDA, crucially in 20% HMPA-THF.43 The two rearrangements (Scheme 1) can however be complimentary. Thus, Wittig rearrangement of the steroidal acid (46) gives exclusively the threo-hydroxy-acid (47) whereas enolate Claisen rearrangement of the benzyloxy acetate (48), derived from the same alcohol, leads only to the erythro-isomer (49) 44 Chiral auxiliaries have been incorporated
.
into such rearrangements [at position "X" in Scheme 11 and although yields, either optical or chemical, are rather variable, some useful examples have been delineated.45 Zirconium enolates can be especially suited to these and also to chiral
rearrangement^^^
transfer in rearrangements of ethers (50) into hydroxy-esters ( 5 1 ) . The syn-isomer predominates ( > 6 0 : l ) and is almost optically pure.46 The unusual (?)-selectivity of the last examples is also observed when trimethylsilyl triflate and triethylamine are used to effect the transformation: the authors propose the intermediacy of an unusual oxygen ylide species.4 7 Heathcock and co-workers have given a full description of their extensive studies on the preparation of 6-hydroxy-esters and ketones by Lewis acid catalysed condensations of enol silanes with aldehydes. 48 Although the diastereoselectivi ties are in general rather moderate, some useful mechanistic rationales of this and other work are given. Similar selectivities (erythro:threo ca. 4 : l ) are _______ observed in preparations of 6-hydroxy-esters by crossed aldol condensations using a-silyl trimethylsilyl esters,49 and in condensations between the trianion derived from glycinol (52) and aldehydes in the presence of a titanium salt. In the latter cases, hydrolysis and a single crystallisation is reported to give enantiomerically pure a-hydroxy-acids (53). 5 0
The dilithio salt of
propionic acid condenses with the chiral aldehyde (54) to give the anti- (55) and syn- (56) isomers (1:l) accompanied by only traces of their enantiomers.51 This lack of selectivity is somewhat alleviated by the potential utility of both products. A synthesis of the highly substituted hydroxy-diacid Crispatic acid (57) features a previously reported route to 6-hydroxy-carbonyl compounds __ via isoxazolines, generated by [ 1 ,3 1 -dipolar cycloaddition reactions.5 2 This example serves to further illustrate the potential of this methodology.
General and Synthetic Methods
0
H2°2 _____)
R
K2C03
162)
R
1c02h (63)
t (65)
(66)
0
TsCL
(69) Scheme 2
0 (EtO),P
II
;
R'CHO ______)
CO,H
0,H
101
3: Carboxyiic Acids and Derivatives
Keto-acids.
-
Fremy’s salt has been found to be capable of oxidising
.
both a-hydroxy and a-amino-acids to the corresponding a-keto-acids 5 3 These oxidations, which can be regarded as simple models of oxidases, are unusual in that chemical oxidations of these substrates usually follow an oxidative degradation pathway. 83%.
Yields range between 37 and
Ketene dithioacetals and vinyl sulphides [(58);
R=SAr or Me
respectively] undergo smooth acylation by oxalyl chloride in the presence of pyridine to give the a-keto-acids (591, after hydrolysis of the initially formed acid chlorides.54 The 1,2 ,4-trioxan-5-ones (60) have recently become available and have been found to be useful precursors of a-keto-acids (61) following base induced 0-0 bond cleavage.
Yields are generally excellent even with very bulky
substituents .
’
4-Nitroalkanals (62) can be easily obtained in 50-56% yield by Michael additions of nitroalkanes to acrolein using chromatographic alumina as base in the absence of a solvent.
Subsequent treatment
with 30% hydrogen peroxide in methanol containing potassium carbonate results in a double oxidation to give y-keto-acids (63) in 40-80% yields. 56
Given cheap and readily available starting materials, this
looks to be a very simple and useful method.
y-Keto-acids can also be
obtained from a-diphenylmethylsilyl butyrolactone by sequential Grignard addition and Jones oxidation:
overall yields are generally
above 7 0 % . ~ ~ In contrast to condensations between silyl enolates and aldehydes, 48 Mukaiyama-type Michael additions of these substrates (64) to a chiral enone (65) afford very largely the keto-acids (66), independantly of enolate geometry.58 It remains to be seen whether less bulky Michael acceptors also provide such good stereoselectivities. 1,2-Cycloalkanediones (67) undergo very efficient (>
90% yield) photo-oxidative cleavage (lo2, MeOH) to give the
’’
6-keto-acids (68)
in contrast to the corresponding
cyclopentanediones which are cleaved under similar conditions to give largely diacid h a l f - e ~ t e r s . ~Unsaturation ~ in the side-chain, ‘ R ’, is not affected. Unsaturated Acids. - Details have been given of a one-carbon homologation procedure for the conversion of acids (69) into the unsaturated acids (70) (Scheme 2) .60
The starting acid is converted
into its dianion and condensed with glyoxal mono(dimethy1hydrazone). The resulting 6-hydroxy-acid salt is treated with tosyl chloride to
102
General and Synthetic Methods
(731
I
Scheme 3
p.’
“iq.f
R 1 (COC 1)2
--+
@ C -02H
R20 N - N
(84)
___)
N-N R2/
COZH
X2
CO, H
(85)
(87)
Scheme A
(86)
3: Carboxylic Acids and Derivatives
103
give the intermediate hydrazones which are then hydrolysed and oxidised. Difficulties in using doubly-stabilised phosphonate anions to prepare a-substituted alkenoic acids (72) have been overcome by using the more reactive dianionic species (71) .61 This intermediate is however still not reactive enough to condense with ketones. 6-Alkyloxy- and aryloxy-unsaturated acids (73) are available by base hydrolysis of the corresponding trihaloacetyl derivatives obtained by acylation of the parent vinyl ether.62 Conditions have been found for preparations of the useful ally1 silanes (74) by addition of cuprates derived from TMSCH21 to a terminal acetylene, followed by carboxylation.6 3 y,d-Unsaturated acids [ (75), or enantiomerl are available in high enantiomeric excess by Michael additions of 1-alkenylcopper reagents to sterically screened a,B-unsaturated esters derived from ( g )- or ( L )-camphor,64 along the lines discussed above.” An alternative route to (22,4E)-dienoic acids (77) features a different ring cleavage procedure to those previously used. Thus, the butenolides ( 7 6 ) , available in four step from ethyl a-phenylselenopropionate, are opened by treatment with zinc in refluxing ethanol.65 Yields are excellent, at least with simple alkyl substituents. Dialkylaluminum acetylides add smoothly to B-propiolactones [ ( 7 8 ) : R = H , Me] giving the acids ( 7 9 ) in 38-95% yields.66 Kinetic resolution of racemic allenic esters has been effected by partial hydrolysis (31-50% conversion) using PLE (Scheme 3) .67 Optical yields are best (up to 93% ee) with highly substituted substrates.
Aromatic Acids.
-
Aryl halides undergo electroreductive carboxylation
upon treatment with carbon dioxide in DMF and using a platinum cathode and anode and a Pd(0) catalyst; 47-92% yields have been obtained.68 Similar transformations [(80) + ( 8 1 ) 1 can be carried out with polyhaloaromatics by photochemically induced carbonylation (CO at 2 kg ~ catalyst.69 Pyrazoles (82) cm-2, 65°C) in the presence of C O ~ ( C O )as undergo direct carboxylation when treated with oxalyl chloride; hydrolysis of the intermediate acid chloride provides the acids (83) The directing ability of carboxylate in generally good yields.” groups in me:z?.llations is well established; this has been exploited rather neat1.y to allow ortho-metallation of anilines which do not underrio direct metallation. Thus, treatment of an g-alkylaniline (84) with a base then C02, and then another equivalent of base generates the dianions (85) which can be carboxylated using C02. The resulting carbamic acid collapses on work-up to provide good yields of the
General and Synthetic Methods
104
Reagents
I,
11,
M e 3 S I C N , Zn lZ , C 6 H6 , 0 "C or M e SiCI, KCN, DMF, O"C, t h e n AC 0 , F e C l , 0 ° C ; 3 2 3 H 2 , P d I C , M e C N or E t O A c , I I I , K O H , H2 0 , E t O H , A t h e n H C I , H20
Scheme 5
'A
0
0
&C02H \ Me0
190)
(91)
(92)
(93)
105
3: Carboxylic Acids and Derivatives
anthranilic acids (86).71 Electron deficient toluenes are efficiently oxidised to the corresponding benzoic acids under phase-transfer conditions using aqueous sodium hypochlorite and catalytic amounts of ruthenium salts as oxidants72
(See also ref. 273).
Arylacetic Acids and Esters.
-
The anti-inflammatory properties of
these compounds continues to stimulate new work in this area; existing approaches have been summarisd in a review.73 Another version of the well established [1.2l-aryl migration route to phenylacetic acids consists simply of treatment of the hydroxy-propiophenone derivatives (87) with sulphuryl chloride (Scheme 4) .74 Yields are 54-87%. Further examples of nucleophilic attack by ester and lactone enolates onto nitrobenzenes have been described.75 While these methods are useful for the preparation of ortho-nitro and -amino-phenylacetic acids, the greater potential of these reactions seems to be in the elaboration of indoles and 2-indolinones.
By contrast, p-dinitrobenzene undergoes displacement
of one of its nitro groups when treated with ester enolates (generated using t-butoxide in ammonia) to give p-nitrophenylacetic acid esters directly in good to excellent yields.76 An alternative route to phenylacetic acids from acetophenones consists of conversion into the corresponding cyanohydrin acetate followed by hydrogenolysis and hydrolysis (Scheme 5) .77 The method looks to be operationally simple and efficient. A somewhat related method has been used to prepare the (2)-naphthylacetic acid (90) [(S)-Naproxen] of 60% ee; this consists of cleavage of the acetal ( 8 8 ) using TMS cyanide and tin tetrachloride to give the cyanohydrin derivative (89) followed by hydrolysis and h y d r o g e n ~ l y s i s . ~An ~ alternative route to both enantiomers of acid (90) is by kinetic resolution of the corresponding (racemic) chloroethyl ester using the lipase from Candida cylindracea conversions (up to 40%) ,
lipase M Y ) . At relatively low is isolated almost optically pure.79
(=
(2)(90)
Perhaps the simplest route to these acids is by nickel-catalysed coupling of arylmagnesium halides and t-butyl bromopropionate (Scheme 6) . 8 0 The t-butyl ester or the corresponding nitrile are used to prevent attack by the organometallic reagent at this function. Benzylic Grignard reagents, derived from the corresponding styrenes by nickel- or titanium-catalysed hydromagnesation, can be carboxylated to provide an a1 ternative anion-based approach to phenylacetic acids .81
General and Synthetic Methods
106
0
0
Ph 197)
( 9 6)
NOH, C I C 0 2 M e
RYCozMe MeO-, M e O H
CO,M e
or K C N , D M F
C0,Me RrCOiMe C0,Mc
Ph (103)
(102)
0 ' *fRO Kl
0 (104)
R'X
+
[ 1 , 5 - H D R h C ( 12
CO
+
HC0,R2 1, 5 - H D = 1 , 5 - h c x a d i e n y l
Scheme 7
R' c 0,R~
107
3: Carboxylic Acids and Derivatives
Finally, it is worth noting that Friedel-Crafts acylations of phenylacetates using bromopropionyl chloride give mixtures of regioisomers and not just the =-substituted
product as previously
reported.82 Acid Anhydrides. - A polymer derived from 4-vinylpyridine has been found to be a very efficient catalyst for the formation of mixed anhydrides (91) from one equivalent each of a carboxylic acid and an acid chloride.8 3 A related co-polymer of pyridine-3-oxide is similarly effective in the formation of mixed formic anhydrides [(91), R 2 = ~ ] from an acid chloride, RICOC1, and sodium f~rmate.'~ These
N- and g-formylation. products are excellent reagents for Trichlorotrifluoroacetone hydrate is an excellent reagent for the formation of symmetrical acid anhydrides from acid chlorides,85 and cyclic anhydrides can be obtained from the corresponding diacids using (trimethylsily1)ethoxyacetylene as the dehydrating reagent; a full report on this latter method has now been published.86 A variety of substituted maleic anhydrides (93) are available from Michael additions of imidazo[l,2-a]pyridinium salts (92) to the parent maleic anhydride followed by acidic hydroly~is.~' Yields overall are usually in the range 4 0 - 5 0 % , and the substituent 'R' can contain ketone, acid and nitrile functions. Finally, highly substituted phthalic anhydrides (95) are available from side-chain nitration at an ortho-methyl group of the corresponding benzoic acid (94), followed by base and acid hydrolysis.'8 Carboxylic Acid Protection. - Increasing the bulk of the substituents generally increases the stability of silyl protecting groups. This has been taken a step further with the introduction of the di-t-butylmethylsilyl (DTBMS) group, which seems certain to find use in the protection of carboxylic acids as their DTBMS esters.89 A comparative stability study o f the ODTBMS group relative to OTIPS and OSitBuPh2 would be useful. The considerable potential of the 4,5-diphenyloxazole function, introduced by Wasserman, both as a masked carboxylate group and as an activator of cationic cyclisations has been demonstrated in a synthesis of the methylenomycin (97) in which the penultimate precursor is the oxazole (96) The orthopropionate ( 9 8 1 , obtained from phenylsulphinic acid and acrylonitrile, is a useful Michael nucleophile and cyclopentannulation reagent and can thus be regarded as a masked form of the propionate
General and Synthetic Methods
108
carbanion (99).91 The reactive C-H site of malonates (100) can be masked by conversion to the corresponding tri-ester (101). Reversion back to the malonate can be achieved either by mild basic alcoholysis (cat.NaOMe, MeOH, 20°C) or by treatment with KCN in warm DMF.92 2
Carboxylic Acid Esters
Esterification.
-
A very simple method for esterification involves
reaction between a carboxylic acid and methyl iodide in the presence of DBU.93
Phenols and alcohols remain unaffected by this reagent
combination.
The dithiocarbonate (102) is yet another addition to the
list of coupling reagents suitable for ester formation;94 used in combination with DMAP and in some cases CuBr2, the reagent couples equimolar quantities of acids and alcohols, including sterically hindered examples, at room temperature giving esters in
E.
90%
yields. An optimum method for the formation of fatty acid esters of long chain alcohols proceeds via the acid bromide, prepared using Ph3P.Br2.95 Polymer-bound Ph2P.Br
functions are also effective
intermediaries in esterificati~ns!~~Virtually quantitative yields of esters are realised by coupling alcoholates with 9-acyloximes (103);
reaction times are usually less than five minutes at room In the presence of an activating metal catalyst such
temperature.97
as FeC12 or ZnC12, oximes (103) can be coupled directly with free alcohols in generally similar yields but require longer reaction times. A useful phase-transfer method for the esterification of sensitive cephalosporins and penicillins consists of treating suspensions of the potassium salts of these compounds in acetonitrile containing 10 mol% of 18-crown-6 with a benzylic or allylic b r ~ m i d e . ’ ~ A related solid-liquid phase transfer technique especially suited to hindered esters avoids the use of a solvent and instead simply involves heating an aromatic acid and an aliphatic bromide with powdered potassium hydroxide containing a little Aliquat 336.99 TDA-1, like Aliquat 336 a cheap and perhaps less toxic substitute for crown ethers, can be used to assist in the formation of phenacyl esters (104) from phenacyl bromides when potassium carbonate is An electrochemical procedure for the employed as the base.”’ alkylation of acids by alkyl halides or tosylates gives variable but often excellent yields and could be useful in special
109
3: Carboxylic Acids and Derivatives
(106)
(105)
F
F
Rd C 0 , M e
Hod (108)
( 1 07)
------ ---
R'*o R2 (110)
RR1*CN 2
CN
(109)
-
RIXC
R2
02Et
(112 1
(111)
R ' = A r , Me, or Et;
X
R 2 = H , Me, or C 0 2 E t Scheme 8 R2
N2
'R
C 02Mc
R'
CO,M e
A3
(115)
(113)
OH
OH
Me 0,C
C02Me
COzMe
C02Me
4°0 H
co
(119)
u
NO,
General and Synthetic Methods
110
circumstances. A very simple transesterification procedure, especially suited to
reactions with secondary or tertiary alcohols consists of treating the latter with
s.one
equivalent of n-butyl lithium in THF followed by
an aromatic or a,B-unsaturated acid. these cases:
Yields are generally high in
particularly noteworthy is the requirement of only one
equivalent of the attacking alcohol . I o 2 A distannoxane transesterification catalyst for primary and secondary but not tertiary alcohols has been reported. l o 3 The near neutral conditions mean that sensitive substrates such as B-keto-esters can be used and protecting groups such as dioxolanes survive;
on the debit side the
reactions are relatively slow ( l l O " C , toluene,
z. 20
h) and an
excess of one of the components is required. General Synthesis. - A further development in the elaboration of esters by carbonylation reactions is the finding that formate esters can be used as the source of the alkoxide component (Scheme 7) . I o 4 The reaction is of broad scope being applicable to primary aliphatic bromides, benzylic bromides and aryl bromides although in the latter cases, an additional palladium catalyst [Pd(PPh3)41 is required. With reaction temperatures of 150°C and CO pressures of 80-100 p.s.i., yields are generally in excess of 80%.
The success of this method
with primary aliphatic bromides is also noteworthy as such systems often undergo 6-eliminations rather than carbonylation; a new platinum catalyst has been developed which also does not suffer appreciably from this limitation.lo5
A widely used approach to homologues of esters is by Michael additions to a,@-unsaturated esters. With organometallic nucleophiles, such additions usually require some special conditions or additives, and in this respect combinations of organocoppers with Lewis acids are especially useful . I o 6 More recent improvements include the modification of organocuprates by trimethylsilyl chloridelo7 or by the addition of a thiolate ligand.lo8 Sterically bulky nucleophiles can thus be added to @-substituted enoates and when taken with other developments especially such as the Lipshutz higher order cuprates, should mean that this type of Michael addition will find as many uses as the corresponding additions to enones.
An alternative
strategy is to employ a bulky ester group in order to prevent [1.2]-additions and a more reactive nucleophile such as an organolithium. Examples of this are Michael additions to the highly hindered 109 esters (105) leading to homologues (106) in excellent yields.
111
3: Carboxylic Acids and Derivatives
Although, as expected, rather resistant to hydrolysis, esters (106) can be converted to the corresponding acids using ceric ammonium nitrate or reduced to the corresponding alcohols using LiA1H4. Yet another alternative is to add lithium dialkylcuprates to the cationic species (1071, derived from the corresponding dioxolanes using trityl tetrafluoroborate as the hydride abstractor, leading to esters (108). Other nucleophiles tend to add to the a-position to give 2 ,2-disubstitut'ed dioxolanesllO (See also ref. 202) . Two new methods for the preparation of a-fluoro-esters are the treatment of silylketen acetals with 3-f luoropyridinium trif late'"
or
by exchange of the corresponding a-chloro-esters using a KF-CaF2 mixture. Dif luoro-esters (109) are readily obtained by stereospecific couplings of vinyl halides with methyl iododifluoroacetate in the presence of copper.ll3 Couplings with aryl halides and allylic halides also work well. A one-carbon homologation method for converting various aldehydes
and ketones (110) into a-halo-esters (112) (Scheme 8) consists of sequential Knoevenagel condensation with malononitrile and oxidation (NaC10) to give epoxide (111) followed by treatment with HX-EtOH (X=Cl, Br) .l14
Yields are generally above 80%.
Full details have been given for the synthesis of a variety of a-diazo-esters (113) and of chiral a-thio-esters (114).l16 a,0-Epoxy-esters (115) can be obtained from the parent unsaturated esters either by using a new epoxidation reagent prepared from fluorine gas and aqueous acetonitrile'" or lithium When this latter reagent is added t-butylhydroperoxide (LiOZtBu). to unsaturated esters derived from chiral alcohols, reasonable diastereoselection is observed but, as yet, not enough (up to 60%) to rival the Sharpless method. All four isomers of the useful epoxy-esters [(116);
(25,35) isomer] have been obtained from the
tartaric acids, in a sequence which features the regioselective reduction, using borane, of the ester group a- to the hydroxyl in a Modified Darzen's glycidic ester hydroxy-succinate [ (117) (118)] .ll' -f
syntheses, using Evans-type enolates of chiral oxazolidinones, N-acylated by an a-halo-acid, give rise to epoxy-esters [e.g. (11911
Presumably this method could often with excellent optical purity.12' be used in place of a Sharpless epoxidation in favourable cases. Cyclic a-nitro-ketones (120) are readily cleaved upon treatment with potassium fluoride in a dry alcohol to provide a general route to to-nitro-esters (121).121
112
General and Synthetic Methods
(122)
(123)
2 pd(0)
OAc
Pd ( 0 )
OAc
C0,Et
I
CO,E t
OH
(127)
(1 2 8)
R'
0 CO, E t C0,Et
R~ =r3 u t or T M S (129)
3: Carboxylic Acids and Derivatives
113
One method by which double bonds can be distinguished in polyunsaturated substrates is to position one or more of them in conjunction with an ester (or ketone) group which renders them open to [1.4]-reduction [(122)+ (123)l amongst other possibilities. Some new reagents for performing this transformation are magnesium in methanol,122 a combination of diphenylsilane, a Pd(0) catalyst and a Lewis acid such as zinc chloride,123 and di-isobutylaluminum hydride (DIBAH) in the presence of a catalytic amount of methyl copper.124 Ylidene-malonate systems can also be reduced using boron hydride. 125 Many substituents are tolerated by these reagents, including isolated double bonds, ketones and two 6-substituents on the unsaturated ester function, a feature which often prevents Michael additions. Diesters. - Malonates have once again featured as appropriately soft nucleophiles in a number of palladium-mediated C-C bond formations. Treatment of the chiral allylic acetate ( 1 2 4 ) with sodio-malonate and a Pd(0) catalyst gives largely (92%) the diester (125) with retention of configuration while the (Z)-reqioisomer (126) reacts with inversion and isomerisation to give the same product (125) Malonate anions generated electrochemically can also participate in Pd(0)-catalysed couplings to allylic acetates and in some cases can give opposite regioselectivities and product stereochemistries relative to reactions in which the malonates are deprotonated using a conventional base.127 Vinyl dihydrofurans (127) and the corresponding pyrans can act as substrates in Pd(0)-catalysed couplings, resulting in the formation of phenols (128). 128 Benzoylmalonates (129) are available in one operation from iodobenzene by carbonylation in the presence of diethyl methylmalonate, triethylamine and a ferrocene-based palladium catalyst. 129 Yields of up to 80% are reported using CO pressures of 20 atm. at 120°C. Malonyl radicals ( 1 3 0 ) can be generated from halomalonates using tri-n-butyltin hydride and perhaps not surprisingly turn out to be electrophilic;
additions of these species to enol ethers leads to the
homologues (131).130
The electrophilic nature of radicals (130)
renders them capable of adding to aromatic systems; a trial study, using ceric ammonium nitrate to generate radical (130) directly from dimethyl malonato, indicates that this species has a distinct preference for ortho-substitutions.13' A full description has been given for the preparation of the
General and Synthetic Methods
114
0
Cl C 0 2 Et
POC13
C0,Et
BujN
C02Bu'
C02Et
C0,Et
R'
%o
R2
NaTeH, HOAc, R 2 N H
R'
0
R2
0
Scheme 9
I
R
o
2
C
A
co2
CO, But (1 3 8)
(1391
NO2
R
3: Carboxytic Acih and Derivatives
115
0 S c h e m e 11 0
General and Synthetic Methodr
116
parent ylidenemalonate (132).132
a-Acyl malonates (133) can be
converted into the chloro-ylidenemalonates (134) by treatment with POC13 and Bu3N, presumably via the corresponding enolphosphorus dichloridate.1 3 3 Attack by Meldrum's acid onto the pyridinium species ( 1 3 5 ) occurs regioselectively at the 2-position to give the extended ylidene derivatives (136).1 3 4 Reductive alkylation of Meldrum's acid can be effected in a single reaction by treatment with a ketone and sodium hydrogen telluride (Scheme 9) Previous work has been extended to a route to chiral glutarates [e.g. (137)l by Michael additions of various chiral propionamides to ethyl crotonate; extension of the methodology to diethyl 2-hexen-1,6-dioate results in a useful route to highly substituted cyclopentanone carboxylates.1 3 6 Chiral glutarates are also available by Michael additions of ester enolates to the sulphoxide (138). Subsequent ring opening (PhSe-) and reduction gives diester ( 1 3 9 ) ; presumably more complex examples could be prepared using this methodology, which clearly has plenty of other potential applications 1 3 7 Allylic nitro groups can be readily removed by Pd(0)-catalysed hydride transfer from, for example, NaBH4 or NaBH3CN; when combined with a Michael addition, this reaction forms the second part of a simple route to 1,5-diesters (Scheme 1 0 )
.
Hydroxy-esters. - The asymmetric oxidation of ester enolates using, among others, Mo05.py. HMPA as the oxygen source has been shown to work well (up to 9 9 % ee) using sterically screened enolates of the Oppolzer type derived from camphor (Scheme 11) Alternatively a chiral oxygen source, namely a (camphorsulphonyl)oxaziridine, can be used. With these materials however,optical yields are generally lower than in the examples using chiral en01ates.l~' Both methods seem to be limited to the preparation of secondary a-hydroxy-esters (See also ref.38). Asymmetric bis-hydroxylation of keten acetals using O s 0 4 and a chiral diamine ligand can also be used to prepare chiral a-hydrox y-es ters .l 4 A wide range of a-keto-esters can be reduced to the corresponding a-hydroxy-esters with > 9 5 % ee using a reagent prepared from 9-BBN and a glucofuranoside acetonide. 142 An alternative way to exploit the steric screening principle in the elaboration of chiral a-hydroxy-esters is by asymmetric alkylations of the dioxolanones (140) and (141) [R=H] derived in a ratio of 1.3:1 from 8-phenylmenthone and a silylated glycolic acid.
3: Carboxylic Acidr and Derivatives
117
S i M e Ph .I, II .’
&
N
iii, i v
R
so2 Reagents:
i, RCU, BF . 0 E t 2 ;
3
it,
~
~
R
S i PhMe,
L
OH
xc,,,e
~
L i O H then CH N
2 2
;
iii, H B F ; iv, MCPBA
Scheme 13
H Scheme 1L
4
c
o
,
M
t
118
General and Synthetic Methodr
After chromatographic separation, (the major drawback of the method) both isomers can be alkylated (LDA, RX) to give the derivatives shown with very high or complete asymmetric inductions. 143 Subsequent alcoholysis returns the chiral auxiliary and optically pure a-hydroxy-esters. Complimentary diastereoselectivities have been observed in condensations of methyl pyruvates with various organometallic nucleophiles, the allylborane (142) giving largely the threo- adducts (143) whereas the silyl allene (144) affords predominantly the erythro-isomers (145) Bulky ester groups favour product (143) while the reverse is found with esters (145). A simple method for preparing a-hydroxy-esters related to esters (143) is by lead-promoted attack of allylic bromides onto ethyl pyruvate.145 Vinyl phosphonates (146), obtained from the corresponding ketones (R'R'CO) by a Peterson reaction, can be oxidised using O s 0 4 to give a-hydroxy-esters (147) following elimination of diethyl phosphite (Scheme 12). Overall the process represents a one-carbon homologation of ketones to a-hydroxyesters effectively by attack of an acyl anion equivalent.146 Methods for obtaining chiral a-hydroxy-esters by Walden inversion of chiral a-sulphonyloxy-esters using a variety of oxygen nucleophiles have been described in detail. 147 Reformatsky reactions can be carried out using a zinc/silvergraphite, prepared from C8K, ZnC12 and AgOAc, at temperatures as low a s -78°C under which conditions much higher levels of stereoselection can be achieved.148 Many other developments have taken place in
aldol-based approaches to p-hydroxy-esters. The use of a complex formed between TiC14 and Ph3P greatly improves the &-selectivity in condensations between acetals (148) and aldehydes to give almost pure isomers (149) In principle, chiral induction in such reactions could be achieved using a chiral Lewis acid; some examples of such a catalyst have been given.lS0 The chiral thiazolidine-2thione derivatives ( 1 5 0 ) are also very effective at controlling Lewis-acid catalysed aldol condensations with a,@-unsaturated aldehydes, using tin (11) triflate and N-ethylpiperidine as reagents, which give rise to aldols (151) with > 9 0 % ee and in 70-80% chemical ~ie1d. l~' Similarly, boron enolates derived from the Evans-type amides (152) condense with aldehydes to give the --esters (153) The enantiomers of esters after hydrolysis and esterif ication.152 (153) can be obtained by using an analogue of amide (152) derived from ephedrine.
3: CarboxyIic Acidr and Derivatives
119
H
OH
Bu'O&
H
OH
C
O
R'O A
(161) R'
C0,Et
, R
= H or Me
( 163 1
(162 1
(164) n = 1 o r 2
(165)
Scheme 15
(166)
S c h e m e 16
(167)
GeneraI and Synthetic Methoa3
120
The useful silyl- and stannyl-esters (154) and (155) can be readily obtained from crotonate esters with good to excellent stereocontrol either by combined Michael addition (of R 2 X e ) and aldol 3
condensation [ (154)l or by quenching the intermediate enolate, re-enolisation and condensation to give esters (155) A combination of the principle of steric screening and Fleming's observation that PhMe2Si-substituents can be converted into hydroxy groups with retention of configuration has been used by Oppolzer in the development of another highly enantioselective approach to B-hydroxy-esters (Scheme 13) The same type of product can also be accessed using aldol condensations of related sterically screened enolates. Highly stereoselective aldol condensations occur between the 6-hydroxy-ester (156) and symmetrical ketones leading to the z - a d d u c t s (157) ( G . 9 0 % ) when enolisation of the ester is carried out at -100°C using lithium diethylamide and lithium triflate as an enolisation promoter. 155 In condensations with aldehydes, control of stereochemistry at the newly-formed secondary alcohol centre is only moderate. A different type of steric shielding method can be used to obtain substituted 0-hydroxy-esters from a dioxanone derived from ( R ) -3-hydroxybutyric acid and pivalaldehyde (Scheme 14) 156 The initial products can be converted into the opposite enantiomer by re-enolisation and protonation while the derived enol acetal (158) undergoes highly selective Michael additions leading to esters (159) via the self-reproduction of chirality principle. A number of reports have further advanced the utility of yeast reduction of 6-keto-esters as an enantioselective route to 8-hydroxy-esters. The use of methanol as carbon source rather than glucose can lead to higher e n a n t i o s e l e ~ t i v i t i e s as ~ ~ ~can reductions of keto-amides, derived formally from NH2CH2C02Et, rather than the usual methyl or n-octyl keto-esters. Specific examples of yeast the reduction products include the 4-t-butoxy derivative (160), and the branched derivative (162)16', one-carbon homologues (161) +
.
obtained by reduction of the corresponding chiral B-keto-ester; these examples clearly indicate some general trend regarding the relationship between substituent hydrophilicity and product stereochemistry. Yeast reduction of 2-methyl-3-oxobutanoate gives largely the =-isomer [ (163): R1=H] especially when the n-octyl ester is used.162 This complements a popular chemical approach to this type of ester using alkylations of 3-hydroxybutyrates, as these
121
3: Carboxylic Acids and Derivatives
. ' HgX Y OR 2
R 1 Y q M e R3
(171 1
R:q
C02Et
C02Me
OH Ph
OH (1 7 3 )
OH
OH a
C
0
n 2
R
o
L
R'
E
t
R'R~CO
,
R2
R+Co2Et OH
C1,TiJ' (176)
(1 78)
(177)
TU
CO2BU'
S
(179)
(1 81 1
(1801
(182)
General and Synthetic Methods
122
lead to the corresponding anti-isomers. An alternative method which provides both enantiomers of esters [ (163), R1=heteroaryl, styryl] consists of enantioselective hydrolyses of the corresponding racemic acetates using various lipases.1 6 3 A variety of micro-organisms are capable of producing cyclic B-hydroxy-esters ( 1 6 4 ) from the corresponding keto-esters usually with the (15)-stereochemistry shown but as cis-trans mixtures, while the useful hydroxy-ester (165) can be obtained by kinetic resolution using fermenting Baker's yeast in 0.1M phosphate buffer in order to preserve the acetal function.165 The remaining keto-ester can be isolated with 94% ee using a different yeast strain (2.bailli) and mild epimerisation (NaOH, EtOH) provides the trans-isomer of ester (165). A highly stereoselective route to B-hydroxy-esters, based on a [1.3l-dipolar cycloaddition pathway is outlined in Scheme 15.166 Overall yields are generally high although problems of regioselectivity will arise with many unsymmetrical olefins; the presence of other olefins is also precluded. An enantioselective alternative to the aldol-based homologation method discussed above for the conversion of aldehydes into 6-hydroxy-esters consists of two-carbon extension using standard phosphonate chemistry, reduction, Sharpless epoxidation, followed by Ru04 oxidation and esterification to give glycidic esters (166). These undergo regioselective attack at C-2 by (167) mixed cuprates, R2CuCNLi2 to provide the &-hydroxy-esters 2 (Scheme 16) Despite the obvious limitations of the method in terms of the functionality which can be present in groups R1 and R2, the selective formation of the anti-isomers is significant as many aldol routes lead to the *-isomers.
Cuprates derived from Grignard
reagents in ether-THF react with epoxy-ester (168) specifically at C-4
when the reactions are carried out at -60°C (at higher
temperatures, enolisation and rapid 6-elimination occurs) to give B-hydroxy-esters (169) in good to excellent yields, thus providing yet another possible "disconnection" for B-hydroxy-ester synthesis. The availability of chiral epoxides ( 1 6 8 1 , for example from yeast reductions, would extend the method to the production of chiral hydroxy-esters. Hydroxy- and alkoxy-mercurals ( 1 7 0 ) ,
readily available by
oxymercuration of the corresponding a,B-unsaturated esters, can be converted into the erythro isomers ( 1 7 1 ) by demercuration using thiols but into the threo-isomers (172) using hydride reduction. a,B-Dihydroxy-esters can also be prepared by yeast reductions;
3: Carboxylic Acidr and Derivatives
123
0
0 Me0
I1 )--CO,R Me0 (184)
-CCO,R
R-E-SiMe,
(185)
(186)
O o 4H MS eO
+
RAC02Me
(1 87)
& He3sin R'
H30+
C0,Et
R'
R*
H
C0,Et
uo RoH
H L C 0 2 R R2
(1921
General and Synthetic Methodr
124
thus racemic hydroxy-esters (173) are converted largely into the (2SI3S)-anti-esters (174) with > 9 7 % ee.170 Up to 20% of the corresponding (2Rr3g)-syn-esters are also formed. Dihydroxy-esters (1751, in racemic form, can be obtained by crossed pinacol coupling between a range of ketones and methyl phenylglyoxalate using aqueous acidic (HOAc) titanium trichloride as reagent. 17' Yields are variable, up to 85%. High selectivities in favour of the *-isomers (176) have been achieved in reduction of 6-hydroxy-B-keto-esters using a variety of methods.172 The products are useful precursors to 8-hydroxy-valerolactones. A full report has appeared173 on the preparation of the isolable homo-enolate equivalents (177) which react readily with aldehydes to provide a simple route to y -hydroxy-esters [ ( 1 7 8 ) , R2=Hl : 3 condensations with ketones require the more reactive alkoxytitanium species, easily prepared by adding a titanium tetraalkoxide to carbanion ( 1 7 7 ) . Yet another use of a yeast reduction is in the preparation of the useful 6-hydroxy-ester (179) from the corresponding ketone, with 9 7 % ee.174 Attempted reduction of the analogous methyl ester resulted only in hydrolysis of the latter function. Alkylations of the 6-hydroxy-ester (156) mentioned above155 lead to the (180) with > 90% selectivity using LiNEt2-THF-HMPA as the =-adducts base-solvent combination. 175 The lithiated sulphone (181) can be regarded as the synthetic equivalent of the propanol carbanion (182) and is useful in, for example,the preparation of 6-hydroxy-hexanoates (183) by Michael additions to u , O-unsaturated esters. 176 A variety of hydroxy-esters can be prepared from the corresponding amino-esters by diazotization using sodium Despite the mildly basic conditions, this reagent nitropr~sside.'~' is especially effective with substrates prone to elimination. Zinc borohydride is especially useful for the reduction of phenylthio esters to the corresponding alcohols and therefore can be used to prepare hydroxy-esters from mixed sulphur and oxygen esters of diacids 78
.
Keto-esters.
-
Enolates derived from the acetals (184) can be
alkylated, especially by heteroaromatic chlorides such as 2-chlorobenzoxazole, and thus represent another synthetic equivalent of the acyl anion (185). Another source of a-keto-esters (187) are silylacetylenes (186) Os04 oxidations using t-butyl hydroperoxide as the re-oxidant for the osmium reagent.l8O Yields on the models
3: CarboxyIic Acirls and Derivatives
OAc
&
C0,Et
C0,Et
ac04
OC0,Et (200)
(201)
Scheme 17
AI-Hg
C02Me7
Me 0
Me0
A
C
0
2
M
e
PPh3
(202)
(203) Scheme 1 8
COzMe
N2
(206)
126
General and Synthetic Methadr
studied are generally around 6 0 % and, with the exception of substrates which contain other unsaturated C-C bonds, should be obtainable from a wide variety of acetylenes. The oxazines (1881, available by [4+2l-cycloadditions of vinyl nitroso compounds, upon treatment with an aqueous acid [4M HC1 or 70% HC104] undergo sequential imine hydrolysis and Peterson olefination leading to the unsaturated a-keto-esters in essentially quantitative yields from the simple oxazines studied. 18' The simplest members of the 8-keto-esters, 8-formyl-esters (191) can be prepared simply by heating formyl Meldrum's acid (190) in benzene containing an alcohol (ROH).182 It is not clear whether the transformation proceeds an alcoholysis-based pathway or by thermal decomposition of precursor (190) into formylketene. Crossed Claisen condensations can be carried out between 2,4,4trimethyloxazoline and symmetrical anhydrides in the presence of A1Cl3 and Et3N to give masked B-keto-esters (192) in 50-70% yield. 183 A perhaps more generally useful method is the crossed condensation between methyl esters and methoxymethyl esters using titanium (IV) bistriflate [TiC12(0Tf)2] and a tertiary amine. Strong chelation by the methoxymethyl group favours enolisation of the latter esters and hence predominant formation of keto-esters (193).184 The method is also particularly effective in Dieckmann cyclisations, e.g. (194)-+(195). Acylation of the bis-enamines (196) by acid chlorides followed by acidic alcoholysis leads to a wide variety of yields (highest in the absence of an a-H in the chloride) of O-keto-esters (197) in an alternative to the direct Claisen method. The intermediate acylated enamines can also be converted into B-keto-amides and methyl ketones185 (See also ref.31). Enantiomeric enrichments of up to 95% have been achieved in low temperature Michael additions of the chiral enamine (198) to di-t-butyl methylenemalonate. 132 Either enantiomer of the product (199) can be obtained by variations in the solvents used; slightly lower eels are obtained from similar additions using the corresponding ethyl 2-methylacetoacetate derivative186 (See also ref. 201) Michael additions of soft nucleophiles such as B-keto-esters to 2-cyclo-
.
hexenones can be accelerated by adding various iron- or copper-acac complexes.187 The allylic carbonates (200) can be readily prepared by an overall addition of acetic acid to the corresponding acetylenic carbonate using a ruthenium catalyst, and react in the presence of Pd(0) with 6-dicarbonyls including 6-keto-esters and malonates to
3: Carboxylic Acid and Derivatives
127
062 (207)
(208)
(209)
( 2 1 0)
H (211)
(212)
H30+
SPh
fiR COzMc SPh
Scheme 19
General and Synthetic Methodr
128
give homologues Ie.9. (201)I . Hydrolysis gives the corresponding diketo-ester; with a-unsubstituted B-dicarbonyis, double addition products only are isolated, as the second addition of carbonate (200) occurs faster than the first.188 A seemingly general and efficient procedure for the a-alkynylation of B-dicarbonyls is illustrated in Scheme 1 7 . l ~ ' An alkynyl-lead triacetate species is the presumed key intermediate. Alkoxy B-keto-esters (203) can be obtained in high yields from acid chlorides (202) by sequential acylation of a suitable phosphorane followed by reduction (Scheme 18) .Ig0 The products are useful as "protected" forms of the corresponding, rather reactive, vinyl ketones. The salt (204) derived from the neutral phosphorane using sodium hydride, "activated" by adding a small amount of water, condenses efficiently with aldehydes to give largely the (Z)-olefins (205). I g 1 The neutral phosphorane is unreactive with aldehydes in refluxing THF while the corresponding phosphonates tend to lead to
( E )-isomers
.
of keto-esters (205) Mesyl azide is reported to be superior to the commonly used tosyl azide for diazo transfer reactions such as in the preparation of a-diazo-acetoacetates (206). Aldol condensation of the bis-silyl enol ether (207) of methyl acetoacetate and (S)-2-benzyloxyhexanal using TiC14 as promoter leads almost exclusively to the z - a l d o l (208). I g 3 In contrast, anion-based aldols give a preponderance of the %-adduct. The homologous tris-silyl enol ether (209) has also been prepared;lg4
in
the presence of TiC14 , or TiC12 (OiPr)2, reactions with electrophiles (e.g. R'R~CO, RICOC1) occurs regioselectively at the terminal C-6 position.
Although the initial adducts [e.g. ( 2 1 O ) l from ketones are
isolable, a more useful pathway is acylation followed by cyclisation to dihydroxybenzoates. Chiral aldehydo-esters (212) are available in high optical purities, typically E. 9 0 % , by Michael additions of lithium dialkylcuprates to the oxazolidines (211) derived from the Hydrolysis of the corresponding aldehyde and E-Z-norephedrine. intermediate adducts is achieved in two steps by BF3-catalysed exchange with ethanedithiol followed by heating with MeI-CaC03 in wet acetone, apparently with little or no racemisation. An alternative route to racemic esters (212) is by Michael addition in the opposite sense using (methy1thio)methyl p-tolylsulphone as a formyl carbanion equivalent and 2-alkenoates as acceptors .Ig6 Y -Keto-esters in general
-
3: Carboxylic A c i d and Derivatives
129
0
OY
C0,E t
(2151
H
CO,E t
(216)
(217)
(218) OTMS I
Ph
L + +,
+/
OSi,
TrC104
T O SPh S i '
&
COSPh
Ph
\
!
Scheme 20
R-C02Et
(224)
-
R
R m C O z E t
HS d C 0 2 M e
(225)
(226)
130
General and Synthetic Methodr
can be prepared in the same way but using trityl or t-butylhydrazones derived from aldehydes as Michael nucleophiles.l g 7 Thermal ene reactions between the hydrazones and methyl acrylate also lead to 6-keto-esters. Another formyl carbanion equivalent (214) is a key element in an approach to substituted y-keto-esters starting from 3-alkoxycycloalkenones (213) (Scheme 19) .lg8 The a-substituents (RCH2) are derived either from an allylic iodide or methyl acrylate; no mono-alkylated derivatives were prepared. Full accounts have been given of further preparations of 6-keto-esters by ring openings of 2-si 1yloxycyc lopropane carboxylates Highly substituted 6-keto-esters [e.g. (215)l having vicinal quaternary centres can be prepared by Michael additions of ketone enolates to highly active acceptors containing two electron withdrawing groups. 2oo Substituted 6-keto-esters (218) have been obtained with good to excellent enanti0meri.c enrichments by Michael additions of the lithioenamide (216) to alkylidenemalonates (217), followed by hydrolysis and decarboxylation201 (See also ref. 186) Kinetic enrichment of the initial products can be achieved by treatment with aqueous NH4C1 in THF, which causes a selective retroMichael reaction of the minor isomer. An approach to 6-keto esters which is related to the Michael reaction involves additions of
.
.
silyl enol ethers to the isolable dithiolanylium salt (219), derived from the corresponding ketene dithioacetal by hydride abstraction using trityl tetrafluoroborate202 (See also ref .110). Largely the anti-isomers (220) are obtained, especially from cyclic silyl enolates. Trityl cations are also crucial to the success of an alternative Michael-type approach to 6-keto-esters with features additions of silyl enolates of thio-esters to enones, and which gives predominantly the anti-isomers (Scheme 20) .203 Finally, two useful preparations have been described i n reliable detail, those of methyl 6-oxohexanoate (221) and the corresponding ~ * of diformyl acetate acetal (222) by ozonolysis of c y c l ~ h e x e n e ~and (223) from monomethyl malonate and the Vilsmeier reagent.205 Unsaturated Esters. - An efficient, single step procedure for two carbon homologation of esters (224) into a,B-unsaturated esters (225) consists of reduction using diisobutylaluminum hydride at low temperature in the presence of a lithiated phosphonoacetate. 206 Yields of largely (E)-isomers are usually above 70% and the method works equally well with lactones to give o-hydroxy unsaturated esters. Both phosphoranes and phosphonates derived from long-chain
131
3: Carboxylic Acids and Derivatives
C0,Et
6""z
CO,E t
A
(228)
(227)
R2
Cp CO-Fe
I
I
C02Et
-111
PPh,
I
R2 R3%c02Me
co
-R3
______)
t
R'
R'
R'
(233) R 3 = Ph o r m a l o n a t e S c h e m e 21
Scheme 22
(234)
BrY
(2351
C02Me
_______)
C02Me
S i Me3
Br
132
General and Synthetic Methods
a-halo-esters condense efficiently with long-chain aldehydes in Wittig-type reactions but the former phosphoranes give greater can be achieved trans-selectivity.207 Reasonable *-selectivity using the Still-Gennari method with bis(trifluoroethy1)phosphonates. Some specfic examples of useful Wittig products are the thiolsubstituted esters (226) available from the corresponding a-phosphoranylj-dene acetate or propionate and the commercially available dimer of 2-mercaptoacetaldehyde1208 esters (227) or (228) from aqueous glutaraldehyde and triethyl phosphonoacetate, (the actual product depends on the rate and order of addition) ,209 and the retinoic acid synthon (229) from pyruvaldehyde dimethylacetal.210 An alternative strategy for this type of olefination is the Reformatsky reaction, which, when mediated by tri-n-butyl stibine, directly gives excellent yields of (El-a,B-unsaturated esters with or without a solvent when aldehydes, both enolisable and non-enolisable, are the substrates.2 1 1 A lower temperature (-20°C rather than +8OoC) is required with Reformatsky reactions using sodium telluride, Na2Te.212 However, these are only effective with non-enolisable aldehydes;
one use of this method may be that (non-enolisable)
ketones are not attacked. Reformatsky or related carbanion chemistry of 4-bromocrotonates or crotonates themselves can be directed largely to the y-position to give, for example, the hydroxy-esters ( 2 3 0 ) . 213 A novel and useful version of the Favorskii rearrangement is in the conversion of dibromo-ketones (231) into essentially isomerically pure (2)-cinnamates (232), using two equivalent of methoxide at -20°C 2-14 (See also ref.270). Full details for preparations of (5)-crotonates and higher homologues using Lindlar reductions as a key step have been given.215 The method is reported to be an improvement on a previous 0rg.Synth. recipe for the preparation of (2)-crotonate. Some 6-heteroaryl acrylates have been successfully isomerised to the corresponding (?)-isomers [ie - (232); 2-fury1 or 2-imidazoyl in place of phenyll using photolysis in the presence of BF3 .0Et2.216
Alkenyliron complexes (233) are available from the corresponding T-alkynyliron complexes and a suitable nucleophile, R3 , and can be carbonylated in the presence of an alcohol to provide a route to highly substituted a , 6-unsaturated esters (Scheme 21) 217
.
Unsaturation can be introduced into an aliphatic ester by conversion to the p s i l y l enolate followed by treatment with an ally1 carbonate and a Pd(0) catalyst (Scheme 2 2 ) ;
a full account of this
3: Carboxytic Acids and Derivatives
133
F
R
F
Me3’3n% F
F
(238)
SnMe3
(240)
(239)
cop
+
+
COzMe
c 1,c
CO,
O + A02I
+
CHCl3
S c h e m e 23 R
\COP.
CSA
HoxYcoz R
+ s - - - p - t 01
-0’
N BS
Et3N
’
Me0 R
C02Me
R
OMe
General and Synthetic Methods
134
method has now been given218 which suggests that it could prove to be at least as good as the now standard alternative based on a-phenylselenation, oxidation and elimination. The a-silyl ester (234) behaves as a typical allylsilane in TiC14-catalysed reactions with a variety of electrophiles (a-halo-ethers, aldehydes, Michael acceptors) to give generally good yields of the trimethyl esters (235).219 a-Bromo-esters (237) can be obtained in fai'r yields by Peterson olefinations using a-silyl ester (236),220 while a variety of 0-fluoro- and BIB-difluoro-a,O-unsaturated esters have been prepared from a-trif luoromethylacrylic acid.221 The a , 4-difluoro isomers (239) can, by contrast, be obtained by carboxylation of the vinylzinc species (238).222 Palladium ( 0 ) catalysis also plays a crucial role in the preparation of the (2)-bis-stannyl esters (240) by addition of hexamethylditin to the corresponding acetylenic esters. 223 Isomerisation of the corresponding (E)-isomers is easily effected by heating the isomers (240) at 75-95°C. A "salt-free'' method for obtaining enol ethers from O-keto-esters consists of heating the latter with the readily prepared silyl ester (241) at 120°C (Scheme 23) .224
Yields are essentially quantitative;
the trimethylsilyl analogue of ester (241) is known to behave similarly. 2-Phenyl analogues of such enol ethers can be obtained directly from 4-keto-esters using a triphenylbismuth diacetate in the presence of elemental copper.225 Full details for the preparation of ethyl 4-hydroxycrotonate [ (243); R=H] from monoethyl fumarate have been given.226 The homologues [(243); R=n-alkyl] can be obtained with 64-72% optical purities by acid-catalysed rearrangement of the chi.ra1 sulphoxides (242).227 The mechanism involves a prototropic shift to give the O,y-analogue followed by a [2.3]-sigmatropic rearrangement. Palladium-catalysed transfer hydrogenolysis, using HC02H-Et3N as hydrogen source, of the epoxides (244) leads to alcohols (245) with inversion of stereochemistry at the methyl substituent.228 The availability of epoxides (244) in optically active form further enhances the potential of this highly selective reaction. Keto-esters (247) can be readily obtained from the dihydrofurans (246) by sequential treatment with NBS and potassium carbonate in wet acetone followed by elimination of HBr using Et3N from the intermediate bromo-ketone formed by collapse of the initially formed bromo-hydrin.229 The furans (246) are derived in three steps from
3: Carboxylic Acidr and Derivatives
135
1252)
Li
BF,OEt
,
RY OEt
(254)
(255)
R’
PhS
(256)
(257)
SEt -c
R
Br-, EtOH
(258)
SnBu, (260)
(261 1
136
Genera! and Synthetic Methodr
Scheme 24
C0,Et
RZ
OH (263)
(266)
(2651
C0,Et
(266)
Br d C0,Et
R
(269)
M e2 C u (CNILi,
C0,Me
R2f&
BF30Et
,
I
OMS
(2711
(270)
s
C 0,Me
R
+
CO,
R M gBr
CuBr
Et (273)
(272 1
kR COzE t
137
3: Carboxylic Acids and Derivatives 2,2-dichlorocyclopropanecarboxylic acid.
Protected forms (248) of the
keto-esters (247) can be prepared by electrolysis of a 2-substituted furan under appropriate conditions.230 The sulphoxide (249) can be regarded as a synthetic equivalent of the cation (250) and as such can be used to trap enolates formed by [1.4l-additions to enones to give for example cyclohexanone (251), starting from 3-methyl-2-cyclohexenone. The a-silylmethyl esters (252), potentially Useful as precursors to a-methylene esters can be prepared by additions of l-ethoxy-3trimethylsilyl-1-propyne to a wide variety of both saturated and unsaturated acetals.232 A Pummerer rearrangement is the key step in a route to the a-thio-esters (253) from the corresponding, saturated a-sulphinyl esters233 whereas the lithiated acrylate (254) can be used to prepare a variety of 6-thio-esters such as derivatives (255) following BF3-catalysed condensation with an oxetane and A ~full account has been given of the route to e~terification.~ ~ y-thio-esters (257) by acid-catalysed [1.2l-PhS shifts involving the lactones (256) for example.235 6-Thio-esters (258) can be converted into unsaturated esters (259) using electro-oxidation.236 A s the Michael adducts (258) can be considered as partly protected forms of unsaturated esters (259), the fact that this "deprotection" method occurs under neutral conditions could contribute to the usefulness of this method. A mild method for the elaboration of B-methylene esters (261) is by radical-mediated alkylations of the allylstannane (260) which produce 70% isolated yields. 237 Extrapolation of this method will not be possible in many cases because of competing [1.3l-rearrangements of allylstannanes, prior to coupling. (Rearrangement of stannane (260) is degenerate). A more common method for the introduction of an a-methylene function is by one carbon homologation
of an a-unsubstituted ester.
Useful in this respect are the bromomethyl benzyl sulphides and selenides (262) 238 The classical method for such homologations is to use a Mannich reaction (using HCHO
.
and Me2NH) although the requirement of a strong acid catalyst can preclude its application to many substrates. Such acidic conditions can be avoided using enolate alkylations by Eschenmoser's salt or by a more recently reported combination of enaminone formation and [1.4]reduction using LiA1H4, followed by quaternisation and elimination. (Scheme 24) .239 The elaboration of hydroxy-acrylates (263) from aldehydes or
General and Synthetic MetltorLr
138
K
(276)
(275)
(277)
OMc
(278) R R Et3N HMPA 160
‘C
EtO
(281) S c h e m e 25
(282)
Thpo-l+
(Prcferred1
(283)
- LpZH OThP
R l(o 0 (284)
(285)
3: Carboxylic Acids and Derivatives
139
ketones and methyl acrylate, using Dabco to form the ester enolate by Michael addition, is greatly accelerated by the application of high pressure :240 an alternative route to acrylates (263) is by aldol condensations using B-dimethylamino propionates. Elimination of the elements of dimethylamine to form esters (263) is effected using mCPBA and alumina. 241 Alkenylboranes (264), obtained from the corresponding terminal acetylene and g-BBN, couple smoothly with ethyl bromoacetate and related a-halo carbonyls in the presence of potassium t-butoxide to give the (E) - -6,y-unsaturated esters (265) in 60-65% yield. 242 Photodeconjugation has been developed as a viable approach to esters (265) in general; a synthesis of a San Jose scale pheromone features the elaboration of ester (266) by this process, using pyridine as an additive to control the regioselectivity.243 The methodology can also be used to obtain ( E , z ) - d i e n ~ a t e sand ~ ~ ~ can be conducted asymmetrically using a chiral base, although as yet, optical yields are poor.245 Vinyl epoxides (267) undergo rapid rearrangement when treated with samarium iodide at -9O"C, using ethanol as the proton source, resulting in formation of the deconjugated esters (268) in high yield.246 The availability of chiral epoxides (267) via the Sharpless method will further enhance the utility of this method. a-Bromo unsaturated esters (269), together with similar lactones, are reductively deconjugated when treated with diethyl phosphonate. 247 Yields of esters (265) are generally above 60%. Attempts to intercept intermediate enolates in the conversion (267).+ (268) have not yet proven successful as a route to a-alkyl homologues of the products.246 However, this type of compound (271) can be obtained by a Michael process applied to the mesylates (270) and using a mixed cuprate species.248 [ l . 3 I -Chirality transfer is essentially complete. Simple a-alkyl esters (274) can be obtained regioselectively in related Michael additions to the benzothiazoleesters (2721, perhaps directed via the intermediate complex (273).249 The high ( > 80%) yields obtained using fully substituted substrates are a highlight of this procedure. Chiral esters (276) result from a stereospecific l1.21-alkenyl shift when acetals (275) are heated with calcium carbonate in aqueous methanol. 250 Deconjugative alkylations of the corresponding a-thio-a,B-unsaturated esters have been used to prepare esters (2771, which upon treatment with thiophenol and AIBN are converted into y-thio-a,B-unsaturated esters by [1.3l-thiol
140
General and Synthetic Methoh
+ (2961 R
(297)
(299) Scheme 27
(300)
141
3: Carboxylic Acids and Derivatives
A full account has been given of an improved method migration.251 for Birch-type reductive alkylations of methoxy benzoates leading to 252 1,4-cyclohexadienes [e.g.(278)1. A rather different approach to B,y-unsaturated esters (280) features successive Cope rearrangements of cyanohydrins (279) followed by methanolysis; prolonged heating at 180°C is required which may preclude the use of some substrates although the method should be applicable to more highly substituted compounds than the example shown. 253 Claisen methodology for the elaboration of y,&-unsaturated acids and esters continues to be developed. The readily available dibromo-ether (281) is useful in the preparation of vinyl ether functions required for such rearrangements: the a-bromine is displaced by an alkoxide derived from an allylic alcohol to give a mixed acetal which undergoes both elimination and rearrangement in HMPA-Et3N at 160°C (Scheme 25).254 It remains to be seen whether substituted vinyl ethers can be prepared in this way. Incorporation of a substituent at the 2-position of an (E)-allylic alcohol (282) gives a preponderance of the --isomers (283) following Johnson ortho-ester Claisen rearrangement. 255 A reasonable rationale has been given, which is in line with some useful observations on substituent effects in Ireland-type Claisen rearrangements. 256 A similar effect of a 2-substituent is probably responsible for the largely regio- and stereo-selective enolate Claisen rearrangement of dienyl ester (284) into acid (285) 257 Sequential enolate Claisen rearrangement of allylic glycolates have been used to prepare esters (2861, the relative stereochemistries being controlled by changes in the allylic alcohol geometry; these initial products are then converted into the tocopherol side chain and a pine sawfly pheromone. 258 Asymmetric
.
rearrangements of allylic glycolates can be effected using an external chiral ligand derived from ( R ) -1-phenylethanol. 259 The major products are isomers (287) accompanied only by the enantiomeric =-isomer; ratios of these two are unfortunately only 3:l. Higher selectivities are observed in aza-Claisen rearrangements (288)+ (289); a full account of this work has been presented.260 Once again, the ally1 group geometry is a crucial controlling feature. An alternative general approach to y,&-unsaturated esters (291) is by palladium induced coupling of the zinc homoenolate (290) with vinyl or aryl halides.261 Yields are generally in excess of 75% for
z.
the relatively simple examples quoted, and elimination from the
General and Synthetic Methodr
142
Scheme 28 Ph
( 3 02 )
(301)
0
GY
PdCI?, MeOH
OTf
R
COzMc
co
______)
R.
( 305 )
(3041
co
________)
C o z C 0 8 , hv, MeO-
(3061
(307)
R’T C02Et
OMe
OMc
(308)
(309) COzMc
Li
-
Nu
i , Nu-
R/\yN02
SPh
R ACOSPh
OMc
(310)
(312)
143
3: Carboxylic Acids and Derivatives
homoenolate to give acrylate is not a problem (See also ref. 265). A palladium catalyst can also be used to couple Reformatsky reagents to allylic acetates to give substituted homologues of esters (291), although only in moderate yield.262 A molybdenum analogue of Tebbe's reagent has been discovered which can convert unsaturated ester (292) while isolated ketone inert; presumably the ester group assists in A systematic study has shown that one of
A-keto-pentanoate into groups are relatively the reaction.263 the best methods for
effecting Michael additions of allyl groups to unsaturated esters is to use a combination of allyltrimethylsilane and fluoride ion; both Lewis-acid catalysed methods and allyl cuprate reagents were found to be inferior.264 Along very similar lines to reactions of the homoenolate (290),261 3-carbethoxy propylzinc iodide (293) couples smoothly with vinyl triflates and iodides to give 6 , -unsaturated ~ esters (294) in generally good yields.265 An alternative approach proceeds by addition of allylzinc bromide to an alkenyl-lithium to give the doubly metallated species (295) which, among many.other uses, ~ these methods seem can be carboxylated to give 5 - a l k e n 0 a t e s . ~ ~All to have limitations in terms of the number and type of substituents that could easily be incorporated. All-trans dienoates (296) can be readily obtained in excellent yields by condensations between sulphones and 4-oxobutanoates followed by base-induced double elimination (Scheme 26) .267 Pyrolysis of the
z.
thiophen dioxides (297) also gives dienoates (296) in 6 0 % yield with excellent stereochemical purity. 268 Another pericyclic process, the Claisen rearrangement, in tandem with a Peterson olefination can also be used to prepare esters (296) and the corresponding (2?,4E)isomers (300).269 Thus rearrangement258r259 of glycolates (298) gives almost exclusively the syn-isomers (299) and thence dienoates (296) or (3001, depending on the method of elimination (Scheme 27). An unusual route to ( E , Z ) -dienoates (300) features a Favorskii rearrangement of tribromoketones derived from 3-alken-2-ones (Scheme 28) . 270 Overall yields for this simple two-step procedure are usually around 6 0 % (See
.
also ref.214) Allenic esters (302) can be obtained in one flask from propargylic carbonates (301) by a palladium-catalysed decarboxylationcarbonyla tion process. 271 The conversion requires 10-30 atmos. of carbon monoxide at 40-50°C for several hours and generally gives upwards of 70% yield. Pentatetraenecarboxylic esters Ie.9. (303)l have been obtained for the first time using Wittig-based methodology.272
General and Synthetic Methodr
144
Aromatic Esters. - Aromatic methyl groups can be ~ x i d i s e d ’ to ~ the -~~ carboxylic acid level electrochemically using tris(2,4-dibromophenyl) amine as redox catalyst.273 Under slightly basic conditions, the corresponding ortho-esters are formed. Methyl benzoates can also be formed from aromatic ketone hydrazones by oxidative degradation using Co(sa1en) in In view of related couplings of enol triflates, it is perhaps not surprising that triflates (304) derived from phenols undergo smooth carbonylation in the presence of palladium acetate and methanol to give good yields of the corresponding methyl benzoates (305). 2 7 5 The method can also be applied to heteroaromatic systems as well as to other esters and amides.
A related system, CO-PdC12-ROH-Hg(OAc)2-
Cu(OAc)2-LiBr, can be used to directly carboxylate unsubstituted heteroaromatics a- to the heteroatom in moderate yields. 276 Poly-halobenzenes can be converted into the corresponding polybenzoates [e.g. (306) (30711 by carbonylation using a cobalt carbonyl catalyst and irradiation at 350 nm.277 Yields are generally excellent -f
and amino, methyl, and methoxy groups are not affected. The useful carbanions (308), obtained from the parent o-toluate using LDA, can be efficiently acylated using N-methoxy-N-methylamides to give the isocoumarin precursors (309): many other more obvious acylating reagents failed to give reasonable yields 27a (See also ref. 194). Nucleoside analogues can be prepared using the vinyl anion (310) derived using LDA.279 Thioesters, selenoesters and related compounds. - Cobalt (11) chloride is an efficient catalyst for the coupling of thiols with acid chlorides or anhydrides giving thioesters in generally excellent yields.2 8 0 In studies of radical-mediated-11.21 thioester migrations,281 it has been indicated that trif luoroacetic anhydride is an excellent dehydrating reagent for the direct coupling of carboxylic acids and thiols.282 A variety of Lewis acids have been found suitable for effecting the alternative coupling of thioacids and alcohols: in general, very high yields of thioesters can be obtained with the appropriate catalyst.283 The nitro-alkenes (311) are readily available using aldol condensations and are good Michael acceptors: direct ozonolysis of the intermediate nitronates gives a-substituted thioesters (312) in good overall yields.284 A range of nucleophiles can be accommodated including alkoxides and amides as well as soft and hard carbon
145
3: Carboxylic Acids and Derivatives
R
Ph
N'
-Ic"
COSBu'
0
'COSBu' 'COSBu' (315)
(313)
I
R\ r C O S B u ' ~
OH
(316) ONa I
(319) RS MeO%oMe
hS
-
S
(3221
Scheme 2 9
i325)
(326) R3
RmSMc 0
SMe
(327)
(328)
General and Synthetic Methods
146
SMe
20 -100 “ C
&SMe
R2
S
H
1 H PhSe
Scheme 3 0
0
0
PhTeSiMe
3 RATePh
(331)
R&==O ( 3 3 L ) R = R ’ S ( O ) , , , PPh,, o r Ck
(3321
(333)
CL
0
( 3 3 5 ) R = C l or CCl,
147
3: Carboxylic Acids and Derivatives
nucleophiles. The a-cyanoacetate (313) has proven to be a good Michael nucleophile, one useful aspect being the relative ease of reduction of the thioester group using sodium borohydride, giving an additional degree of flexibility in further manipulations of the
ad duct^.^^'
initial Michael Thioester functions have again featured in some highly selective aldol condensations. The oxazoline (314), derived from (&)-aspartic acid, gives very largely isomers (315) upon enolisation, aldol condensation and trapping, presumably controlled by chelation effects involving the nitrogen of the heterocycle.286 The latent symmetry and the availability of the optical isomer of oxazoline (314) further contribute to the utility of this protocol. Silyl enolates of thiopropionate esters similarly give largely the @-isomers (316) in Lewis acid catalysed condensations with aldehydes. 287 The =-isomers of esters (316) can be obtained using the corresponding boron or tin288 enolates, and three contiguous chiral centres can be set up by using a chiral a-substituted aldehyde as electrophile. The boron enolate (317) condenses with aldehydes to give thioesters (318) with ca. 90% enantiomeric enrichments. 289 Hopefully, more complex substrates will also be available using this excellent method. 6-Keto-thionoesters (320) are obtainable by acylation of ketone enolates using a trithiodicarbonate (319) in generally excellent yields.290 Unsaturated a-keto-thionoesters (322) have been prepared from dithiono-oxalate (321) by sequential thiophilic Grignard attack, S-allylation and thio-Claisen rearrangement (Scheme 29) 291 Dithioesters (323) can be doubly deprotonated and subsequently regioselectively alkylated at the 8-position to give reasonable yields of homologues (324).292 The intermediate dianion can thus be
.
regarded as an ester homoenolate [cf. structures (99), (1771, (290) and (293) above]. a-Keto dithioesters (326) are available from a-diazoketones (325) by treatment with elemental sulphur and an alkyl iodide; yields are moderate to good.293 The chemistry of 3-oxoketen dithioacetals (327),precursors to 8-keto dithioesters and many other species, has been reviewed.294 Enolates of dithioesters are good Michael nucleophiles and with acyclic enones give largely the anti-isomers (328) 2 the kinetic (E)-enolate. 295 ?-ally1 dienolates (329), prepared by 5-allylation of the corresponding enolates, can be equilibrated to unsaturated dithioesters (330); the latter is usually by far the major component.296
General and Synthetic Methods
148
The equivalent of a selenolactonisation has been used to obtain thiolactones from appropriate unsaturated 2-acylselenosulphides, by a -- radical pathway (Scheme 30) .297 Subsequent selective oxidation and elimination provides unsaturated analogues with variable regioselectivities. Selenocarboxylate salts are not generally available due to the instability of the corresponding seleno-acids. An indiret method to obtain examples of these species (331) is by aminolysis of bis (acyl)diselenides using ~ i p e r i d i n e . ~ ’ The ~ salts can be alkylated at selenium by reactive halides such as a-bromoketones. Tellurol esters (333) can be prepared from acid chlorides (332) using a t e l l u r o ~ i l a n e . ~These ~~ could prove to be useful intermediates as coupling reactions with lithium dialkylcuprates lead to high yields of the corresponding ketones. Two new procedures for the conversion of thiocarbonyl groups into the corresponding carbonyls (C=S to C = O ) consist of sodium hydroxide under phase transfer conditions300 or cuprous chloride in aqueous sodium hydroxide.301 3.
Lactones
-
B-Lactones. Full details have been given302 for the preparation, on reasonably large scale, of the potentially useful 8-lactone synthons [ (334) and (335)I from diketene.303 Butyrolactones. - A variety of ruthenium304 and rhodium hydride305 complexes have been tested for their suitability as dehydrogenation catalysts for the oxidation of l,4-diols into butyrolactones. With 2-substituted and 2,2-disubstituted diols, the regioselectivity can be almost complete and the accompanying excellent yields make the overall transformation [(336) * (33711 a genuinely viable proposition. lI5-Pentanediols can similarly be transformed into valerolactones. An alternative approach to lactones (337) is by oxidation of the corresponding tetrahydrofurans; this can be achieved using mixtures of sodium bromate, NaBr02, and 47% hydrobromic acid.306 No regioselectivity studies have yet been reported with this method. A degradative approach to butyrolactones (339) consists of oxidations of of y-hydroxyalkenes (338) using cetyltrimethylammonium permanganate. 307 A key feature of this reagent is its inability to oxidise primary and secondary alcohols, which allows the preparation of mono- and bicyclic
149
3: Carboxylic Acidr and Derivatives
6r
Br 1342)
-
0 (343)
R'
CO, E t
(3441 Ph I I
'2 MeCN
0 Scheme 3 1
o-.)
r-. "OF
(
346
)
O--
CO, H
RS/Y\I OH
CN
Rs
RS
CN
(349)
R e a g e n t s : i , M ~ ( O A C )R~S,S R , T F A , C H 2 C I Z ; i i , B a s i c h y d r o l y s i s ; iii, CoCI2, H20
Scheme 32
General and Synthetic Methods
150
Scheme 33
O
w
NHAc
N3
HLdQ 0 Scheme 3 4
R3
I
X
= PhSe
or I
S c h e m e 35
3: Carboxylic Acidr and Derivatives
151
lactones by this method, as well as of spiro-lactones from tertiary y-hydroxy alkenes. Some new carbonylation procedures have been reported in this area. A variety of 1-alkynes (340) are regiospecifically carbonylated upon treatment with bromopentacarbonylmanganese, carbon monoxide, and methyl iodide under phase transfer conditions.308 Yields are moderate to good, the conditions mild (35"C, 1 atmos.) but as yet the approach is restricted to the 4-methyl derivatives (341). Nickel tetracarbonyl is useful as a catalyst for the reductive carbonylation of gem-dibromocyclopropanes (342) leading to bicyclic lactones (343).3 0 9 (In the absence of the hydroxymethyl substituent, this represents a good route to cyclopropanecarboxylic acids, esters and amides). One drawback is the requirement of large excesses (up to 7 equivalents) of toxic Ni(COI4. A route to the related derivatives (345) is by regioselective attack by allylzinc organometallics onto the corresponding keto-esters (344).310 Yields are generally excellent for the simple alkyl- and phenyl-substituted examples reported. Full details have been reported of the thermodynamic and kinetic iodolactonisation conditions developed by Bartlett, in which sodium bicarbonate can be added to remove HI and thus prevent the reverse reaction and hence equilibration to the thermodynamically preferred trans-isomer (Scheme 31) .311 Reagent (346) is capable of effecting analogous "tosyloxylactonisations" in good yie1ds3l2 and is especially useful for the bis-lactonisation of unsaturated diacids by specific *-addition to the alkene [e.g. (347)* (348)I .313 The equivalent of sulphenolactonisation can be carried out in two steps, starting with an unsaturated nitrile which is first treated with a disulphide using manganic acetate as oxidant in CH2C12-TFA (Scheme 32) .314 This results in mixtures of both possible acetoxysulphides which are transformed, without separation, into the ~ a m elactone using aqueous cobalt(I1) chloride, nitrile hydrolysis and the necessary thiol migration. Overall yields are good and the method is also applicable to valerolactone synthesis and to butyrolactones (349), a class of isomer not normally available from related lactonisation procedures. Bromolactonisation of the protected a-amino-acids ( 3 5 0 ) leads largely to the cis-butyrolactones (3511, the controlling feature probably being complexation between the nitrogen and the bromonium Similar control in reactions of (E)-(350) also results in the
152
General and Synthetic Methods
HQH
1359)
Ph
,CO2Me
R'--k (363)
Scheme 3 6
(365)
0
3: Carboxylic Acidr and Derivatives
153
formation of the *-isomers, but epimeric, relative to lactones (351), at the secondary bromide position. The products are useful as precursors to highly substituted prolines such as (-1-Bulgecinine. Another route to a-amino-lactones involves Lewis acid induced rearrangements of oxazolones (Scheme 33) .316 A broad generality has not been established for this sequence. An interesting approach to diamino-butyrolactones proceeds formal intramolecular addition of a keto-nitrene to a butenolide (Scheme 34) .317 The somewhat strained intermediates in this sequence should have a number of other uses. A variety of reagents have been shown to be suitable for effecting cyclisations of 4-alkynoic acids (352) to give ylidenebutyrolactones (353), including sulphenyl and selenenyl halides (X=SPh or SePh) ,318 N-iodosuccinimide (X=I)3 1 9 and palladium (11) salts (X=PdY). 3 2 0 The iodolactones [ ( 3 5 3 ) , X=I; R1=Hl can be coupled with 1-alkynes using a palladium catalyst to give the homologues (354)319 and the corresponding vinylpalladium species [ (353), X=PdYl alkylated by allylic chlorides to give lactones ( 3 5 5 ) .320 In addition, the (?)-isomers of iodolactones (353) are available from mercury-induced cyclisations of iodo-alkynoic acids [ (352) ; R1=I] .319 Radical-type ring closure is now established as a generally useful entry into both butyrolactones and valerolactones. Some useful generalisations have been made regarding the radical based ring closure outlined in Scheme 35.321 In general, the method is more suited to butyrolactone formation unless the double bond is activated by a carbonyl ( g radical Michael addition) and tetra-substituted double bonds are often poor radical acceptors. Simple reductive removal of the 'X' group is often predominant. A full report has been published on the related, highly regioselective, cyclisation of acetals (356) to give butyrolactones ( 3 5 7 ) following dealkylation and oxidati Jn.322 One disadvantage of these approaches is that two functionalities, the radical precursor [ X in Scheme 351 and the alkene group are lost. By initiating cyclisations of substrates [cf. (356)l using a cobalt(1) species, the initial cyclisation product is a cobalt complex which then loses the elements of cobalt(1) hydride to provide an unsaturated product [e.g. (358)1, thereby considerably enhancing the overall utility of this methodology.323 An intermolecular approach to butyrolactones (360) by reductive couplings between carbonyls (359) and acrylates may also involve radicals or perhaps a homo-enolate species generated by Michael addition of the samarium iodide to the a ~ r y l a t e . ~ Yields ~~ are variable but can be
154
General and Synthetic Methodr
SnClq
(366)
q Cl
R
+
_____)
CO,H phs+ C0,Me
(369)
(
370)
1371)
Scheme 37
QoH
4 0
(3721
3: carboxylic Acids and Derivatives
155
as high as 82%, and are further improved by the addition of HMPA to the original THF-alcohol solvent system.325 Sm12 also mediates in the addition of iodomethyl groups to ketones in another process which could be either radical- or ~ a r b a n i o n - b a s e d .The ~ ~ ~products are isolable iodohydrins but in the case of reaction with a y-keto-ester (361), the initial product cyclises to butyrolactone (362) (overall yield: 9 3 % ) . The potential of this method as a completely different approach, relative to iodolactonisation routes, to this type of lactone thus seems to be considerable. Recent results from studies of additions of electrophiles to ester enolates suggest that an electron-donating substituent directs additions to the opposite face. This is nicely demonstrated in alkylations of the enolates derived from lactones (363) which give exclusively the homologues ( 3 6 4 ) .327 Condensations with aldehydes are similarly selective. Intermolecular Diels-Alder reactions between 5-substituted butenolides and 1,3-butadiene at 210°C are stereospecific, giving only bicyclic lactones (365) generally in good yields.328 Therefore, when applied to a chiral butenolide, two new and potentially distinguishable asymmetric centres are formed in optically pure form, while retaining the original asymmetric feature. A remarkably efficient intramolecular Diels-Alder sequence can be used to prepare a variety of bi- and tricyclic lactones (Scheme 36) .329 The mildness of this procedure angurs well for its application elsewhere. An alternative type of intramolecular Diels-Alder reaction leading to butyrolactones (368) features the use of a nitroalkene function as the diene (366); these Lewis acid catalysed processes result in higher stereoselectivities with more substituted substrates.330 Hydrolysis of the initial products (367) is achieved by sequential treatment with potassium t-butoxide and HC1-formaldehyde via a nitrile oxide intermediate. The selective production of trans-fused isomers is of significance with respect to the overall synthetic utility of this scheme. Other useful cyclisation procedures include rutheniumcatalysed transformations of dichloro-acids (369) into lactones ( 3 7 0 ) in high yield331 and Lewis catalysed additions of a-chlorosulphides (371) to p-substituted phenols leading to aromatic butyrolactones ( 3 7 2 ) .332The remarkable Michael-Michael-aldol ring closure sequence has been applied to spiro-lactone synthesis by using a-methylenebutyrolactone as the second Michael acceptor (Scheme 3 7 ) .333 The
General and Synthetic Methods
156
5.1. R h - A 1 2 0 3 H 2 ( 7 o t m ) , E t O A c , 13h
* OMOM
I
VN" (383) N u : O R , N,
o r SR
(387)
(3881
157
3: Carboxylic Acidr and Derivatives
overall yield for this example is 37%. Other versions of this idea can be devised and one such has been used in the construction of the tricyclic system (373) (Scheme 37)3 3 4 although in this particular case, at least two separate synthetic operations are required. An unusual reaction which could have other applications is a single flask conversion of unsaturated aldehyde (374) into (2)-Aeginetolide (375), together with some of the corresponding butenolide (Dihydroactinidiolide) 3 3 5 This latter compound together
.
with the tetrahydro-derivative (376) have been obtained optically pure by a classical resolution procedure employing a trans-fused lactone prepared by malonate attack onto a cyclohexane e p ~ x i d e . ~ ~ ~ One of the obvious alternatives to butyrolactone synthesis from ester enolates and epoxides is to use nucleophilic attack by ester homo-enolates (vide supra) onto aldehydes and ketones. Two further versions of this latter method are condensations between ketones and methyl 3-bromopropionate using a-lanthanum metal to provide the presumed homo-enolate species337 or chiral dianion (377).338 In the latter examples, separation of diastereoisomers and desulphurisation gives both enantiomers of the products (3781, or the corresponding butenolides, following elimination of the sulphoxide function. Various simple chiral 5-substituted butyrolactones [ (378); R2=H] have been obtained from B-keto-sulphones by sequential asymmetric yeast reduction and alkylation. 3 3 9 Butyrolactone (379) can be prepared by a highly enantioselective Claisen rearrangement starting with (S)-3-methylbutyrolactone; the usefulness of this reaction has been enhanced by the development of a relatively straightforward method to transpose this initial product into lactone (380) and hence higher homologues, by substitutions at the a-p~sition.~~'An impressive demonstration of the utility of ylidenetetronic acids as precursors of highly substituted butyrolactones is to be found in a recent synthesis of the steroid Brassinolide, in which four contiguous chiral centres are established ~~ in one step [ (381) +(382)] (92%) by h y d r ~ g e n a t i o n . ~Highly substituted a-substituted butyrolactones (383) can be readily obtained by regio- and stereo- controlled nucleophilic ring opening of 1 ,2-epoxy carbamates. 342 A somewhat simpler a-hydroxybutyrolactone, (g)-pantolactone (384) is in demand as a precursor to the B vitamin (+)-D-Pantothenic acid; further methods for obtaining this enantiomer include a practical classical resolution procedure343 and asymmetric hydrogenation of the corresponding keto-lactone. 344
In general,
General and Synthetic Methodr
158
s n Bu,
SnBu3
9 C0,Et
R'
(3891
gr :$ ,R1w
R'
RZ R 3 NMe,
COzMe
CO, R Z
R3
(3921
0 C0,Me
(393)
(39C1
(3951
- Rn -----
P ~ ~ SPrI S
Reagents
(3901 t
SPr'
Pr'S
13961
. )
(3971
I,
Bun2 C U L I ,
v, 5'1.
11,
H2S04,
VO(acoc),, VI,
(396)
ButOOH,
III,
PhCH2Br, N a H ,
MnO,
Scheme 3 8
0
OH
SEMO&O
H
SEMO \
S c h e m e 39
J CzO H
iv,
LI NEt,,
3: Carboxyiic Acidr and Derivatives
159
-cis/trans mixtures
of disubstituted lactones (385) can be converted into largely the cis-(E)-isomers (386) by sequential enolisation and protonation. 3 4 5
Once again, Eldanolide (387) has proven to be a popular target; two asymmetric syntheses have been reported, one based on boronic acid ester chemistry,346 the second starting with ( Q ) - r i b o n ~ l a c t o n e ~ ~ ~ while routes to racemic material have utilised a stereoselective condensation between 2-propenyl-1,3-dithiane and an aldehyde,348 B-lithioacrylate equivalents349 and an unusual dioxepin rearrange70% ment.350 A further synthesis of (-)-Blastmycinone (388) with ee involves an asymmetric [2+21 cycloaddition between an 2-2-menthyl ketene and a vinyl ether followed by Baeyer-Villiger oxidation of the resulting cyclobutanone.351
=.
a-Methylenebutyrolactones. - Recent advances in this area have been reviewed.352 Ally1 stannane species are featured in a number of attractive new approaches to the a-methylenebutyrolactone function. B-Stannyl propenamides (389) condense smoothly with aldehydes in the presence of a Lewis acid typically BF3 or TiC14, to give high yields of lactones (390) following acidic hydrolysis (10% HC1, reflux) .353 Significantly, products with 75-80% enantiomeric excesses are obtained R ’ = ( R ) - or ( 5 ) from reactions using a chiral amide “389); Bz(MeOCH2)CHl, making this one of the few brief methods available for the preparation of such enantiomers. However, one drawback with this method is the final rather harsh acidic hydrolysis step which would certainly remove a wide variety of protecting groups, for example. A solution to this is to use the corresponding esters (391) which condense equally well with aldehydes using BF3 as catalyst; subsequent hydrolysis to the lactones (390) is effected using one equivalent of TFA in methylene chloride at ambient temperature. 354 The possibilities for asymmetric synthesis with this system have yet to be examined. B,y-Disubstituted as well as monosubstituted lactones (390) can also be obtained related condensations of bromomethyl acrylates (392) with aldehydes using metallic tin in aqueous ether to provide the reactive intermediate. 3 5 5 Although perhaps somewhat more practical than the foregoing methods, overall yields are rather lower (50-75%). The most practical but not the mildest version of these methods is undoubtedly the direct condensation of bromomethacrylic acid [ (392), R1=R2=H] with aldehydes using stannous chloride in aqueous, acidic 2-methoxyethanol at 60-70°C; yields are usually
160
General and Synthetic Methods
(399 1
(LOO)
(4021
(LO11
(LO31
co;
R-H Qo
( 40 7)
(LO61
OR’ (415)
(Ll01
(4091
(LO81
- kR co
co
“ P 4
H2S04
(ClCI(a1 R (b1 R
:H
= n-alkyl
R
W
(4171
o
3: Carboxylic Acia3 and Derivatives
161
above 80%. 356 A different approach to a-methylenebutyrolactones is a further development of the chemistry of 2-silyloxycyclopropane carboxylates ( 3 9 3 ) , which, when treated with the trifluoromethanesulphonate analogue of Eschenmoser's salt and a Lewis acid (TMSOTf), are converted into 8-amino-esters ( 3 9 4 ) and thence lactones ( 3 9 5 ) following borohydride reduction and elimination.357 Overall yields are reasonable for this multi-step approach. A carbanion based approach to monosubstituted lactones. ( 3 9 0 ) begins by metallation and regioselective condensation of ketene dithioacetal ( 3 9 6 ) with an aldehyde. The products ( 3 9 7 ) are subsequently sulphenated at the remaining methyl group and hydrolysed; yields are moderate to An efficient new method for the dehydration of a-hydroxymethyl butyrolactones ( 3 9 8 ) to give the corresponding a-methylene derivatives employs a water soluble carbodiimide in the presence of cuprous chloride as catalyst in hot acetonitrile.3 5 9 A procedure which could be useful in the construction of annulated butyrolactones is outlined in Scheme 3 8 .360 Vinyl lithium intermediates do not undergo cyclisation; it is a pity that the introduction of the lactone carbonyl group into the initial product requires so many steps! A rather neat application of the enolate Claisen rearrangement of glycolates is featured in a total synthesis of ( 2 )-Ethisolide (Scheme 3 9 ) .361 The key rearrangement presumably occurs via a chair-like transition state in which the side-chain is positioned over the opposite face to the ethyl group. The same methodology has also been used to prepared the homologous Avenaciolide and Isoavenaciolide.
Two new routes to a-alkylidenebutyrolactonesare worthy of note. Radical mediated cyclisations of selenocarbonates ( 3 9 9 ) afford lactones (400) in good yield, for the simple examples examined.362 Moderate yields (ca 40%) of lactones ( 4 0 2 ) have been obtained by tandem Michael addition-olefination reactions using the butenolide (401). 3 6 3 Nucleophiles used include t-butyl lithioacetate, and Bu2CuLi; annulations are possible by starting with a keto-malonate. Butenolides. - Disubstituted butenolides (404) can be easily obtained in 51-75% yields from the (?I-chloro-acrylate (403) by sequential treatment with a Grignard reagent [RMgBr, 2 eq.], lithium powder and carbon dioxide.364 Related vinyl lithium species can be obtained
162
General and Synthetic Methodr
(4221
(4231
.L R
,+'%fcozH R
(4241
14251
T CO, H
CO, H
EoR3
R2
M R' e0
(OH 1
(431)
3: Carboxylic Acids and Derivatives
163
directly by deprotonation of maleate or fumarate derivatives and condensed with aldehydes to give butenolides (405) in variable yields. 365 Another straightforward route to monosubstituted butenolides (407) is by condensations between dianion ( 4 0 6 ) and epoxides followed by ring closure (carbodiimide-DMAP) and a facile oxidative elimination. Overall yields are 70-75% but the most significant feature is the ease with which chiral butenolides can be prepared because of the availability of so many chiral e p ~ x i d e s . ~ ~ ~ Michael additions of malonate to allenic sulphoxides (408) proceed efficiently to give homologues (409) which, after [2.3]-sigmatropic rearrangement, lactonisation and finally isomerisation, are converted into a-carboxy-butenolides (410).367 Some new ways to convert furans into butenolides have been reported. Low temperature photo-oxygenation of 2-substituted furans followed by reduction using dimethyl sulphide leads to cis-enediones (411) which are converted into cyano-butenolides ( 4 1 2 ) by sequential treatment with TMSCN and PCC. 368 a-Seleno-furans (413) can be directly converted to butenolides (414) using hydrogen peroxide. 369 The ease of introduction of an a-seleno group into a suitable furan should make this a valuable method in complex butenolide synthesis. A very simple if somewhat limited approach to butenolides (416a) consists of carbonylation of allylic alcohols or derivatives (415) thereof in concentrated sulphuric acid.370 Similarly butenolides (416b) can be obtained from aldehydes (417) and the method can be extended to more unsymmetrical products by using preformed a,@-unsaturated aldehydes, the presumed first intermediates in the sequence.371 Yet another development of the Heck reaction is the PdC12-catalysed coupling of aryl iodides with unsaturated ester (418) under solid-liquid PT conditions.372 After acid hydrolysis, the B-aryl butenolides (419) are isolated in 48-71% yields. The olefin geometry presumably changes during the coupling step; applications of this method to more highly substituted substrates have not yet been examined. The chiral hydroxy-sulphoxides (420) and the epimeric alcohols can both be obtained from the same B-keto-sulphoxide by a judicious choice of reducing agent; oxidation to the sulphone, double deprotonation, alkylation by sodium iodoacetate and elimination then affords chiral butenolides (421).373 Overall yields are not spectacular but the optical purities of the final products are high (>
90%).
General and Synthetic Methodr
164
Ar
Ar
(434)
(4321
R -oR
o
d
o
At
(4351
(4331
SEt
( 4 5 1 ) R ’ r H or Me
I5521
(4431
3: Curboxylic Acidr und Derivutives
165
High yields of simple f3-ethynyl butenolides (423) may be prepared by gas-phase thermolysis ( 5 5 0 ° C ) of the propargylic esters (422); the likely mechanism is a tandem ene and [l.S]-hydride shift.374 Readily available hydroxy-esters (424) are easily converted into butenolides [ (425); R3=H] by sequential Michael addition of thiophenol and base-catalysed elimination. 375 If the intermediate 6-thio butyrolactones are converted into the corresponding butenolides [ (425); R3=SPhl using sulphuryl chloride then homologues [ (425); R3=n-alkyll are accessible by an addition-elimination sequence using an n-alkylcopper, in examples where R2=H. From an investigation of various Michael acceptors, it has emerged that ethoxymethylidene malonates are suitable for additionelimination reactions with acetylides to give diacids (426) after hydrolysis and elimination. Upon heating in a -dichlorobenzene, these acids cyclise to give ylidenebutenolides (427) 376 Chromium carbonyl complexes of acetylenes have been used to prepare 2-methoxyfurans and hence ylidenebutenolides; a specific example is a synthesis of bovolide (4281, a component of butter flavour.377
.
-
Tetronic Acids. An improved route to (E)- (and (Z)-) pulvinic acids (430) is by condensations between methoxymaleic anhydrides (429) and 378 zinc enolates of arylacetates followed by dehydration (MsC1; DBN). A further advance is the finding that trimethylsilyl iodide efficiently demethylates the initial condensation products to provide the naturally occurring acids (430). Related intramolecular condensations have been used to prepare tetronic acids [(431); bond indicated] required for various natural product syntheses. 379 A related structure (Ircinianin) has been obtained using an intramolecular Diels-Alder reaction with an ylidenebutenolide --double bond as the dien~phile.~~' Phthalides. - Complimentary procedures for the synthesis of aryl lignans have been developed; hydrogenation [Rh(I) cat., H2, 160°C] of anhydrides (432) leads almost exclusively to lignan (433) whereas dehydrogenation of diols (434) gives very largely the isomeric products (435).381 3-Hydroxyphthalides (437) can be prepared from the known carbanions (436) by carboxylation, followed by reduction and hydrolysis of the oxazoline function,382 and converted into via the 3-cyanophthalides (438) using KCN followed by DCC, corresponding cyanohydrin.383
166
General and Synthetic Methods
(447)
0
n- C5H,,C HO
Scheme 4 0
3: Carboxylic Acia3 and Derivatives
1 4 5 11
"C9H19
Q> *
167
(4521
"-C9H19
no HO'
168
General and Synthetic Methoak
A full account has been given of the preparation of phthalides from 0 -iodobenzyl alcohols by Pd-catalysed carbonylation.384 A related procedure starting with iodophenyl ketones [e.g. (439)l leads to ylidenephthalides (440)-385
Valerolactones. - Dianions (441), derived from the parent acrylic acids using t-butyl lithium, condense smoothly with epoxides in the presence of BF3.0Et2 to give generally excellent yields of the unsaturated lactones (442), useful as precursors to a wide range of valerolactones and other derivatives. 386 Clearly condensations with chiral epoxides will lead to chiral valerolactones as, for example, in a synthesis of the pheromone (443), using a Sharpless-derived epoxide. 387 An alternative asymmetric synthesis of lactone (443) features a further example of the utility of the chiral 1,3-oxathianes developed by Eliel and c o - ~ o r k e r swhereas ~~~ a brief diastereoselective syntheses of both erythro and threo (443) rely on reactions between modified n-decylmagnesium bromide and the acrolein dimer. 389 A relatively rare example of the creation of chiral quaternary carbons has been uncovered in Michael addition-elimination reactions between lactone enolates [e.g. (44411 and a chiral nitro-alkene (445); in this example, the product (446) is obtained with 88% enantiomeric enrichment. 390 Intramolecular Michael additions are also useful for the elaboration of chiral valerolactones. In an extension of previous work, the allylic epoxide (447) has been found to cyclise to give the Vitamin D3 precursor (448) upon treatment with 2.4 mol% Pd2(tba)3.CHC13, without the need for a base.391 Based on observations made during work on Quassinoid synthesis, simpler model substrates [e.g. (44911 have been shown to cyclise to lactones [e.g. (450)] upon exposure to trimethylsilyl iodide.392 A tandem Michael-aldol sequence forms the basis of a stereoselective approach to highly substituted valerolactones (Scheme 40) . 393 Yields for this particular example are 83 and 70% respectively. Carbon radicals are usually noted for their ability to behave as Michael nucleophiles; an example of this is the radical mediated coupling of chiral iodide (451) to acrylate, leading to lactone (452).394 Other applications of this principle will doubtless be forthcoming. Two research groups have reported on the utility of facile intramolecular Diels-Alder reactions between enamine or vinyl One application of sulphide functions and enones [ (453) (454)I .395 +
this methodology is in a synthesis of (+)-Nepetalactone (455). A
169
3: Carboxylic Acids and Derivatives
(6661
(6631
HO,C
C02Mc
OAc
(4651
(6661
H
(467)
H
?-
OMe
-SiO
0 Me
\
SPh
(666)
(Et 012P 1670)
(669 1
H
Y
(471)
170
General and Synthetic Methods
somewhat more conventional intermolecular Diels Alder cyclisation forms the basis of a total synthesis of (+)-Actinobolin (456).396 An oxidative electrolytic fragmentation of carboxylic acids, developed some years ago by Corey and co-workers, has been applied to a synthesis of malyngolide (459) by cleavage of acid (457),leading to ester (4581, using carbon plate electrodes followed by methylation and bis-hyd r~xylation?~~ A total synthesis of ( - ) - (459) from (+)-tartaric acid has been reported with full details.398 Careful acid-catalysed cyclisation of ketene dithioacetals (460) can take place with > 90% selectivity in favour of isomers (461) containing the substitution pattern present in the Prelog-Djerassi lactone (462).399 Further routes to (~)-(462)are based on an improved Diels-Alder cyclisation between benzyl propenyl ether and methacr~lein~ ~ ~ ref. 395) and on the stereoselective elaboration (cf. of a trisubstituted cycloheptenone.401 Iodo-valerolactones (464) can be easily obtained in one step from the corresponding vinyl ether (463) using the iodonium salt I(col1idine) BF4 in dimethyl 2 s u l p h ~ x i d e . ~Iodobutyrolactones ~~ can be similarly prepared. Selenoand sulpheno-lactonisation of 5,7-dienoic acids generally leads to the formal [1.4]-addition products (465); derivatives (466) of the alternative products are best obtained from lactones [(465), XR1=SePh] by sequential oxidation and [ 2.3 ] -sigmatropic 403 rearrangement. Details of some optimised conditions €or PLE-catalysed asymmetric hydrolyses of 3-substituted glutarates have been reported. 404 Reductions of the initial products (467) can then be used to obtain either enantiomer of the related 3-substituted valerolactones. The ability of Mevinolin and Compactin to block HMGCo reductase and hence cholesterol biosynthesis continues to stimulate the development of synthetic methodology in this area, past work in which has been comprehensively reviewed.*05 Two total syntheses of (+)-Compactin rely on a Diels-Alder strategy. An intermolecular version has diene (468) as the key synthon and suffers from a poor yield in the final demethylation step406 whereas an intramolecular approach using the aldehyde (469), derived from tri-~-acetyl-D-glucal, as the lactone synthon suffers from no such drawback at the deprotection stage. 407 A total synthesis of ( + ) -Dihydromevinolin features the use of keto-phosphonate ( 4 7 0 ) for construction of the valerolactone portion of the molecule.4o8 Yet another generally useful chiral synthon is the iodo-lactol ( 4 7 1 ) obtainable in twelve
3: Carboxylic Acids and Derivatives
171
. . H
R'-
R'
( 480)
(479)
H
(4841
(4851a; R b; R
= =
(Z1-n-C5H,, I€)-CHPh
H
(4861
172
General and Synthetic Methodr
OH
OH
0 ________)
DBU
S c h e m e 41
(p0-
173
3: Carboxylic Acidr and Derivatives
steps from a-Q-glucopyranose. 409
Epimerimisation at C-6 in such
lactones (472) may be accomplished by conversion to the open-chain mesylates 8473) which re-close to epimers (474) upon work-up and chromatography. 410 @-Hydroxy-ketones (475) undergo stereospecific attack by the allenylboronic acid (476) to give diols (477) and thence hydroxylactones (478) following ruthenium tetroxide oxidation.4 1 1 BY using chiral derivatives obtained from acid (476) and bulky tartrate esters, the whole sequence can be carried out asymmetrically. Additions of amines and thiols to unsaturated mevinates (479) are stereospecific, 412 giving only the 4- ( R )-derivatives (480) The bulk of the tri-isopropylsilyloxy group in chiral 1,3-oxathianes (481) appears to prevent undesired chelation between the incoming reagent and the @-oxygen so that methylmagnesium bromide (especially) or L-selectride give very largely epimers (482) 413 Subsequent hydrolysis and homologation of product [(482); R=Me] leads to ( S ) -mevalonolactone (483) Both ( 2 )- and (R) -Mevalonolactone have been obtained in excellent optical purities by stereospecific Grignard reactions of keto-acetals derived from (2S,3~)-1,4-dimethoxy-2,3butanediol ,414 and various chiral deuterated mevalonolactones have been prepared using a Sharpless epoxidation to introduce asymmetry.415 Finally, the aldehyde (484) has been used to obtain lactones (485) by sequential Wittig homologation and hydrolysis.416 As well as an
.
.
.
obvious relationship to the foregoing mevinic acids, dehydration of lactones (495) gives the natural lactones (-)-Argentilactone (486a) and
( + ) -Goniothalamin
(48613).
Macrolides. - Although many notable total syntheses of naturally occurring macrolides have been reported this year, most have used previously reported methods to effect the ring closure step. One of the oldest ways to form macrolides is by lactonisation of w-halo-acids; tetra-alkylammonium salts of 2-pyrrolidinone in DMP have been found to be good bases for the promotion of such a l k y l a t i ~ n s . w-Hydroxy~~~ acids can be cyclised using a distannoxane simply by heating in decane with 20 mol% of the latter.418 Both methods give good to excellent yields of 13-17 membered lactones (no examples of the more difficult medium-sized rings are reported) and both require reasonably high dilutions I250ml mmol-1 respectively] A full account of the preparation of 10-membered lactones by fragmentation of hydroperoxides [ e.g. (487) (48811 using +
General and Synthetic Merhoa3
174
Scheme L 2
n = 3; 76 'I. n = 4 ; 9 2 '1. n
( 4 9 5 ) R z H or Me
(496)
1
Ph
H N R 2 R 3 , H20
R'CN
1505)
R u H Z ( P P h 3 ) & , 160
= 5 ; 0 2 *I8
*C'
R ' C O N R ZR 3 (506)
OAr
0
PhANHBu + ArOH
RyCoNH OH
(5071
175
3: Corboxyiic Acids and Derivatives
Cu (OAc)2-FeS04 has been given.419 A precursor to hydroperoxides ( 4 8 7 ) can be the corresponding lactol (489)l; these can be directly cleaved to saturated lactones (490) by photolysis with iodosobenzene diacetate. 420 The alternative and penultimate precursors to
[e
hydroperoxides ( 4 8 7 ) are vinyl ethers [e.g. (49111. Such compounds can be oxidatively cleaved directly using MCPBA to give a keto-lactone [e.g. (492)1, in this example a precursor of (2)-Dihydrorecifeiolide. 421 Keto-macrolides related to the foregoing example (492) are also available from a-nitrocycloalkenones by ring expansion, again by cleavage of an intermediate lactol ,422 Five-atom expansions are particularly favoured because of the relative stability of the intermediate lactol and in such compounds, the ketone group is best removed, if desired, by reduction of the corresponding tosylhydrazone using (Ph3P)2CuBH4. Benzomacrolides can be obtained using a similar fragmentation, but with a Michael addition to a benzoquinone as a first step (Scheme 41) .423 Yields for medium-sized rings are rather low but the simplicity and brevity of the sequence compensates for this. Ring expansion based on a Claisen rearrangement [(493) (494)l can be used to obtain unsaturated eight-membered lactones which are 424 amongst the most difficult to prepare from acyclic precursors. The starting materials (493) are readily obtained by selenoxide elimination from an acetal formed using phenylseleno-acetaldehyde diethyl acetal and the corresponding 1,3-diol. The difficulty in obtaining 8-10 membered lactones is also reflected in the development of an acetylenic oxy-Cope procedured for the synthesis of (5)-Phoracantholide I (Scheme 42).425 Presumably, more complex targets could +
be obtained by this procedure, rather than removing most of the useful functionality! In a preliminary report, it has been claimed that samarium iodide is an excellent reagent for performing intramolecular Reformatsky reactions [(495) (496)] even when the products are 8-10 membered.426 If generally applicable, this will be a significant -f
breakthrough, even though high dilution conditions are required Very large macrolides, such as a (typically 500 ml mmol-'). 26-membered model for the polyene Tetrin A, can be prepared by Pd-catalysed C-C bond formation between a allylic bis-sulphone and a vinyloxirane function; yields as high as 92% have been obtained.427 4
Carboxylic Acid Amides Uncatalysed aminolysis of esters by primary amines usually
requires temperatures of 200°C or more:
such reactions can however be
176
General and Synthetic Methods
performed even with secondary amines at ambient temperature by using high pressure ( 8 kbar) .428 Although yields are essentially quantitative in most cases, the limitations of scale and apparatus availability are drawbacks. A severe test of any aminolysis procedure is the direct conversion of a-chloro-esters (497) into amides ( 4 9 8 ) ; this can be achieved in excellent yield using Et2NH and AlC13 in toluene at 20"C.429 Phenolic benzoates (499) can be readily cleaved by treatment with n-butylamine in benzene at room temperature to give the butylamide ( 5 0 0 ) and phenol (501).430 Although a good deprotection method for phenols, this could also be a useful and selective amide preparation as aliphatic esters are unreactive under these conditions (vide supra). Anilines can be directly acylated by carboxylic acids using polyphosphoric acid trimethylsilyl ester in at higher temperatures the corresponding amidines pyridine at 1 0 0 ° C ; are formed.431 Yet another amide and peptide coupling reagent is the phosphate (502), which appears to rank on equal terms with the best of the rest. It is an easily prepared crystalline solid, stable at O"C, and couples equimolar amounts of acids and amides in CH2Cl2 or DMF containing Et3N at 20°C in 0.5 h. Yields are excellent and minimal racemisation occurs. The known but little used reaction between carboxylic acids and isocyanates has been recommended as a viable route to a wide range of amides. 4 3 3 Ultrasonication of bromobenzene or 0 -bromotoluene in THF with metallic sodium and t-butylisocyanate leads rapidly to the anions [ ( 5 0 3 ) and (504),X=H] which can then be further metallated using n-butyl lithium to give the useful intermediates [ ( S O 3 1 and (5041, X=Li]. Subsequent condensations with aldehydes and ketones generally give reasonable yields.434 Simple aqueous work-up after the first step provides an easy one-carbon homologation method from bromobenzenes to amides. Many phenols can be directly ortho-acylated to give salicylamides by rections with an isocyanate and boron trichloride in ref luxing methylene chloride.4 3 5 Aminolyses of nitriles (505) are catalysed by many ruthenium species, most notably R U H ~ ( P P ~ ~to ) ~give , amides (506) in excellent yields but only with thermally robust substrates as temperatures of ca. 1 6 0 ° C are required.436 a-Hydroxyamides (507) can be readily obtained from the corresponding carboxylic acids and N-sulphinylaniline.437 The functional group combination is crucial as the latter
reagent does
not react with alcohols or carboxylic acids in isolation.
3: Carboxylic Acidr and Derivatives
177
ax
CO, HNEt2)
NHAc
(510)
Pd (cat.)
CONEt2 NHAc
(512)
(511)
OH
0
R V N M c ,
RCHO *TIC I&
CONMc,
(518)
(517)
(5191
CONEt, ____)
OL i
General and Synthetic Methodr
178
Ph
ARp C02Mc \N C02Me (526 1
(525 ) H
R
xC02Mc
(527)
R = (CH2),P(0)(OEt),, (CH21ZON=CMe2, o r (CH,),N B z z
(5281
H (529)
(530)
(531)
179
3: Carboxylic Acidr and Derivatives a - H y d r o x y w a m i d e s are available from 2-TBDMS cyanohydrins by hydrolysis of the nitrile function to C(S)NH2 using diphenylphosphinodithioic acid (Ph2PS2H) [lPrOH, 60°C, 8 h] :
the
silyl group is not removed under these conditions.438 Double carbonylations of o-halo-acetanilides (508) can be used to prepare the amides (509), useful as isatin and quinoline precursors, 439 in up to 80% yields. Unsaturated amides (510) are selectively deprotonated at the
(z)
-y-position (arrowed) and give the deconjugated products (511) on m e t h y l a t i ~ n ~ ~or ' the keten aminal (512) with TMSC1.441 The latter intermediate undergoes a thermal [1.5]-shift leading to allylsilane (513) and thence to the syn-aldols (514) following TiC14-catalysed condensations with aldehydes. Contrary to a previous report in the literature, tertiary benzamides (515) can be reductively alkylated [+(516)1 successfully under Birch conditions;
the presence of a
suitable proton source such as t-butanol is crucial. 442 Double deprotonation of a-keto-amides (517) gives rise to the novel dianionic species (518) which react with alkylating reagents generally at the a-position to give hydroxyamides Use of an Evan's-type keto-amide derived from (S)-2-methoxymethylpyrrolidine, results in asymmetric inductions of up to 75% ee. Dienolates (520) derived from unsaturated amides using LDA in 4:l THF-HMPA react in a Michael fashion with unsaturated esters to give largely the threo-isomers (521); in the absence of HMPA, formation of the corresponding erythro-isomers begins to predominate. 444 additions
to
Michael
a,B-unsaturated amides by a range of carbon acids such as
ketones, nitriles, malonates, and nitro-alkanes are effectively catalysed by the system CsF-(MeO)4Si. 445 An electro-reductive method has been developed for the N-alkylation of secondary amides;
yields are 67-91% and perhaps the
salient feature of this method is the absence of strongly basic conditions.446 5
Amino-acids
a-Amino-acids.
-
Despite being first reported some ten years ago, the
Stork method for a-amino-acid synthesis by homologations of glycine Schiff bases continues to receive considerable attention. Many of the recent developments are extrapolations of methodology used elsewhere in carboxylic acid synthesis.
For example, the pyrrolidine derivative
(522) can be alkylated (LDA, RX) and subsequently hydrolysed (1MHC1)
General and Synthetic Methods
180
to give a-amino-acids (523) in excellent yields and with > 95% enantiomeric enrichments.447 Somewhat lower optical yields
(z.
60% ee) are obtained in alkylations of related Schiff's bases derived
from polyacrylic crosslinked resins containing pendant (S)-methoxymethylpyrrolidine groups. 448
Imines (524) derived from camphor also
undergo asymmetric alkylations using similar methodology, the best results being obtained in reactions with allylic halides when enantiomeric enrichments are between 75 and Similarly, excellent selectivities can be achieved at both new centres from alkylations of carbanions of imine (524) by secondary allylic or benzylic halides.450 Achiral Schiff's bases prepared from amino-acids other than glycine can be resolved with ee's of up to 63% by asymmetric protonation of the derived enolates using a chiral amine ligand for the lithium counter cation and a chiral acid to provide the protons.451 A particularly mild method for the alkylation of glycinate Schiff's bases is by Pd(0)-catalysed reactions with allylic acetates or carbonates: in the latter cases, no base is required452 and moderate levels of asymmetric induction can be achieved by using a chiral diphosphine l i c ~ a n d . Asymmetric ~~~ Michael reactions of this type of glycinate with acylates can be effected using a nickel complex: a full account of this work has been given.454 Complete chiral induction at the a-position only is observed. Michael additions of simple glycinate Schiff's bases can conveniently be conducted under phase-transfer conditions 455 However , under these a
conditions, or using LDA-THF-HMPA, y-bromo butenoates react exclusively at the bromine to give amino-diester derivatives (525). On the other hand, enolates generated using LDA-THF do add in a Michael. fashion to give cyclopropylamino-acids (526) by an addition-el imination mechanism. 56 Cyclic a-amino-acid derivatives [ ( 5 2 7 ) , n=1-41 can be similarly prepared by alkylations using a,ud i h a l i d e ~while ~ ~ ~ reactions with w -halo-esters occur preferentially by displacement of the halogen. 458 Subsequent cyclisation of the resulting amino-diesters leads to various types of lactams. The Sch8llkopf bis-lactim ether method can be used to prepare
*
( p )-glutamic acid and a number of substituted homologues with excellent stereoselectivity at C-2 ( > 98% d.e.1 by Michael additions to a,B-unsaturated esters,459 as well as a range of other non-natural (D) - -amino-esters (528).460 By treatment of the usual bis-lactim ether carbanion with tosyl azide followed by further deprotonation and subsequent elimination of dilithium tosylamide, the diazo derivative
181
3: Carboxylic Acids and Derivatives
R' R ~ C O
OTMS
TMSOTf
ISL2 1
Br ( 5 4 51
Scheme L 3
General and Synthetic Methods
182
(529) is formed which adds smoothly to simple alkenes,presumably via a
-
carbenoid intermediate, to give cyclopropyl derivatives (530) after hydrolysis.461 An entirely different approach to this class of a-amino-acids involves condensations between enolates of isocyanoacetates and epoxides;
the result-ing alcohols [e.g. (531)
from cyclohexene oxide] are then mesylated and cyclised using
K O ~ B 462 ~ . An alternative to the bis-lactim ether approach is based on condensations of saturated five-membered heterocycles such as imidazolidinone (532) which can now be obtained in an optically pure state by a straightforward classical resolution.463 The related oxazolidinone (533) has been obtained from methionine and used to prepare (R)-amino-acids [cf.(528) I as well as the vinyl substituted derivatives (534) by oxidation and elimination of the sulphur group.464 Yet more general routes to chiral amino-acids have been reported using a variety of asymmetrically substituted ester enolate equivalents (535) in combination with the electrophilic nitrogen source di-t-butyl azodicarboxylate (536).
These include the sterically screened camphor
derivatives developed by Oppolzer and co-workers,465 N-methylephedrine derivatives, 466
and Evans-type oxazolidine derivatives.467
All give excellent enantiorneric enrichments in the final products
“523)
or (528)l and generally, but not always, excellent chemical
yields: for many targets there seems to be little to choose between the individual sequences. Similarly excellent asymmetric inductions have been achieved in condensations between imines l e . 9 .
(53711 and
ally1 boranes [e.g. (538)l which give initially the N-benzyl amino-esters (539):
related organometallics such as Grignard
reagents display a much lower level of regioselectivity towards the three electrophilic sites in substrates (537).468
With t.he exception
of this last approach, an advantageous feature of all of the foregoing is that the chiral auxiliary can be recovered. A non-stereoselective route to 6-hydroxy-a-amino-acids (541) proceeds via condensations between aldehydes or ketones and the ketene ~
acetal (540) in the presence of TMS trif late.469 The significance of this procedure is that, in contrast to many of the foregoing methods,
a strong base is not involved.
A wide range of masked a-amino-acids
(543) are available, again non-stereoselectively, by direct addition of a range of organometallic species to the acyl imines (5421, prepared by photo-oxidation of the corresponding N-methoxy
3: Carboxylic Acids and Derivatives
183
Ph
Ph
(5501
(5511
OH
NH2
(553)
(552)
OH
R'do2Me
C02Me
'
0, N
NH2
(5551
(55L)
HNBoc
ZHN A C 0 2 (558)
R'HN
k 3
1559)
(5611
(560)
CO2Et
+
TsNHCHzTs
TsNHCHz
(562)
(5631
T s NH
3<,
0,E t
(565)
Me
184
General and Synthetic Methodr
i m i d a ~ o l e s . In ~~a ~ related fashion, the aspartic acid homologues (544) are obtained with excellent syn-diastereoselectivity from condensations between tin enolates of thio-esters and a-imino-esters derived from ethyl glyoxylate,471 Until recently, such electrophilic a-amino acid synthons were relatively uncommon, but more recent developments such as these have clearly demonstrated the potential of this type of approach which can also be applied to asymmetric synthesis. For example, reactions between the bromide (545) and a range of organo metallics provide enantiomeric enrichments of > 97%, although one disadvantage is the requirement of a final hydrogenolytic step, which generally will preclude the presence of unsaturation or sulphur functionality in the side chain. 472 Effenberger and co-workers have given full details of their method for preparing amino esters (547) from a-hydroxy ester derivatives (546) by direct Walden inversion.473 The triflate derivatives turn out to be most suitable (milder conditions and hence less racemisation and elimination) and as esters (546) can be prepared from a-amino-acids by diazotisation with retention of configuration, this is a good method for obtaining the rarer (D)-isomers of a-amino-acids. A related approach relies upon asymmetric halogenation of sterically screened esters of the type prepared by Oppolzer and co-workers from camphor derivatives. Subsequent S 2 displacement by azide, trans-esterification and hydrogenation completes this versatile approach, which is ~~~ applicable to the elaboration of both ( & ) - and ( g ) - f ~ r m s . The anti-isomers (548) are the major products from reactions between (R)-2,3-isopropylideneglyceraldehyde derived from (D)-mannitol and organometallic reagents (RM); Mitsunobu inversion using phthalimide, hydrolysis and oxidation then completes yet another approach to (g)-a-amino-acids (549) (Scheme 4 3 ) . 475 An alternative route from (p)-mannitol to either (&)-a-amino-acids proceeds via diaziridine intermediates. 476 An example of an asymmetric Strecker synthesis is the reaction between (5)-1-phenylethylamine, benzylmethyl ketone and NaCN to give amino-nitrile (550) and thence the corresponding (El-amino-acid (551) after acid hydrolysis and hydrogenolysis.477 2-Oxazolines feature as intermediates in two diastereoselective approaches to hydroxy a-amino acids. Cycloaddition of ethoxycarbonyl nitrile oxide to 2-propenylpyridine affords the heterocycle (5521, a precursor of the N-terminal acid (553) found in some Nikkomycin n u c l e ~ s i d e swhereas ~~~ asymmetric aldol condensations between aldehydes and methyl
185
3: Carboxylic Acids and Derivatives
isocyanoacetate, catalysed by a chiral ferrocenylphosphine-gold(1) complex, afford mainly the trans-oxazolines ( 5 5 4 ) and subsequently esters (555).479 An alternative and potentially general route to esters (555) has regioselective attack by ammonia at the a-position of a glycidic acid as the key step.480 Diamino acids (557) with different N-protecting groups are available in racemic form by Michael addition of amines to the dehydroalamine derivative ( 5 5 6 ) ;481 differentially protected N-Alkyl a-amino glycines [e.g. ( 5 5 8 ) ] have also been prepared.482 glycines have been obtained from a-azidomalonates by a photolytic procedure which presumably proceeds via a nitrene-type insertion reaction. 483 a-Amino-acids in general are available from a-nitro esters using ammonium formate as a hydrogen transfer reagent.484 Fermenting Bakers yeast has been found capable of selectively hydrolysing lipophilic (&)-a-amino-esters in racemic mixtures; a simple extractive work-up of the brew gives (D)-amino-esters (559) with often excellent recoveries E. 45%1 and enantiomeric enrichments ( > 92%) .4g5 Similar specificities have been reported using alkaline protease.486
[x
8-Amino-acids. - A classical route to 6-amino-acids is by Michael additions of amines to a,@-unsaturated esters. Such reactions can be accelerated by the application of high pressure and performed asymmetrically by using chiral esters such as 8-naphthylmenthyl Almost complete asymmetric induction ha5 been observed in some cases. Another well established route is, by analogy with B-hydroxy-ester synthesis, an aldol condensation between an imine and an ester enolate. Further improvements to this approach include highly diastereoselective condensations between imines and tin(I1) thioester enolates, in the presence of tin(I1) triflate, leading to largely the &-isomers ( 5 6 0 ) 4 8 8 and a related, normal, aldol method which allows the creation of three contiguous chiral centres ( > 95%
derivative^.^"
de) in the thienamycin precursor ( 5 6 1 ) .489 Very similar products can be obtained by condensations of imines with (2)-c-vinyloxyboranes.490 The sulphone (562) can be regarded as a synthon of the cation ( 5 6 3 ) , and as such reacts with a variety of soft nucleophiles to give
B-amino [e.g. ( 5 6 4 ) I and a,B-diamino derivatives [e.g. (565)J in generally good yields. The likely mechanism involves an elimination to give N-methylene p-toluenesulphonamide followed by a Michael
General and Synthetic Methods
186
NHAc
OH
%AoC0,B"'
R3R4NH
C0,Bu'
0-
ENCONE1
E1,NCONH
(570)
2C
0,H
(571)
(572)
R = H or Me
COzMe
""SM, (5751
(5731
NHAc
(5761
NHAc
(5771
3: Carboxylic Acids and Derivatives
. i R w M g B r
CI
I
THF, - 7 0 ° C
RHN"
C0,Mc
ZHN
Z H N*CO,Me (
187
578)
( 5 8 01
(5791
tco2Et 0
(581)
R'O
(5821
(583)
K
F
F
(5861
I5871 R' W N h C OH z R z
I
SES
(588)
Fe
(589)
188
General and Synthetic Methods
addition; hence the requirement for soft nucleophiles.4 9 1 Aminolysis of glycidic esters with ammonia generally results in attack at the a-position;480 however Ritter-type ring opening of epoxy-esters (566) using acetonitrile in the presence of A1P04-A1203 selectively gives the 6-amino derivatives (567).492 Such cleavages can also be performed using trimethylsilyl azide with zinc chloride as promotor.493 It is of course unwise to assume that either of these methods will necessarily always provide such excellent regioselectivities when applied to new substrates. y-Amino-acids. - As mentioned above, a classical route to 6-amino-acids is by Michael addition of amines to a,6-unsaturated esters. A homologous version of this consists of ring opening of doubly activated cyclopropane diesters (568) by amines, in the presence of an equivalent of Et2A1C1.494 Yields of diesters (569) vary between 30% and 89% although these do include some rather sterically congested examples. Amidoethylation of carboxylic acid dianions (570) by aziridines provides a general route to a-aryl-GABA derivatives (571).495 The relatively poor yields in some cases are offset by the simplicity of the method. The related 6-hydroxy-y-amino-acids GABOB and carnitine (572) can be readily derived from (2g,4g)-4-hydroxyproline by electrochemical decarboxylation followed by oxidation and pyrrolidinone ring cleavage.496 The iodo-azide (573) plays the role of cation (574) in reactions with soft nucleophiles such as malonates and acetoacetates to give y-amino-acid precursors (575) in generally very good yields.497 The one carbon homologue behaves similarly leading to 6-amino acids. Unsaturated Amino-acids. - 2-Aminopropenoates (576) are converted into the corresponding butenoates (577) efficiently and stereospecifically by sequential reactions with diazomethane and pyrolysis of the resulting pyrazoline.4 9 8 An alternative route involving ring opening of an arylethylidene oxazolone by methoxide generally leads to both the ( g ) - and (E)-isomers of butenoates (577),499 as does a dehydrative route from the corresponding 0-silyloxy butanoates. The chloro-ester (578) behaves as a glycine cation equivalent in reations with vinyl Grignards leading to respectable yields (usually E. 60%) of 6,y-unsaturated amino-esters
3: Carboxylic Acids and Derivatives
189
(579) The amino-diacid (580) and the corresponding primary amide are obtainable by addition of amino-malonates to ethyl buta-2,3-dienoate or cyano-allene respectively.502 More highly
substituted examples are not reported. The Still-Genari phosphonate method has been applied to the elaboration of the (Z)-amino-diester (581) from phenylalanal; a variety of other phosphonates gave much lower stereoselectivities.
-
A review of recent advances in asymmetric Asymmetric Hydrogenation. synthesis includes a section on this topic.504 New chiral ligands for performing rhodium-catalysed hydrogenations of dehydroamino-acids include bis-l,2- (diphenylphosphinyl) c y c l ~ b u t a n eand ~ ~ ~the corresponding 3,4-disubstituted pyrrolidine derivatives. Both give very high enantiomeric enrichments and the latter has been shown to have an excellent turnover, with substrate/catalyst ratios as high as 50,OOO:l. 80% Aqueous formic acid is a useful source of hydrogen in conjunction with this type of catalyst and can sometimes result in better ee's than with molecular hydrogen.507 Dipamp is a particularly good ligand in Rh(1)-catalysed reductions of a dehydroamino-acid residue in an enkephalin pentapeptide, whereas reductions with achiral palladium catalysts of similar residues in cyclic peptides are often highly stereoselective being controlled, not surprisingly, by other chiral centres within the substrate. 509
Amino-acid Protection. - Carboxyamidomethyl (CAM) esters have been shown to be useful protecting groups in a-chymotrypsin and papain-catalysed peptide hydrolysis and synthesis. 1,3-Dioxans (582) can be obtained from Na-protected serine derivatives by acid-catalysed transacetalation and are sufficiently robust to survive both amino deprotection and peptide coupling reactions. (&)-Histidine benzyl ester can be prepared as the ditosylate salt by direct acid-catalysed esterification, contrary to claims in the literature that this is not possible. Both ally1 esters and Nu-allyloxy carbonyl (Alloc) groups can be cleaved using palladium-catalysed hydrostannolysis by tri-n-butyltin hydride without affecting benzyl- or t-butyl-based protecting groups.513 In contrast, all three N'-protecting groups [BOC, Z, and Alloc] are converted into the t-butyldimethylsiloxycarbonyl function upon treatment with t-butyldimethylsilane and palladium (11) acetate.514 Similarly, benzyl esters are exchanged to give the
General and Synthetic Methods
190
corresponding silyl esters.
Both of these palladium-catalysed
processed should find many applications. The ease with which BOC anhydride (di-t-butyl dicarbonate) can be used to introduce Nu-BOC protecting groups has now led to the development of suitable methods for preparing the benzyl analogue, dibenzyl dicarbonate [Z20?]. It is to be hoped that the compound is sufficiently stable to become commercially available as it will be a welcome substituted for benzyl chloroformate.515 A realisation of the susceptibility of Nu-Fmoc groups to hydrogenolysis has led to an investigation of the homobenzyloxycarbonyl [homo-Z,hZ] function (583) for amino group protection.516 As with Nu-Z groups, the hZ moiety is best removed by transfer hydrogenolysis using freshly precipitated Pd-C and ammonium formate, but much more slowly than benzyl groups allowing the selective unmasking of the ester group in hZ-Gly-OBn. Chloroalkyl carbonates (584) are generally useful reagents for the introduction of a wide range of alkoxycarbonyl groups onto amino functions ( 5 8 5 ) .517 Yields are generally well in excess of 70% and little or no racemisation appears to occur. The carbonate (586) is useful for the introduction of Nu-Fmoc groups; the released phenol can be coupled to the carboxylic acid function prior to work-up by simply adding an equivalent of DCC to give a protected and activated derivative (587) in a single operation.518 Overall yields are generally high. The newly developed B-trimethylsilylethanesulphonyl (SES) function (588) is simply the sulphonamide analogue of the corresponding carbamate and as such will offer similar selectivity of removal and greater stability especially to acidic conditions: the group is unmoved by refluxing TFA or 6M HCl.519 The novel ferrocenylmethyl (Fem) group falls into a rather different category in that Fern derivatives (589) of a-amino-esters can be coupled with Nu-protected a-amino-acids using DCC, but the products are of course then masked at the peptide bond NH group. Features of the Fern group are its high lipophilicity and bright yellow colour making it easy to detect during chromatographic separations. The group is removed by TFA-thionaphthalene at the same rate as t-butyl-based functionalities.s 2 0 Amino groups in a-amino esters can be 5-arylated using triarylbismuth diacylates in good yield, although a minor by-product is the N,N-diarylated derivative.521 A useful review of the synthesis and reactions of Na-hydroxy-a-amino-acids
has been published. 522
3: Carboxylic A c i d and Derivatives
191
A mild reagent for the removal of 2,2,2-trichloro-t-butyloxycarbonyl (TCBOC) and 2,2,2-trichloroethoxycarbonyl groups is sodium 2-thiophenetellurolate.523 The reagent does not attack N-BOC groups. Immobilized penicillinacylase catalyses the removal of rather stable No-phenacetyl groups in aspartame and (&)-aspartic acid a-methyl ester.524 Other substrates have not yet been examined. Na-Protected tyrosines can be efficiently alkylated at the phenolic OH by treatment with an alcohol under typical Mitsunobu conditions;525 the dimethylphosphinyl (Dmp) has also been recommended for the protection of this function.526
The thiol group of cysteines 527 can be effectively blocked by a 9-fluorenylmethyl (Fm) group.
References A . Abiko, J.C. Roberts, T. Takemasa, and S. Masamune, Tetrahedron Lett., 1986, 27, 4537. 2. T. Mukaiyama, N. Miyoshi, J-i. Kato, and M. Ohshima, Chem.Lett., 1986, 1385. 3. E. Dalcanale and F. Montanari, J.Org.Chem., 1986, 51, 567. 4. P.G.M. Wuts and C.L. Bergh, Tetrahedron Lett., 1986, 27, 3995. 5. S. Torii, T. Inokuchi, and T . C h e m . , 1986, 51, 155. 6. H. Firouzabadi, A.R. Sardarian, H. Moosavipour, and G.M. Afshari, Synthesis, 1986, 286. 7. C. Venture110 and M. Ricci, J.Org.Chem., 1986, 51, 1599. 8. K. Maruoka, S. Nakai, M. Sakurai, and H. YamamoG, Synthesis, 1986, 130. 9. T. Hanamoto, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1986, 27, 2463. D.A. Evans and R.L. DOW, Tetrahedron Lett., 1986, 27, 1007. 10. 11. 1986, 25, 462. I. Thanos and H. Simon, Angew.Chem.Int.Ed.Engl., 12. R. Haner, T. Maetzke, and D. Seebach, Helv.Chim.Acta., 1986, 69, 1655. 13. J.G. Deshmukh, M.H. Jagdale, R.B. Mane, and M.M. Salinkhe, Synth.Commun., 1986, 16, 479. 14. G.L. Larsen, V.C. deMaldonado, and R.R. Berrios, Synth.Commun., 1347. 1986, 5, 15. W. Oppolzer, R.J. Mills, and M. Rgglier, Tetrahedron Lett., 1986, 27, 183. 16. Oppolzer and G. Poli, Tetrahedron Lett., 1986, 27, 4717. 17. W. Oppolzer, R. Moretti, and G. Bernardinelli, Tetrahedron Lett., 1986, 27, 4713. 18. K. Soarand A. Ookawa, J.Chem.Soc., Perkin Trans.1, 759. 19. K. Tomioka, T. Suenaga, and K. Koga, Tetrahedron Lett., 1986, 27, 369. 20. T. Kitazume, T. Ikeya, and K. Murata, J.Chem.Soc., Chem.Commun., 1986, 1331. 21. S . G . Pyne, J.Org.Chem., 1986, 2,81.
1.
w.
192
22. 23. 24. 25. 26. 27.
General and Synthetic Methods
F.X. Webster, J.G. Miller, and R.M. Silverstein, Tetrahedron Lett., 1986, 27, 4941. M.W. Anderson, R.C.F. Jones, and J. Saunders, J.Chem.Soc., Perkin Trans.1, 1986, 205 and 1995. Q-M. Gu, D.R. Reddy, and C.J. Sih, Tetrahedron Lett., 1986, 27, 5203. S . Cadamuro, I . Degani, R. Fochi, and V. Regondi, Synthesis, 1986, 1070. P.F. Corey and F.E. Ward, J.Org.Chem., 1986, 51, 1925. H-J. Gais, K.L. Lukas, W.A. Ball, S. Braun, and H.J. Lindner, Liebigs Ann.Chem., 1986, 687; H-J. Gais, H.J. Lindler, T. Lied, K.L. Lukas, W.A. Ball, B. Rosenstock, and H. Sliwa, p. 1179. G. Guanti, L. Banfi, E. Narisano, R. Riva, and S. Thea, Tetrahedron Lett., 1986, 27, 4639. T . Kitazume, T. Sato, T. =bayashi, and J.T. Lin, J.Org.Chem., 1986.. 51.. 1003. A. Gateau-Oleskar, J. Clhophax, and S.D. Gero, Tetrahedron Lett., 1986, 27, 41. E . Rossi, S . Sassano, and R. Stradi, Synthesis, 1986, 765. M. Utaka, M. Nakatani, and A . Takeda, J.Org.Chem., 1986, 1140. J.K. Whitesell, R.M. Lawrence, and H-H. Chen, J.Org.Chem., 1986, 51, 4779. J.K. Whitesell, A. Bhattacharya, C.M. Buchanan, H-H. Chen, D.Deyo, D. James, C-L. Liu, and M.A. Minton, Tetrahedron, 1986, 42, 2993. J.K. Whitesell and C.M. Buchanan, J.Org.Chem., 1986, 51, 5443. K. Soai, T. Isoda, H. Hasegawa, and M. Ishizaki, Chem.Lett., 1986, 1897. J.W. Ludwig, M. Newcomb, and D.E. Berbreiter, Tetrahedron Lett., 1986, 27, 2731. M.P. Gore and J.C. Vederas, J.Org.Chem., 1986, 51, 3700. G. Silvestri, S . Gambino, and G. Filardo, Tetrahedron Lett., 1986, 27, 3429. B.M. T z s t and H. Hiemstra, Tetrahedron, 1986, 42, 3323. For reviews of previous work, see K. Mikami, N. Kishi, T. Nakai, and Y. Fujita, Tetrahedron, 1986, 42, 2911; T. Nakai and K. Mikami, Chem.Rev., 1986, 86, 885. 0 . Takahashi, T. Maeda, K. Mikami, and T. Nakai, Chem-Lett., 1986, 1355. 0. Takahashi, T . Saka, K. Mikami, and T. Nakai, Chem.Lett., 1986, 1599. K. Mikami, K. Kawamoto, and T. Nakai, Tetrahedron Lett., 1986, 27, 4899; M. Koreeda and D.J. Ricca, J.Org.Chem., 1986, 4090. K. Mikami, T. Kasuga, K. Fujimoto, and T. Nakai, Tetrahedron Lett., 1986, 3, 4185; M. Uchikawa, T. Hanamoto, T. Katsuki, p.4577. and M. Yamaguchi, M. Uchikawa, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1986, 7, 4581. K. Mikami, 0 . Takahashi, T. Tabei, and T. Nakai, Tetrahedron Lett., 1986, 27, 4511. C.H. Heathcock7S.K. Davidsen, K.T. Hug, and L.E. Flippin, J.Org.Chem., 1986, 3027. M. Bellassoued, J-E. Dubois, and E. Bertounesque, Tetrahedron Lett., 1986, 27, 2623. R. Devant and M. Braun, Chem.Ber., 1986, 119, 2191. J . Mulzer, P . de Lasalle, and A . Freissler, Liebigs Ann.Chem., 1986, 1152; J. Mulzer and N. Salimi, M., p.1172.
w.,
28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.
41. 42. 43. 44. 45.
z,
w.,
46. 47. 48. 49. 50. 51.
z,
3: Carboxylic Acids and Derivatives 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.
75. 76. 77. 78. 79. 80. 81. 82.
193
D.P. Curran and C.J. Fenk, _________ Tetrahedron Lett., 1986, 27, 4865. Garcia-Raso, P.M. Deya, and J.M. Saa, J.Org.Chem., 1986, 51, 4285. M. Hojo, R. Masuda, H. Sano, and M. Saegusa, Synthesis, 1986, 137. C.W. Jefford, J-C. Rossier, and J. Boukouvalas, J.Chem.Soc., Chem.Commun., 1986, 1701. R. Ballini and M. Petrini, Synthesis, 1986, 1024. R.M.B. de Perez. L.M. Fuentes, G.L. Larson, C.L. Barnes, and M.J. Heeg, J.Org.Chem., 1986, 51, 2039. See also P. Canonnej M. Kassou, and M. Akssira, Tetrahedron Lett., 1986, 27, 2001. C.H. Heathcock and D.E. Uehling, J.Org.Chern., 1986,z, 279. M. Utaka, H. Kuriki, T. Sakai, and A. Takeda, J.Org.Chem., 1986, 51 , 935. B. Zimmermann, H. Lerche, and T. Severin, Chem.Ber., 1986, 119, 2848. P. Coutrot and A. Ghribi, Synthesis, 1986, 790. M. Hojo, R. Masuda, S. Sakaguchi, and M. Takagawa, Synthesis, 1986, 1016. J.P. Foulon, M. Borgain-Commercon, and J.F. Normant, Tetrahedron, 1986, 42, 1399. W. Oppolzer and T. Stevenson, Tetrahedron Lett., 1986, 27, 1139. A.V.R. Rao, J.S. Yadav, and C.S. Rao, Tetrahedron Lett., 1986, 27 , 3297. M. Shinoda, K. Iseki, T. Oguri, Y. Hayasi, S. Yamada, and M. Shibasaki, Tetrahedron Lett., 1986, 27, 87. S . Ramaswamy, R.A.H.F. Hui, and J.B. Jones, J.Chem.Soc., Chem.Commun., 1986, 1545. S. Torii, H. Tanaka, T. Hamatani, K. Morisaki, A. Jutand, F. Pfluger, and J-F. Fauvarque, Chem.Lett., 1986, 169. T. Kashimura, K. Kudo, S. Mori, and N. Sugita, Chem.Lett., 1986, 299. See also S . Tazuke, S. Kazama, and N. Kitamura, J.Org.Chem., 1986, 51, 4548. C.I. Chiriac, Synthesis, 1986, 753. A . R . Katritzky, W-Q. Fan, and K. Akutagawa, Tetrahedron, 1986, 42, 4027; see also D.L. Comins and J.D. Brown, J.Org.Chem., 1986, 3566. Y. Sasson, G.D. Zappi, and R. Neumann, J.Org.Chem., 1986, 51, 2880. See also D.W. Ladner, Synth.Commun., 1986, 16, 157. J-P. Rieu, A. Boucherle, H. Cousse, and G. Mouzin, Tetrahedron, 1986, 42, 4095. T. Yamauchi, K. Hattori. K. Nakao. and K. Tamaki, Synthesis, 1986, 1044. See also S. Uemu-2, S . Fukuzawa, T. Yamauchi, K.Hattori, S. Mizataki, and K. Tamaki, J.Chem.Soc., Perkin Trans.1, 1986, 1983. T.V. RajanBabu, B.L. Chenard, and M.A. Petti, J.Org.Chem., 1986, 51, 1704. G. Iwasaki, S . Saeki, and M. Hamana, Chem.Lett., 1986, 3 1 . T. Hiyama, M. Inoue, and K. Saito, Synthesis, 1986, 645. T. Hiyama, K. Saito, K. Sato, N. Wakasa, and M. Inoue, Chem.Lett., 1986, 1471. Q-M. Gu, C-S. Chen, and C.J. Sih, Tetrahedron Lett., 1986, 27, 1763. T. Amano, K. Yoshikawa, T. Sano, Y. Ohuchi, M. Shiono, M.Ishiguro, and Y. Fujita, Synth.Commun., 1986, 16, 499. T. Amano, T. Ota, K. Yoshikawa, T. Sano, Y. Ohuchi, F. Sato, M.Shiono, and Y. Fujita, Bull.Chem.Soc.Jpn., 1986, 59, 1656. F. Uggeri, C. Giordano, A . Brambilla, and R. Annunziata, J.Org.Chem., 1986, 51, 97.
A.
General and Synthetic Methods
194
83. 84. 85. 86. 87
-
88. 89. 90.
91. 92. 93. 94. 95. 96. 91. 98. 99. 100. 101 *
102. 103. 104. 105. 106. 107. 108. 109. , 110. 111. 112. 113. 114. 115.
W.K. Fife and Z. Zhang, Tetrahedron Lett., 1986, 27, 4933, 4931. W.K. Fife and Z. Zhang, J.Org.Chem., 1986, 3144. S. Abdel-Baky and R.W. Giese, J.Org.Chem., 1986, 3390. Y. Kita, S. Akai, N. Ajimura, M. Yoshiqi, T. Tsuqoshi, H. Yasuda, and Y. Tamura, J.Org.Chem., 1986, 51, 4150. M.E. Baumann, H. Bosshard, W. Breitenstein, and G. Rist, Helv.Chim.Acta., 1986, 69, 396. T. Keumi, T. Morita, K. Teramoto, H. Takahashi, H. Yamamoto, K.Ikeno, M-Hanaki, T.Inagaki, and H.Kitajima, J.Org.Chem., 1986, 51, 3439. R.S. Bhide, B.S. Levison, R.B. Sharma, S. Ghosh, and R.G. Salomon, Tetrahedron Lett., 1986, 27, 671. M.A. Tius, D.P. Astrab, A.H. Fauq, J-B. Ousset, and S. Trehan, J.Am.Chem.Soc., 1986, 108, 3438. For a review, see H.H. Wasserman, K.E. Mc-Carthy, and K.S. Prowse, Chern.Rev., 1986, 86, 845. S . De Lombaert, I. Nemery, B. Roekens, J.C. Carretero, T. Kimmel, and L. Ghosez, Tetrahedron Lett., 1986, 21, 5099. D. Brillon, Synth.Commun., 1986, 16, 291. D. Mall _______ Synth.Commun., 1986, 2,331. S . Kim and S.S. Kim, _____ Synthesis, 1986, 1017. M. Saroja and T.N.B. Kaimal, Synth.Commun., 1986, 16, 1423. R. Caputo, E. Corrado, C. Ferreri, and G. Palumbo, Synth.Commun., 1986, 16, 1081. T . Miyasaka, M. Ishizu, A. Sawada, A. Fujimoto, and S. Noguchi, Chem.Lett., 1986, 871. 1. Ganboa and C. Palomo, Synthesis, 1986, 52. A. Loupy, M. Pedoussaut, and J. Sansoulet, J.Org.Chem., 1986, 51, 740. R.A. Bartsch and J.B. Phillips, Synt.h.Commun., 1986, 16, 1777. T. Fuchigami, T. Awata, T. Nonaka, and M.M. Baizer, Bull.Chem.Soc.Jpn., 1986, 2,2873. 0. Meth-Cohn, J.Chem.Soc., Chem.Commx., 1986, 695. J. Otera, T. Yano, A. Kawabata, and H. Nozaki, Tetrahedron Lett., 1986, 21, 2383. n u c h a n , N. Hamel, J.B. Woell, and H. Alper, J.Chem.Soc., Chem.Commun., 1986, 167. R. Takeuchi, Y. Tsuji, and Y. Watanabe, J.Chern.Soc., Chem.Commun., 1986, 351. For a summary, see Y. Yamamoto, Angew.Chem.Int.Ed.Engl., 1986, 25, 947. A. Alexakis, J. Berlan, and Y. Resace, Tetrahedron Lett., 1986, 27, 1047. M. Behforouz, T.T. Curran, and J.L. Bolan, Tetrahedron Lett., 1986, 27, 3107. M.P. C z k e , Jr., J.Org.Chem., 1986, 51, 1637. See also G.. Hallnemo and C Tetrahedron Lett., 1986, 2,395. T. Mukaiyama, Y. Hayashi, and Y. Hashimoto, -Chem.Lett., 1986, 1627. T. Umemoto, K. Kawada, and K. Tomita, Tetrahedron Lett., 1986,=, 4465. J. Ichinara, T. Matsuo, T. Hanafusa, and T. Ando, J.Chem.Soc., Chem.Commun., 1986, 793. T. Taguchi, 0. Kitagawa, T. Morikawa, T. Nishiwaki, H. Uehara, H. Endo, and Y. Kobayashi, Tetrahedron Lett., 1986, 27, 6103. A. Robert, S. Jaguelin, and J.L. Guinamant, Tetrahedron, 1986, 42, 2275. X. Creary, Org.Synth., 1986, 64, 201.
s, z,
195
3: CarboxyIic Acidr and Derivatives
116.
B. Strijtveen and R.M. Kellogg, J.Orq.Chem., 1986,z, 3664. For a radical-based approach to a-(2-pyridyl)thio-esters, see D.H.R. Barton, D. Crich, and G. Kretzschmar, J.Chem.Soc., Perkin Trans.1, 1986, 39, and D.H.R. Barton and D. Crich, p . 1613. S. Rozen and M. Brand, Angew.Chem.Int.Ed.Engl., 1986, 25, 554. C. Clark, P. Hermans, 0. Meth-Cohn, C. Moore, H.C. Talzard, and G.van Vuuren, J.Chem.Soc., Chem.Commun., 1986, 1378. S. Saito, Y. Nagao, M. Miyazaki, M. Inabe, and T.Moriwake, Tetrahedron Lett., 1986, 27, 5249. A. Abdel-Magid, L.N. P r i d G n , D.S. Eqgleston, and I. Lantos, J.Am.Chem.Soc., 1986, 108, 4595. R. Ballini and M. Petrini, Synth.Commun., 1986, 16, 1781. I.K. Youn, G.H. Yon, and C.S. Pak, Tetrahedron Lett., 1986, 27, 2409. E . Keinan and N. Greenspoon, J.Am.Chem.Soc., 1986, 108, 7314. T. Tsuda, T. Hayashi, H. Satomi, T. Kawamoto, and T. Saegusa, J.Org.Chem., 1986, 51, 537. B.S. Kirkiacharian and A. Danan, Synthesis, 1986, 383. T. Hayashi, A. Yamamoto, and T. Hagihara, J.Orq.Chem., 1986, 51, 723, See also T. Hayashi, A. Yamamoto, T. Hagihara, and Y. Ito, Tetrahedron Lett., 1986, 27, 191. M. Minato, T. Nonaka, and T. Fuchigami, _____ Chem.Lett., 1986, 1071. T. Hosokawa, T. Kono, T. Uno, and S-I. Murahashi, Bull.Chem.Soc. Jpn., 1986, 59, 2191. TKobayashi-%d M. Tanaka, Tetrahedron Lett., 1986, 27, 4745. Chem.Ber., 1986, 119, 444. B. Giese, H. Horler, and M. Leising, ____ E . Baciocchi, D. Dell'Aira, and R. Ruzziconi, Tetrahedron Lett., 1986, 27, 2763. P. BalGsteros and B.W. Roberts, Org.Synth., 1986, 64, 63. O.E.O. Hormi, Synth.Commun., 1986, 16, 997. B. Feith, H-M. Weber, and G. Maas, Chem.Ber., 1986, 119, 3276. X. Huang and L. Xie, Synth.Commun., 1986, 16, 1701. M. Yamaguchi, K. Hasabe, S. Tanaka, and T. Minami, Tetrahedron Lett., 1986, 27, 959. G.M. Posner, M. Weitzberq, T.G. Hamill, E. Asirvatham, H.Cun-Heng, and J. Clardy, Tetrahedron, 1986, 42, 2919. N. Ono, I. Hamamoto, A. Kamimura, and A. Kaji, J.Org.Chem., 1986, 51, 3734. R. Gambori and C. Tamm, Helv.Chim.Acta., 1986, 2,615, Tetrahedron Lett., 1986, 27, 3999. See also Y. Morizawa, A.Yasuda, and K.Uchida, p.1833. F.A. Davis, M.S. Haque, T.G. Ulatowski, and J.C. Towson, J.Org.Chem., 1986, 51, 2402. T. Yamada and K. NaGsaka, Chem.Lett., 1986, 131. H.C. Brown, B.T. Cho, and W . S . Park, J.Org.Chem., 1986, 51, 3396. See also A.I. Meyers and T. Oppenlaender, J.Am.ChG.Soc., 1986, 108, 1989. W.H. Pearson and M-C. Cheng, J.Org.Chem., 1986, 51, 3746. Y. Yamamoto, K. Maruyama, T. Komatsu, and W. Ito, J.Org.Chem., 1986, 51, 886. H. Tanaka, S . Yamashita, T. Hamatani, Y. Ikemoto, and S. Toru, Chem.Lett., 1986, 1611. J. Binder and E. Zbiral, Tetrahedron Lett., 1986, 27, 5829. U . Burkard and F. Effenberqer, Chem.Ber., 1986, 119, 1594. R. Csuk, A. Furstner, and H. Weidmann, J.Chem.Soc., Chem. Commun., 1986, 775. C. Palazzi, L . Colombo, and C . Gennari, Tetrahedron Lett., 1986, 1735. See also T. Tschamber, N. Waespe-Sarcevic, and C. Tamm, Helv.Chim.Acta., 1986, 2,621.
u.,
117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136.
~
137. 138. 139. 140. 141. 142.
143. 144. 145. 146. 147. 148. 149.
m.,
General and Synthetic Methods
196
150. 151. 152.
153.
M.T. Reetz, F. Kunisch, and P. Heitmann, Tetrahedron Lett., 1986, 27, 4721. Y . Nagao, Y . Hagiwara, T . Kumagai, M. Ochai, T. Inoue, K.Hashimoto, and E. Fujita, J.Org.Chem., 1986, 2391. D.A. Evans, E.B. Sjogren, J. Bartroli, and R.L. Dow, Tetrahedron Lett., 1986, 27, 4957; D.A. Evans and E.B. Sjogren, M., p.4961; D.A. Evans and M. DiMare, J.Am.Chem.Soc., 1986, 108, 2476. I. Fleming and J.D. Kilburn, J.Chem.Soc., Chem.Commun., 1986, 305; I. Fleming and M. Rowley, Tetrahedron Lett., 1986, 27, 5417. See also R. Krishnamurti and H.G. Kuivila, J.Org.Chem., 1986, 4947. W. Oppolzer, R.J. Mills, W. Pachinger, and T. Stevenson, Helv.Chim.Acta., 1986, 69, 1542; W. Oppolzer and P . Schneider, ibid., p.1817; W. Oppolzer and J. Marco-Contelles, p. 1699. K. Narasaka, Y. Ukaji, and K. Watanabe, Chem.Lett., 1986, 1755. D. Seebach and J. Zimmerman, Helv.Chiin.Acta., 1986, 69, 1147. K . Ushio, K . Inouye, K. Nakamura, S. Oka, and A. O h n c Tetrahedron Lett., 1986, 27, 2657. C. Fuganti, P. Grasselli, P.F. Seneci, and P. Casati, Tetrahedron Lett., 1986, 27, 5275. D. Seebach and M. Eberle, _____ Synthesis, 1986, 37. M. Hirama, T. Nakamine and S. Ito, Chem.Lett., 1986, 1381. PI. Hirama, T. Nakamine and S . Ito, Tetrahedron Lett., 1986, Z_Z, 5281. K . Nakamura, T. Miyai, K. Nozaki, K. Ushio, S. Oka, and A.Ohno, Tetrahedron Lett., 1986, 27, 3155; for similar reductions of dithioesters, see T. Itoh,Y.Yonekawa, T. Sato, and T.Fujisawa, ibid., p.5405. H. Akita, H. Matsukura, and T. Oishi, Tetrahedron Lett., 1986, 27, 5241. D. Buisson and R. Azerad, Tetrahedron Lett., 1986, 7, 2631. K . Mori and M. Tsuji, Tetrahedron, 1986, 42, 435. P. Caldirola, M. Ciancaglione, M.De Amici, and C.De Micheli, Tetrahedron Lett., 1986, 27, 4647. J. Mulzer and 0. L a m e r , Chem.Ber., 1986, 119, 2178. R. Tanikaga, K. Hosoya, and A. Kaji, J.Chem.Soc., Chem.Commun., 1986, 836. F.H. Gouzoules and R.A. Whitney, _____ J.Org.Chem., 1986, 51, 5024. T . Sato, M . Tsurumaki, and T. Fujisawa, Chem.Lett., 1986, 1367. A. Clerici, 0 . Porta, and P. Zago, Tetrahedron, 1986, 42, 561. F.G. Kathawala, B. Prager, K. Prasad, 0. Repic, M.J. Shapiro, R.S. Stabler, and L. Widler, Helv.Chim.Acta., 1986, 69, 803. E . Nakamura, H. Oshino, and I . Kuwajima, J.Am.Chem.Soc., 1986, 108, 3745. C-Q. Han, D. DiTullio, Y-F. Wang, and C.J. Sih, J.Org.Chem., 1986, 5 , 1253. K . Narasaka and Y. Ukaji, Chem.Lett., 1986, 81. K. Fuji, M. Node, and Y. Usami, Chem-Lett., 1986, 961. G.J. McGarvey and M. Kimura, J.Org.Chem., 1986, 51, 3913. H . Kotsuki, N . Yoshimura, Y. Ushio, T. Ohtsuka, and M . O c h i , Chem-Lett., 1986, 1003. A. Waldner, Tetrahedron Lett., 1986, 27, 6059. ., 1986, 27, 1947. P.C.B. Page ,S . Nakanishi, M. Higuchi, and T.C. Flood, J.Chem.Soc., Chem.Commun., 1986, 30. M. Sato, N. Yoneda, N. Kataqiri, H. Watanabe, and C. Kaneko, Synthesis, 1986, 672.
z,
z,
154.
~
w.,
155. 156. 157. 158. 159. 160. 161. 162.
163. 164. 165. 166. 167. 168. 169. 170. 171. 172.
~
173.
~
174. 175. 176. 177. 178. 179. 180. 181. 182.
197
3: Carboxylic Acids and Derivatives
Y. Tohda, M. Morikawa, T. Kawashima, M. Ariga, and Y. Mori, Chem.Lett., 1986, 273. Y. Tanabe and T. Mukaiyama, Chem.Lett., 1986, 1813. A. Armati, P.De Ruggieri, E.Rossi, and R.Stradi, Synthesis, 1986, 573. 186. K. Tomioka, K. Ando, K. Yasuda, and K. Koga, Tetrahedron Lett., 1986, 27, 715. 187. P. KocGsky and D. Dvorak, Tetrahedron Lett., 1986, 27, 5015. 188. Y. Hori, T. Mitsudo, and Y Watanabe, Tetrahedron Lett., 1986, 27, 5389. F o r a review of related Pd(0)-catalysed reactions, see J. Tsuji, Tetrahedron, 1986, 42, 4361. 189. M.G. Maloney, J.T. Pinhey, andE.G. Roche, Tetrahedron Lett., 1986, 27, 5025. 190. I.H. Sanchez, M.I. Larraza, F.K. Brena, A. Cruz, 0. Sotelo, and H.J. Flores, Synth.Commun., 1986, 16, 299. 191. K.M. Pietrusiewicz and, MonkiewiE, Tetrahedron Lett., 1986, 27, 739. 192. D.F. Taber, R.E. Ruckle, jr., and M.J. Hennessy, J.Org.Chem., 1986, 51, 4077; D.F. Taber, J.C. Amedio, jr., and R.G. Sherrill, ibid., p.3382. 193. H. Hagiwara, K. Kimura, and H. Uda, J.Chem.Soc., Chem.Commun., 1986, 860. 194. T.H. Chan and D. Stossel, J.Org.Chem., 1986, 51, 2423. See also T.H. Chan and C.V.C. Prasad, ibid., p.3012 and C. Abell, B.D. Bush and J. Staunton, J.Chem.Soc., Chem.Commun., 1986, 15. 195. A. Bernardi, S. Cardani, G. Poli, and C. Scolastico, J.Org.Chem., 1986, 51, 5041. 196. K. Ogura, N. YahataTM. Minoguchi, K. Ohtsuki, K. Takahashi, and H. Iida, J.Org.Chem., 1986, 11, 508. 197. J.E. Baldwin, R.M. Adlington, J.C. Bottaro, J.N. Kolhe, M.W.D. Perry, and A.U. Jain, Tetrahedron, 1986, 42, 4223; J.E. Baldwin, R.M. Adlington, J.C. Bottaro, J.N. Kolhe, I.M. Newington, and M.W.D. Perry, ibid., p.4235; J.E. Baldwin, R.M. Adlington, A.U. Jain, J.N. Kolhe, and M.W.D. Perry, ibid., ~.4247. 198. S. Hackett and T. Livinghouse, J.Chem.Soc., Chem.Commun., 1986 , 75; J.Org.Chem., 1986, 51, 879. 199. H-U. Reissig and H. L o r e 5 Liebigs Ann.Chem., 1986, 1914; H-U. Reissig, I. Reichelt, and H. Lorey, ibid., p.1924. 200. R.A. Holton, A.D. Williams, and R.M. Kennedy, J.Org.Chem., 1986 , 51, 5480. 201. K. Tomioka, K. Yasuda, and K. Koga, Tetrahedron Lett., 1986 1 2 7 , 4611. 202. Y . Hashimoto and T. Mukaiyama, Chem.Lett., 1986, 755 and 1623. 203. T. Mukaiyama, M. Tamura, and S. Kobayashi, Chem.Lett., 1986 1817. 204. R.E. Claus and S.L. Schreiber, Org.Synth., 1986, 64, 150. 205. C.R. Hutchinson, M. Nakame, H. Gollman, and P.L. Knutson, Org.Synth., 1986, 64, 144. 206. J.M. Takacs, M.A. Helle, and F.L. Seely, Tetrahedron Lett., 1986, 27, 1257. 207. J.A. Marshall, B.S. DeHoff, and D.G. Cleary, J.Org.Chem., 1986, 51, 1735. 208. R.A. Bunce and J.D. Pierce, Tetrahedron Lett., 1986, 27, 5583. 209. J. Villieras, M. Ramband and M. Graff, Synth.Commun., 1986, 16, 149. 210. R.W. Curley, jr., and C.J. Ticoras, Synth.Commun., 1986, 16, 627. 211. Y. Huang, Y. Shen, and C . Chen, Tetrahedron Lett., 1986, 27, 2903. 183.
184. 185.
I
198
General and Synthetic Method
H. Suzuki and M. Inouge, Chem-Lett., 1986, 403. L. Bo and A.G. Fallis, Tetrahedron Lett., 1986, 27, 5193. T.A. Engler and W. Falter, Tetrahedron Lett., 1981, 2,4119. M.J. Taschner, T. Rosen, and C.H. Heathcock, Org.Synth., 1986, 64, 108. 216. F.D. Lewis, D.K. Howard, J.D. Oxman, A.L. Upthagrove, and S.L. Quillen, J.Am.Chem.Soc., 1986, 108, 5964. 217. D.L. Reger, E . Mintz, and L. Lebioda, J.Am.Chem.Soc., 1986, 108, 1940. 218. I. Minami, K. Takahashi, I. Slimizu, T. Kimura, and J. Tsuji, Tetrahedron, 1986, 42, 2971. 219. H. Uno, Bull.Chem.Soc.Jpn., 1986, 2,2471. 220. A. Zapata and F. Ferrer G., Synth.Commun., 1986, 16, 1611. 221. T. Fuchikami, Y. Shibata, and Y. Suzuki, Tetrahedron Lett., 1986, 27, 3173. See also T. Ishihara, Y. Yamasaki, and T. Ando, ibid., p.2879. 222. J.P. Gillet, R. Sauvetre, and J.F. Normant, Synthesis, 1986, 538. 223. E. Piers and R.T. Skerlj, J.Chem.Soc., Chem.Commun., 1986, 626. 224. A.A. Galan, T.V. Lee, and C.B. Chapleo, Tetrahedron Lett., 1986, 27, 4995. 225. D.H.R. Barton, J - P . Finet, J. Khamsi, and C. Pichon, Tetrahedron Lett., 1986, 27, 3619. 226. A.S. Kende a n d P . Fludzinski, Org.Synth., 1986, 64, 104. 227. H. Kosugi, M. Kitaoka, A. Takahashi, and H. Uda, J.Chem.Soc., Chem.Commun., 1986, 1268. 228. I. Shimizu, M. Oshima, M. Nisar, and J. Tsuji, Chem.Lett., 1986, 1775. 229. O.G. Kulinkovich, I.G. Tischenko, J.N. Romanashin, and L.N. Savitskaya, Synthesis, 1986, 378. For an alternative, see M.Petrini, R.Ballini, G.Rosini, and E.Marotta, Tetrahedron, 1986, 42, 151. 230. S . Torii, H. Tanaka, Y. Tsutsui, T. Ohshima, and S. Yamashita, Chem.Lett., 1986, 1535. 231. F. Leyendecker and M-T. Comte, Tetrahedron, 1986, 42, 1413. 232. J. Pornet, A . Rayadh, and L. Miginiac, Tetrahedron Lett., 1986, 2,5479. 233. J. Durman, J.I. Grayson, P.G. Hunt, and S. Warren, J.Chem.Soc., Perkin Trans.1, 1986, 1939. 234. N.C. Barua and R.R. Schmidt, Chem.Ber., 1986, 119, 2066. 235. P. Brownbridge, P.G. Hunt, and S. Warren, J.Chem.Soc., Perkin Trans.1, 1986, 1695. 236. M. Kimura, S . Matsubara, Y. Sawaki, and H. Iwamura, Tetrahedron E., 1986, 27, 4177. 237. J.E. Baldwin, R.M. Adlington, D.J. Birch, J.A. Crawford, and J.B. Sweeney, J.Chem.Soc., Chem.Commun., 1986, 1339. 238. H.J. Reich, C.P. Jasperse, and J.M. Renga, J.Org.Chem., 1986, 51, 2981. 239. P.F. Schuda, C.B. Ebner, and T.M. Morgan, Tetrahedron Lett., 1986, 27, 2567. 240. J.S. Hill and N.S. Isaacs, Tetrahedron Lett., 1986, 27, 5007. 241. M . Brand, S.E. Drewes, and G.H.P. ROOS, Synth.Commun., 1986, 16, 883. 242. H.C. Brown, N.G. Bhat, and J.R. Campbell, jr., J.Org.Chem., 1986, 51, 3398. 243. D.A. Lombard0 and A.C. Weedon, Tetrahedron Lett., 1986, 27, 5555. 244. F.D. Lewis, D.K. Howard, S.V. Barancyk, and J.D. Oxman, J.Am.Chem.Soc., 1986, 108, 3016. 212. 213. 214. 215.
199
3: Carboxylic Acids and Derivatives 245.
R. Mortezaei, 0. Piva, F. Henin, J. Muzart, and J-P. Pete, Tetrahedron Lett., 1 9 8 6 , 27, 2 9 9 7 ; 0 . Piva, F. Henin, J. Muzart, and J-P. Pete, p.3001. G . A . Molander, B.E. LaBelle, and G. Hahn, J.Org.Chem., 1 9 8 6 ,
c.,
246.
51,
5259. 247. 248.
T. Hirao, Y . Fujihara, K. Kurokawa, Y. Ohshiro, and T. Aqawa, J.Org.Chem., 1 9 8 6 , 51, 2 8 3 0 . T. Ibuka, T. Nakao, S. Nishii, and Y. Yamamoto, J.Am.Chem.Soc.,
249.
V. C a l C L . Lopez, and G . Pesce, J.Chem.Soc., Chem.Commun.,
250. 251.
Y. Honda, A . Ori, and G . Tsuchihashi, Chem.Lett., 1 9 8 6 , 1 3 . P. Brownbridge, J. Durman, P.G. Hunt, and S. Warren, J.Chem.Soc., Perkin Trans.1, 1 9 8 6 , 1 9 4 7 . R.J. Hamilton, L.N. Mander, and S.P. Sethi, Tetrahedron, 1 9 8 6 ,
1986. 108. 7420. 1986, 1252.
252. 253. 254. 255.
42, 2881. -
K. Fischer and S. Hunig, Tetrahedron, 1 9 8 6 , 4 2 , 5 3 3 7 . P.S. Lidbetter and B.A. Marples, Synth.Commun., 1 9 8 6 , 1 6 , 1 5 2 9 . C.W. Daub, P.L. Shanklin, and C. Tata, J.Org.Chem., 1986,z, 3402.
256. 257. 258. 259. 260. 261. 262. 263. 264.
C.S. Wilcox and R.E. Babston, J.Am.Chem.Soc., 1 9 8 6 , 108, 6 6 3 6 . K.A. Parker and J.G. Farmar, J.Org.Chem., 1 9 8 6 , 5 1 , 4 0 2 3 . J. Kallmerten and M. Balestra, J.Org.Chem., 1 9 8 6 7 5 1 , 2 8 5 5 ; see also C.H. Heathcock and P.A. Radel, ibid., p . 4 3 2 2 . J. Kallmerten and T.J. Gould, J.Org.Chem., 1 9 8 6 , 51, 1 1 5 2 . M . J . Kurth and O.H.W. Decker, J.Org.Chem., 1 9 8 6 , 5 1 , 1 3 7 7 . E. Nakamura and I. Kuwajima, Tetrahedron Lett., 1 9 8 6 , 27, 8 3 . G.P. Boldrini, M. Mengoli, E. Tagliavini, C. Trombini, and A.Umani-Ronchi, Tetrahedron Lett., 1 9 8 6 , 27, 4 2 2 3 . T . Kauffmann, M. Enk, W. Kaschube, E . Tolioponlos, and 1986, 25, 910. D. Wingbermuhle, Angew.Chem.Int.Ed.Engl., G. Majetich, A. Casares, D. Chapman, and M. BehnE, J.Org.Chem., 1986,
51,
1745.
268. 269.
Y. Tamaru, H. Ochiai, T. Nakamura, and Z. Yoshida, Tetrahedron Lett., 1 9 8 6 , 27, 9 5 5 . P. Knochel and J.F. Normant, Tetrahedron Lett., 1 9 8 6 , 2 7 , 4 4 3 1 . T. Mandai, T. Moriyama, K. Tsujimoto, M. Kawada, and JFOtera, Tetrahedron Lett., 1 9 8 6 , 2 7 , 6 0 3 . R. Bloch and D. Hassan-GoGalez, Tetrahedron, 1 9 8 6 , 42, 4 9 7 5 . T. Sato, H. Tsunekawa, H. Kohama, and T. Fujisawa, Chem.Lett.,
270. 271.
T.A. Enaler and W. Falter. Tetrahedron Lett.. 1 9 8 6 ,. 2 7 .. 4 1 1 5 . J. Tsuji, T. Sugiura, and.1. Minami, Tetrahedron Lett., 1 9 8 6 ,
265. 266. 267.
1986, 1553.
272. 273. 274. 275.
27, -
731.
F.W. Nader and A. Brecht, Angew.Chem., Int.Ed.Engl., 1 9 8 6 , 25, 9 3 ; F.W. Nader, A . Brecht, and S. Kreisz, Chem.Ber., 1 9 8 6 , 119, 1208. See also idem., E., p.1196. D-H.G. Brinkhaus, E . Steclchan, and I). Degner, Tetrahedron, 1 9 8 6 ,
42, 553. A, Nishinaga, S . Yamazaki, and T. Matsuura, Tetrahedron Lett., 1 9 8 6 , 27, 2 6 4 9 .
276.
S . Cacchi, P.G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1 9 8 6 , 27, 3 9 3 1 . R. Jaouhari, P.H. Dixneuf, and S. Lecolier, Tetrahedron Lett.,
277.
T. Kashimura, K . Kudo, S. Mori, and N. Sugita, Chem.Lett., 1 9 8 6 ,
278. 279.
C.N. Lewis, P.L. Spargo, and J. Staunton, Synthesis, 1 9 8 6 , 9 4 4 . H. Tanaka, M. Hirayama, M. Suzuki, T. Miyaska, A. Mtsuda, and T.Ueda, Tetrahedron, 1 9 8 6 , 42, 1 9 7 1 .
1986, 27, 6315. 851.
General and Synthetic Methods
200
280. 281. 282. 283. 284. 285. 286.
287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297. 298. 299. 300. 301. 302. 303. 304. 305. 306. 307. 308. 309. 310.
311.
S. Ahmad and J. Iqbal, Tetrahedron Lett., 1986, 27, 3791. For an example, see M. Tada, K. Inoue, and M. Okabe, Chem-Lett., 1986, 703. W.M. Best, A.P.F. Cook, J.J. Russell, and D.A. Widdowson, J.Chem.Soc., Perkin Trans.1, 1986, 1139. J.Y. Gauthier, F. Bourdon, and R.N. Young, Tetrahedron Lett., 1986, 27, 15. A.G.M. Barrett, G.G. Graboski, and M.A. Russell, J.Org.Chem., 1986, 51, 1012. H-J. Liu and H. Wynn, Can.J.Chem., 1986, 64, 649 and 658. G.J. McGarvey, R.N. Hiner, J.M. Williams, Y. Matasubara, and J.W. Poarch, J.Org.Chem., 1986, 3742. See also G.J. McGarvey, J.M. Williams, R.N. Hiner, Y. Matsubara, and T. Oh, J.Am.Chem.Soc., 1986, 108,4943. C. Gennari, M.G. Beretta, A. Bernardi, G. Moro, C. Scolastico and R. Rodeschini, Tetrahedron, 1986, 42, 893. T. Mukaiyama, N. Yamasaki, R.W. Stevens, and M. Murakami, Chem-Lett., 1986, 213. S. Masamune, T. Sato, B. Kim, and T . A . Wollmann, J.Am.Chem.Soc., 1986, 108, 8279. M . A . Palominos, R. Rodriguez, and J . C . Vega, Chern.Lett., 1986, 1251. K. Hartke and T. Gillmann, Liebigs Ann-Chem., 1986, 1718. P . Beslin and A. Dlubala, Tetrahedron Lett., 1986, 27, 1687. A. Sawluk and J. Voss, Synthesis, 1986, 968. R.K. Dieter, Tetrahedron, 1986, 42, 3029. K. Kpegba, P. Metzner, and R. Rakotonirina, Tetrahedron Lett., 1986, 27, 1505. P. M e t z e r , T.N. Pham, and J. Vialle, Tetrahedron, 1986, 42, 2025. T. Toru, T. Kanefusa, and E. Maekawa, Tetrahedron Lett., 1986, 27, 1583. H. Ishihara, S . Muto, and S. Kato, _______ Synthesis, 1986, 128. K. Sasaki, Y. ASO, T. Otsubo, and F. Ogura, Chem.Lett., 1986, 977. H . Alper, C. Xwiatkowska, J-P. Petrignani, and F. Sibtain, Tetrahedron Lett., 1986, 27, 5449. N. Narasimhamurthy and A.G. Samuelson, Tetrahedron Lett., 1986, 27, 3911. J.G. Dingwall and B. Tuck, J.Chem.Soc., Perkin Trans.1, 1986, 2081. For a review of diketene chemistry, see R.J. Clemens, Chem.Rev., 1986, 86, 241. Y. Ishii, K. Osakada, T. Ikariya, M. Saburi, and S. Yoshikawa, J.Org.Chem., 1986, 51, 3034. See also S . Kanemoto, H. Tomioka, K. Oshima, and H. Nozaki, Bull.Chem.Soc.Jpn., 1986, 2,105. Y. Ishii, K. Suzuki, T. Ikariya, M. Saburi, and S. Yoshikawa, J.Org.Chem., 1986, 51, 2822. S . Kajigaeshi, T. Nakagawa, N. Nagasaki, H. Yamasaki, and S.Fujisaki, Bull.Chem.Soc.Jpn., 1986, 59, 747. R. Rathore, P.S. Vankar and S. Chandrasekaran, Tetrahedron Lett., 1986, 27, 4079. J-X. Wang and H. Alper,J.Org.Chem., 1986, 51, 273. T. Hirao, Y. Harano, Y. Yamana, Y. Hamada, S. Nagata, and T. Agawa, Bull.Chem.Soc.Jpn., 1986, 2 , 1341. M . Mladenova, F. Gandemar-Bardone, N. Goasdone, and M.Gandemar, Synthesis, 1986, 937. See also A.K. Mandal and D.G. Jawalkar, Tetrahedron Lett., 1986, 27, 99. F.B. Gonzalez and P.A. Bazlett, Org-Synth., 1986, 64, 175.
s,
3: Carboxylic Acids and Derivatives
312. 313. 314.
201
M . S h a h , M . J . T a s c h n e r , G.F. K o s e r , a n d N.L. R a c h , T e t r a h e d r o n L e t t . , 1986, 27, 4557. M . S h a h , M . J . T a s c h n e r , G.F. Koser, N.L. R a c h , T.E. J e n k i n s , 5437. P . C y r , a n d D . P o w e r s , T e t r a h e d r o n L e t t . , 1986, Z.K.M.A. E l Samu, M . I . A 1 Ashmawy, a n d J . M . M e l l o r , T e t r a h e d r o n
27,
E., 1986,
315. 316. 317. 318. 319. 320. 321.
Y.
Ohfune,
2 7 , 5293. K.Hori, and M.
1986,
Sakaitani, Tetrahedron Lett.,
27, 6079. -
H . W i l d a n d W . S t e g l i c h , L i e b i g s Ann.Chem., 1986, 1910. M . E g l i a n d A.S. D r e i d i n g , H e l v . C h i m . A c t a . , 1986, 69, 1442. T . T o r u , S. F u j i t a , M . S a i t o , a n d E . Maekawa, J . C h e m . S o c . , P e r k i n T r a n s . 1 , 1986, 1999. R.W. S p e n c e r , T . F . Tam, E. Thomas, V . J . Robinson, and A. Krantz, J.Am.Chem.Soc., 1986, 5589. N . Y a n a g i h a r a , C. L a m b e r t , K . I r i t a n i , K . U t i m o t o , a n d I . N o z a k i , J.Am.Chem.Soc., 1986, 2753. A.L.J. B e c k w i t h a n d P.E. P i g o u , J . C h e m . S o c . , Chem.Commun., 1986,
108,
108,
85. 322. 323. 324.
Y . U e n o , 0. M o r i y a , K . C h i n o , M . W a t a n a b e , a n d M . O k a w a r a , J.Chem.Soc., P e r k i n T r a n s 1, 1986, 1351. H. B h a n d a l , G . P a t t e n d e n , a n d J . J . R u s s e l l , T e t r a h e d r o n L e t t . ,
1986, 27, 2299. S. F u k G a w a , A . N a k a n i s h i , T . F u j i n a m i , a n d S . S a k a i , 1986, 624. J . C h e m . S o c . , Chem.Commun.,
325.
K.
326.
T. Tabuchi,
O t s u b o , J. I n a n a g a ,
27, 5763. J. Inanaga, 1986, 27, 3891.
and M.
Yamaguchi,
Tetrahedron Lett.,
1986, 327. 328.
Yamaguchi, T e t r a h e d r o n L e t t . ,
1986,
C h u c h o l o w s k i , Angew.Chem.Int.Ed.Engl.,
J . Mulzer and A.
25 , 655. -
and M .
J . Corbera,
R.M. Ortuno, 27, 1081. K . Hayakawa,
330.
S.E.
331. 332.
H e l v . C h i m . A c t a . , 2986, 69, 1971. T.K. H a y e s , A . J . F r e y e r , M . P a r v e z , a n d S.M. W e i n r e b , J.Org.Chem., 1986, 5501. M . K e n n e d y , A . R . M a g u i r e , a n d M . A . McKervey, T e t r a h e d r o n L e t t . ,
333.
G.H.
S.
Ohsuki,
and J. F o n t , T e t r a h e d r o n L e t t . ,
1986,
329.
and K.
Xanematsu, T e t r a h e d r o n L e t t . ,
27, 947. M.S. D a p p e n , a n d C . J . C r a m e r , J.Am.Chem.Soc., 1986, 108, 1306; S . E . Denmark, C . J . C r a m e r , a n d S . E . S t e r n b e r g , 1986,
Denmark,
1986, 27, 761. P G n e r , S-B. L u , a n d E. A s i r v a t h a m , T e t r a h e d r o n L e t t . , 27, 659.
1986, 334.
M.E.
Krafft,
R.M.
Kennedy,
a n d R.A.
Holton,
Tetrahedron Lett.,
1986, 27, 2087. 335. 336.
T . E . . N i c k s o n , T e t r a h e d r o n L e t t . , 1986, 27, 1433. L. S t r e k o w s k i , M . V i s n i c k , a n d M.A. B a t t i s t e , J . O r q . C h e m . ,
51. 4836. - - -
1986,
r
337. 338.
S. Fukuzawa, T. F u j i n a m i , a n d S . S a k a i , J.Chem.Soc., Chem.Commun., 1986, 475. A. A l b i n a t i . P. B r a v o , F. G a n a z z o l i , G . R e s n a t i , a n d F. V i a n i . J . C h e m . S o c . ; P e r k i n T r a n s . 1 , 1986, 1405. S e e a l s o C . C . L e z n o f f , C . R . M c A r t h u r , a n d M . W h i t t a k e r , Synth.Commun., 1986, 225. A.P. K o z i k o w s k i , B.B. M u g r a g e , C . S . L i , a n d L . F e l d e r , T e t r a h e d r o n L e t t . , 1986, 27, 4817. F . E . Z i e g l e r , A . K n e i s l e y T a n d R . T . Wester, T e t r a h e d r o n L e t t . , 1986, 1221; F.E. Z i e g l e r a n d R.T. Wester, i b i d . , p.1225; F . E . Z i e g l e r , E . P . S t i r c h a k , a n d R.T. Wester, i b i d . , p.1229. T . K a m e t a n i , T . K a t o h , M . T s u b u k i , a n d T. H o n d a , ' 7055. J.Am.Chem.Soc.,l986,
16,
339. 340. 341.
27,
108,
202
General and Synthetic Methods
342.
J. Lussmann, D. Hoppe, P.G. Jones, C. Fittschen, and G.M. Sheldrick, Tetrahedron Lett., 1986, 27, 3595. C. Fizet, Helv.Chim.Acta., 1986, 69, 404. T. Morimoto, H. Takahashi, K. Fujii, M. Chiba, and K. Achiva, Chem.Lett., 1986, 2061; H. Takahashi, M. Hattori, M. Chiba, T. Morimoto, and K. Achiwa, Tetrahedron Lett., 1986, 27, 4477. 345. S . Takano, J. Kudo, M. Takahasi, and K. Ogasawara, Tetrahedron Lett., 1986, 27, 2405. 346. D . S . Matteson7K.M. Sadhu, and M.L. Peterson, J.Am.Chem.Soc., 1986, 108, 810. See also C. Gunther and A. Mosandl, Liebigs Ann.Chem., 1986, 2112. 347. R.M. Ortuno, R . Merce, and J. Font, Tetrahedron Lett., 1986, 5, 2519. 348. J-M. Fang and B-C. Hong, Synth.Commun., 1986, 16, 523; J-M. Feng, L-F. Liao, and B-C. Hong, J.Org.Chem., 1 B 6 , 5_1, 2828. 349. N . C . Barua and R.R. Schmidt, Synthesis, 1986, 891. 350. H. Frauenrath and T. Phillips, Tetrahedron, 1986, 42, 1135. 351. G. Frater, u. Muller, and W. Gunther, Helv.Chim.Acta., 1986, 69, 1858. 352. N . Petragnani, H.M.C. Ferraz, and G.V.J. Silva, Synthesis, 1986, 157. 353. K. Tanaka, H. Yoda, Y. Isobe, and A. Kaji, J.Org.Chem., 1986, 51, 1856. 354. J . E . Baldwin, R.M. Adlington, and J.B. Sweeney, Tetrahedron Lett., 1986, 27, 5423. 355. J . Nokami, T. Tamaoka, H. Ogawa, and S. Wakabayashi, Chem-Lett., 1986, 541. See also H . Shibuya, K. Ohashi, K. Kawashima, K. Hori, N. Murakami, and I. Kitagawa, p.85. 356. K. Uneyama, K. Ueda, and S . Torii, Chem.Lett., 1986, 1201. 357 * H-U. Reissig and H. Lorey, J.Chem.Soc., Chem.Commun., 1986, 269. 358. T. Fujisawa, K . Umezu, M. Suzuki, and T. Sato, Chem.Lett., 1986, 1675. 359. R.C. Andrews, J.A. Marshall, and B.S. DeHoff, Synth.Commun., 1986. 16. 1593. 360. M.E. Krafft, Tetrahedron Lett., 1986, 27, 771. 361. S.D. Burke and G.J. Pacofsky, Tetrahedron Lett., 1986, 27, 445; S.D. Burke, G.J. Pacofsky, and A.D. Piscopio, ibid., p.3345. For alternative routes to Avenaciolide, see K. Suzuki, M. Miyazawa, M. Shimazaki, and G. Tsuchihashi, ibid., p.6237 and H. Kotsuki, H. Ohnishi, Y. Akitomo, and M. Ochi, Bull.Chem.Soc. Jpn., 1986, 59, 3881. Bachi and E. Bosch, Tetrahedron Lett., 1986, 27, 641. 362. 363. T. Minami, Y . Kitajirna, and T. Chikugo, Chem-Lett., 1986, 1229. 364. J . Barluenga, J.R. Fernandez, and M. Yus, J.Chem.Soc., Chem.Commun., 1986, 183. 365. B - A . Feit, B. Haag, J. Kast, and R.R. Schmidt, J.Chem.Soc., Perkin Trans.1, 1986, 2027. 366. S. Hanessian, P.J. Hodges, P.J. Murray, and S.P. Sahoo, J.Chem.Soc., Chem.Commun., 1986, 754. 367. H-J. Altenbach and H. Soicke, Tetrahedron Lett., 1986, 27, 1561. 368. I . Saito, Y-H. KUO, and T. Matsuura, Tetrahedron Lett., 1986, 27, 2757. 369. S . I . Pennanen, Synth.Commun., 1986, 16, 877. 370. E.P. Woo and F.C.W. Cheng, J.Org.Chem., 1986, 51, 3704. 371. E.P. Woo and F.C.W. Cheng, J.Org.Chem., 1986, 51, 3706. 372. P.G. Ciattini and G . Ortar, Synthesis, 1986, 7 K 373. G. Solladie, C . Frechou, G. Demailly, and C. Greck, J.Org.Chem., 1986, 51, 1912. 314. V . Bilinski, M. Karpf, and A.S. Dreiding, Helv.Chim.Acta., 1986, 69, 1734. 343. 344.
s.,
_ I
s.
3: CarboxyIic Acids and Derivatives
375. 376. 377. 378. 379. 380. 381. 382. 383. 384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 396. 397. 398. 399. 400. 401. 402. 403. 404. 405. 406. 407. 408.
203
R. Tanikaga, H. Yamashita, and A . Kaji, Synthesis, 1986, 416. N.G. Clem0 and G. Pattenden, J.Chem.Soc., Perkin Trans.1, 1986, 2133. W.D. Wulff, S.R. Gilbertson, and J.P. Springer, J.Am.Chem.Soc., 1986, 108, 520. G. Pattenden, N. Pegg, and A.G. Smith, Tetrahedron Lett., 27, 403; D.R. Gedge, G. Pattenden, and A.G. Smith, J.Chem.Soc, Perkin Trans.1, 1986, 2127. R.E. Ireland and M.D. Varney, J-Org-Chem., 1986, 51, 635; K. Takeda, H. Kato, H. Sasahara, and E . Yoshii, J.Chem.Soc., Chem.Commun., 1986, 1197. K. Takeda, M. Sato, and E. Yoshii, Tetrahedron Lett., 1986, 27, 3903. Y. Ishii, T. Ikariya, M. Saburi, and S. Yoshikawa, Tetrahedrcn Lett., 1986, 27, 365. A.M. Becker, R.W. Irvine, A.S. McCormick, R.A. Russell, and R . N . Warrener, Tetrahedron Lett., 1986, 27, 3431. R.A. Russell, B.A. Pilley, and R.N. Warrener, Synth.Comrnun., 1986, 16, 425. V.P. Baillargeon and J.K. Stille, J.Am.Chem.Soc., 1986, 108, 452. E-i. Negishi and J.M. Tour, Tetrahedron Lett., 1986, 27, 4869. N.C. Barua and R.R. Schmidt, Synthesis, 1986, 1067. N.C. Barua and R.R. Schmidt, Tetrahedron, 1986, 42, 4471. K-Y. KO and E.L. Eliel, J.Org.Chem., 1986, 5353. C.W. Jefford, D. Jaggi, and J. Boukouvalas, Tetrahedron Lett., 1986, 27, 4011. K. Fuji, M. Node, H. Nagasawa, Y. Naniwa, and S. Terada, J.Am. Chem.Soc., 1986, 108, 3855. See also K. Tomioka, K. Yasuda, H. Kawasaki, and K. Koga, Tetrahedron Lett., 1986, 2,3247. T. Takahashi, M. Miyazawa, H. Ueno, and J. Tsuji, Tetrahedron Lett., 1986, 27, 3881. A.S. Demir, R . S . Gross, N.K. Dunlap, A-Bashir-Hashemi, and D.S. Watt, Tetrahedron Lett., 1986, 27, 5567. S . Kobayashi and T. Mukaiyama, Chem.Lett., 1986, 1805. D.B. Gerth and B. Giese, J.Org.Chem., 1986, 51, 3726. S.L. Schreiber, H.V. Meyers, and K.B. Wiberg,J.Am.Chem.Soc., 1986, 108, 8274; S . E . Danmark and J.A. Sternberg, ibid., p.8277. A.P. Kozikowski, T. Konoike, and T.R. Nieduzak, J.Chem.Soc., Chem.Commun., 1986, 1350; A.P. Kozikowski, T.R. Nieduzak, and J.P. Springer, Tetrahedron Lett., 1986, 27, 819. P.G.M. Wuts and M-C. Cheng, _____ J.Org.Chem., 1986, 51, 2844. Y. Tokunaga, H . Nagano, and M. Shiota, J.Chem.Soc., Perkin Trans.1, 1986, 581. K . Suzuki, T. Masuda, Y. Fukazawa, and G. Tsuchihashi, Tetrahedron Lett., 1986, 27, 3661. Y. Yamamoto, H . Suzuki, and M.Moro-oka, Chem-Lett., 1986, 73. A.J. Pearson and H.S. Bansal, Tetrahedron Lett., 1986, 27, 283. R.D. Evans and J.H. Schauble, Synthesis, 1986, 727. M.R. Huckstep, R.J.K. Taylor, and M.P.L. Caton, Tetrahedron Lett., 1986, 27, 5919. L.K.P. Lam, R2.H.F. Hui, and J.B. Jones, J.Org.Chem., 1986, 51, 2047. T . Rosen and C.H. Heathcock, Tetrahedron, 1986, 42, 4909. P.A. Grieco, R . Lis, R . E . Zelle, and J. Finn, J.G.Chem.Soc., 1986, 108, 5908. G.E. Keck and D . F . Kachensky, J.Org.Chem., 1986, 51, 2487. S.J. Hecker and C.H. Heathcock, J.Am.Chem.Soc., 1986, 108, 4586.
204 409. 410. 411. 412. 413. 414. 415. 416. 417. 418. 419. 420. 421. 422. 423. 424. 425. 426. 427. 428. 429. 430. 431. 432. 433. 434. 435. 436. 437. 438. 439. 440. 441. 442. 443.
General and Synthetic Methodr J.D. P r u g h , C . S . R o o n e y , A.A. D e a n a , a n d H.G. R a m j i t , J.Org.Chem., 1986, 648. G.E. S t o k k e r , C . S . R o o n e y , J . M . W i q q i n s , a n d J . H i r s h f i e l d , J.Org.Chem., 1 9 8 6 , 51, 4 9 3 1 . N . I k e d a , K . O m o r i , a n d H . Yamamoto, T e t r a h e d r o n L e t t . , 1 9 8 6 , 27, 1175. W. B a r t m a n n , G . B e c k , E . G r a n z e r , H. J e n d r a l l a , B . v . K e r e k j a r t o , a n d G . Wess, T e t r a h e d r o n L e t t . , 1 9 8 6 , 2 7 , 4 7 0 9 . S . V . F r y e a n d E.L. E l i e l , T e t r a h e d r o n Lett., 1986, 3223. Y . T a m u r a , T . KO, H . Kondo, H . A n n o u r a , M . F u j i , R . T a k e u c h i , a n d H. F u j i o k a , T e t r a h e d r o n L e t t . , 1986, 27, 2117. J . A . Schneider and K. Yoshihara, J.Org.ChG., 1 9 8 6 , 51, 1077. B. O ' C o n n o r a n d G . J u s t , T e t r a h e d r o n L e t t . , 1 9 8 6 , 5201. T . S h o n o , 0. I s h i g e , H . Uyama, a n d S . K a s h i m u r a , J . O r g . C h e m . , 1 9 8 6 , 51, 5 4 6 . J . O t e r a , T . Y a n o , Y . H i m e n o , an? H . N o z a k i , T e t r a h e d r o n L e t t . , 1986, 27, 4501. S . L . S c h r e i b e r , B. H u l i n , a n d W - F . L i e w , T e t r a h e d r o n , 1 9 8 6 , 42, 2945; S . L . S c h r e i b e r a n d B. H u l i n , T e t r a h e d r o n L e t t . , 1 9 8 6 , 4561. R . F r e i r e , J . J . Marrero, M.S. R o d r i g u e z , a n d E . S u a r e z , T e t r a h e d r o n L e t t . , 1 9 8 6 , 27, 3 8 3 . B. M i l e n k o v a n d M . Hesse, H e l v . C h i m . A c t a . , 1986, 69, 1323. H . S t a c h a n d M . Hesse, H e l v . C h i m . A c t a . , 1986, 6 9 , 1 6 1 4 . H . S t a c h a n d M . Hesse, H e l v . C h i m . A c t a . , 1986, 85. R.W. C a r l i n q a n d A.B. H o l m e s , J . C h e m . S o c . , Chem.Commun., 1 9 8 6 , 325. T . Ohnuma, N . H a t a , N . M i y a c h i , T . W a k a m a t s u , a n d Y . B a n , Tetrahedron L e t t . , 1986, 219. T. T a b u c h i , K . Kawamura, J . I n a n a g a , a n d M. Yamaquchi, Tetrahedron L e t t . , 1986, 3889. B.M. T r o s t , J . T . H a n e , a n d P . M e t z , T e t r a h e d r o n L e t t . , 1 9 8 6 , 5695. K . M a t s u m o t o , S. H a s h i m o t o , a n d S . O t a n i , A n q e w . C h e m . I n t . E d . Engl., 1986, 565. R.D. G l e s s , J r . , S y n t h . C o m m u n . , 1 9 8 6 , 1 6 , 6 3 3 . K . H . B e l l , T e t r a h e d r o n L e t t . , 1 9 8 6 , 27,2263. S . Ogata, A. Mochizuki, M. Kakimoto, a n d Y. I m a i , Bull.Chem.Soc. Jpn., 1986, 59, 2171. T K i m a n d S X . K i m , J.Chem.Soc., Chem.Commun., 1 9 8 6 , 7 1 9 . I.S. B l a q b r o u q h , N. E . M a c k e n z i e , C . O r t i z , a n d A . I . S c o t t , T e t r a h e d r o n L e t t . , 1986, 1251. J. Einhorn and J.L. Luche, T e t r a h e d r o n L e t t . , 1986, 27, 501. 0 . P i c c o l o , L . F i l i p p i n i , L . T i n u c c i , E . V a l o t i , andA. C i t t e r i o , Tetrahedron, 1986, 42, 885. S-I. M u r t a h a s h i , T . Naota, a n d E T S a i t o , J . A m . C h e m . S o c . , 1986, 108, 7846. J . M . S h i n a n d Y.H. K i m , T e t r a h e d r o n L e t t . , 1986, 27, 1921. J.L. LaMattina a n d C . J . M u l a r s k i , J.Org.Chem., 1986, 413. F . O z a w a , H . Y a n a g i h a r a , a n d A . Yamamoto, J . O r g . C h e m . , 1986, 415. M . M a j e w s k i , J . R . G r e e n , a n d V. S n i e c k u s , T e t r a h e d r o n L e t t . , 1986, 531. S e e also P . Beak a n d K . D . W i l s o n , J.Org.Chem., 1986, 51, 4627. J . R . G r e e n , M . M a j e w s k i , B.I. A l o , a n d V . S n i e c k u s , T e t r a h e d r o n L e t t . , 1986, 535. A . G . S c h u l t z a n d M . Macielag, J . O r g . C h e m . , 1986, 51, 4983. E.R. Koft a n d M.D. W i l l i a m s , T e t r a h e d r o n L e t t . , 1986, 2227.
z,
27,
27,
27,
69,
27, 27,
27,
25,
27,
2,
27,
27,
27,
2,
205
3: Carboxylic Acidr and Derivatives 444.
M. Yamaguchi, M. Hamada, S. Kawasaki, and T. Minami, Chem.Lett.,
445.
C. Chuit, R.J.P. Corriu, R. Perz, and C. Reye, Tetrahedron,
446. 447.
449. 450.
T. S h o G , S . Kashimura, and H. Nogusa, Chem.Lett., 1 9 8 6 , 4 2 5 . S. Ikegami, T. Hayama, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1 9 8 6 , 2 7 , 3 4 0 3 . M.almes, J.Daunis, R . Jacquier, G . Nkusi, J. Verducci, and P. Viallefont, Tetrahedron Lett., 1 9 8 6 , 27, 4 3 0 3 . J.M. McIntosh and P. Mishra, ______ Can.J.Chem., 1 9 8 6 , 64, 7 2 6 . J.M. McIntosh and R.K. Leavitt, Tetrahedron Lett., 1 9 8 6 , 27,
451.
L. Duhamel, S. Fouquay, and J-C. Plaquevent, Tetrahedron Lett.,
452.
D. Ferzud, J.P. Genet, and R. Kiolle, Tetrahedron Lett., 1 9 8 6 ,
1986, 1085. 1986, 42, 2293.
448.
~
3839.
453. 454. 455. 456.
1 9 8 6 . 2 7 ., 4 9 7 5 .
27, -
23.
J.P. Genet, D. Ferroud,
Lett., 1 9 8 6 ,
27, 4 5 7 3 .
S.
Juge, and J.R. Montes, Tetrahedron
Y . N . Belokon', A.G. Bulychev, M.G. Ryzhov, S . V . Vitt, A.S. Batsanor, Y.T. Struchkov, V.I. Bakhmutov, and V.M. Belikov, J.Chem.Soc., Perkin Trans.1, 1 9 8 6 , 1 8 6 5 . W. Shengde, Z . Changyou, and J. Yaozhong, Synth.Commun., 1 9 8 6 ,
1 6 , 1479. -
M. Joucla, M. El Goumzilil, and B. Fouchet, Tetrahedron Lett., 1 9 8 6 , 27,
1677.
462.
M. J o u z a and M. E l Goumzili, Tetrahedron Lett., 1 9 8 6 , 27, 1 6 8 1 . A. Mkhairi and J. Hamelin, Tetrahedron Lett., 27, 4 4 3 5 . U. Schollkopf, D. Pettig, U. Busse, E. Egert, and M. Dyrbusch, Synthesis, 1 9 8 6 , 7 3 7 . U. Schollkopf, U. Busse, R. Lonsky, and R. Hinrichs, Liebigs Ann.Chem., 1 9 8 6 , 2 1 5 0 . U. Schollkopf, M. Hauptreif, J. Dippel, M. Nieger, and E. Egert, Angew.Chem., Int.Ed.Engl., 1 9 8 6 , 25, 1 9 2 . U . Schollkopf, B. Hupfeld, and R. Gull, Angew.Chem.Int.Ed.Engl.,
463.
R. Fitzi and D. Seebach, Angew.Chem.Int.Ed.Engl.,
457. 458. 459. 460. 461.
1986,
5,7 5 4 .
1986,
25, 3 4 5 ,
766. 464. 465. 466.
T. Weber, R . Aeschimann, T. Maetzke, and D. Seebach, Helv.Chim.Acta., 1 9 8 6 , 6 9 , 1 3 6 5 . W. Oppolzer and R. Moretti, Helv.Chim.Acta., 1 9 8 6 , 69, 1 9 2 3 . C . Gennari, L. Colombo, and G. Bertolini, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 6394.
467.
469.
D.A. Evans, T.C. Britton, R.L. Dorow, and J.F. Dellaria, J.Am.Chem.Soc., p . 6 3 9 5 ; L.A. Trimble and J.C. Vederas, G., p.6397; D.A. Evans and A.E. Weber, ibid., p . 6 7 5 7 . Y. Yamamoto, S . Nishii, K. Maruyama, T. Komatsu, and W. Ito, J.Am.Chem.Soc. , 1 9 8 6 , 108, 7778, T. Hvidt, O.R. Martin, and W.A. Szarek, Tetrahedron Lett., 1 9 8 6 ,
470.
27, 3807. B.H. Lipshutz,
468.
471. 472. 473. 474.
27, 4241. -
B. Huff, and W. Vaccaro, Tetrahedron Lett., 1 9 8 6 ,
T. Mukaiyama, H . Suzuki, and T. Yamada, Chem.Lett., 1 9 8 6 , 9 1 5 . P.J. Sinclair, D . Zhai, J. Riebenspies, and R.M. Williams, J.Am.Chem.Soc., 1 9 8 6 , 108, 1 1 0 3 . F . Effenberger, U . Berkard, and J. Willfahrt, Liebigs Ann.Chem., 1 9 8 6 , 314; F. Effenberger and U. Burkard, ibid., p . 3 3 4 ; U. Berkard, I . Walther and F. Effenberger, G., p.1030. W. Oppolzer, R. Pedrosa, and R. Moretti, Tetrahedron Lett., 1986,
27, 8 3 1 .
206
General and Synthetic Methods
475.
J. Mulzer, A. Angermann, 13. Schubert, and C. Seilz, J.Org.Chem., 1986, 51, 5294. 476. A. D u r G u l t , C. Greck, and J.C. Depezay, Tetrahedron Lett., 1986, 27, 4157. 477. P.K. Subramanian and R.W. Woodward, Synth.Commun., 1986, 16, 337. 478. W.A. Konig, H. Hahn, R. Rathmann, W. Hass, A. Keckeisen, H. Hagenmaier, C. Bormann, W. Dehler, R. Kurth, and H. Zahner, Liebigs Ann.Chem., 1986, 409. 479. Y . Ito, M. Sawamura, and T. Hayashi, J.Am.Chem.Soc., 1986, 108, 6405. 480. N . Kurokawa and Y. Ohfune, J.Am.Chem.Soc., 1986, 108, 6041, 6043. 481. R. Labia and C. Morin, J.Org.Chem., 1986, 51, 249. See also G. Wulff and H. Bohnke, Angew.Chem.Int.Ed.Eng., 1986, S,90. 482. M.G. Bock, R.M. DiPardo, and R.M. Freidinger, J.Org.Chem., 1986, 51, 3718. 483. G. Stoll, J. Frank, H. MUSSO, H. Henke, and W. Herrendorf, Liebiqs Ann.Chem., 1986, 1968; J. Frank, G. Stoll, and H. MUSSO, ibid., p.1990. 484. S. Ram and R . E . Ehrenkaufer, Synthesis, 1986, 133. 485. B.I. Glanzer, K. Faber, and H. Griengle, Tetrahedron Lett., 1986, 27, 4293. 486. S-T. Chen, K-T. Wang, and C-H. Wong, J.Chem.Soc., Chem.Commun., 1986, 1514. See also B.K. Vriesema, W. ten Hoeve, H. Wynberg, R.M. Kellogg, W.H.J. Boesten, E . M . Meyer and H.E. Schoemaker, Tetrahedron Lett., 1986, 27, 2045; R . Chenevert and M . Letourneau, Chem.Lett., 1986, 1151; R. Veoka, Y. Matsumoto, T. Yoshino, N. Watanabe, K. Omura, and Y. Murakami, g . , p.1743; J.W. Keller and B.J. Bamilt.on, Tetrahedron Lett., 1986, 27, 1249. 487. J. d'Angelo and J. Maddaluno, J.Am.Chem.Soc., 1986, 108, 8112. See also J.M. Hawkins and G.C. Fu, J.Org.Chem., 1986751, 2820. 488. N. Yamasaki, M. Murakami, and T. Mukaiyama, Chem-Lett., 1986, 1013. 489. N.Iwasawa and T . Mukaiyama, Chem.Lett., 1986, 637. 490. T. Iimori, Y . Ishida, and M. Shibasaki, Tetrahedron Lett., 1986, 27, 2153. 491. H. Kinoshita, K. Inomata, M. Hayashi, T . Kondoh, and H. Kotake, Chem.Lett., 1986, 1033. 492. J . Riego, A. Costa, and J.M. Saa, Chem-Lett., 1986, 1565. 493. J-N. Denis, A.E. Greene, A.A. Serra, and M-J. Luche, J.Org.Chem., 1986, 51, 46. 494. L.A. Blanchard and T A . Schneider, J.Org.Chem., 1986, E l 1372. 495. H. Stamm and R. Weiss, Synthesis, 1986, 395. 496. P. Renaud and D. Seebach, Synthesis, 1986, 424. See also C. Fuganti, P. Grasselli, P . F . Seneci, S. Servi, and P. Casati, Tetrahedron Lett., 1986, 27, 2061; P. Bey, F. Gerhart, and M. Jung, J.Org.Chem., 1986, 51, 2835; S . S . Patel, H.D. Conlon, and D.R. Walt, ibid., p.2842, 497. M. Khoukhl, M . m t i e r and R . Carrie, Tetrahedron Lett., 1986, 27 , 1 0 3 1 . 498. C. Cativiela, M.D. Diaz deVilleqas, and E. Melendez, Synthesis, 1986, 418. 499. C. Cativiela, M.D. Diaz devillegas, and E. Melendez, Tetrahedron, 1986, 42, 589. 500. T. Seethaler and G. Simchen, Synthesis, 1986, 390. A.L. Castelhano. S . Horne, R. Billedeau, and A. Krantz, 501. Tetrahedron Lett., 1986, 27, 2435. 502. Y.H. Paik and P . Dowd, J.Eg.Chem., 1986, 51, 2910. I_______
207
4: Alcohols, Halogeno-compounds, and Ethers
503. 504. 505. 506. 507. 508. 509. 510. 511. 512. 513. 514. 515. 516. 517. 518. 519. 520. 521. 522. 523. 524. 525. 526. 527.
M.J. Hensel and P.L. Fuchs, Synth.Commun., 1986, 16, 1285. J.W. ApSimon and T.L. Collier, Tetrahedron, 1986, 42, 5157. T. Minami, Y. Okada, R. Nomura, S. Hirota, Y. Nagahara, and K. Fukuyama, Chem.Lett., 1986, 613. U. Nagel, E. Kinzel, J. Andrade, and G. Prescher, Chem.Ber., 1986, 119, 3326; U. Nagel and E . Kinzel, E., p . 1731. H. Brunner and M. Kunz, Chem-Ber., 1986, 119, 2868. J.M. Nuzillard, J.C. Poulin, and H.B. Kagan, Tetrahedron Lett., 1986, 27, 2993. H. Aoyagi, F. Horike, A. Nakaqawa, S. Yokote, N. Park, Y. Hashimoto, T. Kato, and N. Izumiya, Bull.Chem.Soc.Jpn., 1986, 59, 323. P. Kuhl, U. Zacharis, H. Burckhardt, and H-D. Jakubke, Monatsh fur Chimie, 1986, 117, 1195. Z.J. Kaminski and M.T. Leplawy, Synthesis, 1986, 649. J.H. Jones and M.E. Wood, Synth.Commun., 1986, 16, 1515. F. Guibe, 0. Dangles, and G. Balavoine, Tetrahedron Lett., 1986, 27, 2365. M. Sakaitani, N. Kurokawa, and Y. Ohfune, Tetrahedron Lett., 1986, 2 1 , 3753. E. W u n z h , W. Graf, 0. Keller, W. Keller, and G. Wersin. Synthesis, 1986, 958; G. Sennyey, G. Barcelo, and J-P. Senet, Tetrahedron Lett., 1986, 2,5375. L . A . Carpino and A. Tunga, J.Org.Chem., 1986, 51, 1930. G. Barcelo, J-P. Senet, G. Sennyey, J. BensoamTand A. Loffett, Synthesis, 1986, 627. I. Schon and L. Kisfaludy, Synthesis, 1986, 303. S.M. Weinreb, D.M. Demko, T.A. Lessen, and J.P. Demers, Tetrahedron Lett., 1986, 27, 2099. H. Eckert and C. Seidel, Angew.Chem.Int.Ed.Engl., 1986, 25, 159. D.H.R. Barton, J-P Finet, and J. Khamsi, Tetrahedron Lett., 1986, 27, 3615. See also W.H. Pirkle and T.C. Pochapsky, J.Org.Chem., 1986, 51, 102. H.C.J. Ottenheijm and J.D.M. Herscheid, Chem.Rev., 1986, 86, 697. M.V. Lakshmikantham, Y.A. Jackson, R.J. Jones, G.J. O'Malley, K. Ravichandran, and M.P. Cava, Tetrahedron Lett., 1986, 27, 4687. C. Fuganti, P. Grasselli, and P. Casati, Tetrahedron Lett., 1986, 27, 3191. K. B a r x s , M. Lampropoulon, V. Marmaras, D. Papaioannou, Liebigs Ann.Chem., 1986, 1407. M. Ueki, Y. Sano, I. Sori, K. Shinozaki, H. Oyamada, and S. Ikeda, Tetrahedron Lett., 1986, 27, 4181. M. Ruiz-Gayo, F. Albericio, E. Pedroso, and E. Giralt, J.Chem.Soc., Chem.Commun., 1986, 1501. ~~
Alcohols, Halogeno-compounds, and Ethers BY L.M. HARWOOD
Wherever possible, reactions are listed according to the type of compound prepared.
For example, ROH
R C 2 reactions are classified
as halide preparations and not alcohol reactions.
Exceptions are
those reactions which are considered to be protection or deprotection procedures. Within each functional group class, preparations are discussed before reactions and it has been attempted to list the references in any one section in increasing order of reaction selectivity.
Cross referencing to earlier reports
follows the established style. 1 Alcohols ______ Preparation. - By Addition to Alkenes. Triethylborane and phenylborinic acid have been found to catalyse hydroalumination of alkenes, and reaction of the intermediate alane with atmospheric oxygen efficiently furnished alcohols resulting from
&-
Markovnikov hydration. Procedures for the preparation of methylborane and dimethylborane and their use in the synthesis of tertiary alcohols containing a methyl group have been described (Scheme 1) .2 Preparation of 1,3-diols by hydroboration of allylic alcohols with thexylborane has been shown to proceed with high stereoselectivity when the substrates are 1-(1-hydroxyalky1)cyclohexenes.’ Stereocontrol in the hydrosilation of allylic and homoallylic alcohols has been studied jointly by the groups of Tamao and Ito. With certain substrates, notably 3-hydroxycyclohexene and
3-(hydroxymethyl)cyclohexene, high stereoselectivitites were observed for the formation of 1,3-diols (Scheme 2).Moderate success in the asymmetric generation of 1,2-diols by osmylation of alkenes in the presence of chiral amine auxiliaries such as ( 1 ) 5 and ( 2 1 6 has been achieved, enantiomeric excesses in the region of 90% being recorded with certain substrates. Osmium tetroxide catalysed hydroxylation has also been applied to chiral allylic 6-hydroxysulphoxide substrates to obtain vicinal triols with
209
4: Alcohols, Halogeno-compounds, and Ethers
i -iii _____)
Reagents
I,
(MeBH2I2 o r ( M e 2 B H ) Z .
- + 11,
C E O . I I I , H ~ O ~-QH ,
Scheme 1
I-
c;.
iii
-1OO:l d iastereomer ratio i n each c a s e
i -iii
Reagents
I , ( H M ~ ~ S I ) ~ N 1H 1 , , H2PtC16,
111,
MeOH, THF,
Scheme 2
,NMe2
OC,,,
aq. N a H C 0 3 , 6 0 ° C
General and Synthetic Methods
210
?I P --
0I
OH I
OH
OH
I
&R
____)
major
1
OH Reagent:
i, OsOL(cot
+
1, Me3N-O-(2
e q u i v ) , oq THF, r.t
Scheme 3
Reagent:
I,
302,Ph3P, hv, T i ( O P r ' I 4 cat., C H Z C I Z , 0 'C
Scheme 4
2 KBPh3H THF, -78
*c
KBPh3H
*
~
THF, - 7 8 ° C
A
6 '1.
&6 98.5
Scheme 5
94 '1.
:
1.5
4: Alcohols. Halogeno-compounds, and Ethers
diastereoselectivities of 7 0
21 1
-
95% in favour of the material
.'
possessing a C-l/C-2 erythro relationship (Scheme 3) Studies by Vedejs have indicated that hyperconjugative 6 - l r interactions of allylic substituents with the double bond may not be as important as previously suggested in directing the stereochemistry of osmylation of alkenes.8 A one-pot procedure for the synthesis of B,y-epoxyalcohols via photo-oxygenation of alkesles in the presence of a titanium(1V) catalyst has been described (Scheme 4 )
.'
By Reduction of Carbonyl Compounds. Use of high (10 kbar) pressures has been shown to effect trialkylstannane reductions of ketones in the absence of radical initiators or Lewis acids." Zinc borohydride has been demonstrated to be a mild reducing agent for the conversion of benzenethiol esters into alcohols in good yield.'' Use of mixed solvents containing methanol has been found to confer some chemoselectivity upon reductions with lithium borohydride and permits enhanced rates of reduction of esters, lactones, and epoxides in the presence of carboxylic acids, amides, chlorides, and nitro-compounds. l2 In addition, use of lithium borohydride in methanol-tetrahydrofuran or methanol-diglyme is claimed to permit reduction of primary and tertiary amides in the presence of secondary amides. The chemo- and stereo-selective reduction of carbonyl compounds may be carried out using the highly hindered reagent potassium triphenylborohydride in THF at low temperatures. l 3 Methyl ketones are selectively reduced in the presence of higher alkyl ketones and a-substituted cyclic ketones are converted into the reduction products with high stereocontrol (Scheme 5). Regioselective 1,2-reduction of a,B-unsaturated ketones has been achieved by hydroiridium phosphine catalysed hydr~genationl~ or by using lithium aluminium hydride in the presence of lanthanoid salts,15 and the selective reduction of cyclic enones has been shown to occur with a combination of sodium borohydride and B-cyclodextrin. !-protected y-amino-a,$-unsaturated esters derived from naturally occurring amino acids may be reduced selectively to the allylic alcohols using di-isobutylaluminium hydride-BFj etherate at low temperatures without racemization of the chiral centre." The suggestion that chemoselective coversion of B-keto-esters into $-keto-alcohols might be feasible via reduction of the enolates has now been demonstrated by Japanese workers. After initial treatment of the B-keto-ester with potassium hydride or lithium di-isopropylamide at 0 OC, the
General and Synthetic Methorls
212
Reagent :
I,
Me4NHB(OAc)3, CH3CN, AcOH, or P r I 2 S i H C l
anti -selective
s y n - s e l e c t i v e . B I J I ~ A I HTHF, , - 7 8 "C Scheme 6
X
-
Y '
OH
X
I
B
0
n
O
~
C
OH X
> 99
= SiMef
X = H
1
8
OH
H
1
7~
v ~
OH
o
OH
(1
99
Reagent . L i B E t 3 H , THF, - 7 8 'C
Scheme 7
&k H
K+
(3)
m
4: Alcohols, Halogeno-compounds, and Ethers
213
intermediate enolate can be reduced with aluminium hydride. Several research groups have published work on the diastereoselective reduction of aldols to 1,3-diols. Formation of the anti-lI3-diols has been demonstrated using trimethylammonium triacetoxyborohydride” (cf.8, 205) or di-isopropylchlorosilane20 with 20 : 1
z.
diastereoselection, and the alternative reduction products may be obtained in better than 12 : 1 diastereoselectivity using an excess of di-isobutylaluminium hydride at -78 ‘C2’ (Scheme 6). Aldols possessing a 2-(l-trimethylsilyl)vinyl substituent give high yields of the corresponding 1,2-= reduction product with lithium triethylborohydride regardless of the substitution pattern at C-3. 22 The same workers have demonstrated that removal of the silyl group from the C - 2 vinylic substituent cleanly inverts the stereochemistry of the reduction, and have applied this procedure to the synthesis of avenaciolide and its epimer (Scheme 7) .23 Reports of chiral reducing agents continued to appear at an undiminished rate during 1986 and extremely high enantiomeric excesses can now be expected with many of these reagents. Amongst the borane-derived reagents are di-isopinocamphenylborane, which reduces a-tertiary alkyl ketones with e.e ! s consistently greater than (cf.2, 115; 2, 156; 9 , 236) and chiral borohydrides (3) derived from reaction of 9-BBN with chiral alcohols25 or sugar derivatives followed by treatment with potassium hydride. 26 Both optical antipodes of 2,5-dimethylborolane ( 4 ) have been found by Masamune and co-workers to result in high, complementary, enantioselective reduction of dialkyl ketones, u,sually with e.e.’s in the region of 99%, and the mechanism of this reaction has been the subject of study by this group.27 Asymmetric reductions have been attempted with 6-branched alkyl derivatives of beryllium and aluminium but the enantioselectivity of these reagents is disappointing, usually being in the range 25 - 35%.28 Reports on the use of hydride reagents modified with chiral amino-alcohols have been noticeably fewer than in previous years which probably reflects the generally low efficiency of such systems, (cf.8, 208). Indeed, in an example which appeared during 1986, in which (arylmethylamino)butanols were used in conjunction with lithium aluminium hydride, the optical yields were in the range 1 Likewise, lithium aluminium hydride in the presence of quinine forms alcohols from aryl ketones in only about 50% optical yield.30 A rhodium catalyst containing a chiral sulphoxide ligand derived from methionine has been found to promote enantioselective transfer
214
General and Synthetic Methods
sYn
anti
:
2.8 4 1 8 . 3 Scheme 8
OH Tf Reagent :
I,
= CF,SO,-
R2C HO, CrC12(4equiv.), NiCl2(c at.), DMF
Scheme 9
RZ
Lx
I
X = CI, Br or 1 Reagent : i , R’CHO, BiC13-Zn or BiC13-Fe, THF, r . t .
Scheme 10
RCHO I
* I
P
h
Ph
v CL
> R e a g e n t : i, S n C I 2 - A I , aq. THF, 45-5O ’C
Scheme 11
90% t h r e o
1 .O
215
4: Alcohols, Halogeno-compounds, and Ethers
31 hydrogenation of ketones with optical yields of up to 75%. Interest in microbial transformations of ketones continues to flourish and a wide range of substrates may now be reduced with impressive optical yields and frequently high chemical yields (cf.8,210; 2 239). Baker's yeast appears to be the most popular choice for ketone reduction and substrates reduced with this system include simple ketones,3 2 1 ,3-diketonesI3 3 protected derivatives of a-keto-aldehydes,34 and a - 3 5 and f3-keto-este1-s.~~ In the case of acyclic methyl a-keto-esters it has been demonstrated that carrying out the reduction in a medium containing methanol furnishes largely the D-hydroxy-ester reduction products, whereas in the absence of methanol,L-hydroxy-esters are obtained. 37 Various strains of yeast and moulds have been assessed for their efficiency in the reduction of a-a1ky 1-0-keto-esters 38 Reduction of 2-3-chloroa1ken-3-ones
.
with Baker's yeast has been developed to produce either the saturated ketones or the totally reduced alcohols (Scheme 8 ) .39 The e.els in the initial lI4-reduction step vary from 44 to 84%, giving the (S)-configuration at the asymmetric centre, whilst the reduction of the carbonyl group occurs with very high optical yield to give a anti-products in which the syn-(2SI3S)-isomer mixture of syn- and predominates.
Some work has been reported using cell-free systems to
carry out the asymmetric reductions and these systems appear to be equal or superior to the microbial reductions. Alcohol dehydrogenase derived from the thermophilic bacterium Thermoanaerobium brockii, immobilized upon a solid support, reduces ketones with optical yields usually in excess of 97% and these conversions compare favourably with whole-cell fermentations.4 0 Glycerol dehydrogenase has also been used in the conversion of a-hydroxy-ketones into 1,2-diols in chemical and optical yields & fermentation with Baker's which are similar to those obtained y yeast.41 By Nucleophilic Alkylation. In situ generation of chromium(I1) by reduction of chromium(II1) chloride with either zinc dust or sodium amalgam in THF has led to an improved procedure for the generation of homoallylic alcohols from aldehydes and ally1 halides. 42 An excess of chromium(I1) chloride and catalytic quantity of nickel(I1) chloride have been shown to form a system capable of mediating the formation of allylic alcohols from enol
.
trif lates and aldehydes in moderately good yields (Scheme 9) 43 Similarly, the Cr(I1)-mediated coupling of vinyl iodides with
216
General and Synthetic Methods
aldehydes to form allylic alcohols in which the original geometry of the vinylic component is retained has been found to benefit from the presence of Ni(I1) or Pd(II), and this has proven particularly useful in highly oxygenated substrates such as sugar derivatives.44 Lead mediates the coupling of ally1 bromide with ketones in the presence of a quaternary ammonium salt and chlorotrimethylsilane,45 and the chemoselective allylation of aldehydes with allylic halides using metallic zinc or iron in conjunction with boron trichloride has been described.46 In this latter procedure, the allylic alcohols produced result from three-carbon inversion of the allylic unit and the reaction is highly chemoselective, leaving nitriles, esters, and even carboxylic acid groups untouched (Scheme 10). In an electrochemical procedure using a tin cathode and a carbon anode, 8- and y-aryl ketones have been converted into didehydrodecalinols by a process which results in both cyclization and reduction of the substrate. 47 In another electrochemical procedure, it has been demonstrated for the first time that aldehydes may be carboxylated to form a-hydroxy-acids using a sacrificial aluminium anode in a diaphragmless cell.48 Di-isopropyl tartrate modified E-crotylboronates have been shown to act as highly enantioselective propionate E-enolate equivalents furnishing mainly threo-Cram adducts on reaction with a-chiral aldehydes in the molecular seives. 49 a-Heteroatom substituted presence of 4 allylboronates undergo a similar addition to aldehydes to furnish homoallylic alcohols in which the major geometric isomers, formed in good yield and with about 90% stereoselectivity, possess the Z-conf iguration. 50 A study of factors influencing the stereochemistry of reaction of substituted allylboronates with chiral aldehydes has been published. 5 1 Allyl- and crotyl-di-isopinocamphenylboranes have been used in the chiral synthesis of
x
homoallylic alcohols in high enantiomeric excess52 (cf. 3 , 144; 2, 164; 5 169; 2, 2451, and the practical application of chiral allenylboronate esters for the enantioselective preparation of homopropargylic alcohols has been demonstrated by the use of these reagents in a synthesis of ( - ) -ipsenol 53 The reductive generation of Sn(0) by the action of aluminium metal on tin(I1) chloride has permitted the highly diastereoselective reaction of cinnamyl chloride with various aldehydes under neutral conditions to furnish good yields of
.
.
threo-adducts (Scheme 1 1 ) 54
Samarium iodide in the presence of
Pd(0) results in the efficient reductive coupling of a ~ r y l a t e sor ~~
4: Alcohols, Halogeno-compounds, and Ethers
217
X X = Br o r I Reagents.
I,
CH212, S m I Z , THF, r t . , 3 m i n ,
11,
CHzIP Sm m e t o l p o w d e r , THF, 0 ‘C
Scheme 12
OH
0
OH
H
H
Fe I k i n -An h .
Chelat ion
R = ButMeZSi
>99
<1
R =Bz
>99
R e a g e n t s : i, M e T i ( O P r l ) 3 , n e o t . r t 4 8 h ; ii. H 0’
3
Scheme 13
SO2 R
218
General and Synthetic Methods
HN
ca. 9
Reagents
Ar =
1
I , ArS02NHNH2, MVK solvent,
short reaction times,
Me OC H 2 C H20M e, - 7 8 - O o C ,
111,
11,
M eLi - L i B r ,
RCHO, - 7 8 'C
Scheme 14
R' = p e r f l u o r i n a t e d a l k y l c h a i n Reagent
'
I,
R'CHO,
B u 4 N t F - ( 0 25 e q u i v ) ,
( M e 3 S ~ ) 2 0 ( 0 . 2 5e q u i v ) , THF, r t
Scheme 15
R'
R' = Me or MeOCH2, n
R'
= 1 or 2
>95 Scheme 16
:
5 (R'=MeOCH2)
219
4: Alcohols, Halogeno-compounds, and Ethers
allylic acetatess6 with carbonyl compounds, and the application of SmI2 -induced room-temperature iodomethylation of carbonyl compounds to furnish iodohydrins in high yield has also been explored.57 Another group of Japanese workers has investigated a similar samarium-based procedure for iodohydrin formation and the elaboration of a-halogeno-ketones into cyclopropanols (Scheme 12) Organomanganese halides are reported to undergo synthetically useful chemoselective reaction with aldehydes in the presence of ketones,59 and also to furnish tertiary alcohols 2 sequential reaction with acid chlorides followed by standard conversion of the ketonic products.6o An electrosynthetic procedure for the addition of alkyl halides to carbonyl compounds utilizes a sacrificial anode composed of aluminium, manganese, zinc, or iron.61 A reagent prepared from methyl-lithium and titanium(1V) chloride acts as a non-basic Grignard analogue which reacts chemoselectively with ketones in the presence of nitriles, esters, and nitro-compounds. 62 This reagent shows similar stereoselectivity to tris(iso-propoxy)methyltitanium but reacts more readily than this reagent, being particularly useful for enolizahle ketones. It has been shown that the reduced Lewis acidity of tris(isopropoxy)titanium alkyls results in these reagents adding to a-t-butyldimethylsilyloxy-ketones to furnish products resulting from Felkin-Anh type addition. 63
Interestingly, these
reagents undergo complementary chelation-controlled addition to the analogous a-benzyloxy-ketones (Scheme 13) (cf 9, 241). Methyltitanium reagents (5) which have been chirally modified with N-sulphonylated derivatives of norephedrine have proven useful in the preparation of chiral alcohols from aromatic aldehyde^.^^ A full paper describing the procedure for generating 2-lithiobutadiene via - a Shapiro type pathway and the addition of this reagent to aldehydes giving diene alcohols has been published (Scheme 14) ' 6 5 a-Hydroxyalkylacrylonitrile derivatives have been prepared in good yields by condensation of acrylonitrile with aldehydes in the
presence of DABCO which catalyses the reactions by undergoing initial reversible Michael addition to the unsaturated nitirile. 6 6 In the presence of catalytic quantities of hexamethyldisiloxane and tetrabutylammonium fluoride, perfluoroalkynylation of aldehydes to the corresponding propargylic alcohols is possible in high yield using 1H-1F-alkenephosphonates - as an in situ source of nucleophilic species (Scheme 15) .67 Cyclopentanol and cyclohexanol derivatives of sugars have been
General and Synthetic Methods
220
x, uo 0
CO, H
Reagents
I, 111,
VII,
--&
R'CHO, pyH+Ts-,
II
0
or
&COzH
C6H6, r e f l u x ,
R2Li, CuBr.Me2S, EtzO,
IV,
11,
v or VI,VII
Me3SiR2, CH2CIZ, T 1 C l 3 X , - 7 5 * C ,
HZO, v, L D A , THF, - 3 0 ' C + r t ,
K O B U ~ ,T H F , r t
Scheme 17
major
R e a g e n t s : i, B U ' ~ A I H ;ii, KZC03, PCC
S c h e m a 18
OH
VI,
CHZNZ;
22 1
4: Alcohols, Halogeno-compounds, and Ethers
ca. 5+10
OH
?"
+
R H +
erythro
2-26 R e a g e n t s : i, L D A , THF, HMPA,-78"C; ii, R h C H O ;
Scheme 19
OH -?, threo
1
iii, ( M e 0 ) 3 P or Et2NH, MeOH
222
prepared in good isolated yields
General and Synthetic Methods
via
a procedure involving intra-
molecular radical cyclization onto an aldehyde. The radical species were generated by the action of tributylstannane and a catalytic quantity of AIBN on a primary iodide. 68 Diastereoselective additions of Grignard reagents to chiral a-keto-acetals have been shown to occur when the dioxolane moiety was substituted with methoxymethyl substituents although the results were disappointing with the simpler dimethyl derivatives (Scheme 16)69 (cf. 2, 247) . Two research groups have described similar approaches towards the preparation of optically active secondary alcohols nucleophilic attack on chiral lr3-dioxan-4-ones with silane-Ti (IV) or o r g a n o ~ u p r a t e s ,followed ~~ by base cleavage (Scheme 17) . Optically pure propargylic alcohols have been obtained by reductive cleavages of a,B-alkynyl acetals with organoaluminium reagents followed by oxidative removal of the chiral auxiliary (Scheme 18) ,72 and the same research group has achieved direct, highly efficient reductive cleavages of chiral acetals using Lewis acid-hydride systems such as TiC14-triethylsilane.73 Enantioselective allylations of aldehydes have been reported by two groups using tin(I1)-mediated processes in the presence of chiral auxiliaries. Use of tin(I1) triflate in the presence of the chiral diamine (6)leads to homoallylic alcohols with optical yields in the region of 80% when allyldialkylaluminium reagents are used.74 The chiral
--
tin reagent derived from (+)-diethy1 tartrate ( 7 ) has also been used with optical yields varying from 25 to 6 2 % . ” Highly enantioselective addition of dialkylzincs to aldehydes has been demonstrated to occur in the presence of (-)-3-=-(dimethylamino) isoborneol(8) with e.e!s of the product alcohols in the range 90 99%.76 The Cram selective addition of anions derived from ally1 sulphoxides followed by quenching of the L2.31 sigmatropic rearrangement products from the adducts has ben developed into a useful means of synthesizing E-lr4-dihydroxyalkenes with erythroproducts predominating (Scheme 19) .77 In a reqiocontrolled approach towards homopropargylic alcohols, trimethylsilylallenes have been added to carbonyl compounds in the presence of titanium (IV) chloride.78 The rate of publication of investigations into systems for carrying out diastereo- and enantio-selective aldol condensations has continued unabated during the year (cf.2,241). Chiral boron enolates continue to invoke much interest: the dimethylborolane enolates of thioesters form adducts in which the ___ anti-aldols
223
4: Alcohols, Halogeno-compounds, and Ethers
K-0' .-i-i/-o ""I('0 I-IV
OSiButMe2
O S i Bu'Me;,
,
OH
0
OH
99 R e a g e n t s . i , L D A , THF, - 7 8 ill,
'C,
RCHO, -78+L0°C.
11,
1
C l T i (O P r' )g, - 7 8
'C
-30 'C.
-+
IV,NH&F
S c h e m e 20
RYHo
>99
1
*Yn
unti
OBz
I I I
I
$. R =n-pentyl
0
R
0Me OH
( - 1 - pestalotin Scheme 2 1
Si Mej
"+"O
R3
RZ (1 1)
( 1 2 ) s y n or
anti
224
General and Synthetic Methods
P h M e Si
OLi
A
R’-OHc
.C02Me
Reagents
I, ( P h M e 2 S i ) C U L I .
2
11,
NH4CI,
111,
LDA, THF, -78’C.
IV,
RCHO, - 7 8 ’ C
Scheme 22
OH C02SiMe3
i, ii
&COzH
+
R2
R2
I
SiMc3 erythro Reagents, i, R‘CHO,
-4
: 1
thrco
-9 : 1
anti
Bu”&N+F- or C s F ; i i ; H 3 0 +
Scheme 23
R’
\.=.c=o
-
u ’ ~ o SRZ snsR2 syn
R e o g e n l s : i, S n ( S R 2 ) 2 , THF, -78’C. ii, R3R4C0
S c h e m e 26
225
4: Alcohols, Halogeno-compoundr, and Ethers
dominate in ratios typically >80 : 1 , 7 9 whereas di-isopinocamphenylboron enolates of ketones favour syn-adducts in ratios of 10 - 30 : 1.80 The aldol addition reactions of boron enolates derived from the chiral carboximides (9a) have been investigated, 81 and workers in the same research group have used tin(I1) enolates of related precursors (9b) in the successful synthesis of the unusual C9 amino-acid 'MeBmt' found in cyclosporine.82 A variable-temperature n.m.r. study into the titanium-mediated chelation-controlled aldol condensation with 6-benzyloxy-aldehydes has provided evidence for the formation of a conformationally rigid 1 : 1 complex of the substrate with TiC14 (10) in which the bulky a-substituent of the aldehyde is in a pseudoequatorial position.83 In the titanium-mediated aldol condensation of chiral a-silyloxy-esters, diastereofacial selectivity of 99 : 1 is observed in the formation of the erythro-adducts (Scheme 20) .84 Ratios of anti : syn adducts of up to 26 : 1 have been reported in the condensation of thioester silyl ketene acetals with aldehydes under boron trif luoride etherate ~atalysis,~'and similar anti selectivity has been observed in the TiC14-PPh mediated enantio3 selective condensation of N-methylephedrine ester silyl ketene acetals with aromatic or a,8-unsaturated aldehydes.86 In the latter examples, enantiomeric excesses of up to 9 4 % were reported, but : omission of the triphenylphosphine markedly reduced the selectivity. The chelation controlled, syn-diastereoselective TiC14mediated aldol condensation of the bis-t-butyldimethylsilyl enol ether of ethyl acetoacetate with a-benzyloxy-aldehydes has been used as the key step in an enantioselective synthesis of ( - 1 -pestalotin (Scheme 21) .87 The continued effort of Heathcock and co-workers into studies of factors affecting disastereoselection in the Lewis acid mediated reactions of enol silane derivatives has resulted during 1986 in the appearance of this group's 36th publication on this subject88 (cf. 2, 241). Complementary disastereoselectivity has been found for B-silyl-enolates depending upon whether the enolates are generated directly from the 6-silyl-ester derivatives or by 1,4-addition of lithium bis(phenyldimethylsily1)cuprate to a, 6-unsaturated esters (Scheme 2 2 ) 89 Fluoride-mediated crossed aldol condensations of a-silylated trimethylsilyl esters with aldehydes have been shown to lead selectively to erythro-adducts (Scheme 23) The stereoselective addition of Grignard reagents
.
to chiral a-substituted 6-silylated unsaturated aldehydes ( 1 1 ) has
General and Synthetic Methodr
226
Scheme 25
0PhA' 0
R2
BuLi
-70
A r xR
'C
R2
Ar
R3
Scheme 26
X
(13) a ; X = L i
b;X=H
Reagents.
, THF,
i,
-9O'C;
LI iv, NaBH4, MeOH
Scheme 27
ii, BunLi; iii, c y c l o h e x e n e , r e f l u x ;
4: Alcohols, Halogeno-compounds,and Ethers
227
been used in the disastereo- and enantio-selective synthesis of aldols and O-alkylhomoallylic alcohols (12). Tin thioester enolates have been prepared from ketenes and shown to react with ketones to yield --adducts as the major products (Scheme 24) . 9 2 The rate of nucleophilic ring opening of epoxides with unreactive organocuprates has been demonstrated to be vastly enhanced by the addition of boron trifluoride etherate to the reaction mixture. Under such conditions, dimesitylcyanocuprate reacts with cyclohexene oxide. 93 Organocuprate opening of chiral glycidic esters derived
via a Sharpless epoxidation pathway has been utilized in the enantio- and diastereo-specific synthesis of anti-a-alkylO-hydroxy-esters in good yield (Scheme 25) .9 4 x g a n o - y t t r i u m and organo-lanthanoid reagents open up terminal epoxides regioselectively to furnish the primary alcohols. In addition, SN2' 95 opening of vinyl epoxides is suppressed with these reagents. Epoxide ring opening with tin(I1) halides in the presence of water has also been reported as a convenient means of forming halohydrins,9 6 and the action of excess n-butyl-lithium on a,O-epoxysulphoxides has been found to furnish allylic alcohols (Scheme 26) . 9 7 Miscellaneous Methods. Bis(trimethylsily1) peroxide has been used as a hydroxyl cation equivalent in its reactions with alkyl lithium reagents followed by hydrolysis of the resultant trimethysilyl ethers.98 Certain lithiated species, such as 2-lithio-furans and thiophenes do not furnish hydroxylation products by this procedure, however, forming the 2-trimethylsilylated materials instead. The 4-lithiated species (13b) generated from 2,2-dimethyl-1,3-oxathiane 3,3-dioxide (13a) has been developed as a y-hydroxypropyl anion equivalent for the preparation of y-hydroxy-ketones via an addition-oxidation sequence with aldehydes.9 9 A one-pot procedure for converting primary halides into alcohols and dichlorides into diols has been described which utilizes a high-yielding phase-transfer catalysed conversion into the corresponding formate ester followed by hydrolysis. l o o Oxidative cleavage of carbon-silicon bonds with trimethylamine N-oxide in the presence of KHF2 has provided a novel means of access to primary alcohols from the corresponding alkyldiethoxymethylsilanes which may themselves be generated by hydrosilation of terminal alkenes. Alcohols have been obtained in a procedure which results in overall reductive homologation of esters alkynolate anion derivatives (Scheme
General and Synthetic Methodr
228
Scheme 28
L R e a g e n t s : i, Bun4N+Br-,
ZnCI,
BF3.Et20, C H C 1 3 ; ii, M e C O B r , ZnCI,,
O’C; iii, H 3 0 t
Scheme 29
OH COR~
CO, R3 H ( 1 4 ) a ; R’
R = Me, R 2 = M e , R3
OPr’ ,-OMOM
b; R’ = Me, R 2 = H , R 3 = N
(15)
229
4: Alcohols. Halogeno-compounds, and Ethers
27) .Io2
Tin(I1) halide opening of epoxides has been used as a
means of accessing halohydrins. Treatment of 2-substituted chloromethyloxiranes with telluride ion has been used in the preparation of 2-substituted ally1 alcohols via a mechanism which is postulated to involve the intermediacy of an epi-telluride species. Selective reductive cleavage of y , 6-epoxy-a,Bunsaturated esters to the corresponding u-hydroxy-a,B-unsaturated systems has been demonstrated in a limited number of examples using ammonium formate in the presence of a palladium catalyst.'" Regioand chemo-selective reduction of a,@-epoxy-ketones to the corresponding aldols has been achieved using samarium iodide and, as the starting materials can be obtained via a Sharpless epoxidation route, this provides a means of access to chiral aldols. The titanium-mediated regioselective reductive opening of 2,3-epoxyalcohols with lithium borohydride provides a useful means of obtaining the 1,2-diols with good selectivity over the alternative 1 ,3-diol products.lo7 Epoxides may be isomerized to allylic alcohols using 3
-
4 equivalents of methylmagnesium This reagent is obtained as a white precipitate on adding methylmagnesium bromide to lithium cyclohexylisopropylamide at 0 " C . A procedure has been described for the preparation of L3-hydroxyalkyl ketones via rearrangements of a,B-epoxyalkyl silyl ethers with titanium tetrachloride. This procedure has found particular use in conversions resulting in ring expansion to yield B- (hydroxymethyl) cyclic ketones (Scheme 28) l o g Regioselective cleavage of 2-substituted tetrahydrofurans to furnish either 4-halogens-alcohol isomers has been accomplished using a mixture of
N-cyclohexylisopropylamide as the base.
.
BF3.Et20 and a tetrabutylammonium halide to form the secondary alcohol or ZnC12-acetyl bromide to form the primary alcohol (Scheme A high-yielding regioselective alkylative cleavage 29) procedure for 2-substituted tetrahydrofurans has been described which utilizes TiC14-catalysed allylation or propynylation with the respective silanes. Alkylation occurs at the most substituted a-position of the tetrahydrofuran to furnish 4-substituted
.
hept-6-enols and hept-5-ynols. 111 Nickel-catalysed coup1 ing of Grignard reagents with 5-alkyl-2,3-dihydrofurans has been found to furnish homoallylic alcohols with a fair degree of stereoselectivity Asymmetric about the trisubstituted double bond of the product. [2,31 Wittig rearrangements have continued to attract interest (cf. 8, 222; 9 , 249). Alkenyloxyacetic acid derivatives in which the
General and Synrheric Methods
230
1-111
J.
I
TR
YR X o>--.F%
C
56-
\\
IV,
II,
L
p
84 ‘1. e.e.
82
It.
Ill
-
HO‘
e
C02Me
96 *la e.e.
(16)
Reagents
I,
K H ( 2 equiv) , THF, r t ,
11,
H,O+,
111,
CH N , 2 2
IV,
KH, 1 8 - c r o w n - 6 , THE-ZO’C
Scheme 30
Reagents
I,
Hg(O2CCF3I2, C H Z C I Z , r t ,
11,
sot
S c h e m e 31
aq
NaCI,
III,
L I A I H ~ ,T H F
4: Alcohols, Halogeno-compounds, and Ethers
231
chiral moiety is in the alkenyl component (14al1l3 or as an amide derivative (14b) have both been found to give rise to rearrangement products (15) in extremely high optical yields. Others have demonstrated the dramatic influence of the presence of 18-crown-6 on the rearrangement of the potassium azaenolate of the chiral precursor (16) which gives rise to complementary product chirality dependent upon the presence or absence of the crown ether (Scheme 30)
Enantioselective [2,3]-rearrangement of chiral
E-a,@-unsaturated esters possessing a chiral sulphoxide substituent
at the a-position has been developed for the enantioselective synthesis of 5-Y-hydroxy-a,@-unsaturated esters. '16 The asymmetric cyclization of 7,7-dimethyl-6-7-unsaturated aldehydes to chiral isopropylidenylcyclohexanols via a catalysed ene reaction has been achieved using chiral Lewis acids such as (17).l17 'Magnesium-graphite' (prepared from C8K and MgC12) has been used to effect reductive, pinacol type coupling of ketones to furnish 1,2-diols eff iciently.ll8 An oxymercuration procedure resulting in the reductive cleavage of cyclopropyl carbinols has been developed €or the preparation of 1,3-diols possessing a 2-methyl substituent in which a high degree of control over the three stereocentres is possible (Scheme 31) . Protection and Deprotection.A convenient procedure for preparing t-butyl chloromethyl ether, used for protecting alcohols as their BUM ethers, has appeared in the literature (Scheme 32) .120 Trimethylsilyl azide is a reactive silylating agent for primary and secondary alcohols 12' and, in the protection of hindered alcohols, t-butyldimethylsilyl chloride in the presence of potassium hydride-18-crown-6 has been shown to succeed where the triflate-triethylamine system fails.122 An alternative means of introducing the t-butyldimethylsilyl protecting group utilizes the diethylboryl ether, obtained from the alcohol by treatment with triethylborane, which undergoes trans-silylation with the silyl enol ether of pentane-2,4-dione in the presence of a catalytic quantity of trimethylsilyl triflate. The deprotection can be carried out by treating the silyl ether with bis(diethylbory1) ether in the presence of trimethylsilyl triflate. 123 Monosilylation of symmetrical diols is conveniently carried out by treatment with sodium hydride in THF followed by addition of t-butyldimethylsilyl chloride.
In some cases it is advisable to heat the alcohol-sodium
hydride mixture before adding the chloride.124
232
General and Synthetic Methods
Reagents.
i, AcZO, B u t O H , ii, S 0 2 C l z
Scheme 32
cw
CHO
@OR
OH
CHO
OR
OMe (19) a; R = Me
(18)
b; R = H
Reagents
I, 111,
CH2=CHCHz0COCI,
b a s e ; ii, [ R u H 2 ( P P h
)
31,
I cat.,
C H 2 C H C H z C O C O M e , [ R u H 2 ( P P h 3 ) & ] , CgH6, r e f l u x
Scheme 33
C6H6, r e f l u x ;
4: Alcohols, Halogeno-compounds, and Ethers
233
K-10 montmorillonite, an acidic clay, has been found useful for
the conversion of alcohols and phenols into their tetrahydropyranyl ethers,125 and zeolites have been used in the benzylation of decanol in refluxing hexane. 12' Methylation of alcohols and phenols with dimethyl sulphate has been shown to be carried out efficiently in the presence of alumina, and this system has particular use in the selective monomethylation of diols. 12' The protection of phenols as their t-butyl ethers has been described using isobutene and triflic acid catalyst at -78 OC, under which conditions Friedel-Crafts alkylation of the aromatic nucleus does not occur.128 Rapid and selective detritylation of primary alcohols has been achieved with formic acid in various solvents (ether, acetonitrile, ethyl acetate) and the conditions are mild enough to ensure the survival of t-butyldimethylsilyl and isopropylidene protecting groups. 129 A comparative study has appeared into the selectivity of oxidative and reductive deprotection of benzyl, 4-methoxybenzyl, and 3,4-dimethoxybenzyl ethers130 (2. 9 , 252) . The mild hydrolytic conditions necessary for the conversion of alkoxymethyl aryl ethers into phenols (P214, CH2C12, 0 "C) has been used to advantage in the synthesis of ascofuranone (18)13' and the selective deprotection of
2,3,4-trimethoxyarylcarbonyl substrates such as (19a) to the 2,3-dimethylated products (19b) has been achieved using two equivalents of boron trichloride in dichloromethane at room temperature. 132 Conversely, selective removal of benzyl groups to furnish phenols in which the liberated hydroxy-group is capable of hydrogen bonding to a carbonyl group has been demonstrated with magnesium bromide in refluxing 7: 1 benzene:ether. 1 3 3 Methyl and benzyl ethers may be cleaved to the corresponding acetates using trimethylsilyl chloride in acetic anhydride in the presence of a catalytic amount of concentrated sulphuric acid and this procedure might prove a useful alternative to the more usual BF3-Ac20 system. 134 Chemoselective reductive deprotection of benzyl ethers is possible using metallic calcium in liquid ammonia which is a much more discriminating system than lithium in liquid ammonia. 135 Of particular note is that the deprotection of acetylenic benzyl ethers is possible under these conditions without reduction of the triple bond. The selective cleavage of trimethylsilyl ethers in substrates possessing a C-silylated terminal acetylene, without unmasking the acetylene, is possible in fair isolated yields using the sulphonic acid exchange resin Rexyn 101 in ether at room temperature.136
234
General and Synthetic Methods
minor
major
n = l o r 2
S c h e m e 34
P h3P'C H2PP ' h3
(201
OH
Reagents: i,
-
I1
a y > s - s < ' n '
s
72 -
(21)
R2xH R'
Cr 0
, Bu3P,
5
A I B N ( c a t . ) , C6HW r e f l u x
Scheme 3 5
t o l u e n e , r e f l u x ; ii, B u 3 S n H ,
235
4: Alcohols, Halogeno-compounds,and Ethers
Reactions. - Oxidation. Oxidation of primary alcohols with sodium bromate/hydrobromic acid has been shown to furnish acids which undergo in situ esterification with remaining starting material and these reagents provide a useful means of converting diols into the corresponding lactones. 13' A two-step procedure for oxidizing alcohols & y (Scheme 33)
the corresponding ally1 carbonates has been reported The key step in the conversion, which may be carried
out as a one-pot procedure, is the ruthenium-catalysed decomposition of the carbonate. An electro-oxidative procedure utilizes electrochemically regenerated Ru04 to oxidise primary alcohols to carboxylic acids. Molybdenum and tungsten derivatives have been used under phase-transfer conditions to catalyse the oxidation of alcohols with hydrogen peroxide which can A series of be used in diluted form under these conditions.14' papers describing ruthenium hydride complex catalysed dehydrogenation of l14-diols to lactones has appeared.
The
method requires the presence of an excess of benzalacetone as the hydrogen acceptor and selectively furnishes the 2-alkylated lactones with unsymmetrical substrates (Scheme 34). The same research group has applied the use of chiral rhodium hydride complexes to this conversion to obtain 2-alkylated lactones with optical yields of less than 30%. 142 Oppenauer type oxidations have been successfully carried out using samarium(I1) iodide143 and zirconocene complexes144 and, with the latter system, chemoselective oxidation
of primary alcohols in the presence of secondary alcohols is Chromium(V1) oxide supported on montmorillonite clay has been used to oxidize a-nitro-alcohols to ketones146 and, as always, modified chromium(V1) oxidants have continued to attract much attention during the year. These include zinc chromate trihydrate which is stable to prolonged storage and oxidizes primary alcohols to acids,14' complex chromates in both their soluble and polymer-supported [w.(20)1 forms,1 4 * and bisphosphonium dichromates (21), which show some selectivity for oxidizing benzylic and allylic alcohols faster than simple aliphatic substrates. 14' Imidazolinium dichromate has been developed as a selective oxidizing agent for benzylic and allylic alcohols150 and it has been demonstrated that quinolinium dichromate distinguishes effectively between primary and secondary alcohols, oxidizing the former to aldehydes. A modification of the reaction conditions €or carrying out lead(1V) acetate oxidations has permitted the use of this reagent for the preparation of aldehydes from primary alcohols. possible. 145
General and Synthetic Methods
236
0 R ’ ~ o P ( o IIP r l ) *
R’roH Reogents
I,
(Pr’0)2POCI, pyridine, 0°C;
MeOH-CH2CI2,
Na[Fe(C0)2Cpl, THF,
11,
iii,
HBF,,
iv, N o l , o c e t o n e
S c h e m e 36
ROH 0 ( Et
II
0 J2 P N H CO, But
(Et0I2PNCO2But
RkH3CI-
I
Reogents.
I,
DEAD,
Ph3P, C6H6,
0-5°C
30min,
C6H6,
S c h e m e 37
r t
2h.
11,
anhyd
HCI,
4: Alcohols, Halogeno-compounds. and Ethers
231
The oxidation is carried out in refluxing benzene in the presence of
.
manganese ( II acetate Substrate-selective oxidants have continued to be an important focus for attention. The use of silver153 and barium f e r r a t e ~ ' ~ in~ refluxing benzene has been developed to oxidize allylic and benzylic alcohols and other workers have reported the use of a K2FeOq/A1203/CuS04 system which oxidizes secondary alcohols in addition to allylic and benzylic alcohols but,not saturated primary alcohols.155 The oxidation of secondary in the presence of primary alcohols has been achieved using t-butyl hydroperoxide together with hexacarbonylmolybdenum and cetylpyridinium chloride in benzene. 156 Yields are greatly reduced in the absence of the quaternary ammonium salt and this system has been developed further by the same workers who have prepared [PMo 1 2 0 4 0 ] 3- [cetylpyridinium'] as a catalyst for this chemoselective conversion.15' Cerium- or ruthenium-catalysed oxidations with sodium bromate as biphasic systems in aqueous acetonitrile have also been applied to the chemoselective oxidation of secondary alcohols. 1 5 * Deoxygenation. Radical-mediated reductive deoxygenations of alcohols via their benzothiazolyl thioether derivatives using tributyltin hydride in the presence of AIBN (Scheme 35)' and via their esters using triphenylsilane with di-t-butyl peroxide have been reported.16'
In the latter instance, acetates are the most
efficiently reduced. Propargylic to the corresponding acetylenes by cobalt carbonyl adduct followed by borane-dimethyl sulphide and acid,
alcohols have been deoxygenated initial formation of the sequential treatment with and final decomplexation.161
This procedure furnishes the acetylenic products cleanly and no allenic material is formed. Allylic alcohols may be converted regioselectively into the rearranged alkenes by a procedure involving formation of an organoiron complex (Scheme 36) Lithium diphenylphosphide has found use in the conversion of a-hydroxy-ketones into simple ketones in good overall yield after treatment of the adduct with methyl iodide.163 Benzylic, allylic, and tertiary alcohols may be reduced to hydrocarbons using a combination of zinc iodide with a large excess of sodium cyanoborohydride in ref luxing dichloroethane, and phenols may be converted into aromatic hydrocarbons via the triflates by reduction with ammonium formate in the presence of a homogeneous palladium(0) catalyst.165 Other reducible groups such as ketones,
General and Synthetic Methods
238
0
Reagents:
+
i,
CIZC=NMe2CI-,
E t 3 N , CH2C12, r e t l u x ; ii, NaOMe, MeOH
Scheme 38
( E t 0I2PPh3
RL
O
H
4 0 "C
R
Scheme 3 9
R e a g e n t s : i, Bun4N+I-, T I C I ~ CH2CIZ, , -78°C or O ' C ;
S c h e m e 40
ii,
R3CH0
4: Alcohols, Halogeno-compoundr,and Ethers
239
esters, lactones and nitro-groups survive the reaction conditions and this procedure represents an improvement over previous methods using molecular hydrogen and heterogeneous catalyst. Miscellaneous Reactions. Zinc halide catalysis has been found to promote the formation of thiolesters from thioacids and benzylic, allylic, or tertiary alcohols, and represents a means of converting the hydroxy-group into a thiol after saponification.lbb Zinc salts in the presence of triphenylphosphine and diethyl azodicarboxylate have been shown to cause complete inversion of the alcohol group of menthol, giving rise to a wide range of chirally functionalized menthol derivatives (ester, ether, halide, azide) resulting from the counterion of the zinc salt used.167 Alcohols have been converted into primary amines by means of a Mitsunobu variant of the Gabriel synthesis (Scheme 3 7 ) . The key reagent is t-butyl N-(diethoxyphosphory1)carbamidate (22) and the conversion results in complete inversion of the substituted carbon.l b 8 A two-step procedure has been described for converting 1,2-diols to epoxides and 1,2-diols &v intermediate chlorocarbamates (Scheme 38) undergo phosphoramylation-dehydration using d i e t h o x y t r i p h e n y l p h o s p h o r a n e to furnish epoxides selectively ( Scheme 39) 2
Halogeno-compounds
Preparation. - From Alcohols. Although usually a transformation which promotes much interest, there has been a dearth of alcohol into halide conversions reported during the year. However, it has been shown that a-cyclopropane alcohols may be converted into the corresponding chlorides using an excess of trimethylsilyl chloride in dichloromethane whereas the use of one equivalent together with lithium iodide led to the formation of the E-homoallylic iodide resulting from ring cleavage. 17' By Addition to Unsaturated Substrates.
Bromo- and iodo-
functionalization of alkenes using a combination of the halogen and a mercury(I1) salt has enabled the preparation of a series of lI2-disubstituted products in which the second substituent, derived from the mercury salt, may be another halide or a series of other groups including esters, nitrate, thiocyanide, or a sulphone.172 Stereoselective bromination of acetylenes to furnish
General and Synthetic Methods
240
.
..
I , II
____I_)
Br
Reagents:
i, Br2, CHZC12, - 4 O O C ; ii, MeOH, NaOMe, -4O'C
S c h e m e 41
Reagents:
I,
Bu'Li,
THF-Et20-pentane,
ii, PhS02ButNF, -120'C-r.t
-120.C;
Scheme 4 2
+
Me2S-0-
+ Me3SiC I
-[
+cl-
M e 2S
]-
-0S i M c3
RYo
R2
Reagents
Scheme 43
+
Me2S-C
I
M e 3 S i 0-
(24)
4: Alcohols, Halogeno-compounds, and Ethers
241
E-1,2-dibromoalkenes has been demonstrated using tetrabutylammonium
tribromide, the high product stereoselectivity being rationalized by the formation of an intermediate cyclic brominated zwitterion (23) Acetylenes have also been found to react with a bis(pyridine)iodine(I) tetrafluoroborate in the presence of a wide variety of nucleophiles to furnish 1,2-iodofunctionalized alkenes.174 Conversion of vinylsilanes into vinyl iodides has been achieved with an iodine-Lewis acid combination, iododesilylation procedure may be controlled to or the 2-vinyl iodide dependent upon the amount (SnC14, A1C13) used.175 Exclusive formation of
and this favour either the of Lewis acid E-O-iodo- and
E-
a-bromovinyl ketones from the corresponding acetylenic ketones has been described using NaBr or LiI in trifluoroacetic acid whereas use of acetic acid as solvent led to predominance of the Other reagents which have been found to promote the same conversion are trimethylsilyl iodide177 and tetrabutylammonium iodide-TiC14 at 78 "C.178 With the latter reagent system, the initial allenolate intermediates could be trapped by addition to aldehydes, and the stereoselectivity of the initial 1,4-addition to generate the vinyl iodide was found to be temperature dependent (Scheme 40). Disubstituted organoboranes, obtained from acetylenes, are precursors to E- or 2-disubstituted vinyl bromides depending upon the stereochemistry of the initial borane. The conversion involves a two-step sequence of low-temperature addition of bromine followed by elimination (Scheme 41)17' (cf. 8, 231). Interhalide Conversions. Two inexpensive preparations of benzyl fluoride from benzyl chloride or bromide have been described. In the case of the bromide, treatment with tetrabutylammonium fluoride is sufficient to permit a 66% yield of isolated material, whereas with the chloride, KF and PEG 2 0 0 in refluxing acetonitrile permit a 95% yield of material.l8' Vinyl iodides may be converted into the corresponding fluorides stereospecifically with retention of double bond geometry in good overall yield using a two-step process which proceeds via generation of the vinyl-lithium intermediate (Scheme 42) .181 Vinylic and aromatic iodides have been prepared from the corresponding bromo-precursors by using a Ni(0) catalyst generated in situ electrolytically in the presence of potassium iodide. 182
General and Synthetic Methodr
242
Halogenation of a- to Carbonyl Groups.
Regioselective a-bromination
or chlorination of unsymmetrical ketones at the more substituted a-position has been demonstrated with trimethylsiiyl halides in DMSO;
the halogenating species is presumed to be the
trimethy1 si1 y 1 oxyha logenodime thy 1su lphonium intermediate ( 24) l8 The regioselective chlorination of unsymmetrical ketones at the more substituted a-position has also been carried out using aqueous TiC13 to produce organothallium(II1) derivatives which then react more slowly to furnish the halogenated materials.la4 Ketones have been converted into vinyl iodides in a two-step process which involves the initial preparation of the vinyl triflate followed by reaction with magnesium iodide (Scheme 43) . I o 5 Miscellaneous Methods. A paper describing directed catalytic steroid chlorination with a billion-fold turnover rate which was published during the year186 has since been retracted as the results have been found to be untenable, despite rigorous attempts to verify their validity prior to publication. The chemical community appreciates the speed with which Professor Breslow has publicly denied these results. The very significant achievements of his group in this area must not be overlooked by the chemical world simply because of the tortuous dishonesty of one research student. Benzyl ethers may be cleaved oxidatively to yield benzaldehyde and the alkyl halide using the oxoaminium salts (25),18' and trimethylsilyl ethers may be converted into the corresponding bromides using triphenylphosphine dibromide in dichloromethane.188 The second procedure can be catalysed by zinc bromide, although yields are unaffected. The reaction of two equivalents of triphenylphosphine with carbon tetraiodide in dichloromethane yields a solution which converts added aldehydes into homologous 1 ,1-di-iodoalkenes by a Wittig type process. Aldehydes may be converted selectively into 1-halogenoalkenes using
trihalogenomethanes and CrC12 in THF at 0 OC, when ketones react The conversion of aldehydes into their
far more s1uggishly.lg0
corresponding 1,l-dihalogenoalkanes may be accomplished by conversion first into the 1,l-ditriflate and then reaction with magnesium bromide or iodide or TiC14 (Scheme 44). However, in the conversion of a-branched aldehydes into the dichloro- and dibromo-compounds, some rearrangement also competes with formation of the desired material. The overall replacement of the oxygen of
243
4: Alcohols, Halogeno-compounds, and Ethers
X-
+N=O
( 2 5 ) X = Br or C I
VSozcF3
R' R2-f
I
CHO
R 2R3 R3
OS02CF3
R e a g e n t s . i , ( C F 3 S 0 2 ) 2 0 ; ill M g l Z or M g B r 2 ; i i i , TiCl4, CHZC 2
S c h e m e 44
PhC02H
Reagents
I,
PhCH,C
S O CI , DMF ( c a t 1, t o l u e n e , 1 0 0 ° C , 2 2 NaBH4, H 0, 2
IV,
11,
cool to r t ,
111,
Bun4N+Br- (Cat),
SOCl2
Scheme 45
4 SiMe,
I
Br
Reagents,
I,
[Ni(COD),],
SiMe3
-f: NiBr
toluene, r t ,
11,
RX
S c h e m e 46
-4
S i Me3
R
244
General and Synthetic Methods
ketones with two fluorine atoms is possible by treating the thioacetals with bromine fluoride. I g l This reagent is generated in situ using pyridinium poly(hydrogen fluoride) (a convenient source of HF which can be handled in glass apparatus) and
1,3-dibromo-5,5-dimethylhydantoin.
A one-pot, multi-step procedure,
in which aromatic acids can be converted into benzylic chlorides, has been described in which the key step involves sodium borohydride reduction of the in situ generated acyl chloride (Scheme 4 5 ) I g 2 . The Cr(I1)-mediated reduction of a-trichloromethyl carbinols in DMF at 0 “C has been found to lead selectively to Z-l-chloroalkenes.193 Geminal halogenonitro-compounds have been prepared in generally good yield by first generating the a-anion of nitroalkanes followed by treatment with N-chloro- or 1-bromosuccinimide. I g 4 Regioselective --halogenation of phenols in good yield and greater than 98% purity has been achieved using dimethylsulphonium halides as the halogenating agent.Ig5
-
Elimination and Dehalogenation. Mild conditions for Reactions. eliminating primary alkyl halides to form 1-alkenes have been reported in which a solution of the halide and DBU in THF is added to a solution prepardd by the reaction of an equivalent of dichlorobis(tripheny1phosphinato)nickel and two equivalents each of triphenylphosphine and butyl-lithium.I g 6 Polyethylene glycol promoted basic dehydrohalogenation of 1,l-dibromoalkenes has been developed as a means of preparing 1-bromoalkynes in moderate to good yield. Reductive dehalogenation of aryl iodides and some bromides has been accomplished by UV photostimulated reduction with sodium borohydride in the presence of a radical initiator in DMF solution: chlorides and fluorides remain untouched under these conditions. Two Pd ( 0 ) -catalysed reductive dehalogenations of aryl halides have been reported. In one instance the reaction is carried out under hydrogen (or deuterium to furnish deuterated products)”’ whereas in the other case the reaction is performed in the presence of base and polymethylhydrosilane as a hydrogen donor.2 o o Coupling Reactions.
The palladium-catalysed cross-coupling of
E-(1-alkyl-1-alkeny1)boronates with alkyl halides has been shown to permit stereo- and regio-specific access to trisubstituted alkenes in which the introduced alkyl group occupies the position formerly occupied by the boron substituent. 201 Allyl-silanes may be obtained
245
4: Alcohols, Halogeno-compounds, and Ethers
( 2 6 ) n = 7, 11 o r 15
E:Z
Reagents .
I,
ii,
ethylmorpholine
N - o x i d e , DMF, r t - 5 O ' C ;
ethylmorpholine
N - o x i d e , DMF, L i l . 2 H 2 0 ,
Scheme
47
70:30
r.t -+ 5 0
'C
246
General and Synthetic Methods
from 2-(bromomethyl)allyltrimethylsilane by initial formation of the n-ally1 nickel bromide followed by treatment with an alkyl halide, and it is proposed that this system should act as a synthetic equivalent of the trimethylenemethane dianion (Scheme 46) .2 0 2 Alkyl iodides have been cross-coupled with alkyl Griqnards derived from primary or secondary or aryl halides usiny a palladium catalyst prepared by prior reduction of [ (dppf)PdCl21 with two equivalents of di-isobutylaluminium hydride. 203 The alkylation of aryl or vinyl halides has been carried out with organoboranes in the presence of [ (dppf)PdC12 1
. 204 Aryl- and alkynyl-silanes are stereo- and
regio-selectively converted into 2,2-disubstituted vinylsilanes by Pd-catalysed cross-coupling in the presence of piperidine or tributylamine-formic acid. 2 0 5 The copper-catalysed coupling of methyl iododifluoroacetate with alkyl halides has been found to lead efficiently to 2,2-difluoro-estersf and couplings with vinyl iodides retain the orqinal double bond stereochemistry of the iodide. 2 0 6 Aryl or vinyl iodides and benzyl or ally1 halides may be reductively formylated with carbon monoxide to give the corresponding aldehydes as the major products under palladium catalysis in the presence of tributyltin h ~ d r i d e . ~ ' (cf.8, ~ 234). The use of octacarbonyldicobalt and carbon monoxide in the presence of calcium hydroxide and methyl iodide has been found to furnish mixtures of the carboxylic acids and a-keto-carboxylic acids with aryl and benzyl halides.208
In contrast, in the absence of
methyl iodide and in methanolic sodium hydroxide, the C O / [ C O ~ ( C O ) ~ ] system furnishes high yields of carboxylic esters under photochemical conditions. 209 All halogen substituents on the aromatic nucleus can be replaced by carboxy ethyl groups in one pot in this way. Terminal halide systems (26), ( 2 7 ), and (28) undergo free-radical induced reductive macrocylization in the presence of tributyltin hydride and a catalytic quantity of AIBN.210 The optimal conditions involved concentrations of 3 - 6 mM; iodides gave better results than bromides, and substrates (27) and (28) generally cyclized more efficiently. Miscellaneous.
The substance (29) has been developed as a polymeric
analogue of N-methyl-2-pyrrolidinone for use in nucleophilic displacement reactions with alkyl halides. 211 An improved synthesis of
sulphonyl
chlorides from aryl halides has been
developed
which
involves conversion into the corresponding aryl-lithium followed treatment with sulphuryl chloride. 2 1 2
A direct, one-step
by
oxidation
4: Alcohols, Halogeno-compounds, and Ethers
241
S c h e m e 48
L
Scheme 49
R
J
248
General and Synthetic Methods
of alkyl halides to aldehydes has been published wherein the halide is heated in DMSO in the presence of NaHC03-NaI to produce the desired materials in good to excellent yields.213
In a related conversion, allylic chlorides have been converted into a,B-unsaturated aldehydes by heating with ethylmorpholine N-oxide in
DMF.
In the case of 3-chloro-1-alkenes such as (29), hydrated
lithium iodide is added to the reaction mixture and the rearranged oxidized product is obtained (Scheme 47) .214 3
Ethers
Preparation (see also Alcohols - Protection) .- Fluoroisopropenyl aryl ethers, of interest in certain aspects of drug design, may be prepared using the benzenesulphonake
(30) via reaction with
phenolate anion followed by fluroide ion promoted displacement/elimination. 2 1 5 Methoxymethyl ethers are claimed to be versatile precursors to chlorornethyl ether derivatives by means of boron trichloride mediated cleavage of the methoxy-substituent. 2 1 6 The acidic resin Nafion H catalyses the reductive cleavage of acetals to ethers by triethylsilane in ref luxing d i c h l ~ r o m e t h a n e ~ ' ~ As this resin also catalyses the carbonyl group acetalization with orthoesters, this permits a one-pot conversion of ketones into ethers. Triethylsilane in the presence of borontrifluoride etherate has also been used in the conversion of y-lactols into tetrahydrofuran derivatives.218 The enantioselective reduction of a-halogeno-ketones by lithium borohydride modified with N,N-dibenzoylcysteine has been used for the asymmetric synthesis of 2-aryl-substituted oxetanes.219 a-Allylated lactols and their acetal derivatives have been converted into 2,3-=-fused difurans and furopyrans by an iodocyclization procedure (Scheme 48) 2 2 0 The formally 5 - e - t r i g cyclization of
.
homoallylic alcohols in the terpene series with thallium(II1) acetate has been demonstrated t o be high yielding irrespective of the presence of other functionality in the substrates (e.g. hydroxy 2 2 1 or carbonyl groups, esters, and unsaturated linkages). Hydroperoxides have been cyclized onto a,@-unsaturated esters to furnish eventually 9-tetrahydrofurans possessing the necessary 222 functionalization for elaboration into polyether type structures. Initial 1,4-attack of the hydroperoxide onto the unsaturated ester gives a six-membered cyclic peroxide which then undergoes anion-promoted ring opening producing an epoxide which is in turn
249
4: AIcohoS Halogeno-compounds. and Ethers
,e,, [ Me2S04*
~
SPh
:OH
Scheme 50
“‘“cfJoH 0 (32) n = 1 or 2
(31)
I I
I
I
I
I
A : i - iii
8 :i
(33)
Conditions A
54
46
Conditions B
0
100
R e o g e n t s : Conditions A : i, P ~ ( O A C ) ~ , A C O Hii, ; K2C03, M e O H , iii, PCC Conditions
B:
i, PCC, CH2C12, r e f l u x
Scheme 51
250
General and Synthetic Method
attacked by the oxyanion to produce the tetrahydrofuran (Scheme 49). The high stereoselectivity observed for secondary hydroperoxide precursors can be rationalized by the formation of the sterically favoured cyclic hydroperoxide in which the substituents are all equatorial. During synthetic studies using a-sulphinyl anions it has been shown that 2-thio-substituted 1,4-diol derivatives may be cyclized efficiently to form highly functionalized tetrahydrofurans via episulphonium intermediates (Scheme 50). 23
Tetrahydrofurans have been prepared from active methylene compounds via __ radical
cyclization of precursors such as (31)224 and by carbenoid intermediates generated from diazoester structures ( 3 2 ) .225 Transannular oxidative cyclization of the cyclic alcohol (33) has been found to lead to two isomeric bicyclic ethers, the ratio of which is dependent upon the oxidizing system used [Cr(VI) or Pb(1V) , Scheme 511 .226 Tetrahydropyrans have been prepared by the TiC14-promoted cyclization of acetals possessing an alkyl group with 3 ,4 - u n ~ a t u r a t i o nand, ~ ~ ~ in an analogous procedure, SnC14 has been used to cyclize unsaturated acetals to eight- and nine-membered cyclic ethers.228
The full paper describing an earlier report on
the bromonium ion assisted opening of unsaturated epoxides has been published. 229 (See also Alcohols - Deprotection).- A full paper has appeared describing the utility of aromatic chromium tricarbonyl complexes for suppressing competing Wittig rearrangements in the
Reactions
elaboration of benzyl ethers via benzylic anions230 (cf.8, 2 3 6 ) . The base-promoted [2,3] Wittig rearrangement continues to excite interest in the field of terpene synthesis and work has been reported describing ring conctractions of both cyclic diallylic ether231 and allylic-propargylic ether systems. 232
The elimination
of terpene-related allylic ethers with potassium t-butoxide/l8-crown-6 has been used to prepare 2-alkylated buta-1,3-dienes in high yield, permitting access to terpenic natural products possessing this troublesome structural sub-unit. 233 The cyclization of chiral ethers derived from farnesol and geraniol with (R)-1,l1-bi-2-naphtholhas been carried out to furnish optically active terpenes biomimetically.234 Various aluminium reagents were used but the best results, obtained with 2,4,6-tri-t-butylphenoxyisobutylaluminium triflate, gave limonene in 77% e.e. (cf.8, 229). Anchimeric assistance by the aluminium reagent is proposed to be an important factor in the cyclization.
4: Alcohols, Halogeno-compounds, and Ethers
251
ii,
iii
,R,4sR2 , iv
Reagents
I, 111,
Me3SiCI,
HZS, p y r i d i n e , i i . B u " L i ,
- 60°C -r
R'Br,
t ,
IV,
R*SH
OSi Me3
OSiMe3
DMF, h e x a n e , - 60'C,
KF, MeOH, r t
Scheme 52
-.*to
0
0/ I - P h
RCO,'
(35) a; M = S e
0
b; M = Te
( 3 6 ) R = Me.Ph or B u t
Ps
SMe
Reagent : I, P d , CHC13, 2 5 " C
S c h e m e 53
0
0
SPh Reagents'
I,
MeO(PhS)CHLi, - 7 8 ' C ; i i , H 3 0 +
S c h e m e 54
252
General and Synthetic Methods
Regioselective reductive ring opening of oxetanes with LiAIH4 has been shown to occur with assistance by a neighbouring hydroxy-group, possibly an intermediate such as (34).235 4 Thiols Aliphatic thiols may be prepared from the corresponding halides 2 a procedure which involves preparation of a-trimethylsiloxy-sulphides followed by extremely mild, two-step,reductive desilylation (Scheme 52) 236 Polymer-supported diary1 selenoxides (35a) and tel luroxides
.
(35b) have been shown to be mild and selective oxidizing agents which convert thiols into disulphides in very high yields.237 The efficient coupling of thiols with anhydride to furnish thiol esters has been demonstrated using cobalt (11) chloride in acetonitrile. 238 5 Thioethers Aluminium iodide has been found to effect the reduction of sulphoxides to thioethers in refluxing acetonitrile and this reagent also converts sulphonyl chlorides into disulphides.239 Phenylthiotrimethylsilane undergoes palladium-mediated allylation with allyl carbonates and also reacts with a-B-unsaturated epoxides to give a mixture of products resulting from direct opening of the epoxide or opening with allylic rearrangement. 240 In another instance of palladium-mediated synthesis of methyl allyl thioethers, 0-allyl-5-alkyl dithiocarbonates expel carbonyl sulphide to furnish the thioether in a catalytic cycle which results in net retention of configuration of the initial dithiocarbonate (Scheme 5 3 ) . 241 Vinyl sulphides have been prepared by the addition of phenylthiocarbenes to nitrile anions.242 A straightforward one-pot synthesis of aryl alkyl thioethers has been developed in which the aryl halide is first converted into the 2-aryl-isothiouronium salt with thiourea in the presence of a nickel catalyst, followed by sequential treatment with calcium oxide, to generate the thiolate, and the alkyl halide.243 Another procedure which has been developed for preparing aryl alkyl thioethers involves the Lewis acid catalysed nucleophilic displacement on nitroalkanes with phenylthiotrimethylsilane. 244 Diary1 sulphides may be prepared by the reaction of arenediazonium tetrafluoroborates with aryl thiolates. The experimental procedure involves the addition of a solution of the diazonium salt in DMSO to the stirred thiolate.245
4: Alcohols, Halogeno-compounds,and Ethers
253
The use of a-chlorosulphides in organic synthesis has been the subject of review,246 as has the synthesis of sulphoxides by oxidation of thioethers.247 The results of a study into optimization of the oxidation of thioethers to sulphoxides with calcium hypochlorite or sodium chlorite have been published248 and sulphoxides have also been obtained by the phase-transfer controlled oxidation of diary1 sulphides with potassium hydrogen persulphate (oxone) in a water-dichloromethane biphasic reaction. 249 The chiral iodine(II1) reagent (36) derived from iodosylbenzene and L-tartaric acid has been used in attempts to obtain asymmetric induction in the conversion of thioethers into sulphoxides. 2 5 0 The best results were obtained with aryl methyl thioethers with enantiomeric excesses of up to 53% but aliphatic thioethers gave disappointing results. Greater success has been obtained with sodium periodate oxidation of phenylthioethers in the presence of A-tris(1,lO-phenanthroline)nickel(II) adsorbed onto sodium montmorillonite.2 5 1 Enantiomeric excesses of up to 78% were recorded and the success is proposed to be due to a template effect of the clay-chelate adduct with only one enantiomer of the nickel chelate being absorbed, leaving half the clay surface unoccupied. Sodium percarbonate has been found to be a convenient and stable source of hydrogen peroxide for conversions of thioethers into sulphones.2 5 2 Nickel boride, prepared in situ by the borohydride reduction of NiC12 in methanol, has been found to be an efficient reagent for the reductive desulphurization of thioethers. 253 Direct dilithiation of thioanisole derivatives followed by reaction with electrophilic reagents has led to the formation of products substituted both at the methyl group and on the aromatic ring. The electrophile adds to the ortho-position in the absence of substituents. 254 The anion derived from methoxy(pheny1thio)methane has been used in the synthesis of polyfunctional y-keto-ester derivatives (Scheme 5 4 ) . 2 5 5 The advantage of this reagent (prepared by the BF3 etherate mediated reaction of thiophenol with formaldehyde dimethyl acetal) over the previously used bis(pheny1thio)methyl-lithium is the greater ease of hydrolysis of the intermediate lI4-adducts. Use of this reagent for homologation reacitons has been the subject of a Japanese review. 256
254
General and Synthetic Methodr
References 1. 2. 3. 4.
5. 6. 7.
8. 9. 10. 11. 12. 13. 14.
15. 16. 17. 18.
19. 20. 21. 22. 23. 24.
25. 26. 27.
28. 29. 30.
K. Maruoka,, H. Sano, K. Shinoda, S. Nakai, and H. Yamamoto, J.Am.Chem.Soc., 1986, 108, 6036. H.C. Brown, T.E. Cole, M. Srebnik, and K.-W. Kim, J.Org.Chern., 1986, 51, 4926. D.H. Birtwhistle, J.M. Brown, and M.W. Foxton, Tetrahedron __Lett., 1986, 7, 4367. X. Tamao, T. Tanaka, T. Nakajima, R. Sumiva, ~. . . . H . Arai. and Y. Ito, Tetrahedron Lett., 1986, 21, 3377; K. Tamao, T. Nakajima, R. Sumiya, H. Arai, N. Higuchi, and Y. Ito, J.Am.Chem.Soc., 1986, 108. 6090. M. T o k E ' a n d J.K. Snyder, Tetrahedron Lett., 1986, 27, 3951. T. Yamada and K. Narasaka, Chem.Lett., 1986, 131. G. Solladie, C. Frecho, and G. Demailly, Tetrahedron Lett., 1986, 27, 2867. E. V e d G s and C.K. McClure, J . A m . C h e m Z . , 1986, 108, 1094. W. Adam, A. Griesbeck, and E. Staab, Tetrahedron Lett., 1986, 27, 2839. J.Org.Chem., 1986, g , 1672. Degueil-Castaing and A. Rahrn, _____ H. Kotsuki, N. Yoshimura, Y. Ushio, T. Ohtsuka, and M. Ochi, Chem.Lett.. 1986. 1003. K. Soai and A. Ookawa, J.Org.Chem., 1986, 51, 4000. N.M. Yoon, K.E. Kim, and J. Kanq, J.Org.Chem., 1986, 226. E. Farnetti, M. Pesce, S. Kaspar, R. Spogliarich, and M. Graziani, J.Chem.Soc., Chem.Commun., 1986, 746. S . Fukuzawa, T. Fujinami, S . Yamauchi, and S. Sakai, J.Chem.Soc., Perkin Trans.1, 1986, 1929. R. Fornasier, V. Lucchini, P. Scrimini, and U. Tonellato, J.Orq.Chern., 1986, 2,1769. T. Moriwake, S. Hamano, D. Mi-ki, S. Saito, and S. Torii, Chem-Lett., 1986, 815. K. Isobe, K. Mohri, H. Sano, J. Taga, and Y. Tsuda, Chem.Pharm.Bul1. , 1986, 34, 3029. D.A. Evans and K.T. Chapman, Tetrahedron Lett., 1986, 27, 5939. S. Anwar and A.P. Davis, J.Chem.Soc., Chem.Commun., 1986, 831. S. Kiyooka, H. Kuroda, and Y . Shimasaki, Tetrahedron Lett., 1986, G I 3009. K. Suzuki, M. Shinmaki, and G. Tsuchihashi, Tetrahedron Lett., 1986, 27, 6233. K. Suzuki, M. Miyazawa, M. Shimazaki, and G. Tsuchihashi, Tetrahedron Lett., 1986, 27, 6237. H.C. Brown, J. Chandrasekharan, and P.V. Ramachandran, J.Org.Chem., 1986, 51, 3394. H.C. Brown, W.S. Park, and B.T. Cho, J.Org.Chem., 1986, 3278. H.C. Brown, W . S . Park, and B.T. Cho, IJ.Org.Chem., 1986, 1934, 3396. T. Imai, T. Tamura, A. Yamamuro, T. Sato, T.A. Wollmann, R.M. Kennedy, and S. Masarnune, J.Am.Chem.Soc., 1986, 108, 7402; S. Masamune, R.M. Kennedy, J.S. Peterson, K.N. Houk, and Y. Wu, ibid., p . 7 4 0 4 . M. Falorni, L. Lardicci, C. Rosini, and G. Giacomelli, J.Org.Chem., 1986, E l 2030. M. Ceqla, Pol.J.Chem., 1986, 59, 1265. 0. Cervinka, A. Fabryova, I. Brozova, and M. Molik, Coll.Czech. Chem.Commun., 1986, 51, 684. P. Kvintovics, B.R. James, and B. Hell, J.Chem.Soc.Chem.Com., 1986, 1810. A.P. Kozikowski, B.B. Muqrage, C.S. LI., and (in part) L. Felder, Tetrahedron Lett., 1986, &7-, 4817.
z,
s, z,
~~
31. 32.
4: Alcohols, Halogeno-compounds, and Ethers 33.
R. C h g n e v e r t a n d S. T h i b o u l o t , Can.J.Chem., 1986, 64, 1599; J . B o l t e , J.-G. Gourcy, a n d Veschambre, T e t r a h e d r o n L e t t . ,
34.
1986, 27, 565. G u a z i , L . B a n f i , A. G u a r a g n a , a n d E . N a r i s a n o , J . C h e m . S o c . , 1986, 138; G. G u a n t i , L. B a n f i , a n d E. N a r i s a n o , T e t r a h e d r o n L e t t . , 1 9 8 6 , 27, 3 5 4 7 . S . T s u b o i , E . Nishiyama, M. Utaka, a n d T. Takeda, T e t r a h e d r o n L e t t . , 1986, 1915. K . Nakamura, T. M i y a i , K . N o z a k i , K . U s h i o , S . Oka, a n d A. Ohno, T e t r a h e d r o n L e t t . , 1986, 3155. K . U s h i o , K . I n o u y e , K . N a k a m u r a , S . O k a , a n d A. O h n o , T e t r a h e d r o n L e t t . , 1986, 2657. D. Buisson and R. Azerad, T e t r a h e d r o n L e t t . , 1986, 2631. M. Utaka, S. K o n i s h i , a n d A. Takeda, T e t r a h e d r o n L e t t . , 1986, 27. 4737. E . K e i n a n , E.K. H a f e l i , K . K . S e t h , a n d R. L a m e d , J . A m . Chem.Soc., 1 9 8 6 , 162. L.G. L e e a n d G.M. W h i t e s i d e s , J . O r g . C h e m . , 1 9 8 6 , 51, 2 5 . P.G.M. W u t s a n d G.R. C a l l e n , S y n t h . C o m m u n . , 1 9 8 6 , 1 6 , 1 8 3 3 . K . T a k a i , M. Tagashura, T. Kuroda, K. Oshima, K. U z m o t o , a n d H . N o z a k i , J.Am.Chem.Soc., 1 9 8 6 , 108, 6 0 4 8 . H . J u n , J . U e n i s h i , W . J . C h r i s t , a n d Y . K i s h i , J.Am.Chem.Soc., 1 9 8 6 , 108, 5 6 4 4 . H . Tanaka, S . Y a m a s h i t a , T. Hamatani, Y . Ikemoto, a n d S . T o n i , Chem.Lett., 1986, 1611. M . Wada, H . O h k i , a n d K . A k i b a , T e t r a h e d r o n L e t t . , 1 9 8 6 , 4771. T . S h o n o , N . K i s e , T . S u z u m o t o , a n d T . Morimoto, J.Am.Chem. SOC., 1986, 4676. __ G . S i l v e s t r i , S . Gambino, a n d G. F i l a r d o , T e t r a h e d r o n L e t t . , 1986, 3429. W.R. R o u s h a n d R . L . H a l t e r m a n , J . A m . C h e m . S o c . , 1986, 294. R.W. Hoffmann a n d B. Landmann, Chem.Ber., 1 9 8 6 , 1039. W.R. R o u s h , M . A . Adams, A . E . W a l t s , a n d D . J . H a r r i s , J.Am. Chem.Soc., 1 9 8 6 , 3422. P . K . J a d h a v , K . S . B h a t , P . T . P e r u m a l , a n d H.C. B r o w n , J . O r q . 1986, 51, 432; H.C. Brown a n d K . S . B h a t , J.Am.Chem. __ SOC., 1986, 5919. N . I k e d a , I . A r a i , a n d H . Y a m a m o t o , J.Am.Chem.Soc., 1 9 8 6 , 108, 493. K . Uneyama, H . Nanbu, a n d S . T o r i i , T e t r a h e d r o n L e t t . , 1 9 8 6 , 27, 2395. F u k u z a w a , A. N a k a n i s h i , T . F u J i n a m i , a n d S . S a k a i , J . C h e m . S O C . , Chem.Commun., 1 9 8 6 , 6 2 4 . T . T a b u c h i , J . I n a n a q a , a n d M. Y a m a q u c h i , T e t r a h e d r o n L e t t . , 1986, 1195. T . Tabuchi, J. I n a n a g a , and M. Yamaguchi, T e t r a h e d r o n L e t t . , 1986, 3891. T . I m a m o t o , T . T a k e y a m a , a n d H . Koto, T e t r a h e d r o n L e t t . , 1 9 8 6 , 2 7 , 3 2 4 3 . G . C a h i e z a n d B . F i g a d e r e , T e t r a h e d r o n L e t t . , 1 9 8 6 , 27, 4 4 4 5 . G. C a h i e z , J . R i v a s - E n t e r r i o s , a n d H . Granger-Veyron, Tetrahedron L e t t . , 1986, 4441. S. S i b i l l e , E. d ' I n c a n , L. L e p o r t , a n d J . P e r i c h o n , T e t r a h e d r o n ___ L e t t . , 1 0 9 6 , 27, 3 1 2 9 . M.T. R e e t z , S.H. K y u n q , a n d M . H u l l m a n n , T e t r a h e d r o n , 1 9 8 6 , 42, 2931. M.T. R e e t z a n d M . H u l l m a n , J . C h e m . S o c . , Chem.Commun., 1 9 8 6 , 1600. M.T. R e e t z , T . K r u k e n h o h n e r , a n d P . W e i n i g , T e t r a h e d r o n L e t t . , 1986, 5711. G.
,Chem.Commun.,
35.
7,
36.
27,
37.
7,
38. 39 *
27,
~
~
40.
108,
41. 42. 43. 44. 45.
27,
46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64
255
-
108, 2,
108,
m.,
208,
s.
27, 27,
27,
7,
General and Synthetic Methods
256 65.
P.A. Brown and P.R. Jenkins, J.Chem.Soc., Perkin Trans.l.,
66. 67.
H. Amri and J. Villieras, ________ Tetrahedron Lett., 1 9 8 6 , 27, 4 3 0 7 . T. Isihihara, T. Maekawa, and T. Ando, Tetrahedron Lett., 1 9 8 6 ,
1986, 1129.
27, 357. 68. 69. 70. 71.
R. Tsang and B. Fraser-Reid, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 8 1 0 2 . Y. Tamura, H. Kondo, H. Annoura, R. Takeuchi, and H x u j i o k a , Tetrahedron Lett., 1 9 8 6 , 27, 8 1 . D. Seebach, R. Imwinkelried, and G. Stucky, Angew.Chem.Int.Ed. Engl., 1 9 8 6 , 2 5 , 1 7 8 . S.L. Schrieberand J. Reagan, Tetrahedron Lett., 1 9 8 6 , 27, 2945.
72. 73. 74. 75. 76.
K. Ishihara, A. Mori, I. Arai, and H. Yamamoto, Tetrahedron Lett., 1 9 8 6 , 2 7 , 9 8 3 . A. Mori, K . Ishihara, and H . Yamamoto, Tetrahedron Lett., 1 9 8 6 , 27, 987. -
T. Mukaiyama, N. Minowa, T. Oriyama, and K. Narasaka, Chem.Lett., 1 9 8 6 , 9 7 . G.P. Boldrini, E. Tagliavini, C. Trombini, and A. Umani-Ronchi, J.Chem.Soc., Chem.Commun., 1 9 8 6 , 6 8 5 . M. Kitamura, S . Suga, K. Kawai, and R. Noyori, J.Am.Chem.Soc.,
77.
1 9 8 6 , 108, 6 0 7 1 . R . Annunziata, M. Cinquini, F. Cozz and L Raimondi, J.Chem.Soc., Chem.Commun., 1 9 8 6 , 3 3 6 ; R. Annunziata, M. Cinquini, F. Cozz, L. Raimondi and S. Stefanelli, Tetrahedron, 1 9 8 6 , 42, 5 4 4 3 .
78.
R.L. Danheiser, D.J. Carini, and C.A. Kwasigroch, J.Org.Chem.,
79.
S . Maszune, T. Sato, B.M. Kim, and T.A. Wollmann, J.Am.Chem.
1986, 51, 3870.
SOC., 1 9 8 6 , 80.
108,8 2 7 9 .
I. Paterson, M.A. Lister, and C.K. McClure, Tetrahedron Lett., 1986,
27,
4787.
86.
D.A. Evans, E.B. Sjorren, J. Bartroli, and R.L. DOW, Tetrahedron Lett., 1 9 8 6 , 27, 4 9 5 7 . D.A. Evans and A.E. Webster, J.Am.Chem.Soc., 1 9 8 6 , 108, 6 7 5 7 . G.E. Keck and S. Castellino, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 3 8 4 7 . C. Siege1 and E.R. Thornton, Tetrahedron Lett., 1 9 8 6 , = , 457. C. Gennari, M. Grazia Beretta, A. Bernardi, G. Moro, C. Scolastico, and R. Todeschini, Tetrahedron, 1 9 8 6 , 42, 8 9 3 . C. Palazzi, L. Colombo, and C. Gennari, Tetrahedron Lett.,
87.
H. Hagiwara, K. Kimura, and H. Uda, J.Chem.Soc., Chem.Commun.,
88.
91.
C.H. Heathcock, S.K. Davidsen, K.T. Hug, and L.A. Flippin, J.Org.Chem., 1 9 8 6 , 51, 3 0 2 7 . I . Fleming and J.D. Kilburn, Tetrahedron Lett., 1 9 8 6 , 2 7 , 3 0 5 . M. Bellasoued, J.-E. Dubois, and E. Bertounesque, Tetrzedron Lett., 1 9 8 6 , 27, 2 6 2 3 . Y . Kobayashi, Y. Kitano, Y. Takeda, and F. Sato, Tetrahedron,
92.
T . Mukaiyama, N. Yamasaki, R.W. Stevens, and M. Musakami,
93.
Chem.Lett., 1 9 8 6 , 2 1 3 . A. Alexakis, D . Jachiet, and J.F. Normant, Tetrahedron, 1 9 8 6 ,
81. 82. 83. 84. 85.
1986,
27, 1 7 3 5 .
1986, 860. 89. 90.
1986,
42, -
42, 2 9 3 1 .
5607.
96.
J. Mulzer and 0. L a m e r , Chem.Ber., 1 9 8 6 , 119, 2 1 7 8 . I. Mukerji, A. Wayda, G. Dabbagh, and S.H. Bertz, Angew.Chem. Int.Ed.Engl., 1 9 8 6 , 25, 7 6 0 . C. Einhorn and J.-L. Luche, J.Chem.Soc., Chem.Commun., 1 9 8 6 ,
97 *
T. Satoh, Y . Kaneko, and Y. Yamakawa, Tetrahedron Lett., 1 9 8 6 ,
94. 95.
138. 98.
27, 2379. -
M. Taddei and A. Ricci, Synthesis, 1 9 8 6 , 6 3 3 .
4: Alcohols, Halogeno-compounds, and Ethers
99. 100. 101.
102. 103. 104. 105. 106. 107. 108. 109. 110. 111.
112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134.
257
K. Fuji, M. Node, and Y. Usami, Chem.Lett., 1986, 961. H.A. Zahalka and Y. Sasson, Synthesis, 1986, 763. H. Sakurai, M. Ando, N. Kawada, K. Sato, and A . Hosomi, Tetrahedron Lett., 1986, 27, 75. C.J. Kowalski and M.S. Haque, J.Am.Chem.Soc., 1986, 108, 1325. C. Einhorn and J.-L. Luche, J.Chem.Soc., Chem.Commun., 1986, 1368. G. Polson and D.C. Dittmer, Tetrahedron Lett., 1986, 27, 5579. I . Shimizu, M. Oshima, M. Nisar, and J. Tsuji, Chem.Lett., 1986, 1775. G. Molander and G. Hahn, J.Org.Chem., 1986, 51, 2596. L. Dai, B. Lou, Y. Zhang, and G. Guo, Tetrahedron Lett., 1986, 27, 4343. P. Mosset, S . Mauna, J. Vialaand, and J.R. Falck, Tetrahedron Lett., 1986, 27, 299. K. Maruoka, M. Hasegawa, H. Yamamoto, K. Suzuki, M. Shimazaki, and G. Tsuchihashi, J.Am.Chem.Soc., 1986, 108, 3827. V.K. Yadav and A.G. Fallis, J.Org.Chem., 1986, 51, 3372. A. Oku, Y. Homoto, and T. Harada, Chem.Lett., 1986, 1495. S. Wadman, R . Whitby, C. Yeates, P. Kocienski, and K. Cooper, J.Chem.Soc., Chem.Commun., 1986, 241. M. Uchikawa, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1986, 27, 4581. M. Uchikawa, T. Hanamoto, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1986, 27, 4577. K. Mikami, T. Kasuga, K. Fujimoto, and T. Nakai, Tetrahedron Lett., 1986, 27, 4185. H. Kosugi, M . Kitaoka, A . Takahashi, and H. Uda, J.Chem.Soc., Chem.Commun., 1986, 1268. S. Sakane, K. Maruoka, and H. Yamamoto, Tetrahedron, 1986, 42, 2203. R . Csuk, A. Furstner, and H. Weidmann, J.Chem.Soc., Chem.Commun., 1986, 1802. D.B. Colluin, W.C. Still, and F. Mohamadi, J.Am.Chem.Soc., 1986, 108, 2094. J.H. Jones, D.W. Thomas, and M.E. Wood, Synth.Commun., 1986, 16, 1607. D. Sinon and M. Emziane, Synthesis, 1986, 1044. T.F. Braish and P.L. Fuchs, Synth.Commun., 1986, 16, 111. W.V. Dahlhoff and K.M. Taba, Synthesis, 1986, 561, P.G. McDougal, J.G. Rico, Y.-I. Oh, and B.D. Condon, J.Org.Chern., 1986, 51, 3388. S . Hoyer, P. Laszlo, M. Orlovic, and E . Polla, Synthesis, 1986, 655. M. Onaka, M. Kawai, and Y. Izumi, Bull.Chem.Soc.Jpn., 1986, 59, 1761. H. Ogawa, Y. Ichimura, T. Chihara, S. Teratani, and K. Toga, Bull.Chem.Soc.Jpn., 1986, 59, 2481. J.L. Holcombe and T. Livinghouse, J.Org.Chem., 1986, 51, 111. M. Bessodes, D. Komiotis, and K. A v T e t r a h e d r G Lett., 1986, 27, 579. K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, and 0. Yonemitsu, Tetrahedron, 1986, 42, 3021. H. Saimoto, Y. Kusano, and T. H i y s a , Tetrahedron Lett., 1986, 27, 607. L . Kaisalo, A. Latvala, and T. Hase, Synth.Commun., 1986, 16, 645. J.E. Baldwin, and G.G. Heradldsson, Acts Chem.Scand.Ser.B. 1986, 40, 409 J.C. Sarma, M. Borbaruah, D . N . Sarma, N.C. Barua, and R.P. Sharma, Tetrahedron, 1986, 42, 3999.
258 135. 136. 137. 138. 139. 140. 141.
General and Synthetic Methods
J.R. HWU, V. Chua, J.E. Schroeder, R.E. Barrans, K.P. Khoudary, N. Wanq, and J.M. Wetzel, .J.Org.Chem., 1986, 51, 4731. R.A. Bunce and D.V. Hertzler, J.Orq.Chem., 1986, 3451. S. Kajigaeshi, T. Nakagawa, N. Nagasaki, H. Yamasaki, and S. Fujisaki, Bull.Chem.Soc.Jpn., 1986, 59, 747. I. Minami, M. Yamada, and J. Tsuji, Tetrahedron Lett., 1986, 27 , 1805. S. Torii, T. Inokuchi, and T. Sugiura, J.Org.Chem., 1986, 51, 155. 0. Bortolini, V. Conte, F. DiFuria, and G. Modena, J.Org.Chem., 1986, 51, 2661. Y.Ishii, T. Ikariya, M . Saburi, and S. Yoshikawa, Tetrahedron Lett., 1986, 27, 365; Y. Ishii, K. Osakada, T. Ikariya, 2034. M. Saburi, a n d S . Yoshikawa, J.Org.Chem., 1986, Y. Ishii, K. Suzuki, T. Ikariya, M . Saburi, and S. Yoshikawa, 2822. J.Org.Chem., 1986, J. Collin, J.-L. Nancy, and H.B. Kaqan, Nouv.J.Chim., 1986, 10, 229. Y. Ishii, T. Nakano, A. Inada, Y. Ishigami, K. Sakurai, and M. Oqawa, J.Org.Chem., 1986, 51, 240. T. Nakano, T. Terada, Y. I s h i c and M . Ogawa, Synthesis, 1986, 774. J.-M. Melot, F. Texier-Boullet, and A. Foucaud, Tetrahedron Lett., 1986, 27, 493. g i r o u z a b a d r A.R. Sardarian, H. Moosavipour, and G.M. Afshari, Synthesis, 1986, 285. T. Brunelet, C. Jouitteau, and G. Gelbard, J.Org.Chem., 1986, 51, 4016. H.-J. Cristau, E. Torreilles, P. Morand, and H. Christol, Tetrahedron Lett., 1986, 27, 1775. S. Kim and D.C. Lhim, Bul~Chem.Soc.Jpn., 1986, 59, 3297. J. Singh, P.S. Kalsi, G.S. Jawanda, and B . R . Chhabra, Chem.Ind. (London), 1986, 751. M . L . Mihailovic, S. Konstantinovic, and R. Vukicevic, Tetrahedron Lett., 1986, 27, 2287. H. Firouzabadi, D. M o h a y e r and M.E. Moghaddam, Synth.Commun., 1986, 16, 211. H. FirGzabadi, D. Mohayer, and M.E. Moqhaddam, Synth.Commun., 1986, 16, 723. K . S . Kim, Y.H. Song, N.H. Lee, and C.S. Hahn, Tetrahedron Lett., 1986, 27, 2875. K. Yamawaki, T. Yoshida, T . Suda, Y. Ishii, and M . Ogawa, Synthesis, 1986, 59. _____ K. Yamawaki, T. Yoshida, T . Suda, Y. Ishii, and M. Ogawa, Synth.Commun., 1986, 16, 537. S. Kanemoto, H. Tomioka, K. Oshima, and H. Nozaki, Bull.Chem.Soc.Jpn., 1986, 59, 105. Y. Watanabe, T. Arakai, Y. Ueno, and T. Endo, Tetrahedron Lett.., 1986, 27, 5385. H a n o , M. O z t a , and T. Migita, Chem.Lett., 1986, 77. D.F. McComsey, A.B. Reitz, C.A. Maryanoff, and B.E. Maryanoff, Synth.Commun., 1986, 16, 1535. S. Araki, M. Hatano, and Y. Butsuqan, J.Orq.Chem., 1986, 51, 2127. J.Orq.Chem., 1986, 51, 2378. A. Leone-Bay, ___C.K. Leau, C. Dufresne, P.C. B e l a E e r , S. Piertre, and J. Scheiqetz, J.Orq.Chem., 1986, 51, 3038. S. Cacchi, P.G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1986, 27, 5541. _-
s,
s,
142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165.
z,
4: Alcohols, Halogeno-compounds, and Ethers
166. 167. 168. 169. 170. 171. 172. 173 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. 202.
259
J.Y. Gauthier, F. Bourdon, and R.N. Young, Tetrahedron Lett., 1986, , 27.. 15. P. Rollin, Synth.Commun., 1986, 2,611. E. Slusarka and A. Swierzak, Liebigs Ann.Chem., 1986, 402. U . Sunay, D. Mootoo, B. Molino, and B. F r G - R e i d , Tetrahedron Lett., 1986, 27, 4697. J.W. Kelly and S.A. Evans,J.Am.Chem.Soc., 1986, 108, 7681. G. Balme, G. Fournet, and J. Gore, Tetrahedron Lett., 1986, 27, 1907. J. Barluenga, J.M. Martinez-Gallo, C. Najera, and M. "us, J.Chem.Res. ( S ) , 1986, 275. J. Berthelot and M. Fournier, Can.J.Chem., 1986, 64, 603. J. Barluenga, M.A. Rodriguez, J.M. Gonzalez, and P.J. Campos, Tetrahedron Lett., 1986, 27, 3303. T.H. Chan and K. Kuomaglo, Tetrahedron Lett., 1986, 27, 883. M. Taniguchi, S. Kobayashi, M. Nakagawa, T. Hino, andY.Kishi, Tetrahedron Lett., 1986, 27, 4763. S.H. Cheon, W.J. Christ, L.D. Hawkins, H. Jin, Y. Kishi, and M. Taniguchi, Tetrahedron Lett., 1986, 27, 4759. M. Taniguchi, T. Hino, and Y. Kishi, Tetrahedron Lett., 1986, 27, 4767. H.C. Brown, N.G. Bhat, and S. Rajagopalan, Synthesis, 1986, 480. T.J Mason, J.P. Lorimer, A.T. Turner, and A.R. Harris, J.Chem.Res.(S), 1986, 300. S.H. Lee and J. Schwartz, J.Am.Chem.Soc., 1986, 108, 2445. G. Meyer, Y. Rollin, and J. Perichon, Tetrahedron Lett., 1986, 27, 3497. F. Bellesia, F. Ghelfi, R. Grandi, and U.M. Pagnoni, J.Chem.Res.(S), 1986, 426, 428. J. Glaser and I. Toth, J.Chem.Soc., Chem.Commun., 1986, 1336. A.G. Martinez, R. Martinez Alvarez, A. Garcia Fraile, L.R. Subramanian, and M. Hannack, Synthesis, 1986, 220. R. Breslow and M. Mehta, J.Am.Chem.Soc., 1986, 108, 2485. T. Miyazawa and T. Endo, Tetrahedron Lett., 1 9 6 F 2 7 , 3395. J.M. Aizpura, F. Cossio, and C. Palomo, J.Org.Chem.., 1986, 51, 4941. F. Gavina, S . V . Luis, P. Ferrier, A.M. Costero, and J.A. Marco, J.Chem.Res.(S), 1986, 330. K. Takai, K. Nitta, and K. Utimoto, J.Am.Chem.Soc., 1986, 108, 7408. S.C. Sondej and J.A. Katzenellenbogen, J.Org.Chem., 1986, 51, 3508. A.T. Costello and D.J. Milner, Synth.Commun., 1986, 16, 1173. R. Wolf and E. Steckhan, J.Chem.Soc., Perkin Trans.171986, 733. A. Amrollah-Madjdabadi, R. Beugelmans, and A. Lechevallier, Synthesis, 1986, 828. G.A. Olah, 1. Ohannesian, and M. Avanaghi, Synthesis, 1986, 869. S. Jeropoulos and E.H. Smith, J.Chem.Soc., Chem.Commun., 1986, 1621. P. Li and H. Alper, J.Org.Chem., 1986, 2,4354. A.N. Abeywickrema and A.L.J. Beckwith, Tetrahedron Lett., 1986, 27, 109. Y. A k i G , A. Inoue, K. Ishida, K. Terui, and A. Ohta, Synth.Commun., 1986, 3, 1069. I. Pri-Bar and 0. Buchman, J.Org.Chem., 1986, 51, 734. M. Satoh, N. Miyaura, and A. Suzuki, C h e m - l e t t z 1986, 1329. G.A. Molander and D.C. Schubert, Tetrahedron Lett., 1986, 27, 781.
260
203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219.
General and Synthetic Methods
P.L. Castle and D.A. Widdowson, Tetrahedron Lett., 1986, 2, 6013. N. Miyaura, T. Ishiyama, M. Ishikawa, and A. Suzuki, Tetrahedron Lett., 1986, 27, 6369. Marinaelli, Tetrahedron Lett., A. Arcadi, S. Cacchi, and?. 6397. 1986, 7, T. Taguchi, 0. Kitaqawa, T. Morikawa, T. Nishiwaki, H. Uehara, H. Endo, and Y. Kobayashi, Tetrahedron Lett., 1986, 27, 6103. V.B. Baillarqeon and J.K. Stille, &Am.Chem.Soc., 1986, 108, 452. F. Francalaci, E. Bencini, A. Gardano, M. Vincenti, and M. Foa, J.Orqanometa1. Chem. 1986, 101,C27. T. Kashimura, K. Kudo, S. Mori, and N. Sugita, Chem.Lett., 1986, 851. N.A. Porter, D.R. Magnin, and B.T. Wright, J.Am.Chem.Soc., 1986, 108, 2787. V. Janout and P. Cefelin, Tetrahedron Lett., 1986, 27, 3525. T. Hamada and 0. Yonemitsu, Synthesis, 1986, 852. P. Dave, H.-S. Byun, and R. Engel, Synth.Commun., 1986, 16, 1343. S. Suzuki, T. Onishi, Y. Fujita, H. Misawa, and J. Otera, Bull.Chem.Soc.Jpn., 1986, 59, 3281. M. Shimizu, Y. Nakahara, and H. Yoshioka, J.Chem.Soc.,Chem. Commun., 1986, 867. D.A. Goff, R.N. Harris, J.C. Bottaro, and C.D. Bedford, 4711. J.Org.Chem., 1986, G.A. Olah, T. Yamoto, P.S. Iyer, and G.K.S. Prakash, J.Org.Chem., 1986, 2826. C. Bruckner, H. Lorey, and H.-U. Reissiq, Angew.Chem.Int.Ed. Enql., 1986, 25, 556. K. Soai, S. Niwa, T. Yamanoi, H. Hikima, and M. Ishizaki, J.Chem.Soc.. Chem.Commun.. 1986. 1018. M. Jalali-Naini and J.-Y. Lallemand, Tetrahedron Lett., 1986, 27, 497. H.M.C. Ferraz and T.J. Brocksom, Tetrahedron Lett., 1986, 2, 811. P.A. Bartlett and C. Chapuis, J.Org.Chem., 1986, 51, 2799. 3013; D.R. Williams and J.G. Phillips, Tetrahedron, 1986, see D.R. Williams, J.G. Phillips, and F.H. White, Tetrahedron, 1986, 42, 3003 for related studies into the synthesis of the precursors for this conversion. 0. Moriya, Y. Urata, Y. Ikeda, Y . Ueno, and T. Endo, 4708. J.Org.Chem., 1986, J.C. Heslin, C.J. Moody, A.M.Z. Slavin, and D.J. Williams, Tetrahedron Lett., 1986, 27, 1403. M.F. Schlecht and H.-J. Kim, Tetrahedron Lett., 1986, 27, 4889. R.C. Winstead, T.H. Simpson, G.A. Lock, M.D. Schiavelli, and D.W. Thompson, J.Org.Chem., 1986, 51_, 275. L.E. Overman, T.A. Blumenkopf, A. Castaneda, and A.S. Thompson, J.Am.Chem.Soc., 1986, 51, 3'516. S.G. Davles, M.E.C. Polywka, a n d S . E . Thomas, J.Chem.Soc., Perkin Trans.1, 1986, 1277. J. Blagg, S . G . Davies, N.J. Holman, C.A. Laughton, and B.E. Mobbs, J.Chem.Soc., Perkin Trans.1, 1986, 1581. T. Takahashi, H. Nemeto, Y . Kanda, J. Tsuji, and Y. Fujise, J.Orq.Chem., 1986, 51, 4315. J.A. Marshall, T.M. Jenson, and B.S. Dehloff, J.Orq.Chem., 1986, 2,4316. J . Otera, Y. Niibo, and K. Okuda, Chem.Lett., 1986, 1829.
z, z,
'
220. 221. 222. 223.
224. 225. 226. 227. 228. 229. 230. 231. 232. 233.
s,
z,
4: Alcohols, Halogeno-compounds, and Ethers
234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256.
26 1
S. Sakane, J. Fujiwara, K. Maruoka, and H. Yamamoto, Tetrahedron, 1986, 42, 2193. M. Katoh, H. KitahaE, and A. Yoshikoshi, Bull.Chem.Soc.Jpn., 1986, 2,1647. D.N. Harpp and M. Kobayashi, Tetrahedron Lett., 1986, 27, 3975. N.X. Hu, Y. Aso, T. Otsubo, and F. Ogura, Bull.Chem.Soc.Jpn., 1986, 59, 879. S . A h m a and J. Iqbal, Tetrahedron Lett., 1986, 27, 3791. J.R. Babu and M.V. Bhatt, Tetrahedron Lett., 1986, 27, 1073. B.M. Trost and T.S. Scanlon, Tetrahedron Lett., 1986,27, 4141. P.R. Auburn, J. Whelan, and B. Bosnich, J.Chem.Soc., Chem. Commun., 1986, 146. T. Harada, A. Karasawa and A. Oku, J.Org.Chem., 1986, 51, 842 K. Takagi, Chem.Lett., 1986, 1379. N. Ono, T. Yanai, and A. Kaji, J.Chem.Soc., Chem.Commun., 1986. 1040. G. Petrillo, M. Novi, G. Garbarino, and C. Dell'Erba, Tetrahedron, 1986, 4007. B.M. Dilworth, Tetrahedron. 1986, 42, 3731. M. Madesclaire, Tetrahedron, 1986, 42, 5459. J.V. weber. m. Schneider. B. SalamiTand d. Pasuer, Recl.J.Roy:Nth.Chem.Soc.; 1986, 105; 99. T.L. Evans and M.M. Grade, Synth.Commun., 1986, 16, 1207. T. Imamoto and H. Koto, Chem-Lett., 1986, 967. A. Yamagishi, J.Chem.Soc.Chem.Commun., 1986, 290. T. Ando, D.G. Cork, and T. Kimura, Chem.Lett., 1986, 665. M.R. Euerby and R.D. Waigh, ., 1986, 16, 779. S . Cabiddu, C. Floris, and S. Melis, Tetrahedron Lett., 1986, 27 , 4625. S . Hackett and T. Livinghouse, J.Chem.Soc., Chem.Commun., 1986, 75. J. Otera, J.Synth.Org.Chem.Jpn., 1986, 44, 459.
c
J
Amines, Nitriles, and Other Nitrogencontaining Functional Groups BY C.M. MARSON 1
Amines
Primary Amines.
-
Reductive methods in the preparation of amines
continue to be popular.
In particular, anilines can be prepared
under mild conditions and in good yields by reduction of nitrobenzenes with the new system of diborane-nickel(I1) chloride. Selective reduction in the presence of a number of functional groups is the chief advantage of the method. Nitrobenzenes are also reduced to anilines by di-isobutyl telluride in the presence of titanium(1V) chloride. The sensitivity of sulphide salts to the steric environment of the nitro group in a Zinin reduction has allowed
3-methyl-2-nitrobenzotrifluoride to be isolated unchanged from a mixture of the four nitro isomers, the three other isomers being reduced to the corresponding anilines. a-Alkyltryptamines were prepared by conjugate addition of indoles to 2-nitroalkenes, and reduction of the nitroalkanes so formed with hydrazine hydrate and nickel boride.
4-Aminoindoles, suitable
precursors of the telocidins, have been prepared by regioselective nitration of indoles with nitric acid in acetic acid, followed by reduction. Reduction of nitriles has been used to prepare branched primary amines by alkylation of the nitriles followed by reduction of the imine intermediate with lithium-ammonia.
4-Amino-2-quinolones were
produced by the cyclization of N-(a-halogenoacyl)-N-alkyl substituted anthranilonitriles induced by Grignard or organolithium reagents. I
Carbocyclic 2-amino-esters can be obtained by
cyclization of ethyl ylidene cyanoacetates i.n sulphuric acid (Scheme
1)
.* Several azides have been converted into primary amines in high
yields using tin (11) chloride in methanol.
Catalytic reduction of
an azide to an amine was used in a synthesis of the antibiotic oxetin."
Aryl azides can be converted into anilines by the water
262
263
5: Amines, Nitriles, and Other Nitrogen-containingFunctional Groups
Reagent.
I,
H2SOL, 0 ° C
Scheme 1
Reagents
I, C F 3 C 0 2 H ,
11,
CF3C02H, CF3S03H
Scheme 2
Reagents
I,
M g , EtZO,
11,
Bu”LI,
III,
(Ph0)2P(0)N3,
Scheme 3
IV,
LIAIH~
General and Synthetic Methods
264
SCPh3
A
x2
X,= 0 or -N
4:HzI,,
k N \5J N
$(CH,)n
CO,H
HN CO,PN B
HNC0,PNB
(1) n = l o r 2
J& 0
( 2 ) n = 1 or 2
4 r H , ) n
S
R CO, H
(4)n = 1 or 2
( 3 ) R =CN R = CH2NHC02PNB
R = NH,, NHCH=NH,
or CONH,
( P N B = p-CH,C,H,NO,) R e a g e n t s I , HCL aq , 1 1 , P h CCL, C H N , 3 5 5
CIC0,Et.
111,
V I I , H ~ S ,vIII,NH~OH, MeOH, IX,TICI,,
Et3N.
Me--NAO.
u
IV,
NaN3, v, PNB-OH,A,
Scheme 4
1
I,
B u t O K , DMSO,
11,
NHLCI a q
Scheme 5
Hg(0Ac)Z.
T H F , x , L I A I H , + , x l , M e 3 S I C I , Pr;NEt,
MeCN , X I I , CLC02 PNB
Reagents
VI,
265
5: Arnines, Nitriles, and Other Nitrogen-containing Functional Groups
Reagents
I,
B u n L i , THF,-45
" C , 11,
(Ph0I2P(O)N3,
v, N a O H a q , MeOH ( R = O M e ) ,
111,
NaAIH2(0CH2CH20Me)2,
IV,
HCI,
HI, P ( R = H )
VI,
Scheme 6
fi &
R'
IH z N 2 f i
\
N
R
I
0Reagents
I,
KNHZ, NH3;
11,
R'
A
R1
H 2 i f i
,NH N+
N:
0-
0-
I
I
KMn04
Scheme 7
- x,
+
RI-CHO
?*Me
I
R'
SAMP
I1
NH2
I
81 - 9 4 % e.e. R e a g e n t s : 1,
R 2 L i , T H F , ii, H 2 , N i
Scheme
8
q O M e
N ''
I
266
General and Synthetic Methods
gas reaction, using a catalytic quantity of rhodium(111) trichloride. Amino-dihydrophenanthridines and benzo [c]chromans have been prepared by the intramolecular trapping of nitrenium ions obtained from azido precursors (Scheme 2) . I 2 Aromatic and heteroaromatic amines have been prepared in a one-pot process by treatment of Grignard or organolithium reagents with diphenyl phosphorazidate followed by reductive work-up of the triazene anions (Scheme 3) . l 3 Two new amino-substituted carbapenems (4) have been ~ynthesised.'~ The syntheses involved the stereospecific preparation, via a Diels-Alder reaction, of the cis-substituted cycloalkylthiols (l), (2), and (3) which were
~
reacted with a 2-oxo-(5~)-carbapenam-(3R)-carboxylate, and the resulting carbapenem esters converted into the desired derivatives (4)
(Scheme 4). The direct amination of nitrobenzenes by vicarious nucleophilic
substitution has been achieved using 4-amino-lI2,4-triazole in the presence of potassium t-butoxide (Scheme 5) . Guanosine undergoes amination to give 7-arninoguano~ine~~ when treated with 2,4-dinitrophenoxyamine; deoxyguanosine affords 7-aminoguanine, deglycosylation occurring because 7-substituted cationic deoxyguanosines are readily susceptible to hydrolysis. 3-(Trifluoromethoxy)aniline was prepared by the regiospecific arynic amination of 2-chloro (trifluoromethoxy)benzene. I 7 3-Alkoxyanthranilic acids have been prepared by regioselective amination of aryl oxazolines using diphenyl phosphorazidate (Scheme 6) . l 8 Photochemical amination of 1 ,2,4 ,5-tetracyanobenzene in the presence of N-methylpyrrolidine or nicotine gave tricyanoaniline as well as substitution products.
An amination-oxidation procedure
allows an amino group to be introduced into the 5-position of 4-nitropyridazine 1-oxides (Scheme 7) . 2o A similar procedure allows alkylamination at the 4-position of 6,7-disubstituted pteridines. 21 Enantiomerically pure 2-substituted cyclopentanamines are obtained from racemic cyclopentanones by reductive amination; the ketone is condensed with an optically active 1-phenylethylamine, the imine mixture hydrogenated with Raney nickel, and the optically active, diastereoisomerically pure secondary amine is hydrogenolysed with palladium-on-carbon to give the enantiomerical ly pure 2-substituted cyclopentanamine.22 Aminoarylhydrazones can be prepared by selective reduction of nitroarylhydrazones by catalytic transfer hydrogenation using cyclohexene and palladium-on-carbon.23 Nucleophilic addition to
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
2 ArCHO
267
+ H,NSO,NH,
(ArCH=N),SO,
Y R
I
I
I V
A rCHN H 2
Reagents
R
R
'
,'H
I,
PhMe,
11,
RLI o r RMgX;
111,
I
iii
(ArCH-NH3),S04
CgH5N a q ,
(ArCH-
IV,
NaOH aq
N
H
NH),SO,
Scheme 9
'D4
N'
Reagents.
I,
I
B u t O K ( 2 e q u i v ), T H F ,
11,
H30+
S c h e m e 10
NHCN
P h~
Ph
Reagents
I,
p-xylene, 125'C;
11,
p-xylene, 138°C
Scheme 1 1
C
N
268
General and Synthetic Methods
99 '1. e.e,
1.
99'1. e.e. Ph I
0-
L ( - H
NH2HCI
NHzHCI
> 99 '10 e.e.
99 *I. e.e.
99 'I. e.e.
0
0
II
II
?H
PhC,
mu I t istep
H bH
Cif+Hm
W C14H29
O NHZ
(6)
(7) 0
II
R e a g e n t s : i, Ph3P, Et02C - N=N-CO
2 Et, C6H/>NH,
ii
0
S c h e m e 13
THF
OH
269
5: Amines. Nitriles, and Other Nitrogen-containing Functional Groups
0
II (EtO),P-N-C02CMe3-
ROH
RhH3CI-
I
R
0
I1
R e a g e n t s : i , (Et0)2P-NHC02CMe3,
EtO CN=NCO
2
2
Et, P h P; 3
HCI
ii,
Scheme 14
phv* y0
111, I,lV,V,
I1,vI
HO C
0
VI
Ph&
I
NH2
1
H N C O ~ B ~
NH 2
(8) Reagents
I,
PhLi,
11,
CF CO H, HCL, Et20, 3 2
III,
Bu"LI,
IV,
CF3C02H, v, H2C204,Et20,
VI,
base
S c h e m e 15
H,N+
Reagents
m C H 2 0 H
HNTS
+
CI-
TsNH
TSNH
+NH3
HNTs
I,
u -CMS Msol Ill, I V
NTs
TsN
T s C I , NaOH aq ; I I , B H , T H F ,
2 6
III,
CI(CH2)30H, K2C03, D M F ,
CH2C12, E t 3 N , v, Cs2C03 ( 4 e q u i v 1, DMF, 8 0 ° C , MeOH ( 4 e q u i v )
S c h e m e 16
VI,
IV,
MsCL,
L I , NH3, THF,
270
General and Synthetic Methods
hydrazones derived from ( R ) - or (z)-l-amino-2methoxymethylpyrrolidine is the basis for an enantioselective conversion of aldehydes into alkyl-substituted primary amines (Scheme 8). L 4 Primary amines, as their alkylammonium toluenesulphonates, were prepared by refluxing primary amides in acetonitrile containing A new route to primary amines [ hydroxy (tosyloxy)iodo]benzene. 2 5 involves the addition of organometallic reagents to
.
diarylidenesulphamides, followed by hydrolysis (Scheme 9) 2 6 Aminomethylphosphonic acid can be prepared by treating N-hydroxymethylbenzamide with a mixture of phosphorus trichloride and trimethyl phosphite, followed by hydrolysis of the intermediate ester. 2 7 Asymmetric reduction of chiral oxime ethers with lithium aluminium hydride or diborane-THF gives the optically active primary amines in modest optical yields: 28 the chiral portion was derived from B-pinene or a-amino acids.
2,2-Dialkylcyclopropylamines can be
prepared by the base-induced cyclization of a-chloroimines,followed by hydrolysis (Scheme 10); activating groups, which enhance 29 deprotonation of the a-chloroimine, are required. Allylic thermal rearrangement of cyanamides constitutes a method for the formal lI3-isomerization of allylamines (Scheme 1 1 ) . 3 0 Oxidative conversion of allylic selenides into allylic selenilimines and [3,2] sigmatropic rearrangements of the latter afford a route to allylamines."' Primary amines of essentially 100% optical purity have been conveniently obtained by the asymmetric hydroboration of a prochiral olefin, subsequent removal of the chiral auxiliary, and conversion of a boronic ester derivative into the primary amine with hydroxylamine-2-sulphonic acid (Scheme 12) .
A Mitsunobu reaction
also afforded an enantiomerically pure amino compound ( 6 1 , but with the expected clean inversion of configuration. Thus, in a synthesis of D-ribo-C-phytosphingosine (7), 3 3 the amino group was introduced by treating alcohol (5) with triphenylphosphine, diethyl azodicarboxylate, and phthalimide to give the phthalimido olefin (6) (Scheme 1 3 ) . Primary and secondary alkyl alcohols are converted in good yields into amine hydrochlorides, in a new version of the Mitsunobu reaction (Scheme 14). 3 4 An azaparacyclophane bearing an amino group on each of its eight hydrocarbon chains has been prepared and found to act as a cationic host for hydrophobic derivatives of vitamin B12 . 3 5
Chiral
27 1
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
0-J
A OHC
NO2
OHC
w
HOH,C
(9) Reagents.
I,
Me2NCH(OMe$, Me2NCH0,
11,
T i C L 3 a q (13equiv1, C5H5N, THF
Scheme 17
nitramine Reagents
I,
CH,=CHCN,
KOH, M e C N ,
11,
NaBH4,MeOH,
111,
ti2' P t 0 2 , E t O H .
IV,
L I A I H ~ T, H F
Scheme 18
R~CH,SO,NR,
I- Ill
------+
A~'NH
I
A r CH-
C H S O , N R,
I
R' Reagents
I,
LDA (1.1 e q u i v ) ,
11,
ArCHENArl,
i(i, H 3 0 +
S c h e m e 19
Reagent
I,
ally1 -9-BBN
Scheme 20
272
General and Synthetic Methods
a-ferrocenylalkylamines have been prepared and tested as templates in peptide synthesis.36r37 Primary amines can be protected with the t-butyldiphenylsiiyi group which is smoothly cleaved with mild acid or with pyridine-HF. 3 8
A1 lyl and a1 lyloxycarbonyl amino acid derivatives
are deprotected by the action of tributyltin hydride, an acid, and a palladium catalysti3’ a considerable advantage of the method is the stability of benzyl and benzyloxycarbonyl groups under those conditions.
The naturally occurring amines cathinone (8) and
merucathinone have been prepared from Boc-L-alanine (Scheme 15) . 40 Secondary Amines. - Monoalkylation of primary amines continues to be an important route to secondary amines, despite the problem of overalkylation.
Irradiation of primary amines in alTohols
containing a suspension of titanium dioxide and platinum gives N-alkylated and N,N-dialkylated products .41
An optically active
spermine macrocycle has been synthesized from L-ornithine hydrochloride (Scheme 16) ; 4 2 macrocycle is formed with ATP.
a 1:1 complex of the protonated Ten kinds of linear pentaamines with
various combinations of three or four methylene chains have been prepared by successive alkylation of secondary amino derivatives of benzylamine with N-(3-bromopropyl)- or N-(4-bromobutyl)phthalimide. 43 Reduction of functionality containing nitrogen is a key method of obtaining secondary amines.
6-Indolemethanol was conveniently
prepared by reduction of the nitroenamine (9) with titanium(II1) chloride (Scheme 17) .44
The alkaloid nitramine was prepared
via
a
reductive cyclization of a y-cyano ester t o a spirolactam (Scheme 18) .45
Derivatives of 6-arylaminoethanesulphonic acids have been
prepared by the addition of sulphonamido carbanions to imines (Scheme 19) . 4 6
Phenyl azide reacts with toluene, cumene,
chlorobenzene, bromobenzene, and biphenyl in the presence of trifluoroacetic acid or trifluoromethanesulphonic acid to give mixtures of 2- and 4-substituted diarylamines, ions. 47
phenylnitrenium
Three bis (triptycyl)amines were prepared by thermolysis of
the corresponding lI3-bis(9-triptycyl)triazenes, which were obtained by the reaction of 9-triptycyllithiums with 9-triptycyl azides. 48 Unsymmetrical diarylamines have been obtained by reduction of t h e azo linkage in compounds derived by electrochemical reaction of 1arylazo-2-naphthols with anilines.49
273
5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups
n
:
l
n=2-19 Reagents,
p - T s O H , PhH,
I,
11,
H2, Pd-C
S c h e m e 21
CH=NPh
CH,NHPh
Q
I
R Reagent.
I,
R
B2H6, MeOH
S c h e m e 22
1-111
RLi
Reagents
I,
RN1Me)COPh
MeLi, M e N H O M e ,
11,
H20.
III,
PhCOCl
S c h e m e 23
RCSCSiMe3
+
Me3SiCN
A> NC
WMe3 N( SiMe3I2
H
Reagent
'
I,
PdCI2, A
Scheme
24
General and Synthetic Methods
274
Imines have been reduced to secondary amines using a stoichiometric quantity of bis(dimethylg1yoximato)pyridine cobaltate(1) ;50
although in catalytic runs the maximum optical
yield reported using a cobaloxime quinine complex was 20%, that value is near the highest known for asymmetric hydrogenation of imines.
Secondary amines have also been prepared by the reaction of
allyl-9-borabicyclo [3.3.1]nonane with chiral imines;51
very high 1,2- and lI3-asymmetric induction was realized (Scheme 20). Amines containing two chiral centres directly attached to a nitrogen atom
were prepared in 33-90% diastereoselective excesses by catalytic hydrogenation of imines (Scheme 21) ; 52 hydrogenation occurred at the less hindered face of the imine.
Macrocycles Containing four
secondary amino groupings were obtained by condensing 4-methyl-2, 6-diformylphenol with a,w-diamines, followed by reduction of the imine complex so produced.53
Just as an aromatic nitro group can
be reduced by diborane-nickel(I1) choride to an amine,' imine derivatives afford secondary amines in excellent yields when reacted with diborane-methanol (Scheme 22) ; 54
the range of
p-substituents which are unaffected is wide in both cases, even a p-nitro group remaining unchanged upon reduction of the imino group.
Reductive amination is a versatile method of preparing secondary amines.
A general route to unsymmetrical triamines
involves formation of a secondary amine by reductive amination of an aldehyde, and subsequent incorporation of a guanidine moiety; 55 acarnidine was so prepared. 55
an
9-Hydroxy-14-azaprostanoic acids have
been prepared by conjugate addition of nitromethane to
2-(6-carbethoxyhexyl)cyclopent-2-en-l-one and
via subsequent steps
including ozonolysis of nitronate salts followed by reductive amination.56
N-Isopropyl p-haloamphetamines were prepared by
sequences involving boronic acid intermediates. 57
A water-soluble,
dimeric steroid with catalytic properties can be formed by reductive amination of terephthalaldehyde with a substituted 5a-androstane-36-amine using cyanoborohydride.58 Related to the Sheverdina-Kocheshkov amination of organolithium or Griqnard reagents with methoxyamine is an amination using N-methylmethoxyamine (Scheme 23) . 5 9
The method appears to be the
only one which allows direct conversion of an organolithium reagent into a secondary amine, usually isolated as the benzamide.
5-Amino-2-cyano-4-silylpyrroles can be prepared by the palladium or nickel catalysed condensation of silylacetylenes with trimethylsilyl cyanide (Scheme 24) . 6 0
215
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
R2 )C
=c
(11) R2, R 3 = H or
(10)
I,
I
____)
'OMe
R3
Reagent
/OSi M e 3
Me
CF3S03H ( c a t )
Scheme 2 5
TsNHCH2Ts
Reagents
I,
DBU,
A
THF,
ii,
lCH2=
NTsI
C - or N - n u c l e o p h i l e s ;
NuCH2NHTs
111,
H30t
S c h e m e 26
Ph
Ph Ph Ph
Ph
Ph
Reagents
I,
(E)-PhCH=CHSiMe3,
11,
Z n , HCL a q o r
v, ( z ) - P h C H = C H S l M e 3
Scheme 27
Ra-NI, H2,
111,
H+,
IV,
KH,
General and Synthetic Methods
276
-%
R'-SePh
Reagents
I,
NCS, MeOH.
[Rid
11,
R'N-SePh
R2NH2,
III,
1-
R2NSePh
&5
[3,21
R1
R'
MeOH
Scheme 28
0
Me
I
Me
Reagent
I,
O=C=N
v
Ph
I
Me
S c h e m e 29
I
H
Me
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
211
Aminations which afford 8-aminocarboxylates are of interest in relation to monobactam antibiotics. A secondary aminomethyl group can be introduced at the a-position of carboxylic esters by reaction of hexahydro-1,3,5-triazines with ketene silyl acetals in the presence of a catalytic quantity of trifluoromethanesulphonic acid (Scheme 25). 61 The triazine (10) is considered to be converted into an y-silylated methyleneiminium salt which undergoes addition of the ketene silylacetal (11). An aminomethylation procedure involves addition of enamines or carbanions to the labile g-methylene-p-toluenesulphonamide (Scheme 26);62 the scope and limitations of this promising reaction are under investigation. a-Amino acids can be smoothly decarboxylated to the corresponding amino compounds by refluxing in mixtures of 2-cyclohexen-1-one and cyclohexanol.6 3 N-Phenylation of primary aliphatic amines and of variously substituted anilines was achieved in high yield by using a catalytic amount of copper added to triphenylbismuth diacetate.6 4 Allylic and homoallylic secondary amines were prepared by reductive cleavage of isoxazolidines formed by dipolar cycloaddition of nitrones with vinyl- and allyl-silanes, respectively (Scheme 27) . 6 5 The approach is useful because the geometry of the alkene can be controlled by choosing the conditions of elimination. Azaphospha macrocycles have been prepared from diethylenetriamine. 66 Rearrangement of selenilimines obtained by the oxidation of allylic selenides affords a route to allylic secondary amines.[31] Amines obtained by allylic rearrangement were prepared by treating a variety of aliphatic or aromatic primary amines with an allylic selenide activated by N-chlorosuccinimide (Scheme 28) .67 Chemical resolutions of (+)-mecamylamine (12) and of (+)l-noreseroline 2-methyl ether (15) have been reported which give the optically active amines in high yield and excellent optical purity (Scheme 29) .68 Thus, the diastereoisomers (13) and (14) of (a-methylbenzyllurea underwent thermal fragmentation in refluxing ethanolic sodium ethoxide, affording ( - ) - (12) and (+)-(12), respectively. A similar procedure was used to resolve the ether (15).
B-Trimethylsilylethanesulphonyl chloride is a useful reagent
for the protection of primary and secondary amines as their sulphonamides which can be cleaved using fluoride anion. 69
General and Synthetic Methods
278
p- + vy
NHTs
Y
I, I1
___)
TsHN
Ts
1
Reagents
I,
Y = TsN
Y = TsN
Cs2C03, D M F , 8 0 " C ,
11,
33 "1. H B r , AcOH, P h O H
Scheme 30
Ts
( X = CH, Reagents
I,
BrCH2XBr,
11,
H2S04. HCL
S c h e m e 31
or p - C 6 H 4 C H z )
279
5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups
Ar
k,
A
CI r k
7
+
NMe2 ClOi
N Me2
A
r
S
NMe,
R R e a g e n ts
I,
DMF, P0CL3
11,
MeOH, HCIOL a q ,
111,
NaBH3CN, MeOH,
IV,
R M g X , THF
S c h e me 3 2
+
ArSnR,
-
[R,N=CH,l+Cl-
ArCH2NR2
+
R3SnCI
S c h e m e 33
n =1,2or3 Reagent
I,
CF CO H ( 1 0 e q u i v ) , HCHO (1 2 equiv) , H 2 0 - THF ( 3 1 )
3
2
S c h e m e 34
R’
Reagent
I,
Lewis a c i d ,
+
11,
vNM R*
R3 C02Me
(16)
CH =NMe2
C1-, ( M e3Si0SO2CF3) , CH2CIZ
S c h e m e 35
280
General and Synthetic Methods
Irradiation of N-tosylamines in aqueous ethanol in the presence of an aromatic electron donor such as 1,4-dimethoxybenzene, and a reductant such as sodium borohydride induced detosylation and liberation of the corresponding primary or secondary amine;70 selective deprotection of some NE- tosyl-lysine peptides was successful. Some macrobicyclic polyamines, isolated as their hexatosylate salts, have been prepared (Scheme 30) ; 7 1
in their hexaprotonated
forms they bind strongly a variety of anions, including nitrate, sulphate, and chloride. Tertiary Amines.
-
Alkylation under a variety of conditions
continues to be an important route to tertiary amines. Irradiation of secondary amines in alcohols containing a suspension of titanium dioxide and platinum gives tertiary amines, the incorporated alkyl chain being derived from the alcohol .41 Macrocycles containing two tertiary amino groups have been synthesized (Scheme 3 1 ) ; binuclear complexes with nickel (11) or copper(I1) ions.72
they form If the
length of the chain joining the tetra-aza units is sufficiently short, (e.g.X=CH2), two distinct one-electron redox processes can be observed, indicating that the two metal ions interact with each other. Tertiary allylamines have been prepared by several routes, including reductive methylation of imines, Mannich condensations involving acetophenones followed by reduction and dehydration, or by Mannich reactions employing alkynes, with subsequent h y d r ~ g e n a t i o n . ~The ~ scope of N-phenylation of aromatic secondary amines by condensation with cyclohexane-lI4-dione has been investigated;7 4 a variety of diphenylamines and certain other diarylamines may be used. N,N,N',N'-Tetraphenylbenzidine was prepared in good yield.74 (E)-l-Chloro-3-(~,~-dimethylamino)-l-arylprop-l-enes are conveniently prepared from aryl chloropropeniminium salts by Those iminium salts also
reduction with sodium cyanoborohydride.7 5
undergo 1 I 2-addition of Grignard reagents (Scheme 32) .76 N,N-Dialkylaminomethyl arenes can be obtained by the reaction of
aryl trialkylstannanes with dialkylmethyleneiminium salts (Scheme 33) .77 Cyclic tertiary amines can be prepared by intramolecular cyclization of iminium salts with allylsilanes (Scheme 3 4 ) ,78 a method particularly relevant to the synthesis of alkaloids; a similar procedure affords 3-vinylpyrrolidines. a-Amino-methylated
28 1
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
Reogent
I,
E t Z A I C L R 2 R 3 N H ( 2 equiv.)
Scheme 3 6
qNHC0,Et
I ii
I
NHC0,Et
N3
\
CI
N H CO, E t \
N3 Reagents
I,
CI,NC02Et,
11,
NaHS03,
III,
N o N 3 , iv, N O H , D M F ,
v, N a N j , NH4CL
Scheme 37
17
Reogent :
I,
n
0
NH, 3 0 "C
LJ
S c h e m e 38
282
General and Synthetic Methods
-oxo-esters (16) can be obtained by the Lewis acid-promoted addition of cyclopropanes to iminium salts (Scheme 35) ; 7 9
these
y-0x0-esters can serve as precursors of a-methyleneY -butyrolactones.
The first examples of anodic amination of saturated aliphatic ethers have been reported: 2-aminotetrahydrofurans were prepared by the anodic oxidation of lithium amides and aminomagnesium bromides in
Tertiary amines have been prepared by the aminolysis of
activated cyclopropanes, amidation being minimized by choosing the di-t-butyl esters (Scheme 36) .81 New 'shell-shaped' macrobicyclic compounds containing a tertiary amino group have been prepared from monoaza-crown ether diols.82
Crown ethers consisting of a benzo-crown unit and a
monoaza-crown unit connected by an oxyethylene linkage have been reported;83 their complexation is closer to that of lariat monoazacrown ethers than to that of bisbenzo-crown ethers.
Macrocycles
characterized by a parent macrocyclic liqand and cation-ligating donor 'arms' have been prepared, 1,4,8,11-tetrabenzy1-1,4,8,11-
tetra-azacyclotetradecane being representative: 8 4
a furan-bearing
macrocycle of this category showed high catalytic activity in certain phase-transfer reactions. Amino ethers of trans-2-phenoxycyclohexanol have been prepared by coupling the anion of 2-phenoxycyclohexanol with halogenated tertiary amines under anhydrous conditions or those involving phase-transfer catalysis.85 Optimized conditions for the synthesis of bis(4-dialkylaminoary1)squaraines from di-n-butyl squarate and
_N,N-dialkylanilines _ have been reported;86 yields are comparable with routes based upon squaric acid. Diamines. - Traditional approaches to vicinal diamines involve the opening of epoxides or aziridines.
An alternative approach (Scheme
37) involves the addition of N,N-dichlorourethanes to olef ins;87 both the cis- and trans-azides underwent reduction to the corresponding diamines. Chiral ligands containinq 1,2-diamino groups have been prepared which afford useful enantioselectivities in the addition of cuprate reagents to 2-cycloalken-1-ones.88 Bicyclic diamines can be prepared in a one-pot reaction between alkane-lr2-diamines and triethyleneglycol ditosylate (or similar tosylamines) , without using conditions of high dilution.89 An improved resolution of (+)-lr2-diphenylethylenediamines using optically active mandelic acid has been reported.
283
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
Me
+
Me
1,
Me
I
I - 0 1
(17)m= n = 1 ;
m=2,
n = I ; or
m = n = 2 Reagents
I,
Et3N, P h H ,
11,
B2H6,THF,
111,
M ~ ( O A C ) ~ - A C O bHu f f e r ,
12, THF
Scheme 39
Reagents
0
I,
& , 11,
HCL, MeOH
I
III,
SOC12,
IV,
S c h e m e 40
KPPh2, d i o x a n e
284
General and Synthetic Methods
Reagents
I,
T S O [ ( C H ~ ) ~ O C H N~ aI 2~C,0 3 , M e C N ,
11,
T s O [ ( C H 2 ) 2 0 C H 2 ] 2 , Cs2C03,MeCN
S c h e m e 41
+NHTS
+
I$
Ts
TsN
NHTs
Br Ts
( 1 9 ) n = 1 , 2 or 3
Ts R = H or M e Reog e n t .
I,
KZC03, DMF
Scheme 4 2
285
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
lJ3-Alkanediamines have been prepared by reduction of 4-amino-1-azabutadienes with sodium-isopropanol . Two amino functions have been introduced into a dibrominated steroid nucleus by the action of a large excess of either morpholine, or piperazine, or an N-substituted piperazine (Scheme 38) : the same regio- and
'*
stereo-selectivities are observed in the case of 1,8@-dibromo-10-methyl-A1 -octal-2-one. Disiloxanediyl diamines were prepared by the homocondensation of amino silanols such as (4-aminopheny1)methylphenylsilanol in the presence of tetrabutylammonium hydroxide. 9 3 A cyclophanediamine has been condensed with a crown ether diacid dichloride to give a new type of dissymmetric macrotricyc1 ic cryptand. The cryptahemispherands (17) are members of a new class of host which are half spherand and half cryptand. They were synthesized by condensing diacid chlorides with appropriate cyclic diamines (Scheme 39) ,9 5 followed by reduction and decomplexation. The cryptahemispherands are highly selective, binding strongly hosts for alkali metal ions J 9 6 and are in general more powerful complexing agents than the cryptands.
A
series of phosphine-functionalized diamine macrocycles has been prepared (Scheme 40) ;9 7 the 1 ,7-dithia-4,lO-diazacyclodecanes were prepared similarly. The combination of 2- and 0- (or 2-1 sites with P-sites provides ligands capable of bonding to dissimilar metals in proximity.9 7 Polyamines. - The macrotricyclic triamine (18) has been synthesized and reacted with palladium(I1) acetate and subsequently with sodium perchlorate to give a new kind of organometallic macrocycle, in which one carbon atom of the multidentate ligand is directly metallated.98 Bi- and tri-cyclic triamino azacrowns have been prepared from 1,4,7 10-tetra-azacyclodecane;9 9 using caesium carbonate, the reaction proceeds to a tricyclic product (Scheme 41) whose complex with sodium iodide involves only two rings; internal conversion via a symmetrical octacoordinate complex is proposed for this unsymmetrical complex. In a search for chemical congeners of coenzyme-B6, series of polyazapyridinophanes and polyazaparacyclophanes were synthesized in excellent yields (Scheme 42) , l o o the former by condensing ~
dichloropyridoxine derivatives with ethanamines (19). a:y-Diamino derivatives of steroids have been prepared by displacement reactions on a, v-dibromo-a,6-enone steroids. lo' Syntheses and coordination properties of twelve- and fourteen-
286
General and Synthetic Methods
Ts
"<:"
R2?-\.
'X
(20) X = CN o r C 0 2 M e Reagent
'
(21 1
R2NCH=CH2
1,
Scheme 43
Reagent
I, Me3SiOS0 CF , Et3N 2 3
S c h e m e 44
R = H or
Me Scheme 4 5
+
3(RCH,CH,),N
ZR,CF,I
1'
R,CF,C=
CHN(CH,CH,R),
I
+ R,CF,
H
R (22) R = H, Me or Et R,
= CF3(CF2),;
R, = CI(CF2),; Reagent
I,
n = 2 or 4 n = 1,3,5 or 7
[Pd(PPh3)&1
Scheme 46
+
2(RCH,CH,)3N.HI
287
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
0 R lLR + XYCHNMe2 2
R'
yo
C-CHNMe,
4R' b
N
M
e
,
R2
(23) X = Y = O M e ; X = N M e 2 , Y = O B u ' ; or X Reagent
= Y =NMe,
I, L l A L H L
S c h e m e 47
NHR'
--
-
CH,OH
Reagent
+
R
D
R'
\
--!.-+
E
~
~
/
CHO
,N-CH=C Ar
Hg(OAc),,
I,
2
'NR'(Ar
N
S c h e m e 48
H
R2
I
+
R'O-CH-C-CH
(11
R ' = MeCO, PhCO or Et R 2 = a l k y l o r Ph Reagents
1,
R2
-k R'O-CH-C=CH, I
I
Z =CH2 o r 0
Hg ( O A c ) 2 , THF ,
11,
H20 ( 3 e q u i v )
S c h e m e 49
"*No-
d/" Reagent
H
-
R2-C=C(N0,)CONHPh
I
HNR'
I , P h N C O , MeCN
Scheme 50
R2
0
I II R'O-CH---Me
1
288
General and Synthetic Methods
membered t e t r a a z a m a c r o c y c l i c - N , N " " , N "-' - t e t r a - a c e t i c
acids have
been reported. 1 4 ,8 ,11-Tetra-azacyclotetradecanes having a pendant carboxy group have also been prepared. ' 0 4 Two approaches to the synthesis of ~,N'-di(2-hydroxybenzyl)ethylenediamineN,N'-diacetic acid and its derivatives have been reported: I o 5
the
diacid is a useful chelating agent for iron(II1) and other metal ions. New polyamine macrocycles were prepared by an in situ reduction of thiophen-2,5-dicarbaldehyde and a 1,n-alkanediamine using a mixture of sodium borohydride and borax. lo' Thirty-two- and thirtyeight-membered macrocyclic diamines containing two 'di(trimethy1ene) triamine' groups have been synthesized and shown to act as ditopic coreceptor molecules. I o 7 Azacyclophanes containing ethylenediamine groups and open-chain analogues have been prepared. ' 0 8 a-Hydroxy, (4-NrN-dimethylaminophenyl)polystyrenes have been prepared'" by using the anionic initiator derived from l-(4-IjrN-dimethylamino) phenylethyl ethyl ether and potassium, and ethylene oxide as the
terminator. 2
Enamines
New routes to enamines and several new applications of enamine chemistry have been reported. Treatment of tosylated isonitrosomalono derivatives (20) with dialkylenamines afforded the 2-aza-lr3-dienes (21) (Scheme 431, which can be used as precursors of lumazines and pteridines. 'I1 Thermally stable N-trimethylsilyldivinylamines can be prepared stereoselectively by reacting 2-aza-lr3-dienes with trimethylsilyl trif luoromethanesulphonate (Scheme 44) .
The uncommon 1-aza-Cope
rearrangement affords a stereospecific route to endocyclic enarnines;ll3 the rearrangement is facilitated by a methoxy group on the 1-aza-1,s-diene (Scheme 45). The enamines (22) were prepared by the palladium-catalysed reaction of triamines with perfluoroalkyl iodides (Scheme 46) .'I4 Enaminones (23) have been prepared from activated methylene compounds and amide acetals; lithium aluminium hydride gave exclusively the Mannich bases derived from lr4-reduction (Scheme 47). Enaminic carbonyl compounds have been detected in reactions leading to Hantzsch syntheses of pyridines; the rate-determining step has been shown to be the formation of an enaminic ketone.'" Cyanoenamines have been prepared from a-cyanoketones and
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
+
+
+
I
Ph3P-CHz-C~C-CCH2-PPh3
289
+
Ph,P-
CH=C-CHzCH2-
PPh,
I
HNPh 21Reagent
I,
21 -
(24)
PhNHZ
Scheme 51
0 Reagents
It
I,
( E t 0 ) 2 P N C 1 2 , CH2CIZ.
11,
Na2S03 aq,
111,
HCI, T H F
S c h e m e 52
OMe Reagents
(CHZ)5C(C1)N=0,
1,
11,
Zn,HCI.
III,
OA c
Ac20, DMAP
S c h e m e 53 EtSiO
C02Me
OCONHz
0 (2)
OH
- isomer
Reagents
I,
(25)
B u t O K , T H F , 11,lM NaOH, E t O H ,
I I I ~PhCOCI,NaHCO
- 70 "C Scheme 54
, Me CO a q , IV, D I B A L , T H F ,
3
2
290
General and Synthetic Methods
aniline.
A catalytic, two-phase synthesis of a-cyanoenamines
from carbonyl compounds and a-(N-methylani1ino)-acetonitrile has been described. l8
a-Cyanoenamines have been prepared by condensing
orthoesters, cyanoacetic acid, and secondary amines in a one-step procedure. Oxidative aminomercuriation of prop-2-ynol affords a route to 2,3-bis (N-alkylanilino) propenals (Scheme 48) . 120
Terminal,
oxyfunctionalized enamines derived from methyl ketones can be prepared by the catalytic aminomercuriation of 1-substituted prop-2-ynyl esters and ethers: 12'
hydrolysis of the enamines furnishes a-oxy-ketones (Scheme 49). Dienamines continue to find use as Diels-Alder dienes. 122' 123 2,4-Diamino-2-alkenes were prepared by reacting 3-alken-1-ynes with secondary amines, using rnercury(I1) salts in catalytic
quantities. 124 B-(Substituted carbamoyl) B-nitro-enamines are obtained by reaction of appropriate B-nitro-enamines with isocyanates (Scheme 50)
In certain cases, the analogous reaction with
isothiocyanates afforded the B-(substituted thiocarbamoy1)-4-nitroenarnines. Deprotonation of the chelating enamine derived from cyclohexanone and _ N,N,N'-trimethylethylenediamine led to complete formation of the vinyl carbanion, rather than the expected ally1 carbanion;126
several examples of direct formation of B-lithio-
enamines were given. 126 Enaminic bistriphenylphosphonium s a l t s (24) have been prepared by the addition of arylamines to but-2-yn-1 , 4-ylenebistriphenylphosphonium diiodide (Scheme 51) . 127 3
Allylamines, Homoallylamines, and Alkynylamines
6-Chloroallylamine hydrochlorides can be readily prepared from the 1,4-adducts obtained by reacting 1,3-dienes with diethyl
El!-dichlorophosphoramidate
(Scheme 52) . 128
Polyalkoxycyclohexenylamines can be prepared from Diels-Alder adducts formed from a dimethoxycyclohexa-lI3-diene and an a-chloronitroso compound (Scheme 53) . 129 Di-[~-(organosilyl)-N-alkylamlno]acetylamino]acetylenes are formed from alkyl isocyanides by treatment with phenyldirnethylsilyllithium and trialkylchlorosilanes.130 Hexatriynides can be prepared from lithium aminoacetyl ides by reaction with perchlorobutenyne. 13'
29 1
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
R ' = ~2 = B U "
96
:
4
R ' = (CH,),Ph,
R 2 = (CH,),Ph
94
:
6
R ' = (CH2),Ph,
R 2 = Me
97
:
3
90
:
10
R ' = Ph, R 2 = Me
OH rnult I step
Ar'
A r = 3, 4-(MeO),C6H3 (26) Reagents
i , L i A L H 4 , NaOMe,
THF, - 7 8 - - + 0 ° C ,
11,
L i A I H 4 , KOMe, THF, - 7 8 - + 1 5 " C
Scheme 55
P
111 1
C13H27
(27 1 OH N H C 0 C17H3 5 OH
(28)
(29) Reagents
I,
IV,
PhCH,NCO,
NaH, T H F ,
N-succinimidyl
11,
L I , EtNH2,ButOH,-78"C.
o c t a d e c a n o a t e . THF
Scheme 56
111,
NaOH, E t O H ,
292
General and Synthetic Methods
L
(30)
(31) 11,
Ill
1
Reagents
I, IV,
RCHO, S n ( O T f ) 2 , T H F ,
11,
MeMgBr, MeOH,
III,
1
Me30+ BF4-, P r o t o n Sponge,
2 M K O H , v, H30+
Scheme 57
RCHO
+
-
+
I
CNCH,C02Me
7,i'
0
vN
WCh2 PPh2
(33)
=
OH
I$
III,
R = Ph; 49'1. c.e.
Ph)
JIIt(R
OH
)II(
ph+OH
OH
~ h / $ 0 " 2 ~ '
NH2 Reagents
O*N
R = Ph; 96 *I. e.e
N Me CH, CH2NR2
% ph%c02H
NH2.HCI
[ A u ( C - C ~ H , ~ N C ) ~ ] + B F( ~ 3 3- , R
= Me
or E t ) ,
11,
NH2 HCL a q , M e O H ,
L i A l H , T H F , iv, 6 M H C I , a m b e r l i t e l R - l 2 0 8 ( H + )
S c h e m e 58
RHco
293
5: Amines, Nitriles, and Other Nitrogen-containingFunctional Groups
1
11) 111
Reagents
I,
Me2NCN, N a H ,
11,
Hg(02CCF312, THF,
III,
NaBHL,
IV,
Ba(OH)Z a q
S c h e m e 59
CCI, I
HNAO
I V
_____)
Ho&
C15H31 I
CC13
cl$43
-
H YAc
vii
Ho9 Aco9 -
OH
C15H31
OA c
(38)
General and Synthetic Methods
294
Reagents
I,
NaH(O1 equiv), THF,
i v , Me 2 C 0 a q ,
ii,
CCI3CN, THF.
v, A m b e r l y s t
III,
N - i o d o s u c c i n i r n i d e , CHC13.
A 26, P h H , vi, 2M H C L ,
Scheme
VII,
A c 0, C5H5N
2
60
NO2 threo and e r y t h f o
R 1 = H, R 2 = NO, ( t h r e o ) ~1 = NO,,
Reagents
I,
Et3N,
11,
A'=
Me2C(OMe)2, (?)-camphor -10-sulphonic
i v , e t h o x y c a r b o n y L p h t h a l i m i d e , E t 3 N , v, p - T s O H ,
S c h e m e 61
VI,
H (erythro)
acid,
III,
N2HL, K O H
AI-Hg,
5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups
4
295
Amino-alcohols
New methods of preparing amino-alcohols continue to be reported owing in part to the importance of hydroxylated amino acids and aminodeoxy-sugars.
A route to 3-amino-sugars of the daunosamine
type proceeds a hetero Diels-Alder reactionof vinyl ethers with N-acylenaminones, and subsequent transformation of the cycloadducts. 13* A stereocontrolled synthesis of g-benzoyl L-daunosamine (25) (Scheme 54) involves the intramolecular conjugate addition of a carbamoyl amino group, the reaction proceeding with exclusively 1,3-=
diastereoselectivity.1 3 3 The reduction of
0-benzyl-oximes with lithium aluminium hydride in the presence of
-
sodium or potassium r n e t h ~ x i d e lcan ~ ~ be a highly selective method for the preparation of syn-0-amino-alcohols, starting from 0-hydroxy-ketones (Scheme 55). The method afforded a stereoselective synthesis of ( 2 )-1asubine ( 2 6 ) . Ring opening of epoxides is an effective route to _ an amino-alcohols. The epoxide (27) was transformed, _via oxazolidinone route, into D-erythro-sphingosine (28) (Scheme 56) . 135 1-Phenethanolamines can be efficiently synthesized by the reaction of N-trimethylsilylated primary amines with styrene oxides; 136 isolation is straightforward, and the formation of dialkylated products is avoided. Ring opening of heterocycles, often with good stereochemical control, is an increasingly common route to amino-alcohols. The chiral glycine synthetic equivalent ( 3 0 ) , as its tin(I1) enolate, undergoes a highly diastereoselective aldol addition reaction with aldehydes to give the 2-oxazolidinones (31) (Scheme 57) The latter were transformed into enantiomericaly pure N-methyl-4-hydroxy-amino acids, such as the amino acid MeBmt
(32). The aldol condensation of aldehydes with isocyanoacctate in the presence of a chiral ferrocenylphosphine-gold(1) complex afforded
optically active 5-alkyl-2-oxazoli.ne-4-carboxylateswith high enantio- and diastereo-selectivities;138 The carboxylates are precursors of amino-alcohols and 0-hydroxy-amino acids (Scheme 58). The pyranoside (35) was synthesized by cyclization of the imidate (34) to an oxazoline which was then hydrolysed (Scheme 59) .13' A route to (-~ + ) -erythro-sphinqanine triacetate (38) (Scheme 60) depends upon the formation of 4,5-dihydrooxazole (36) via iodocyclization of an irnidate.'*'
Whereas the arnide (37) is
296
General and Synthetic Methods
R'
L -2e
)\/NHT~
R2
R'
NHTs
a
R q o M e
OMe NHTs
-NH T s
T sNH -(CH,),
-
T s N H (CH
Le
I,,
NHTs or
-
(
c
OMe
n =
I,
g
I
OMe
Reagents
t
Ts
3
6 2 "1.
-
L
-
91 'la
5 6
7 'I.
79 "lo
K B r ( 0 5 e q u i v ), KOH ( 0 5 e q u i v ) , M e O H
Scheme 6 2
,OCOP h
0
-
Br
OCOPh
,OCOPh
VII,
VIII
I
I
OCOMe Reagents
I
OCOPh I,
IV,
P h P, E t O Z C N = N C 0 2 E t ,
H3i+,
V,
6 M HCI,
VI,
OCOPh (PhCO)*NH.
o-HOC6HLCHO,
S c h e m e 63
11,
VII
NBS, C H C l 3 , E t O H . HO-,
VIII,
III,
Bun3SnH,
Ac20, C H N
5 5
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
297
RNH
R
Y
Reagents
I,
Bu‘COCl.
Et3N,
11,
b””
L i A l H , E t 2 0 , III, NaBHq, E t O H
Scheme 6 4
RO
R?
threo : erythro 3 9 7 .3 Reagents
I,
R’LI ( 1 5 equiv), Et20, - 1 O ” C ,
11,
0 1 M HCL,
III,
H2, P t O Z
Scheme 65
-.-,I
Me0
Li
R
Me0
+
R Reagents
I,
RX,
11,
(40)
HCI a q
S c h e m e 66
Reagents
I , Bu”LI,
11,
TsNJ,
III,
R’RZC=CR3R4,
IV,
S c h e m e 67
H30+
298
General and Synthetic Methods
-
HO,C
TCozH HNCOPh
H2oc ' , ) , N H : N y
4steps
II NH
Meo2C
C02Me HNCOPh
Me02C
CO, Me HNCOPh
NHZ
(L1) Reagents
I,
CH2N2, MeOH,
11,
hv, P h M e
Scheme
68
OH
OMe
I
I
-aR, 1
0 0
Reagents
I,
NO+BF4-, M e C N ,
11,
N a H , M e l , iii,'02;
S c h e m e 69
Reagents
I,
LDA,THF, - 7 5 " C ,
EtI.
11,
A ,
III,
HCL a q
Scheme 70
IV,
R'MgBr
o r R'LI
299
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
obtained by hydrolysis under neutral conditions, acidic hydrolysis affords threo-2-amino-3-iodo-octadecan-l-ol hydrochloride, which by N- and 0-acetylation affords (+)-threo-sphinganine ____ triacetate. Another route to the triacetate (38) similar to the above is based on the acidic hydrolytic ring opening of oxazine (39)
A new
route to (2)-erythro-sphingosine involves a Knoevenagel condensation of hexadec-2-enal with 2-nitroethanol (Scheme 61) : 142 modification of the route affords ceramides.
Four diastereoisomers
of a thiophosphoryl analogue of sphingomyelin have been synthesized by a general method employing phosphoramidites. 143
a-(N-Tosy1amino)aldehyde dimethyl acetals, synthetic equivalents of a-amino-aldehydes, were prepared by anodic oxidation of primary N-tosylamines in methanol containing halide ion
(Scheme
62) ; 144 a reasonable mechanism involves the transformation of a,a-unsaturated N-tosylamines into aziridines which undergo ring opening. __ cis-lI2-Hydroxyamines and related systems have been prepared by using modified Mitsunobu reactions (Scheme 63) - 145 Vicinal N-alkylamino-alcohols were prepared by
acylation-rearrangement of nitrones, followed by hydride reduction (Scheme 64) 2-Amino-alcohols have been prepared efficiently by the reaction of 9-trimethylsilylated cyanohydrins with Grignard reagents, followed by r e d ~ c t i 0n . l ~ ’ threo-2-Amino-alcohols have been prepared by addition of organolithium reagents to dimethylhydrazones (Scheme 65) ( - 1 -norpseudoephedrine was prepared by using that method. 5
Amino-carbonyl Compounds
The formation of a-amino-carboxy compounds __ via heterocyclic intermediates is rapidly gaining importance. Optically active amino acid esters (40) can be prepared from lithiated bislactim ethers by alkylation and subsequent hydrolysis (Scheme 66) .I4’
The
bislactim ether method has also been used to prepare (R)-glutamic acids150 and methyl esters of 1-aminocyclopropane-1-carboxylic acids; in the sequences which afford the latter (Scheme 671, aminocarboxycarbenes are probably involved. amino acid carnosadine (41) proceeded degradation of a pyrazoline (Scheme 68)
A synthesis of the
thermal or photochemical a , a-Disubstituted
amino acid bis-amides were prepared by photo-oxygenation of
N-methoxy-2,4-disubstituted imidazoles to give imines which were
-
300
General and Synthetic Methods
Reagents
I , M e 2 C u L 1 ( Z e q u i v ) , T H F , - 7 8 t o - 3 O " C , 11, C F 3 C 0 2 H a q , 0 ° C . III, C r 0 3 , NaI04, A c O H aq
S c h e m e 71
k 4 4-
Reagents
I,
KZC03, P h C H 2 N E t 3 C I - ,
11,
1M H C I ,
III,
6 M HCI
S c h e m e 72
(G2) X = H X = B r or CI
ya H
Y
=YO
Y
= OCH,Ph
R 9 4 - 9 8 'I. e. e.
IV,
v
( 4 31 Reagents
I,
IV,
E t L i , CUI, BF3 O E L , ( 2 e q u i v ) , - 7 8 " C , 11, L D A , M e 3 S i C I , NBS, T i ( O C H 2 P h ) & , v, H 2 , Pd
Scheme 7 3
111,
NaN3,
30 1
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups R’
R3
R2 R3 NHCOR
C0,Me R’
k
SePh CHO
R2
Reagents
NBS, CCIL, h v ,
I,
P h S e N a , EtOH,
11,
v, ( M e 0 ) 2 P ( 0 ) C H R 3 C 0 , M e .
111,
N a H , THF,
LDA, D M P U ,
IV.
PhSeCI,
C C I 3 C H 2 0 C O N H Z , P r i Z N E t , NCS, MeOH
VI.
S c h e m e 74
OH Reagents
I,
RMgX,
11)
EtOZCN=NCOZEt, P h P, p h t h o l i m i d e , THF,
Pb(OAc)L, PhH,
IV,
3
v, J o n e s ’ r e a g e n t ,
VI,
III,
MeOH, CF3C02H,
N2HL, E t O H
Scheme 75
(LL) C a n a l i n e
Me-CH-C02Et
I
( L 5 ) Polyoxa mlc a c i d
-
M e -C H
I
I
H2
I,
MeCH(OS02CF,)C0,R,
Et
Me-CH-
I NH I
NH
I
Me -CH Reagents
-CO,
11,
HCI,
-CO,Et I I I ~Me3N
S c h e m e 76
Me-
CO,H
C H - C0,H
302
General and Synthetic Methods
then reacted with organometallic reagents (Scheme 69) Imidazoles have also been used to prepare B,v-unsaturated amino acids (Scheme 70). 154
Precursors of D- and L-a-amino acids were
prepared by the regiospecific ring opening of diaziridines obtained from D-mannitol (Scheme 71). 155 Oxazole intermediates afford routes to a-amino-carboxy compounds.
threo-0-Hydroxy-L-glutamine has been prepared by the
epoxidation of
( 2 )-3-benzyloxycarbonyl-5-oxo-4-vinyltetrahydro-l,3-
oxazole and regioselective ring ~ 1 e a v a g e . l ~Serine ~ derivatives have been synthesized by hydrolysis of oxazolidine intermediates, obtained by condensing aldimines with aldehydes (Scheme 72) Asymmetric syntheses of a-amino acids were achieved using a-halogenated 10-sulphonamido-isonorbornyl esters (42) (Scheme 73) : 158
the route involves a 'face-selective halogenation followed
by displacement with azide (99% inversion of configuration) and then transesterification and hydrogenolysis (with retention of configuration).
The methodology afforded a synthesis of
L-alloisoleucine (43) (Scheme 73).
0 , +Unsaturated amino acids are
accessible by the reaction of a vinyl Grignard reagent with N-benzyloxycarbonyl a-chloroglycine methyl ester. 159 Protected B,Y-unsaturated a-amino acids were prepared by the oxidative rearrangement of allylic selenides using 0,0,0-trichloroethyl carbamate as the nitrogen nucleophile (Scheme 74) ; deprotection afforded the parent a-amino acids.31 In addition, D-a-amino acids have been obtained from D-mannitol derivatives _ via erythro-selective __ ___ addition of organometallics to (R)-2,3-?-isopropylideneglyceraldehyde and a Mitsunobu inversion which substituted _N-phthalimido for hydroxyl (Scheme 75) . 160 2-Aminobut-3-enoic acids deuterated at the vinylic positions have been prepared by reaction of appropriately deuterated diethyl acetamidomalonate with phenyl 2- (trimethylsilyl)ethynyl sulphone. 161 L-Canaline (44) and u-functionalized 2-aminobutyric acid derivatives have been prepared via ring opening of ~
2-aminosubstituted-4-butyrolactones. A derivative of 2,3-diaminopropionic acid has been prepared by Michael addition of benzylamine to a protected dehydroalanine - 163 A route to polyoxamic acid (45) has been reported in which the a-amino acid functionality was introduced by an imidate rearrangement.164 N-Substituted (R)-a-amino carboxylates can be prepared from
(S)-a-(trifluoromethylsulphony1oxy)carboxylatesand a primary or
secondary amine.165
a, a'-Iminodicarboxylic acids have also been
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
303
C02Bu' R,,N I - - N C O ~ B U '
R
H
(46) Reagents
1,
(47)
L D A , Me3SiCL,
11.
(NC02But)Z, T ~ C \ ~ , l l ( O P r ~ L , CF i t i3,CO 2 ti,
IV,
Hz, p t 02 ,
V,
HCI aq
Scheme 7 7
OMOM
OMOM
( 4 81
111/
R
2 Reagents
is
L D A , THF,
11,
RX,
111,
95
e.e
1M H C I
Scheme 78
R4
CO, Bun
HKCozBun R2+M
R3
M = 9 - B B N , Z n B r , MgCl, or T i ( O P r ' I g
S c h e m e 79
General and Synthetic Methods
304
N -N H C O ~ B ~ OSiMe3 H
1
ii-iv
Reagents
I,
BU~O~CN=NCO~BU T I~C, I ~ , CH2C12, - 8 O ’ C ,
11,
CF3C02H,
III,
LIOH .
D o w e x 5 0 W , v, H2, P t 0 2
IV,
Scheme 80
CH2Ph
Reagents
I, III
CHzPh
H
H
L I N R ~ , B O C N = N B O C ,11, L i O H ( 2 3 e q u i v 1 , T H F a q ( R ’ M e O M g B r ( 2 0 e q u i v ), MeOH ( R ’ THF (R’
=
= Me),
IV,
H),
PhCH20Lt ( 2 0 e q u i v ),
CH2Ph)
S c h e m e 81
,OSi
R’
Me3
I , I1
R2
R 3 = S i M e 3 o r Me Reagents
is
Me3SiOTf ( 1 1 e q u l v ) ,
R’R2C(OH)CH(NHR4)C02H
R 4 = H or M e
11,
H C I aq
Scheme 82
305
5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups
-
0 HO,C
y II
Vlll
I-OH
N", R =
Reagents
I,
P
llv-vl
OEt HZN
NPhth
R =
M e (49)
IV,
II
MeO2C\(\/
R
or OH
/
0
Phth = o-C6H,(CO),
M e or OEt
(50) o -C6H4(CO),NK, N a H , T H F , v,
PhMe,
VIII,
DMF, 100 6M HCI,
"C, 1 1 ,
VI,
Her, A c O H ,
Dowex WGR-2,
6 M H C I , A c O H (10
III,
MeZC(OMe)Z, MeOH, MeCOCL,
VII,
MeP(OEt1,
1)
Scheme 8 3
p - C 1 C6H4CH=N \
+
,CHNa
E10,C (51I
p
- C LC6H4C H=
N
E i 0, C
Et0,C
R =H Reagents
I ,
or Me
[ P d ( d p ~ e ) ~1 1], , H C I a q
S c h e m e 84
l o r P(OEt)31,
General and Synthetic Methods
306
prepared (Scheme 76).
(z) -N-Trif luoroacetyl-dehydroamino acids
have been prepared from 2-(N-trifluoroacetyl-3-trimethylsilylamino) -3-trimethylsiloxyalkanoic acid esters by treatment with methanesulphonic or trif luoroacetic acid anhydrides. 167 (2S)-a-Amino acids (47) were prepared in high enantiomeric & addition of the anion of the chiral ester (46) to purity y di (t-butyl)azo-dicarboxylate (Scheme 77) ; 168 the chiral auxiliary ( X ) can be recovered efficiently. A very promising asymmetric synthesis of a-amino acids involves a highly diastereoselective Other alkylation of the 3-protected amide (48) (Scheme 78).
asymmetric syntheses were also achieved using a polyacrylic crosslinked polymer with pendant chirality as the chiral auxiliary.170 The synthesis of optically active 6-hydroxy-amino
via an asymmetric aldol condensation has been described (Scheme 58). 138 Amino acid derivatives of high enantioselective and diastereoselective purity were prepared by the addition of ally1 compounds, particularly allyl-9-borabicyclo[3.3.l]borane, to a-imino a-Amino and B-hydrazino acids of high optical esters (Scheme 79) .51 acids
purity were prepared by electrophilic 'amination' of silyl ketene acetals derived from ( l R I 23)-N-methylephedrine (Scheme 80) Similar strategies172' 173 involved the stereoselective amination of the lithium enolates of N-acyloxazolidones (Scheme 81)
again,
both a-amino and a-hydrazino acids were obtained, the former without appreciable loss of enantiomeric purity. a-Amino-6-hydroxy-acids were obtained by condensing silylated ketene acetals with aldehydes or ketones (Scheme 82);174 although high diastereoselection was not achieved, the formation of three unprotected functional groups is noteworthy. L-Tyrosine specifically labelled with 2H, 1 3 C ,
l80, or 15N has
been synthesized by the reaction of a labelled phenol with L-serine, mediated by the enzymic activity of E. herbicola.175 Labelled L-phenylalanine was prepared from L-tyrosine by chemical methods, in an overall yield of 75%.
A series of peptides containing
a-aza-amino acid residues has been prepared;176
one member of the
series, (l-carboxyethyl~carbamoyll-valylglyclyl-a-aza-alanine benzyl ester, is substantially more potent than several azapeptide inhibitors of elastase hitherto reported. D,L-Phosphinothricin (49), D,L-2-amino-4-phosphonobutyric acid ( 5 0 ) , and aminocyclopropanecarboxylic acid have all been prepared from methyl-4-bromo-2-phthalimidobutyrate (Scheme 83)
using simple procedures
307
5: Arnines. Nitriles, and Other Nitrogen-containing Functional Groups
II A* R’-C-NH-CH-C-R~ II
II
+ OHC-C-R~
R’CONH,
0
0
0
I
OH
0
0
0
R’-
II II C-NH-CH-C-R~ I
Cl 0 (53) Reagents
SOCLz,
I,
11,
Et3N
S c h e m e 85 11,
RCOCH,Br
Ill
RCOCH,N,
RCOCH,NHCHO
.1IV
R CO CH R’ N H CHO
R C 0 C H R1N H,. H Br Reagents
I,
NaN,,
DMSO,
11,
HZ, P d / C , H C I ;
III,
HCOZH, A c 2 0 , H C 0 2 N a ,
IV,
N a H , DMF, R ’ X ,
v, H B r , M e O H
S c h e m e 86
0
[
0
II
Ph-S-CHR’
I
II
+ R2--C-R3
-*
Ph-S-C-
CI
I: ;: ] C- R 3
(54)R’ = H or a l k y l
0
II
0
NR4R5
I R1-C-C-R3 I
a
R*
Scheme 87
ph
+
HNR4R5
308
General and Synthetic Methods
S c h e m e 88
RCOCH(R')NO~ Reagent
I,
5 " / 0 Pt-S-C,
1 RCOCH(R~)NH,.HCI
H 2 ( 3 O e q u r v ) , EtOH-HCL
a q , 50°C
S c h e m e 89
Reagents
1,
S ~ ( S B L I ~ )T~H,F . - 7 8 " C ,
R = Ph
96
R = PhCH=CH
81
R = MezCH
92
R = Ph(CH,),
92
11,
RHC=NCHPh2,Sn(0
Scheme 9 0
X
X = Ph, NEt,,
or O E t
:
4
19 :
8 8
2
CCF 1 3 2
309
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
N-(2-Naphthyl)-2-amino acids have been prepared by the Bucherer enriched ~ ~ reactyon of 2-naphthol with amino a ~ i d s . 1 Phenylalanine in either the (5)-or the (5)-enantiomer was obtained by an enantioselective addition of benzenethiol to a benzamidocinnamic acid in the presence of either quinine or quinidine.17' N-Cyanomethyl ethoxycarbonylformamidines can be prepared by the reaction of a-aminonitriles with ethyl ethoxycarbonylformimidate:180 they afford routes to imidazole-2-carboxylates. Substituted a-amino esters can be prepared by hydrolysis of imines obtained by alkylation of imine (51) with allylic acetates or carbonates in the presence of a catalytic amount of palladium(0) An asymmetric allylic alkylation of the (Scheme 84) .I8' benzophenone imine of glycine methyl ester using chiral palladium complexes provides a route to an allylated amino acid derivative of up to 57% optical yield.182 Optically active N-acetylamino acid esters were obtained by enantioselective hydrolysis of their racemates using baker's yeast.la3 N- (a-Hydroxyacyl)-a-amino esters were prepared in high optical yields by the asymmetric hydrogenation of N-(a-ketoacy1)-a-amino esters with Cydiop-rhodium(1) complex catalysts. N-Acyl-a-oxoaldimines (52) can be prepared from primary amides and a-oxoaldehydes via the hemiamidals (53) (Scheme 85) .185 Various a-nitro-esters were selectively and rapidly reduced to the corresponding amino-esters using anhydrous ammonium formate as a catalytic hydrogen transfer reagent.18' A versatile route to a-alkyl-a-amino-ketones proceeds y & alkylation of a-formamido-ketones prepared from bromo-ketones (Scheme 8 6 ) .I8' A new route to a-amino-ketones involves nucleophilic attack by amines on the highly reactive B-carbon atom of a,B-epoxy-sulphoxides, easily prepared in good yields from
sulphoxides (54) and a carbonyl compound (Scheme 87) .188 2-Aminoalkyl ketones were prepared by reduction of 4-amino-1-azabutadienes with LiAlH4 followed by hydrolysis. Mannich bases have been conveniently prepared from silyl enol ethers and iminium salts, both generated in situ before reaction. 18' NIP-Dialkylaminomethyl ketones can be obtained by reacting (N,N-dialky1aminomethyl)tributyltins with acid chlorides (Scheme 88). Polycyclic dimethylamino ketones, precursors of rigid toroidal azamacrocycles, were prepared from the corresponding ketones by treatment with Bredereck's reagent. a'-Amino-a,B-ynones have been prepared and used in a chirospecific synthesis of sphingosine.lg2
' '
3 10
General and Synthetic Methods
NHCOMc
-
CO,E t
+ =c-\
MeCONH--(
CO, E t
C0,Et
CI-
E t 0,C
T O 2 " C02Et
C I - H,N +
H3L
ACozHA +
CO,H
Reagents
NaOEt,
I,
iiI
20"1. H C I , 5 0 ° C
Scheme 92
CO,H
x!l4 ;40-
CO, C H, P h
I
L
I
___)
I
OSi Me2 B u t OSi Mez But
1
rnult istep
P h C H,O,C N H AcO MeO&
Me
OMe
(55) Reagent
'
I,
PhCHZOCONSO, P h M e
S c h e m e 93 I-
-1
R N H C N H,
II
0
RNHC-NH-C-
II
II
_j
I
II
RNHC=N
A
0
[HCL
0 Reagents
II
I,
Cl3C0CCl,
RNHC=N-C-NN=CNHR CI
NH-CNHR
0
0
1
RNH-C=N
HzO
I I ~
S c h e m e 94
CI I
II
0
-C=N-
CI 1
CI
'I
C=NR CI
31 1
5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups
a-Amino ketone hydrochlorides have been obtained by chemoselective hydrogenation of various a-nitro-ketones using 5% platinum sulphide on carbon as the catalyst (Scheme 89) : lg3 these reagents are not usually influenced by steric inhibition, although for aryl a-nitroalkyl ketones the carbonyl group is hydrogenated instead of the nitro group, the corresponding 6-nitro-alcohol being obtained.
The method has been used to prepare
terephthaloylbis(methy1amine)dihydrochloride. N-Protected a-amino-dialdehydes have been prepared by oxidation of !-protected
amino-diols or from amino-diacids by reduction of 194 N-Boc-di(N-methoxy-2-methy1)amides. One of the simplest methods of obtaining 6-amino-esters is by the conjugate addition of amines to a,B-unsaturated esters. At high pressures the addition is efficient, and the use of a p-substituted 8-phenylmenthyl group as a chiral auxiliary attached to the
-
a,@-unsaturated ester afforded enantioselective syntheses of the 6-amino-esters.l g 5 A stereoselective synthesis of 6-amino acid derivatives by an aldol-type condensation of tin(I1) carboxylic thioester enolates with imines has been reported (Scheme 90) ;lg6 the method was used to synthesize an intermediate of the carbapenem antibiotic PS-5. of
Aspartame has been prepared by the asymmetric hydrogenation
(z) -! ( I\ 1 - f o r m y l - a - L - a s p a r t y l ) -6-phenylalanine methyl
ester, lg7
prepared from L-aspartic acid, benzaldehyde, and glycine. A synthesis of (R)-y-amino-6-hydroxybutanoic acid (GABOB) proceeded
electrochemical decarboxylation of C-Amidoethylation of the
(2S, - 4R)-PJ-acetyl-4-hydroxyproline.lg8
enolates of simple ketones has rendered accessible v-amido-ketones (Scheme 91); the use of an excess of enolate usually suppresses two-fold amidoethylation. N-Acylaziridines also react with the disodium enediolates of substituted acetic acids to give a-substsituted v-amidobutyric acids. 2 o o 6-Methyleneglutamic acid and 0-methyleneglutamine were prepared by addition of protected aminomalonates to allenes containing electron-withdrawing groups, and subsequent hydrolysis (Scheme 92) .201 4-Substituted derivatives of
(E)-4-aminocrotonic acid were
prepared by routes involving trichloroacetamidation and the use of fluoroacetonitrile.202 ( 5 )- ( + ) -5-Amino-4-hydroxypentanoic acid has been prepared by the alkaline hydrolysis of (5)-(-)-5-hydroxy-2-0xopiperidine, available from L-glutamic acid by a five-step sequence.203
312
General and Synthetic Methods
Reagent
[ C O ~ ( C O ) ~C6H6, I. H20, 8 5 0
1,
PSI,
170-180°C
Scheme 95
[ 3pr12] 3
CONPr’,
CON PrI2
I
Reagents:
I,
Bu’Li,
TMEDA, T H F ,
11,
Me2C=CHCONMePh
S c h e m e 96
-&
@,R
RNHCHO
+
Me2NH +
q:.
0 Reagent
’
0
N2 H 4 . H 2 0 (5 e q u i v ), DMF
1,
S c h e m e 97
Nu
Nu =OR,SPh or Ph Reagents
I,
(Me3Si)2NCH0. I I > MeOH or EtOH, C F 3 S 0 3 S i M e 3 , 111, PhSH, CCI,,
IV,
PhMgBr, E t 2 0
S c h e m e 98
(57)
(58)R
= N H -CHO
+
( 5 9 ) R = N=CR e a g e n t s i.PhMe, 80°C.
11,
Me3SICH2CH20H, iil,B14F, THF, IV, MeCO CH0,Et 0 , v, p - T s O H , C H N 2 2 5 5
S c h e m e 99
313
J: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
Mono- and di-carbamate metabolites of felbamate (2-phenyl-lr3-propanedioldicarbamate) have been prepared by ammonolysis of mono- and bis-chloroformates.204 The carbamate ester
(55) which possesses the erythro stereochemistry of staurosporine has been synthesized from a 3,6-dihydrothiazine oxide, obtained by a hetero Diels-Alder reaction using N-sulphinyl benzyl carbamate (Scheme 93) .205 Alkylcarbamoylureas are readily obtained by hydrolysis of trichlorodiazapentadienes formed by the reaction of substituted ureas with trichloromethyl chloroformate (Scheme 94) . 206 6 Amides and Thioamides Relatively general routes to amides include the preparation of mixed anhydrides by the addition of a carboxylic acid to an isocyanate, and subsequent decarboxylation to give N-substituted amides;207
the reaction is applicable to both aliphatic and
aromatic carboxylic acids, and a range of isocyanates. the form R'C(0)NR2"
Amides of
are generated by the unimolecular
fragmentation of mixed anhydrides of the type (RO)(R "N)P(O)OC(O)R' derived from carboxylic and amidophosphoric acids.308 Amides are the principal products of the reaction of thiophenols or p-methylbenzyl mercaptan with aliphatic, benzylic or aromatic imines and carbon monoxide, in the presence of cobalt carbonyl.209 Those amides arise from cleavage of a reactant imine
R'CH=NR"
which occurs
via nucleophilic attack on an acyliminium
intermediate (Scheme 95).
A formal [3+21 cyclization of
(2-carbamoylallyl)lithium reagents with certain acrylamides gave 1 ,3-cyclopentanediamides (Scheme 96) , and also acyclic diamides. 2 1 0
A detailed study of the Favorskii rearrangement of a-chloro ketimines induced by base has been made;211 imidates or amides are produced by ring opening of the intermediate cyclopropylideneamines. The mechanism was found to be parallel with the Favorskii rearrangement of a-halo-ketones. N-Alkylformamides can be obtained by the N-formylation of phthalimides (Scheme 97);*12 the yields are good, and the reaction appears to be of wide scope. Reaction of N,N-bis(trimethylsily1) formamide with aldehydes gives 1-formamido-1-trimethylsilyloxyalkanes which are transformed by a variety of nucleophiles into a-substituted amides (Scheme 98) .213 The crystalline carbamate (57) has proved to be a convenient intermediate in the synthesis214 of the sesquiterpenoids axamide-1
General and Synthetic Methods
314
111
-v
__3
Ac
H
H
(60)
(61 1
I,
A , CHZC$,,
11,
H:
R 4 = NHAc
R ' = H; R Z = N
xyfo
R3=
R' = N3; R 2 = H
lyxo
R 4 = NHAc, R 3 = H
3
Reagents
0
YN3, N a N , MeCN,
111,
H B r , AcOH,
IV,
H C I , v, A c Z 0 , C 5 H 5 N
S c h e m e 100
Reagents
I
B u " L 1 , THF, COz, - 7 8 " C ,
II>
(COCI)2, PhMe.
III,
R2R3NH
S c h e m e 101
I
R X = H or Me; R = p
X = H ; R = p-FC,H, Reagent
I ,
P h X , A \ C I 3 , C6H6
S c h e m e 102
-CIC6H4
X Y ~ O
lyxo
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
315
0
Reagents.
N a O M e , MeOH,
I,
11,
HBr
S c h e m e 103
@,",Me
CHO
q--+H
I
Boc
q +
Boc
+
Boc
CO, Et
+
KI c' o
OH
Boc
4
p
OH 1
' I ;
OH
I V
F-------
OH
(68)
(67)
Reagents.i,DIBAL, PhMe, -78°C. IV,
C 0, Et
C F3 C0,H.H
0
11,
LiCH2C02Et, THF, - 7 8 " C ,
K2C03 a q
S c h e m e 104
III,
CF3C02H,25"C,
General and Synthetic Methods
316
(58) and axisonitrile-1 (59) (Scheme 99). Curtius rearrangement of the acyl azide (56) followed by treatment of the resultant isocyanate with 2-trimethylsilylethanol afforded the carbamate (57) which was deprotected. The resultant primary amine afforded axamide-1 (58) when treated with acetic formic anhydride, and axisonitrile-1 (59) when dehydrated. N-Alkylformamides can also be obtained by the 3-formylation of phthalimides (Scheme 97) ;212 yields are good, and the reaction appears to be of wide scope.
Rotamers
of several propionamides, acetamides, and formamides have been separated using high-performance liquid chromatography at low temperatures.215 Several routes to amides __ via heterocycles have been reported. A route to amino-sugar lactones (61) proceeds 2 nitrene addition to give an aziridine ring which is cleaved with azide ion to give heterocycle (60) (Scheme 100). Since stereoisomers were always found to be separable, both the xylo- and lyxo- products are available.216
Imidazoles available from methionine undergo diastereoselective alkylation, thus affording a route to a-branched vinylglycines (Scheme 70) and other amino acids.
(E,E)-Conjugated
dienamides (63) of high stereoisomeric purity can be prepared
via
extrusion of sulphur dioxide from the __ cis-disubstituted-2,5-dihydrothiophene-l,l-diox~~es(62),generated
by a retro Diels-Alder reaction (Scheme 101) .215
The naturally occurring insecticide pellitorine (63; R'=C5H11I R2=H, R3=Bui was so prepared. N-Substituted-2-benzoylamino-3-benzylthiopropenamides have been obtained by ring opening of 4-ethoxy-2-phenyl-2-oxazolin-5-one with
a mixture of benzylthiol and a primary amine.218 B-Amino-y-ketobutyric acid derivatives can be prepared by Friedel-Crafts reaction of benzene, toluene, or furan with the aspartic acid azalactones (64) (Scheme 102) .219 Substituted (a-arylethylidene)-5 (4E) -0xazo1ones (65) undergo stereospecific ring -amino-esters (66) (Scheme opening220 with methoxide to give the
(z)
103), which are related to 2,3-dehydroamino acid moieties present in some small peptides of antimalarial activity. The E-isomers were prepared by isomerization of the corresponding Z-isomers with HBr. A number of heterocyclic amines has been prepared. The lactam (68), which possesses the pyrrolizidine alkaloid skeleton,
2 conversion of an epimeric mixture of 3-protected hydroxy esters into a single crystalline
was synthesized from Boc-L-prolinal amine salt (67) (Scheme 104) .221
Protected pyrrole-2-carboxylic
5: Amines. Nitriles, and Other Nitrogen-containingFunctional Groups
317
L
R’
CON H, R4 Reagent.
I,
CF3S03H. CF3C02H ( 1
20)
S c h e m e 105
N
C
W
Me
NHMe ____)
0
Me
H*N-N
Reagent.
I,
KR 0
f---
H2, R h l C
S c h e m e 106
HO
R
General and Synthetic Methods
318
(S-NHz
s.
Br
S-NH,
CO, H
COCl
Reagents
I,
HS(CH2),NH2,
KOH,
11,
SOC12,
111,
Et3N, P h M e
S c h e m e 107
S c h e m e 108
OAC
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
319
-
O -H
H NCOCC1-j
H NCOC C l3 \
ASePh CN /ylSePh
(CH-)
+
"I
I
I
H
n =1-4 Reagent
I,
CF3S0 H (Sequlv), IH20(5equiv)
S c h e m e 111
OH
.Jt
OH
I
0-C
- RY
o;
0,
7
cOz-+ ,NW,Ar
S
II
0 S c h e m e 112
I
ArNH2
-
N,N*
Ar,
IV, v
Ill
+ ArN=N-NHCH,CO,Et
---+ HO
0
II
ArNH-C-CHzOMe R e a g e n t s I , HNO , O T , VII,
11,
H,NCH
2
CO E t . H C t , 2
111,
NaOAc,
MeOH, A
Scheme 113
IV,
PN
1
v1
0
It
ArNH-C-CHN,
K O H , v, A c O H ,
VI,
A1203,CHC13,
General and Synthetic Methods
320
acids and their derivatives have been coupled using DCC and subsequently transformed into analogues of distamycin A containing three 4-aminopyrrole-2-carboxylate residues.2 2 2 2-Methylbenzofuran3-carboxamides are formed by the acid-catalysed [ 3 , 3 ] sigmatropic rearrangement of 0-aryl-N-acetoacetylhydroxylamines (Scheme 105). 223 N-(Acylamino)alkylenediamines, required for the synthesis of some 2,4-quinazolinediamine derivatives of antihypertensive activity, can be prepared by catalytic hydrogenation of the 3-[ (N-acy~)methylaminolpropanenitriies (Scheme 106);
selective
ring opening of the putative hexahydro-l,3-pyrimidin-2-01~ was achieved using a catalyst of rhodium-on-carbon.224 A triazatrithiacyclophane has been prepared (Scheme 107) and shown to contain a central cavity towards which the three amide NH groups point.225
A synthesis of N-acetylneuraminic acid226 starts with a
Michael addition of the 1-nitro-D-mannopyranose (69) to t-butyl
2-(bromomethyl)prop-2-enoate, and subsequent hydrolytic removal of the nitro group to give the tautomeric 4-nonulosonate (70) (Scheme 108). A stereoselective synthesis of (2EI4E)-dienamides was achieved through a double elimination reaction of O-acetoxy-sulphones (Scheme 109) .227
Homogeneous hydration of unsaturated nitriles such as
acrylonitrile, methacrylonitrile, and crot-ononitrile to the corresponding unsaturated amides has been carried o u t in water at
80 " C by usinq
colloidal copper dispersions as catalysts.228
The
hydration of acrylonitrile and acetonitrile to the corresponding amides is catalysed by hydridobis(phosphine)platinum(II) complexes.229
The reaction of trichloroacetonitrile with dienic
alcohols, originally developed by Overman, has been used to prepare trichloroacetamides (Scheme 110) which were converted into daunosamine and
(2)-
( 2 )-vancosamine.230
Amides of acrylic and n-pentenoic acids have been prepared by a metal-catalysed condensation of ethylene with phenyl isocyanate. 2 3 1 6 , r-unsaturated-a-keto-amides can be prepared by a double
carbonylation of alkenes in a aminopalladation reaction. 232 Some previously reported limitations on the amidoselenation reaction have been overcome;
cyclic and acyclic 6-(acry1amido)alkyl
phenyl selenides free from side-products have been prepared using stoichoimetric quantities of nitriles (Scheme 111) ;233
the
reactions proceeded with retention of stereochemistry.
Amides have
been prepared by reacting a carboxylic acid with (trimethylsily1)ethoxyacetylene to give a 1-alkoxyvinyl ester which
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
X = Br or I
Scheme 114
Reagent
I,
Reagent:
NoOEt, EtOH
I,
Scheme 115
HN03, A c O H
S c h e m e 116
32 1
322
General and Synthetic Methods
0 PhCH,O-C-N
11 0
=r H
0
0 Si Me,Bu'
II
SC,H4 N
P h CH, OCN H
+
____)
HO,C Reagent
0
'OSiMe2But
HO,C EtNPr',(O
I,
1 equiv)
Scheme 11 7 0 R1R2N-CH--COZH
I R3
+
I
0
II
NH-CH-C-R5
f + R 2 ~ - ~ ~ K ~ - ~ ~ - ~ - R 5
I
I
R3
Fern R L
Fern = C,H, Reagent
0
II
I
I
Fern R 4
FeC,H,CH2
DCC
I,
S c h e m e 118
+
H2N 0
Reagents
I,
DCC
S c h e m e 119
5: Amines, NitriIes, and Other Nitrogen-containing Functional Groups
323
is then reacted with an amine.234
2-Hydroxyarylcarboxamides are obtained in good yield by the reaction of phenols with isocyanates in the presence of one equivalent of boron trichloride.235 a-Hydroxyanilides have been prepared by the reaction of a-hydroxycarboxylic acids with N-sulphinylanilines; 2 3 6
the reaction appears to involve
intermolecular catalysis by the carboxylic acid moiety and intramolecular catalysis by the hydroxy group (Scheme 112). Moderate yields of the uncommon a-methoxyacetanilides were obtained by decomposition of a-diazoacetanilides (Scheme 113) . 237
Tertiary
amides containing at least one N-t-butoxycarbonyl moiety are conveniently prepared from a wide variety of secondary amides by the action of di-t-butyl dicarbonate in dry acetonitrile with 4-dimethylaminopyridine as catalyst;238 the yields are generally excellent.
Ceramide (29) can be prepared in good yield on a 135
multigram scale via an oxazolidine route (Scheme 5 6 ) . ~
a-Keto-amides, convertible into isatin and quinoline derivatives, were prepared by the palladium-catalysed double carbonylation of aryl halides (Scheme 114) .239
A preparatively
useful route to acenaphthylenone carboxamides by base-catalysed N-substituted homonaphthalimides has been reported rearrangement of (Scheme 115). 240 3,4-Diacylaminobutanetosylamines have been prepared
the Bamberger ring cleavage acylation of
N-p-toluenensulphonyl histamine.241
Nitration of certain
substituted indoles with a mixture of hot nitric and acetic acids affords 3,3-diaryloxindoles;
a pathway involving the rearrangement
of an indolenine intermediate has been tentatively proposed (Scheme 116) .242
Oxalic acid ethyl ester-N'-acyl amidrazones can be
prepared by acylation of suitable amidrazones. 243 An efficient peptide forming reaction employs 1-(trimethylsily1)imidazole as the agent for coupling an amino acid with a thiopyridyl ester;244 when an imino acid was used, only a catalytic quantity of a tertiary amine was required for the condensation (Scheme 117).
A derivative of 6-alaninamide has been
formed by cleavage of the cyclopropane ring of
N-(benzyloxycarbonyl)-l-aminocyclopropane-l-carboxamide with
-
[L,I-bis(trifluoroacetyl)iodolbenzene. 245 L-Serine stereospecifically labelled with deuterium at C-3 has been prepared __ via catalytic addition of deuterium to (Z)-2-acetamido-3methoxyacrylic acid.246
324
General and Synthetic Methods
NH,
A z o t o m y c in
R = Ph C e l a b e n z i n e R = CH,CH,Ph
(71)
a , R = Me, R ' = Z b , R = CH,Ph, R ' = Z
(74)
( 7 2 ) c , R = Me, R ' = COCF3 ( 7 3 ) d ; R = a n i o n , R ' =H: Reagents
I,
CH2N2,
11,
( c o c ~ ) E~t 3,N ,
lII,
cIC02B~1
S c h e m e 120
> 9 8 'Ie e e Reagents
I
NaCN,
1 1
H 50,-5"C, 2 L
III,
HZ, P d l C ,
Scheme 121
Dihydrocelacinnine
I V
HBr aq.
325
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
The ferrocenylmethyl group, which can be introduced by catalytic reductive alkylation of amino acids or amino acid esters with ferrocenecarboxaldehyde and hydrogen, allows peptide synthesis to be effected without racemization (Scheme 118) ; 247 deprotection can be achieved with trifluoroacetic acid.
DCC acts as a coupling
agent in a reaction yielding tripeptides (Scheme 119) ;248 camphor-10-sulphonic acid catalyses the reaction and also suppresses troublesome side reactions.
A synthesis of (-)-azotomycin has been
achieved, in which the mixed carbonic anhydride method was used to form the peptide bonds; the azo groups were introduced by a modified Arndt-Eistert synthesis. 249 The thirteen-membered lactams celabenzine and dihydrocelacinnine have been synthesized by using a BOC protecting group.250 Syntheses of virginiamycins S1 and S4, using both cyclic and acyclic hexapeptides, have been described.251 A total synthesis of the cyclotetrapeptide chlamydocin has been reported,252 and methods of preparing cyclopeptides containing non-essential amino acids have been described. 252
A cyclotetradepsipeptide has been synthesized
by using the 2,4-bis(methylthio)phenoxycarbonyl group in a protection-activation sequence. 253 Phosphonic and phosphinic acids can be converted into their amides by activation with diphenyl phosphoryl azide and displacement with ammonia;254 in this way, a phosphinamide analogue of pepstatin has been prepared. Approaches to the syntheses of the Streptomyces anticancer antibiotics 6-diazo-5-0x0-L-norleucine (73 ; DON) and azotomycin using conversions of carboxylic acids into diazoketones have been described.255 The DON precursor (72) can be prepared from the v-carboxylic acid (74) by approaches involving either acyl chlorides (oxalyl chloride route) or mixed carbonic anhydrides (isobutyl chloroformate route) (Scheme 120). An alternative route to (73) involves selective attack at the Y-carbonyl of anhydride (71) with diazomethane; however the DON precursor (72) could not be prepared using this method. Two new carbamyl-substituted carbapenams (4) have Seen prepared by a route involving a hetero Diels-Alder reaction (Scheme 4) .14 Amides were prepared by the ruthenium-catalysed condensation of nitriles with amines in the presence of two equivalents of water; syntheses of polyamides were also effected.256 Tetraethylurea or diethylformamide can be obtained selectively from diethylamine, carbon dioxide, and a palladium catalyst. 2 5 7 Aromatic cyclic ureas have been prepared from 2-amino- or
326
General and Synthetic Methods
N S0,C I
(75) Reagent
I,
CHZC12, 0°C
OCN-SO,CI,
S c h e m e 122
0 R’O -C
II
RL/ II
0
II
R3 N=C-CH-
I
Reagent
1,
1
C H-C O R ~
I
I
C O R ~
RZ CUCL~.ZH~O
Scheme 123
A
c0
RCO-N
O HN-CH,X 3
c,u
OJ
(76)X = C0,- o r CH,SO,-
Scheme 1 2 4
R5
R2
I
HNCO,R’
321
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups o-amino-alkyl substituted arylamines by reaction with carbon
monoxide and selenium. 2 5 8 Other syntheses of aromatic and heteroaromatic amides have appeared.
(g)-(+)-2-Methyl-3-phenylalanine has been synthesized by
a four-step asymmetric Strecker synthesis using (5)-(-)-1-phenylethylamine as the chiral auxiliary reagent (Scheme 121) . 2 5 9 A series of 5- (alkylsulphonyl)salicylanilides was prepared from a salicylic acid, thionyl chloride, and an aniline using a catalytic quantity of dimethylformamide;2 6 0 benzoic acids have been converted into substituted benzanilides by the same procedure. 261 New routes have been developed to y- (w-tosyloxyalkyl) phthalimides, from which polyamines have been prepared. 2 6 2 Triphenylantimony dicarboxylates react with amines to give the corresponding amides;263 amidation of a carboxylic acid with a primary amine is also catalysed by organoantimony compounds. react with chlorosulphonyl isocyanate to a,a,N-Triaryl-nitrones
form N,N-diaryl-arylamides (Scheme 122) , 264 an electron-rich aryl group migrating in preference to an electron-deficient aryl group. Whether the configuration of the nitrone is
S J J
or
anti was
found to
have no effect upon the migration of the aryl group; that is consistent with the postulation of the cycloadduct (75) as an intermediate. 1-Alkoxycarbonylamino-3-carbonylpyrroles can be prepared by the copper(I1) chloride-catalysed reaction of alkoxycarbonylazoalkenes with B-diketones (Scheme 123) . 2 6 5 If copper(I1) chloride is omitted, the reaction proceeds only to the lI4-adduct. 2-Pyridon-1-yl diphenyl phosphate is a useful coupling agent for the synthesis of amides and peptides; racemization of the latter is avoided. 2 6 6 The hydrolysis of a-aminophenylacetonitrile to phenylglycinamide is catalysed by various bifunctional compounds including ethane-1 2-diol, 2-mercaptoethanol and glutathione.267 Alkyl amphiphiles of the crown ether type (76) have been synthesized and shown to form membranous aggregates. 2 6 8 Aqueous cyanine dyes are adsorbed onto a monolayer of alkylammonium amphiphiles containing an amide group.2 6 9 _ N,N-Diethyl-2-chloropropionamide _ can be prepared by reacting methyl 2-chloropropionate with diethylamine and aluminium I
I
chloride.2 7 0 Ynamines and 1,3-thiazole-5(4H)-thiones undergo an addition reaction on heating in toluene, yielding mainly the thiazolylidene thioamides of type (77) (Scheme 124) .271
By analogy with other
328
General and Synthetic Methods
HowHz X
EtOCH=CHC
II
s
II
II
"'d
0
+
0
Et OCH =CHCNHCNH
+
NCS
X Y (78) X=OH,Y=H X =H,Y=OH X =Y=OH
Y
Scheme 125
R2 R3 H,N
x
CO,H Z
= PhCH,OCO
(79)
R2
(80) S Reagents
I,
CICO2CH2Ph,
I I DCC, ~
HNMe,,
111,
M e O e ! / S ' P e O M e ,
's' IV,
HBr, MeCOZH,
v, R'COCl
I1
S
S c h e m e 126
(81)X
=O
(82)X = S OSi Me2But
I
I
RCHO
R-CHCN
-!!-+
OH I
O S i Me2But
I
111
R-CH-C-NH,
_j
R-CHCNH,
II
II
S Reagents
1,
NCSIMe2But, KCN, 1 8 - c r o w n - 6 ,
11,
THf
S c h e m e 127
PhZPSZH, P r ' O H ,
S III,
(NBun):F;
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
329
reactions of ynamines, a [2+2] cycloaddition to thiete intermediates, followed by electrocyclic ring opening is suggested as the mechanism of the reaction. Thiophenecarbothioamides are prepared by reacting thiophene or 2,5-dimethylthiophene with isothiocyanates in nitromethane, in the presence of aluminium chloride.272
A route to the carbocyclic analogues of 2-thiouracil nucleosides involves the condensation of 3-ethoxypropenoyl isothiocyanate with appropriate hydroxy derivatives of cis-3-aminocyclopentanemethanol to give the +hiocarbamoylpropenamides (78) (Scheme 125)273 which are cyclized in aqueous ammonia to give the 2-thiouracil nucleosides. Thioamides (79) can be conveniently prepared by thiation of the corresponding amides using Lawesson’s reagent (Scheme 126) .274 Thioamides ( 8 0 1 , preparable from thioamides (791, or by reaction of 3-amino-2s-azirines with thiocarboxylic acids, are readily converted into 1, 3-thiazole-5 (4H)-thiones (Scheme 126) ,274 a class of In searches
heterocycles hitherto available only with difficulty.
for an efficient route to thioamide analogues of peptides, Lawesson’s reagent was shown to distinguish between different amide groups; thus, tripeptide (81) can be selectively thiated to give the thioamide analogue (82) in excellent yield. 275 Various thioformamides were prepared by heating secondary amines with dimethylthioformamide.276
a-Hydroxy-thioamides were
prepared from aldehydes in a three-step route which appears to be general (Scheme 1 2 7 ) .277 Certain unsymmetrical N,”-dialkylthioureas can be prepared by heating a sodium N-alkyldithiocarbamate, an alkylamine, and a catalytic quantity of
sodium hydroxide in a two-phase system.2 7 8 The lithioketene-5,N-acetal derived from N,N-dimethylthioacetamide was reacted with aryl isocyanates to give
-
monodithioamides which were subsequently transformed into enaminonitriles.279
_ N,N-Dialkyl derivatives of thiopivalamide S-oxide have been prepared. 280 The cyclopeptide ulithiacyclamide has been synthesized, the ring-closure reactions to give amide groups being performed under
-
moderate dilution.281 Thioamides have been converted into amides with dinitrogen tetroxide. 2 8 2
330
General and Synthetic Methods
Q
&CN
1
o//c--5+
(83) Reogent :
I,
NCCH2COSB~', D A B C O
S c h e m e 128
R
R = M e , E t , CH2Ph, o r P h Reagent
1,
( E t 0 ) 2 ~ ( o ) ~ LN ~, C N
S c h e m e 129
5: Amines, Nirriles, and Other Nitrogen-containing Functional Groups
33 1
RCONHZ
Reagent
I,
Cl3C0COCI
Scheme 130 R C =N S i Me,
[
RCONH,
Reagents
I,
bSiMe,
]
RCN
M e 3 S I C l , E i 3 N , Z n C I z 2 1 1 , FeCI3 o r ALC13, A
S c h e m e 131
coza
R Y c N ,
Reagents
I,
III
c o y
CN
R C H 2B r, K2C03,
CH =CHCHZOH, 2
11,
,
p-TsOH,
R
111,
W
C
N + COz
+ CH, ,
Pd( O) - PPh,,EtC N ,
A
S c h e m e 132
SEt
I
I
R-CHCH,CN
+RCH=CHCN
R e o g e n t : i , L i ar, E t O H , P t e l e c t r o d e ( 0 Z A )
S c h e m e 133
RHC=C=CH,
+
I
Me,SiCN
RHC=C
rCN ‘5iMc3
R e a g e n t : i, P d C I Z , C 5 H 5 N
Scheme 134
332
General and Synthetic Methods
7
Nitriles and Isocyanides
Nitriles have been synthesized by a variety of methods.
The
formation of nitriles by the alkylation of potassium cyanide using solid-liquid phase-transfer catalysis without added solvent is optimized when a definite amount of water is present.283
Cyanation of aryl iodides has been achieved using trimethylsilyl cyanide and a palladium catalyst.284
Perf luoroalkyl nitriles were prepared from
perf luoroalkyl azides and triphenylphosphine.285
S-t-Butyl
-
cyanothiolacetate acts as a B-hydroxypropionitrile equivalent
in
Michael reactions with a,B-unsaturated ketones (Scheme 128) :286 addition to a carbonyl group is also possible, and afforded a synthesis of a-costal (83).287 The reagent diethyl
phosphorocyanidate-lithium cyanide can be used to prepare 2-cyano-3-indoleacetonitriles (Scheme 129) 288 which act as dienes in base-induced cycloaddition reactions which afford carbazole-fused ring systems.
The first direct observation of a thermally generated
nitirile ylide has been reported.289 Dehydration of nitrogen compounds is a well-known route to nitriles. Alkyl, aralkyl, aryl, and heteroaryl amides are readily converted into the corresponding nitriles using trichloromethyl chloroformate as the dehydrating agent (Scheme 130);
the work-up is
usually very simple owing to the gaseous nature of the side-products.290
Nitriles have also been prepared from amides
in a two-step procedure involving the catalysed elimination of hexamethyldisiloxane (Scheme 131) . 291 Oximes can be converted in good yields into nitriles using di-2-pyridyl sulphite in refluxing toluene;292
similarly, formamides are converted into isocyanides.
A variety of alkyl, aryl, and heteroaryl aldoximes have been converted into the corresponding nitriles using trichloromethyl carbonochloridate as dehydrating agent. 293 Recently reported methods of preparing a,B-unsaturated nitriles include the palladium-catalysed decarboxylation-dehydrogenation of ally1 a-cyano-carboxylates (Scheme 132) ,294 and electro-oxidative desulphenylation of Michael-type thiol adducts (Scheme 133) . 295 B,y-Unsaturated nitriles have been prepared from allenes and trimethylsilyl cyanide in the presence of a palladium or nickel E-isomer predominated. catalyst (Scheme 134) ; 2 9 6 the y
, 6-Unsaturated nitriles can be prepared297 by reduction of ,&-unsaturated nitronates using low-valent titanium;
the
nitronates are generated by the catalysed addition of allylic
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
Reagents
333
T I CI4, C H Z C 1 z , ii,Zn,THF
1,
S c h e m e 135
+
+ +
Reagents
I,
ButNHZ,
11,
NaH, CH2(COMe)z,
111,
LDA.THF,
IV,
COMe
Me1
Scheme 136 Li
+
R
A CN
(85) Reagents
I,
M e ] , THF, -78'C.
11,
Me3SiCN, B u n 4 N I ,
S c h e m e 137
111,
EtOCOCN, K C N
334
General and Synthetic Methods
R:
,R3
c=c
4’
R’
A
\ CHO
,R3
R’
\
\c=c
/
R/z
R/z
\CH(OSiMe,)
I
\\C..rOSiMe3
>
CN Reagents
KCN, 1 8 - c r o w n - 6 ,
1.
R3
CH-C
CN
Me3SiCN,
11,
DBU
Scheme 138
R
c
Reagents
[
N I,
LDA, THF, -78OC,
11,
-
‘$CN]
R
Me3Si0
CN
Me3S1CI, - 7 8 ° C
nR
S c h e m e 139
R’qC + PNo2 + R’
R’
Me3SiCN
R2 R3
R2 R 3
0
&R-[(&R
go
NC
-*
CN N
C
OP(O)(OEt), ]-(&R
a
c
N
-&R-(&R
(
OP(O)(OEt l2
OH
n = 1 or2
R = H or Me Reagents
(EtO)ZP(O)CN, L I C N , T H F ,
11,
BF3.EtZ0,
S c h e m e 142
111,
HCL o q ,
IV,
Mn02
CN
335
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups silanes to a-nitrostyrene (Scheme 135).
Acyl cyanide-enol sulphonates, carboxylates, and phosphates can be prepared from enol esters of acyl cyanides, or acyl cyanides and trimethylsilyl choride.298 Suitable acyl cyanides can be prepared from ketenes and trimethylsilyl cyanide,298 or from acyl cyanides and trimethylsilyl chloride.
The (1-cyanoviny1)methanesulphonates
provide routes to keto- and carbo-cyclic nitriles (Scheme 136). Allylic cyanides, preparable from siloxyacrylonitriles, afford a route to B,y-unsaturated carbonyl compounds.2 9 8 The action of trimethylsilyl cyanide on aldehydes is one route to the B,v-unsaturated nitriles (84): dienenitriles can be prepared similarly. 2 9 9 r 3 0 0 The addition of cyanoformates to aldehydes gives esters (85).301 Deprotonation of a suitable a,B- or 0, Y-unsaturated nitrile affords a single anion which undergoes predominantly a-alkylation with methyl iodide (Scheme 137).3 0 1 While temperature and leaving groups have little effect, an increasing amount of the Y-product is formed in relatively polar solvents, or with large alkali-metal ions, or on the addition of HMPT. The nickel-catalysed addition of hydrogen cyanide to cyclic 1,3-dienes shows some promise; 2-cyclohexene-1-carbonitrile has been so prepared. 3 0 2 2-Aryl-4,4-bis (methylthio)buta-l,3-diene-l , 1-dicarbonitriles react with N-bromosuccinimide or sulphuryl chloride to give the 3-bromo- and 3-chloro-butadienedicarbonitriles, respectively.3 0 3
O-Substituted-a- [ trimethylsilyl)oxy]acrylonitriles
can be readily prepared by condensation of trimethylsilyl cyanide with a,B-unsaturated aldehydes, followed by DBU-catalysed isomerization of the intermediate 2-silylated cyanohydrins (Scheme
(z)
138) .304 A synthesis of -6-siloxyacrylonitriles by ring cleavage of isoxazoles has been reported (Scheme 139) .305 The nitro group in allylic nitro compounds (86) is replaced by the cyano group upon treatment with cyanotrimethylsilane (Scheme 140), although the regioselectivity is low.3o6 a-Cyanovinyl ethers have been prepared from the corresponding vinyl ethers by a sequence involving bromination, reaction with copper (I) cyanides, and dehydrobromination.3 0 7 Applications of tetracyanoethylene have been reviewed;308 recent information on molecular complexes, ozonization of alkenes and alkynes (the Criegee reaction), and reactions with ketones is included.
Dicyanoketene has been prepared in situ from
2,5-diazido-3,6-dicyano- and 2,6-diazido-3,5-dicyano-lI 4- benzoqu inones.
The new bar re 1eno- te tracyanoquinodimethane
( 88)
General and Synthetic Methods
336
-
C N OEt
R~ O P ( O ~ ( O E t , ,
(89)
R
CN
(90)( Z ) - i s o m e r
R -+w
NC LOP(0)
(OE t
,
( 9 2 ) (€1 - i s o m e r Reagent
I,
(EtO),P(O)CN,
LiCN
S c h e m e 143
R’CH=NR’
I R’-cH-NHR’ I
C H,CN Reagent
K02,DCC, M e C N
S c h e m e 144
Reagent
I,
ButNC(Z equiv). TiCIG(l equiv)
S c h e m e 145
0
(97) Reagents
I,
CH’CICN,
Et
3
N , 11, NHj, B u t O H .
111,
POCl
3’
Scheme 146
C H N, 5 5
IV,
HC0,H.
v, N H 3 . M e O H , v i , T s C I
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
0
337
0
t
+
Ar-S-CH,CN
*
RCH,CHO
A[ Ar-S-C *t
-
OH
I
R-CH-CH=CHCN
*
( C N ) =C
H CH,R
0
.t
Ar-z-CH(CN)-CH=CHR
1
(€1 -isomer Reagent.
I,
C 5 ~ , , N . MeCN
S c h e m e 147
Reagents
I.
LiZNiBr4,THF,
11,
A c Z O , C 5 H5 N
S c h e m e 148 R’R’CHC H, CH,COR3 Reagent
I,
Na,S2O8,
R’R’C (CN)CH,CH,COR3
NaCN a q
S c h e m e 149
R e a g e n t s : I, Me3SiCN, Z n l Z , A ,
11,
N B S , h v , CCL,
+ S c h e m e 150
NC
TBAQ
CN
(98)
(99)
338
General and Synthetic Methods
has been the dihydro analogue was also prepared by catalytic hydrogenation of the dione (87) followed by the sequence depicted in Scheme 141.
Their 1:1 charge-transfer complexes with
thiafulvalenes were prepared and the conductivities were measured. l o Allylic rearrangements (as in Scheme 142) afford the (Z)-butenenitriles (90) starting from n,O-unsaturated ketones, whereas the
(E)-isomers (92) predominate when
a , O-unsaturated
(z)
aldehydes are used (Scheme 143) .311 The high -stereospecificity in the former cases can be explained by considering the [3,31 sigmatropic rearrangement of conformer (89) (R=Me), which is sterically favoured over that of conformer (91; R=Me). Cyanomethylation of various imines with superoxide ion in acetonitrile affords 3-arylamino-3-arylpropionitrilcs (Scheme 144). 3 1 2
The novel B-alkoxycyanoenamines (93) are obtained by
reacting aldehyde acetals with t-butylisocyanide (Scheme 145). 3 1 3 314
The (E ) - and
(z)-forms
of imino-acetonitrile are
formed by photolysis of azidoacetonitrile in an argon matrix. 315 (-)
-L-Alanyl glycinc nitrile (96) can be prepared316 from the
protected dipeptide (94)
via the amide (95) (Scheme 146). Nitrile
(96) affords the amidinium bis(tosy1ate) (973, a key precursor in the synthesis of poly(dipeptamidinium) salts, of interest in view of their constitutional relation to polynuclcotides. Trimethylsilylcyanohydrins (and acylcyanohydrins) were prepared by reacting an aldehyde or ketone with chlorotrimethylsilane (or an acyl chloride) in the presence of lithium cyanide.317
Optically active cyariohydrins (in 33-38%
5s.)
were obtained from benzaldehydes by the asymmetric addition of hydrogen cyanide, using cyclo [ ( ~ ) - p h e n y l ~ ~ l a n y l - ( ~ ) - h i s t i das y l the ] catalyst.318 Transcyanohydrination has been achieved in up to 63% optical yield by the reaction of an aldehyde with acetone 319 cyanohydrin, catalysed by cyclo [(~)-phenylanlanyl-(S)-histidyll. Optically active 4-hydroxyalk-2-enenitriles have been prepared via rearrangements involving transfer of chlrality from optically
~
active 2-(arylsulphinyl)acetonitriles to t.he a carbon atom of an aldehyde (Scheme 147) . 320 2-Acetoxy-3-bromoprop-2-ene nitriles can be prepared by the nucleophilic ring opening of gem-dicyanoepoxides with Li2NiBr4 (Scheme 148) : 321
the (?)-isomer is favoured when the
epoxide bears an aryl substituent. Several ketones can undergo remote oxidat-ive cyanation to give y-cyano-ketones (Scheme 149) ;322
the reaction is believed to
339
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
ArMgX
ArCu.MgXBr
ArCHCN
I
Me Reagents
I, C uB r ( 1 e q u i v ) ,
11,
MeS020-
CH(Me)CN
Scheme 151
Reagents
1,
NaBH4, T H F a q ,
11,
HCL,
ill1
NaOH,
IV,
NaEHq, E t O H
Scheme 152
X = Reagent
I,
CI or Br
KCN
S c h e m e 153
RS
Me CN
Me CN Reagents
I,
RSCL, CH2C12,-500C,
11,
Et N,
III,
M e 0 C- CEC- CO
Scheme 154
Me,
IV,
NSC-CO
2
Et
General and Synthetic Methods
340
proceed via two competitive routes involving 0-centred radical cations. A cyano group can be introduced at the O-position of a, 6-unsaturated ketones;3 2 3
the resulting cyanophosphates undergo
rearrangement to allylic phosphates, which upon hydrolysis and oxidation afford the O-cyano derivatives (Scheme 143). Aryl cyanides can be prepared by a Wohl-Ziegler oxidation of 0-silylated cyanohydrins of both aliphatic and aromatic aldehydes
(Scheme 150) .324 Cyanophenols were prepared via the thermolysis of 4-alkynyl-3-azido-l,2-benzoquinones to give (2-alkynylethenyl)ketenes.325 3-Cyanophthalides can be prepared from an hydroxyphthalide by generation of the appropriate cyanohydrin and cyclization with DCC.326 29,29,30,30Tetracyanobianthraquinodimethane (TBAQ) has been prepared by the reaction of bianthrone with malononitrile in pyridine;327 studies of complexation of TBAQ with various donors are in progress. Thiophene-fused tetracyanoquinodimethanes including (98) and (99) have been prepared, some of which are powerful electron acceptors. 328
a-Arylpropionitriles have been prepared by reacting a-methane-sulphonyloxypropionitrile with arylcopper reagents (Scheme 151) .329 A variety of heterocyclic nitriles have been prepared.
Selective reduction of substituted a-cyano epoxides with sodium borohydride provides simple routes to amino- and hydroxy-functionalized epoxides (Scheme 1 5 2 1 . ~The ~ ~scope of and influences on the generation of a-cyanoaziridines from a-halogenated ketimines and cyanide ion have been thoroughly investigated (Scheme 153) .331
The use of a-bromoketimines placed no restriction on the
nature of the solvent, while a-cyanoaziridines can be obtained exclusively from a-chloroketimines using polar aprotic solvents.
A
cyclopropanation process affording
1-(N-alky1)aminocyclopropanecarbonitriles operates when cyanide reacts with tertiary monochlorinated methylketimines. organolithium reagents to a-cyanoaziridines produces
Addition of
a-imidoylaziridines which can be converted into pyrroles.
5-Aminopyrrole-2-carbonitriles were obtained by the reaction of alkynes with trimethylsilyl cyanide in the presence of a palladium or nickel catalyst.332 4-Cyanobutenolides are obtained
via photo-oxygenation of furans
followed by treatment with dimethyl sulphide and trimethylsilyl cyanide.333
Nitrile ylides (100) of a new class have been prepared
and shown to undergo 1,3-dipolar cycloadditions (Scheme 154) . 334
5: Amines, Nitriles, and Other Nitrogen-containingFunctional Groups
34 1
R
do- 4
( n o
( n o
(qc CO, E t
A
CN
CN
1 4
1
v
-
CN
0
v
(Q n 0
t
( no
0
0 R = H, E t , Ph, OMe, or OEt Reagents
Bu”Li, MeCN,TIiF,
I,
11,
(E)-Et02CCH
= CHCOZEt,
MeCOCH=CHZ,
III~
IV.
NBS,
v, N a B H 4 , VI, H C I . MeOH
S c h e m e 155
(101)
A r = 2, L - ( N 0 z ) 2 C,H, Reagents
I,
PC15(1 e q u l v ) ,
11,
NaOH a q S c h e m e 156
e C O , E t Reagents
I,
-
(CF3CO)z0, HBFL a q
,
o ” w C 0 2 E t
NH4N03. CH2CI2,
S c h e m e 157
11,
KOAc.
Et,O
342
General and Synthetic Methods
Cyano-substituted dienes, formed by reaction of a-ylidene and a-alkoxylidene lactones with the lithium salt of acetonitrile, are converted into precursors of benzofurans by a regioselective (and, in the case of the former derivatives, a stereoselective) 335 Diels-Alder reaction (Scheme 1 5 5 ) . 4(5)-Cyanoimidazoles were prepared from the 4(5)-trifluoromethyl derivatives by treatment with ammonium A 4-cyanoimidazole nucleoside is obtained when
hydroxide. 3 3 6
acylation of 2',3',-~-isopropylideneadenosinewith p-cyanobenzoyl chloride results in ring cleavage.337
8-Cyano-NE,NE-dimethyladenosine, obtained by treating the 8-methylsuphonyl analogue with cyanide anion, can be converted into derivatives with methyl imidate, carbamoyl, or carbothioamide groups at the 8-position.338 A stereoselective synthesis of (+)-cyanocycline, a congener of the antibiotic napthridinomycin has been reported: 339
the cyano
group at C-7 was introduced by reacting a carbinolamine precursor with aqueous sodium cyanide. X-ray structure of an a-nitrile 'carbanion', namely The [a-cyanobenzyl-lithium (tetramethylethylenediamine)*benzene], has been reported.340 Isocyanides bearing a heteroatom on nitrogen are uncommon: the N-aminoisocyanide ( 1 0 1 ) has been formed in solution by the base-catalysed decomposition of an N-methylformohydrazonoyl chloride (Scheme 156) .341 Epoxides have been ring-opened with t-butyldimethylsilyl cyanide in the presence of zinc iodide to give 4-hydroxy-isocyanides:342 this is an extension of the previously reported reaction which employed trimethylsilyl cyanide. 2-(2-Furyl)ethyl isocyanide and similar isocyanides containing heterocyclic substituents were prepared by the dehydration of the corresponding formamides with phosphorus oxychloride.343 An improved synthesis of trimethylsilylmethyl isocyanide which avoids the use of methyl isocyanide proceeds __ via the Ugi dehydration of r J - [ (trimethylsilyl)methyllformamide with phosphorus oxychloride and di-isopropylamine.344 8
Nitro- and Nitroso-compounds
Unsaturated nitro-compounds have been prepared by various methods. l-Nitro-1,3-dienes can be prepared by elimination of
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
@ Reagent
343
QNo2
N a N 0 2 a q , I 2 , HO(CH2)20H. E t O A c . 0°C
I,
S c h e m e 158
Reagent
I,
MeZN(CH2)2 N H Z , PhH
Scheme 159
I
OH N0,
r Reagent
'
I,
DBU
S c h e m e 160
1
344
General and Synthetic Methods
(102) Reagent
HgCIZ, H M P A
I,
S c h e m e 161
Reagent
I,
-
F 3 C S O Z O S i M e 3 ( 2e q u i v . ) , E t 3 N
S c h e m e 162
R’
R2
R’ R’ R’ R’
z‘N-
(CH, InL O R 3
RZ R3 = H or a l k y l
n =1,2 or 3 Reagent
I,
R O H , K F ( 0 5 e q u l v ) , or
H 2 0 , T H F , KF ( 0 5 e q u l v )
S c h e m e 163
R = Me or Reagents.
I,
N a O H aq.,
11,
NaN3,
111,
K3Fe(CN)6 a q
S c h e m e 164
R, = ( C H 2 1 5
345
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
nitrotrifluoroacetate adducts, obtained from 1,3-dienes by the action of trif luoroacetyl nitrate (Scheme 157) .345 Nitroacetamidation of conjugated dienes is efficient when a solution of nitronium tetrafluoroborate in acetonitrile obtained by anodic oxidation of dinitrogen tetroxide is used;
substantial
amounts of both 1,2- and 1,4-adducts are usually obtained.346 Some conjugated nitroalkenes can be readily prepared by reaction of alkenes with sodium nitrite and iodine under mild conditions (Scheme 158) .347 Nitro-olefination of a-substituted lactones using chiral nitro-enamines affords the corresponding nitro-olefins in high enantiomeric excess.348 1-Nitro-1-(phenylthio)alkenes were prepared by the reaction of aldehydes with the anion of (phenylthio)nitromethane, followed by treatment with methanesulphonyl chloride.349 Condensation of aliphatic as well as alicyclic ketones with primary nitroalkanes in the presence of N,N-dimethylethylenediamine afforded allylic nitro-compounds free
from the a-nitro-olefins (Scheme 159) .350 Products of thermodynamic control were obtained from condensations of 2-alkanones and 2-methylcyclopentanone with nitromethane, while the kinetic product was obtained from 2-methylcyclohexanone. allylic nitro compounds undergo palladium-catalysed substitutions.351 A synthetic equivalent for syntheses of
Such
prostaglandins, ( 3 g ,4R) -3- (benzyloxy)-4- (formyloxy)-1nitrocyclopent-1-ene, has been prepared from D-glucose.352 2-Nitroalkanols can be prepared by the condensation of aldehydes with nitroalkanes in the presence of alumina-supported potassium fluoride;353 subsequent oxidation with chromium trioxide affords the a-nitroketones.
Ring enlargement of
2-nitrocycloalkanones by reaction with 1,4-benzoquinone in the presence of DBU affords (hydroxybenz0)nitro-lactones (Scheme 1 6 0 ) .354 The transformation involves a Michael reaction, aromatization, and ring enlargement a five-membered intermediate. Nitration of certain polysubstituted phenols affordec the corresponding 4-hydroxy-dienone,355 presumably by rearrangemenl of the 4-nitro-dienone to the 4-nitrito-dienone which underwent hydrolysis. In an approach to phytuberin, the vicinal dinitroacetal (102) was prepared and the nitro groups reductively eliminated in a Kornblum olefin synthesis (Scheme 161) .356 N,N-Bis(trialkylsi1oxy)-1-alkenamines (nitrosoalkene acetals) can be
-
346
General and Synthetic Methods
Reagents
PhSH, Et3N,
1,
11,
S02CL2, C H 2 C L 2 ,
111,
m - C P B A ( 1 e q u l v ) , CH2CL2,
I V , ( € 1 - p e n t a - 1 . 3 - d i e n e , v. m - C P B A ( Z e q u l v ) , C H 2 C I 2
Sc h e me 165
HO
- I? - Howo HO 0 -A ,J
_.
hH ON O-H O Reagents
1,
H
HO
OH
p - O Z N C 6 H L C H 0 , T s O H , DMSO, ii,W3, M e O H
S c h e m e 166
Reagents.
I,
98’1.
HN03;
11,
HN03-H~50L(50-50),650C
S c h e m e 167
HO
OH
341
5: Arnines, Nitriles, and Other Nitrogen-containing Functional Groups
0
OH
HO
0
HO OH
HO OH
R = EtO or M e Reagents
Et02CN=NC0
1,
Et,
11,
P h P, 3
III,
RCOCH=PPh
Scheme 168
OzNQNo2
0-
NHNO?
R = C I or M e Reagents
HN03. H p S 0 4 . A c O H , O " C ,
1,
O"C,
IV.
11,
CH2CL2, r e f l u x ,
H 2 S O L , v. P h O M e , H 2 S 0 4
S c h e m e 169
III,
90'1,
HN03, H
2
so4'
348
General and Synthetic Methods
isolated from the reaction of trialkylsilyl
trifluoromethanesulphonates with nitroalkanes (Scheme 162) .357'358 a-Nitro-a-(arylthio)acetates, prepared by reacting the potassium salts of ethyl and benzyl nitroacetates with arenesulphenyl chlorides, provide routes to nitrogen-containing chiral compounds possessing four different labile groups. 3 5 9 Conjugate addition of nitroalkanes to a,B-unsaturated carbonyl compounds has been achieved using basic alumina, in the absence of a solvent. 360
3-Nitropropanal has been prepared by conjugate addition
of nitrite anion to acrolein;
reduction to 3-nitropropanol was
effected with borane-dimethyl sulphide.361
w-Nitro-acids and
w-nitro-esters have been prepared by ring cleavage of 2-nitrocycloalkanones (Scheme 163) .362 a-Azido-nitroalkanes can be prepared by reaction of azide ion with nitroalkanes in processes involving radical-anions (Scheme 164) .363
a-Substituted azides are formed by reacting the
azido-nitroalkanes with suitable anions,
SRNl processes. N-(2-Nitrobenzyl)aza-l5-crown-5 and a hexadeuterio analogue have
-
been prepared. Electron-deficient olefins which are ef€ective dienophiles in Diels-Alder reactions include B-phenylthio-nitro-olefins and their j3-sulphonyl nitro derivatives;
they can be prepared from
substituted 1-acetoxy-2-nitroethanes (Scheme 165). 3 6 5 Improved procedures for the isolation of the 1,4-adducts obtained from the reaction of nitronium acetate and furfural diacetate or methyl 2-furoate were reported.366 Nitroanthrafurans, required for mutagenic studies, were prepared by reacting bromonitromethane with ortho-hydroxy-aldehydes . 67 1 -Deoxy- 1 -nitro-D-aldoses are convenient1y prepared3
by ozono lysis
of a nitrone, itself obtained by the acid-catalysed condensation of p-nitro-benzaldehyde with an hydroxylamine;
Scheme 166 depicts the
conversions for D-ribose-oxime. Nitro and nitroacetyl derivatives of glycouril can be prepared by nitration of tetra-acetylglycouril (Scheme 167) .369 The method involves nitrodeacetylation and/or hydrolysis.
aci-Nitro-esters of
~
several uridine, cytidine, and adenosine derivatives have been prepared370 by selective reaction of the 5'-hydroxy group with
2,6-di-t-butyl-4-nitrophenol in a Mitsunobu reaction;
protection of
the 2'- and 3'-hydroxy groups is not required (Scheme 168). these &-nitro-esters
Since
react with stabilized phosphoranes,
nucleosides with an extended carbon-chain can be conveniently
5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups
* COR
02"
/
R'
COR
R =
jR-)&P /
fuming
I,
H, Me, Me(CH2In, o r A r
R1,R2 = H, Me, OMe, Br, o r C l
R2
R2
Reagent
349
NO,
HN03, A c 2 0
S c h e m e 170
X
F
X
eH-
( 1 03)
X = C l , OMe, o r NHCOMe
OAc (104)
i l X = Br
"OAc
,(
J ($
/
/
Br
Br
(105)
(1 0 6 )
Reagents
1,
A c Z O , H N 0 3 . [(CFjCO),O],
11,
HCI, Et20.-780C
Scheme 171
Sc h e me 172
(107)
General and Synthetic Methods
3 50
OEt
OEt NO, Reagents’
S1O2, ( N H L ) 2 C e ( N 0 3 ) 6
1,
S c h e m e 173
&o.z
Reagent
H
I,
OI
, -
&
CHZ=CH-CH-CH2,
[Pd(PPh3)&1
‘0’
Scheme 174
R 2 = P h or CH=CHPh
R = Hor Me
Reagents
I,
Bu”Li,
THF, H M P T ,
11,
ButLi,
111,
R2CH2Br,
S c h e m e 175
Reagent
I,
N a N 0 2 , AcOH aq
S c h e m e 176
IV,
PhCHO
5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups
35 1
prepared (Scheme 168). Phenols can be readily and selectively nitrated at room temperature with dilute nitric acid or metallic nitrates, by using an acidic two-phase system. 371
Mononitration of phenols and arylmethyl esters in high yield can be achieved using nitric acid adsorbed onto silica
Mixed acid nitration of anilines can
proceed by reaction at the amino group to give the nitramine, followed by rearrangement of the nitramine, the 3-nitro group migrating to a vacant ortho- or =-position; that is one route to tetranitroanilines (Scheme 169) .373 Three isomeric aminotetranitrotoluenes have been prepared by nitration of the appropriate aminodinitrotoluene;374 the apparent ips0 nitration of 4-amino-2 ,6-dinitrotoluene has been discussed. 374 A variety of acylpentamethylbenzenes were nitrated to give
2-(nitromethyl)-3,4,5,6-tetramethylacylbenzenes (Scheme 170); the same side-chain nitration was observed for other polymethylbenzenes.375 A striking feature in the nitration of 4-substituted toluenes is the change in the preference of 1,2- versus 1,4-adduct formation as a function of the 4-substituent. Thus, nitration of 4-acetamido-,4-chloro-, and 4-methoxy-toluene in acetic anhydride gives in each case a c&-lI2-nitronium acetate adduct (103) in addition to the nitro substitution product(s) (Scheme 171) .376 Nitration of 4-fluorotoluene gives a pair of diastereoisomeric lI4-nitronium acetate adducts (104) and the e - l I 2 - a d d u c t . Nitration of 4-bromotoluene in acetic anhydride containing trifluoroacetic anhydride afforded the *-1,2-adduct (105) as a single d i a ~ t e r e o i s o m e r ~ which ’~ underwent rearrangement to diene (107) when heated in benzene containing p-cresol. Since omission of p-cresol affords diene (107) together with its diastereoisomer, it is thought that both a stereorandom radical pathway and a stereospecific sigmatropic pathway operate, and that the former is suppressed by p-cresol, allowing only the (Z)-isomer (107) to be formed via a suprafacial process. Formation of the dienyl chloride (106) proceeds with retention of configuration. Nitrocyclohexadienones are effective nitrating agents for naphthols; products are obtained from reactions in dry diethyl ether at room temperature, and the resulting perhalogenated phenols can be recycled (Scheme 172) .378 Functionalized nitrobinaphthalenes have been prepared by treatment of ethoxynaphthalenes with cerium(1V) ammonium nitrate supported on silica gel (Scheme 173) .379
352
General and Synthetic Methods
(1091 Reagent
1,
NaNO,,
HCI aq
S c h e m e 177
SNHC0,Et R = CO,Et, Reagent:
1,
C0,Ph
or p -S02C6H,Me
cyclohexene
S c h e m e 178
PhN(R)NH,
+
R’
/-\ Me R
x-
Nltl, R’= H or P h
Reagents
I,
NaOEt, E t O H ,
11,
RI,
111,
1M N a O H
S c h e m e 179
HOCH,CH,CO,Na
+
NH3
5: Amines. Nitriles, and Other Nitrogen-containing Functional Groups
353
Nitration of 2-t-butyl- and 2,7-di-t-butyl-pyrene affords molecules with severely hindered nitro groups. 380 Dinitro-and trinitro-fluoranthenes were obtained by the action of dinitrogen pentoxide on 2-nitro- and 3-nitro-f luoranthene.381 Nitration of the zinc complex of octaethylporphyrin with nitronium tetrafluoroborate in pyridine proceeds more rapidly than does the uncomplexed porphyrin, the F - n i t r o p o r p h y r i n being formed in both cases.382 Primary amines are readily oxidized to nitro compounds in high yields using dimethyldioxirane in acetone;383 stepwise oxidation to the hydroxylamine, then to the nitroso derivative, and finally to the nitro compound appears likely. Bromonitromethane is a versatile electrophile which is attacked by dimethyl sulphide initially to give the nitromethyl sulphonium salt which decomposes to methylthionitromethane and trimethylsulphonium bromide. 38 The reductive cleavage of aliphatic nitro groups using tri-n-butyltin hydride has been reviewed. 385 2-Nitrocycloalkanones have been used to prepare allylic alcohols which can be modified to give 2-(4-hydroxybutyl)-2nitrocycloalkanones, and hence, by a ring-expansion reaction using KH in DME, lactones such as 12-tridecanolide (108) (Scheme 174) .386 Secondary nitroalkanes can be doubly deprotonated to give bis(1ithiooxy)-enamines containing exclusively a terminal double bond (Scheme 175); the dianion reacts with benzyl bromide, alkyl benzoates, or aldehydes. 3 8 7 For cyclic nitroalkanes, three newly created chiral centres are formed stereoselectively with 60-95% d.e. Aliphatic nitro compounds were converted into the gem-halonitro derivatives by treatment with N-chloro- or N-bromo-succinimide in protic solvents.388 Ethylidyne N-nitroso compounds have been prepared from monoand di-terpenylalkanolamines containing an isopropylidene group by reaction with sodium nitrite in aqueous acetic acid (Scheme 176);389 the mechanism of the alkene-alkyne transformation is not yet clear. The first stable a-hydroxy g-nitrosamines have been reported,390 incluing the mutagen ( 1 0 9 ) , prepared by the nitrosation
of 4-chloroindole (Scheme 177). (2-Chloroethy1)sulphinyl nitrosoureas have been prepared by nitrosation of the corresponding sulphinyl ureas in formic acid, using sodium nitrite.391 N-Nitroso-N-benzylmethylamines were prepared by N-nitrosation
General and Synthetic Methods
354
Ar
Ar
N'
-%
-L
CN CN Reagents
I,
CH2=CHMgBr,
THF,
11,
KN;A
ArNiCI-
S c h e m e 180
CH-CH=N-NMe2
OLi Reagents
I,
Z L D A , 11,
(110)
OHC-CH=N-NMe2,
III,
TsCl
S c h e m e 181
OEt
OE t
I
R:C,C,
0
HNHN
I
I
RZ
R2 (,?)-isomer
(€1
- isomer
S c h e m e 182
Reogents
I,
Bu'L!,
THF,-78'C,
1 1 ,
Me2S, - 7 8 " C ,
111,
S c h e m e 183
Mel, - 7 8 ° C
CN
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
355
of N-benzylmethlamines using sodium nitrite in aqueous hydrochloric and acetic acids. 392 1-Phenyl-3- (pyridylmethyl)ureas undergo nitrosation chiefly at the 3-position when gaseous nitrosating agents in organic solvents are used; however the 1-nitroso derivatives predominate when sodium nitrite and aqueous HC104 or HC1, or 99% HC02H are employed.393 Thiophene g,N-ylides undergo cycloadditions with nucleophilic alkenes to give [4+21 adducts with concomitant extrusion of acylthionitroso compounds which can be trapped by alkenes to give an ene reaction (Scheme 178) .394 acylthiohydroxylamines 9
Hydrazines and Hydrazones
Phenylhydrazine can be converted into 1-alkyl-1-phenylhydrazines the base-promoted hydrolysis of substituted 15-pyrazolium iodides (Scheme 179) .3 9 5 Hofmann-type ring opening of certain 1H-pyrazolium halides afforded N',N'-disubstututed hydrazones of trans-cinnamamide and acrylamide (Scheme 179). Complete oxidation of various 2,2-diaryl-l-picrylhydrazines to the corresponding hydrazyls can be achieved with potassium permanganate. 396 N-Cyclopropylidene-!',El-dialkylhydrazines were prepared by the dehydration of 1- (N,g-dialkylhydrazino)cyclopropanols.397
Phosphinylhydrazines, prepared from alkyl hydrazines and diethyl chlorophosphite, were converted by peroxides into phosphinylhydrazyls.398 The first example of an azo-Cope rearrangement, & the [ 3 , 3 1 sigmatropic shift involving conversion of an azo compound into a hydrazone, has been reported (Scheme 180) .399 Azo compounds bearing electron-withdrawing groups gave excellent yields of the hydrazones in various solvents. Dilithium salts of carboxylic acids add to glyoxal mono(dimethy1hydrazone) to give salts which with p-toluenesulphonyl chloride afford the corresponding unsaturated aldehyde hydrazones (110) (Scheme 1811, which are readily converted into unsaturated carboxylic acids. 385 By this method, aldehydes and/or carboxylic acids may be extended by one methine group, or by three methine groups if vinylogous monohydrazones are used. 400 In the preparation of phenylhydrazone derivatives4'' of some a-ketoesters, the (E)-isomer was found to predominate, but could be partially isomerized into the (?)-isomer by keeping as a solution in lI2-dichloroethane or trichloroethane, in the dark (Scheme 182); six
General and Synthetic Methods
356
COCO, K
R
/o:
CI a
I
H -N=C -CO,
N
Me
CI
NH
A CO C OzNa
R
R
I -N= C - C 0,Me
COC0,H (111)
R = H o r Br Reagents
NOZ. H 2 S O L a q ,
1,
11,
MeCOCH(CI)C02Me, N a O A c ,
111,
HCI o q
S c h e m e 184
H
I
Ar-C--N=N-p-C6H48r
_____) I
‘\OH
ArC02H
O ‘H
+
HN=N-p-C6H4Br
Scheme 185
PhCH 0 \N
Reagent
Ar-C=N-N---p-C6H4Br H
I
I
I,
H S i M e Ph, C F 3 C 0 H, ZO’C
S c h e m e 186
(11 2 )
A r -C-NHNH--p-C6H4Br
II
+o\ o-
357
5: Amines. Nitriles, and Other Nitrogen-containing Functional Groups
R
I 4Ph-CHN-OSiMe3
R
PhCH=k’
I
I
‘0-
CN Reagents
Me3SICN, Zn12.
I,
11,
AgF
Scheme 187
Me C ‘’ Me’
Me
N=O
\
‘cI
OH R’
I I c=$J-c-c
M e/
CHR4
I
R3
li Reagents.
(Et0)3P,
I,
1 1 ~
H2S0 aq
S c h e m e 188 HNBoc
HNBoc
I
@ 0-
/
HN Reagent
’
1,
I
__3
I
HN 3
MeCN
S c h e m e 189
(113) Reagents
I,
NH20H.HCI aq,
11,
XCR1(R2)COR3,
III,
S c h e m e 190
HCI o r
I
R2
/ NCHR~ CI -
358
General and Synthetic Methods
of isopropylidene and cyclopentylidene cyclopentanones have been prepared (Scheme 183) :402r403 the former undergo the Shapiro reaction to give isopropenyl derivatives.
The hydrazonoyl chlorides
(ill), which on treatment with aqueous sodium acetate afford
substituted-4-oxo-dihydroquinazolines, are obtained by coupling the diazonium salts of isatic acids with methyl 2-chloroacetoacetate (Scheme 184) . 4 0 4 3-(4-Bromoanilino)peroxycarboximidic acids (112) have been implicated in the decomposition of a-azobenzyl hydroperoxides (Scheme 185 ) , 4 The lithiation of hydrazones derived from
( E l - or (~)-l-amino-2-methoxymethylpyrrolidine,followed by Michael
addition, is the basis of a diastereoselective and enantioselective synthesis of 5-0x0-esters. 406
Lithiated heterocyclic hydrazones can
undergo Michael addition to 2-alkenoates with at least 96% asymmetric induction. 407 10
Hydroxylamines and Hydroxamic Acids
Mixtures of hydrosilanes and acid reduce oximes to hydroxylamines in good yields: 408 an (E) -oxime gave erythro-1-phenyl-1-benzyloxyamino propan-2-01 in 99% selectivity (Scheme 186); the reduction with lithium aluminium hydride gave only an 82:18 ratio of the ( E ) - to
(z)-isomers.
The g-(2-Hydroxyethyl)-oximes of several ketones have been prepared and converted into pyrroles. 4 0 9
2-Benzoylhydroxylamines have been formed by reaction of 1-benzoylimidazole with aliphatic hydroxylamines. 410 Addition of trimethylsilyl cyanide to N-alkyl-gphenylnitrones afforded cyano-g-silylhydroxylamines (Scheme 187) :411 reaction of the latter with silver fluoride regenerates the nitrone in excellent recovery, thereby providing a blocking group €or nitrones. !-A1
lylhydroxylamines can be prepared412 from nitrone
hydrochlorides, which are produced by the reaction of nitroso compounds with alkenes, in an ene-type mechanism (Scheme 188). Analogues of potent dopaminomimetic ergot derivatives have been prepared, in which N 6 of a (5R,SS,lOE)-6-a1 lylergoline N6-oxide was converted into a substituted hydroxylamine function. The key step is a Meisenheimer [ 3 , 2 1 sigmatropic rearrangement of the N6-oxide (Scheme 189) .413 The reduction of aromatic nitro compounds to N-aryl-hydroxylamines by o-xylene-a,a'-dithiol occurs when an iron
-
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
I
359
RyJpy
I
/
0 (119) R = H
(118)
(120) R = C H 2 N = C H C 5 H L N Ph
Reagents
I,
Ph
B u n L i . THF, 0 ° C .
11,
R4X.
111,
H 0 2
S c h e m e 195 R 3~
~C6H4Br
~
R2 Reagent
-
i,p-BrC6HltSO2N3, A
S c h e m e 196 Ph
Ar’COCI
Reagent
+
Ph
I
A r zdN--(Ph
I, NaH, H M P A
S c h e m e 197
R3
0
CN
>
R2
R3 RJ$R’
N
>
CN Reagent
1,
Me3S~N=C-Ns
‘Me3,
S c h e m e 198
RZ
360
General and Synthetic Methods
+
PhB r Reagent
+
Bu'NC
Bu3SnR
PhCR-NBu'
[Pd ( P P h 3 l 4 1
I,
S c h e m e 191
+
CHR'R~
R ' = R 2 =Et or Ph R ' = Ph, R 2
Me
R', R ' = f l u o r e n y l Reagent'
ButOK
DABCO o r
1,
S c h e m e 192 R2
R'
R2
R'
0
0 X = C l o r 8r
Ph,P=N
0
R2 Reagents
I,
Nard3,
1 1 ,
Ph3P
S c h e m e 193
(116) Reagents
I,
L D A , THF,
(117) 11,
HMPA, R X
S c h e m e 194
36 1
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups complex of the latter is present.414
N-Hydroxyamino acids, and in particular hadacidin (113) can be prepared by reaction of a-halogenocarboxylic acid derivatives (115)
with (2)-2-furaldehyde oxime to give the nitrones (114) which can be subsequently hydrolysed (Scheme 190)415 11
Imines, Iminium Salts, and Related Compounds
Imination of aldehydes, ketones, and acid chlorides has been achieved using bis(dichloroa1uminium) phenylimide, prepared from ethylaluminium chloride and aniline.416
Imines can be obtained by
the palladium-catalysed reaction of ternary systems comprising bromobenzene, t-butyl isocyanide, and an organotin compound (Scheme 191) .417 Ketimines can be prepared by the reaction of imidoyl chlorides with a variety of organotin compounds in the presence of a catalytic quantity of one of several palladium complexes.418 Relatively stable ketimines were obtained by the base-catalysed decomposition of N-alkyloxaziridines (Scheme 192) . 419
Five-, six-,
and seven-membered cyclic imines are formed by the reaction of a-azidoketones with triphenylphosphine in anhydrous media (Scheme 193) .420
Tributylphosphine-diphenyl disulphide reduces
ketoximes and secondary aliphatic nitro compounds to the corresponding imines, under anhydrous conditions.421
The imine may
be acetylated to give an enamide, or reduced to an amine, or captured by hydrogen cyanide to give an a-amino-nitrile. Chiral imines were prepared from cyclohexane and methoxyamines derived from D-camphor derivatives; the imines undergo metalation and alkylation to give 2-alkylcyclohexanones of high enantiomeric purities. 422 Alkylation of the
(R)-camphor
imine of t-butyl
glyciriate ( 1 1 6 ) affords imines (117) for which d.e.s. of 75-100% were observed when R=allyl (Scheme 194) .423
The greater
diastereoselectivities in the cases of allylic imines compared with other substituents studied (with d.e.s.
of about 50%) were
explained by invoking an interaction between the n-systems of the allylating agent and the imine, such that alkylation must occur from the pro-R - face, for steric reasons.423 The di-imine (118), prepared from glyoxal and (m-iodobenzyl)amine, as its nickel(I1) complex, catalyses the directed chlorination of steriods,424 as do the related imines ( 1 1 9 ) and ~ ~ ~ (120).426
1,3-Di-imines can be prepared by alkylation
of 3-substituted 4-amino-1-azabutadienes (Scheme 195) .427
362
General and Synthetic Methods
SO,H
S H 11 RN-C-NH, Reagents
H202,
I
NHR
I J RN=C-NHH,
I
II
___)
RNZC-NH,
R1NH2
11,
S c h e m e 199
Reagents
I,
Arii,
11,
H20
S c h e m e 200
R NC
CI Reagent
I ?
CI
CLOC-COCI
Scheme 201
(121)
J
0
Reagents
I,
Bu”NH2,
0
11,
D o w t h e r m A,
200°C,
Scheme 2 0 2
111,
EtOH. HCI
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
363
Symmetrical lI4-di-imines have been prepared by dehydrodimerization of a-bromoimines using lithium di-isopropylamide,4 2 8 in a process which probably involves single electron transfer. Cyclopentenecarboximidates were produced by the reaction of p-bromobenzenesulphonyl azide with cyc1ohexa-ll4-dienol ethers, the
-
latter having been prepared by Birch reduction:
the cycloaddition-
rearrangement results from selective attack at the more electron-rich bond of the two double bonds of the diene (Scheme 196) . 429
Several N-acylimidates have been prepared by acylation of
ethyl acetimidate and ethyl b e n ~ i m i d a t e . ~ ~ ' 2-Azabuta-l ,3-dienes have been prepared431 in which the imino
group is conjugated with an enol ester;
acylation of carbanions
derived from N-(diphenylmethy1)arylmethanimines affords a wide range
of the 2-azadienes (Scheme 197). The site selectivity for the attack of the electrophile on the aza-ally1 anion depends upon the substituents on the carbanion, and on the hardness of the electrophile. Unactivated 2-aza-1,3-dienes undergo cycloaddition reactions with dialkyl azodicarboxylates and heterocumulenes. 432 Several substituted 1-thia-3-azabutadienes have been prepared: 433 reaction with ketenes afforded bg-1,3-thiazine-b-ones. 1-Aza-allyllithium reagents are of interest in synthesis, and on account of their stereoisomerism.
The structure of the diethyl
ether adduct of N-(2,2-dimethyl-l-methylenepropyl)-Nlithiobenzenamine has been shown to be a centrosymmetric dimer. 434 The structure of a lithiated cyclohexanone phenylimine was shown to be a dimer with significant disorder in the cyclohexenyl and phenyl moieties. 435 Syntheses and photochemical reactivity of 6 , a-unsaturated imines have been reported,436
A general approach
to quinone imine acetals involves anodic oxidation of aryl trif luoroacetamides and subsequent cyclization.437
N,N'-Dicyanoquinonedi-imines, a new class of quinone derivatives,
- -
can be synthesized by the reaction of quinones with bis (trimethylsilyl)carbodi-imide (Scheme 198). 438 Cyanimides have been obtained by treatment of cyanamides with cyanimides can be hydrolysed to lead t e t r a - a ~ e t a t e . ~Since ~~ carbonyl compounds, the method can be used to prepare aldehydes and ketones Erom primary amines. An efficient route to guanidines from thioureas and amines has been developed (Scheme 199) .440 Imination at the 2-position of 5-methylpyridinium salts has Some
been achieved using liquid ammonia-potassium permanganate. 441
364
General and Synthetic Methods
0 (124) R ' = P h or But Reagents.
1,
RICOCI.
(126)
(125) C5H5N,
THF,
M e C O C I . C5H5N, T H F
11,
Scheme 203
R'\\
+
/ OR"
R2 i c = N = c \
PhHC=iHCOR
I
CF,So,
R3
(127) Reagent
I,
(128) R:
O+SbC16-,
[I,
R = P h o r But
CF3S03H
S c h e m e 204 NHCOR NHCOR
c1(129) Reagents
I,
I H
c LoL-
l n d o l ~ n e1 1 , K O I i . M e O H ~
Scheme 205
IReagent.
1,
M e ] , Me
co S c h e m e 206
365
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
azahexamethine merocyanines have been prepared by carbanionic attack at the a-position of a pyridinium ring, followed by ring opening.442 Arylimines can be obtained by the addition of N-silylated the imines may be
amides to aryl-lithium compounds (Scheme 200) ;443
isolated or reduced in situ to amines, or hydrolysed to carbonyl compounds.
a-Ketodicarboxylic acid chloride imine chlorides, which
readily undergo cyclization to !-heterocycles,
have been prepared
by a-addition of dicarboxylic acid chlorides to isocyanides (Scheme 201) .444
Two new formimidoylamino-substituted carbapenems (4) have
been prepared by a route involving a hetero Diels-Alder reaction (Scheme 4 ) .I4 A 6-(alkylamino) group can be introduced into 5-ethyenyluracils
by displacement of chloride anion (Scheme 202); the resulting uracil (121) can undergo two consecutive [1,5] migrations of hydrogen to give the imine (122) which can be hydrolysed to the 6-aminouracil (123).445
The secondary enaminones (125) react with
benzoyl or pivaloyl chloride to give the previously unknown iminovinyl carboxylates (124):
with acetyl chloride, the
g,N-diacetyl compounds (126) are formed (Scheme 2 0 3 ) . 446 N-Substituted imines have been detected in the Paal-Knorr condensation of acetonylacetone with primary amines. 447 6-Chloroimines can be prepared by reacting 6-chloroaldehydes with primary amines and either TiCl or MgS04.44a 4 Acyliminophosphates were prepared by treating 1-acylaminomethylphosphonates with NBS followed by a tertiary A wide range of 3-(cyanomethyl)- and N- (a-cyanobenzyl)imines have been prepared;450 they undergo tautomerism to the N-protonated azomethine ylides which give cycloaddition reactions with olefinic dipolarophiles. amine.449
Trimethylsilyl trifluoromethanesulphonate is useful as a removable group for the activation of imines by conversion into iminium salts; the reagent forms complexes with 3,4-dihydroisoquinolines and 3,4-dihydro-i3-~arbolines which react with lithio derivatives of 3-cyano-4-methylpyridines to give
precursors of the Alangium alkaloids. 451 Organosilyl(3-substituted imino)stannanes can be prepared by the palladium(0)-catalysed insertion of nitriles into the silicon-tin bond of organosilylstannanes. 452 Monomeric bis(azomethines) have been prepared and used as templates for the introduction of substitutents bearing amino groups at predetermined distances apart along the surface of modified
Meov
366
General and Synthetic Methods
\
~
N
H
HN
(130)
lea*
CH
1li
1
HN
/ CIR
H
N
~
(131)
.NHR Reagents
I,
HC(OMel3. MeOH,
11,
CHCL3, hv
S c h e m e 207
(OdL - (:&AMe (
O
0
R’
r
n
L
N
N
H R
R’= Me o r P r
R2
R2
0
I
Me
2 , 4 , 6-Me,C6H7SO;
NHZ R Z = Me or (CH,$CO,Et Reagent
I,
2 , 4 , 6-Me3C6H2S07-ONH7
Scheme 2 0 8
, $!:
SbCI, NMe2
Rea g e n t s
I,
[ Ts -N= S= N MeZ1+Sb Ct6-
S c h e m e 209
R
361
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
Me
I
0
CH,-C=NOH
CH=CNO,
-($
Br Reagent
I,
Br
PdlC, Na2HP02
S c h e m e 211
Reagents
1,
Me3S1N3(2 e q u i v ) , B F E t O ( ? e q u i v ) , E i 2 0 , 3' 2
11,
NoHC03 aq
S c h e m e 212
PI
I 1 Y OCH,Ph
N3
OH
' O v : ° IC H 2 P h N3
368
General and Synthetic Methods
silicas.453 A Schiff base bis(crown ether) ligand containing recognition sites for alkali and transition metal guest cations has been prepared.454 1-Alkoxy-2-azaallenium salts (127) were prepared by the reaction of 3-methyleneamides with trialkyloxonium salts (Scheme 204) ;455 protonation of the amides (128) occurs exclusively at nitrogen to give N-acyliminium salts. 1,3-Dialkoxy-2-azapropenylium salts (127) (R2=alkoxy) have also been prepared. 56 A one-pot synthesis of nonamethine cyanine dyes with a planar, rigid methine chain has been reported.457
Model compounds (129)
containing the 1,7-diazaheptamethinium chromophore of the betalaine plant pigments were prepared by ring opening of pyridinium salts with indolines, saponification, and intramolecular amine replacement (Scheme 205) .458
A new feature in the preparation of quinone-
iminium dyes from aromatic amines is the use of DMSO as the methylating agent, TiC14 being the usual catalyst.459 3-(~-Dialkylaminoarylidene)-l-alkylthiotriazenes,readily obtainable from thioamide salts, afford diamidinium iodides when treated with methyl iodide (Scheme 206) .460 Blue diquinolinylmethine dyes (131) have been prepared by irradiation of N-acylated primaquines ( 1 3 0 ) in chloroform solution with ultraviolet light (Scheme 207) .461
Another route involves
condensation of a primaquine with trimethylorthoformate. Quinazolines unsubstituted at the 4-position react with 0-mesitylenesulphonylhydroxylamine to give the corresponding
(quinazolin-3-io)amides; however, certain 4-substituted quinazolines are aminated at N-1 to give 1-aminoquinazolinium salts (Scheme 208) .462 Cationic sulphur diimides react with alkenes to give thiazetidinium salts, a new class of heterocycles (Scheme 209) -463 12
Oximes
Oximes have been generated by electrocylic ring opening of intermediate N-hydroxy-1 ,2-dihydroazetes (Scheme 210) .464 Modification of the strategy provides several routes to oxime ethers.465
Various
a,
@-unsaturated nitroalkenes were readily
reduced to the corresponding oximes by sodium hypophosphite in the presence of palladium (Scheme 211) .466
Conversion of aldoximes into
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
369
ketoximes has been achieved by using a mixture of a peroxyester and a cycloalkane or etner as the C-alkylating agent.467 The syntheses and reactions of a-hydroxylamino-oximes have been reviewed. 468 Syntheses of the four isomers of benzylideneacetone oxime ?-methyl ether have been reported;469 direct or sensitized irradiation of the E,E-isomer or the Z,E-isomer leads to equilibration of all four isomers. 2-(Trialkylsiloxy)oxime 0-trialkylsilyl ethers can be formed from nitroalkanes by reaction with trialkylsilyl trifluoromethanesulphonates; a 1 3-trialkylsiloxy migration is involved (Scheme 162) .357 I
Hydroxyiminoyl chlorides, precursors of the versatile nitrile oxides, can be conveniently prepared by the action of t-butyl hypochlorite on a solution of an oxime in carbon tetrachloride.470 13
Carbodi-imides
Carbodi-imides can be prepared in high yields from N,"-disubstituted thioureas and di-2-pyridyl sulphite by reaction in methylene chloride at room temperature. 292
-
(N-Alkylbenzimidoy1)- and (y-arylbenzimidoy1)-carbodi-imides can be prepared from imidoylthioureas directly, or iminothiadiazolines.4 7 1 14
Azides and Diazo-compounds
Azides have been prepared in excellent yields by the reaction of various aryl-, carbonyl-, and sulphonyl-hydrazines with dinitrogen tetroxide at low temperatures.4 7 2 When treated with trimethylsilyl azide and a catalytic quantity of titanium tetraisopropoxide, substituted epoxides undergo regioselective ring opening to give termina11y substituted az ides.
1 -Az ido-2-hydroxya 1 kylsi1 anes
have been prepared by the stereoselective ring opening of 1,2-epoxyalkylsilanes with azidotrimethylsilane or sodium azide; a three-step conversion of one such azide into 1-phenyl-2-azadeca-1, 3-diene was reported. 474 Ring opening of 2,3-epoxy-a1coho1s by attack of azide at predominantly C-3 can be achieved using sodium azide supported on a calcium ion-exchanged Y-type zeolite.475 Vicinal azidohydrins have been prepared by treating epoxides with Et3A1/NH3 in toluene.476 This mild and selective transformation of epoxides has been applied to 14,15-epoxy-14,15-dihydromilbemycin D.476
General and Synthetic Methods
370
u
X = H or OMe Reagent.
I,
0 2 , Co(L), MeCN
S c h e m e 215
N2HQ 0
(132)
(133)
R
R
NHNO, R = C L or M e
L 0-
Reagent
I,
100 “1.
H N 0 3 , A c Z O , AcOH, 0°C
Scheme 216
C02 Et
Et 0,C
N
(134) Reagents
I,
ArNiCI-,
11,
NaOEt ( 0 1 e q u i v ) , E t O H
S c h e m e 217
C0,Et
I
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
371
(2)-1-Alkenyl azides have been prepared by the regio- and stereo-selective reaction of trans-1,2-epoxyalkylsilanes with azidotrimethylsilane (Scheme 212) .477
7-Azidohepta-lI3-dienes have
been prepared and decomposed thermally to give dehydropyrrolizidines.478 Ally1 azides can be prepared by the palladium-catalysed reaction of ally1 acetates with azide ion (Scheme 213) ;479 the azides can then be reacted with triphenylphosphine to give the iminophosphoranes (the latter being key precursors of various nitrogen compounds) which are converted into primary allylamines by treatment with alkali. Iodoallyl azides have been prepared by the monoaddition of iodine azide to alkyl-substituted allenes;
allene itself is an exception, forming a
bisadduct of a gem-diazide structure.480 Azide-substituted a-diazo-amides were prepared from glycyl amides by diazotization.481 protect hydroxy groups;
4-Azidobutyryl chloride can be used to
removal of the 4-azidobutyryl group is
effected by catalytic reduction to the 4-aminobutyrate which undergoes spontaneous deacylation to give the alcohol and pyrrolidin-2-one.4a2 Methanesulphonyl azide has been shown to be superior to p-toluenesulphonyl azide in diazo transfer reactions which afford
a-diazo-carbonyl compounds.483
Configurationally different
3-azido-2,3-dideoxy-2-fluoro- and 2-azido-2,3-dideoxy-3-fluoro-sugars, precursors of fluoro amino acids, have been synthesized.484 A typical route involves selective ring opening of an epoxide with azide anion, and subsequent displacement of a trifluoromethanesulphonate group with fluoride anion (Scheme 214). The addition products of iodine azide to several 1-arylcyclohexenes have been shown485 to be the 2-azido-l-iodo-l-ary1cyclohexanes, and not the l-azido-2-iodo-larylcyclohexanes, as previously reported. A ferrocenylalkylamine
has been prepared by stereoselective azidation of a ferrocenyl carbocation, and reduction of the resultant azide.486 Polymeric quaternary ammonium azides permit clean nucleophilic substitution of both activated and unactivated alkyl halides at room temperature, and in almost complete conversion.487 A convenient synthesis of diazo compounds (Scheme 215) involves the oxiation of hydrazones, and is catalysed by N,N’-ethylenebis (salicylideneiminato)cobalt (11) Schiff base complexes.488 Polynitrodiazophenols have been prepared by the nitration
of suitably substituted anilines and rearrangement of the nitramines
372
General and Synthetic Methods
R 2 = a r y l or alkyl bromide or i o d i d e Reagents
I,
Bu"LI
or
LOA,
11,
R2X,
111,
CF3C02H,
IV,
(C02H12 a q
S c h e m e 218
PhKPh 11
HN/N
7
R1+a2 E t
(136)
R'
TR2 E
(137) Reagents
I,
RLI, e l e c t r o p h l l e ,
11,
CF3C02H,
111,
H2,Pd/C,10M
S c h e m e 219
Reagent
I,
ArN;CI-
Scheme 2 2 0
HCI, E t O H ,
IV,
10M HCI, E t O H
373
5: Arnines, Nitriles, and Other Nitrogen-containing Functional Groups so formed (Schemes 169 and 216) .373
15N-Labelling studies show that
the two nitrogen atoms of the nitramine group are retained in the diazo group of the diazophenol. The diazo-ether obtained from the reaction of benzenediazonium cation with 1-naphthol has been isolated for the first time.489 Several diazo-ketones have been prepared from the acid chloride and diazomethane; rearrangement of a-diazo-carbonyl compounds oxonium ylides afforded heterocycle^^^' and cyclobutanones.491
The
diazo-ketone (132), synthesized from ethyl 2-oxocyclopentanecarboxylate, afforded 5-methyltricyclo[3.3 .O. 0 2 ' oct-6-en-3-one (133) upon t h e r m o l y ~ i s . ~ ~ ~ 15
8l
Azo- and Azoxy-compounds
By using the malonic ester variation of the Japp-Klingemann reaction, the stable azo compounds (134) have been prepared, 493 and are usually crystalline:
a wide variety of heterocycles has been
synthesized, including 5-aminopyrazoles (Scheme 217). cis- and trans-l,l,l',l'-tetracyclopropylazomethanes have been prepared: the trans-isomer was converted into the yellow cis-isomer upon irradiation.494 t-Butylhydrazones (135) can be deprotonated to give stabilized azo anions which undergo chiefly C-alkylation (Scheme 218)) ;495 tautomerization to the hydrazones and subsequent hydrolysis can provide ketones, a-hydroxy-ketones, or Y-keto-esters. If the lithio derivatives of hydrazones (135) are reacted with carbonyl compounds, a subsequent elimination provides a new route to azo-alkenes.495 Tritylhydrazone anions, when treated with electrophiles followed by ethanethiol, afford alkanes 2 homolytic decomposition.496 Azo anions generated from t-butyldiphenylmethyl-hydrazones (Scheme 219) undergo C - a l k y l a t i ~ n ~ ~to ' give azo-alkanes which via the hydrazones (136) afford amines, hydrazines, and also alkanes under mild conditions; the method affords access to the general a-amino anionequivalent (137). 2,6,2',6'-Tetramethylazobenzene has been prepared by the sodium tungstate-catalysed oxidation of 2,6-dimethylaniline with hydrogen peroxide to give the azodioxide, and subsequent reduction of the latter with h e x a c h l o r ~ d i s i l a n e . ~ ~ ~ Arylazo-methoxy-diphenylmethanes have been isolated as stable yellow crystals by reaction of benzophenone arylhydrazones with bromine, followed by methanolysis of the resulting
374
General and Synthetic Methods
0-
0-
HO Reagents
I,
hv, M e O H ,
11,
hv, P h H
-
S c h e m e 221
0
II Cl-C-CI
+
Bun3Sn-NC0
100°C
0
II
+
OCN-C-NCO
Bun3SnCI
Scheme 222
0 Ph (139) Reagents
I,
KOH, M e O H ,
I!,
Ph
COCIz
Scheme 223
:j' tSCN 2cN +
(cN
CI Reagents
SCN i,KSCN,
1 1 ,
___) Ill
1 'I A
I
SCN
DMSO, h e a t ,
111,
DBU, C H 2 C I 2
Scheme 224
1
J.' MeSwSCN
Ill, I V
MeS
wNCS
5: Arnines, Nitriles, and Other Nitrogen-containing Functional Groups
375
1- (arylazo-diphenylmethyl)-pyridinium bromides.499 Those arylazo-methoxy-diphenylmethanes are a special type of N,g-acetal, and undergo acidic hydrolysis to give the aryldiazenium cation (ArN2H2+). The novel 1,3,5,7-tetraazabicycl0[3.3.l]nonanes~(138) were prepared by the reaction of diazonium salts with either hexamine or
.
an aqueous mixture of ammonia-formaldehyde (Scheme 220) 500 trans-Azobenzene-4,4'-disulphonyl y-cyclodextrin has been prepared; 5 0 1 displacement of the sulphonyl groups by 2-naphthyl acetate afforded bis(2-napthylacetyl) Y -cyclodextrin, capable of being a flexible host, unlike native Y-cyclodextrin which is rigid. T h e (1,l'-Bicyclopropyl) -1-diazonium cation502 and 1-arylcyclopropanediazonium cations503 have been generated by alkaline cleavage of the analogous nitrosocarbamates in methanol. Several brilliant blue azo dyes have been prepared by the conventional procedure of diazotization and coupling with N,N-dialkylanilines.504 Monoazo dyes absorbing in the near infrared have been prepared from 2-(4-amino-2-acetylaminophenylazo)-4-chloro-5-formylthiazoles by condensing the formyl group with active methylene compounds, such as malononitrile.505 Photochemical reactions of azoxybenzene derivatives bearing a methoxy and/or a dimethylamino group in the 4/4'-positions involve several processes (Scheme 221) .506 The photo-Wallach rearrangement occurs for all except the disubstituted derivatives. An oxygen shift to give the azoxybenzene with the N-0 group remote from the ring bearing the stronger electron-donating substituent was found to be general. The 4,4'-disubstituted azoxybenzenes afforded both deaminated and N-formyl derivatives. 16
Isocyanates, Thiocyanates, and Isothiocyanates
A new route to carbonyl di-isocyanate (Scheme 222)507 can be regarded as the formal reaction of urea with phosgene, since tri-n-butyltin isocyanate can be prepared from urea and the trialkyltin oxide, which is obtainable from the trialkyltin choride produced in the isocyanate reaction. Carbonyl di-isocyanate can be used to prepare t r i a ~ i n e s . ~ ' ~Recent advances in the chemistry of chlorosulphonyl isocyanate have been reviewed. 5 0 8 Synthetic 509 applications of isocyanatophosphines have also been reviewed. (-)
- ( 5 )- (1-Phenylethyl) isocyanate, prepared from the carbamate
General and Synthetic Methods
316
(140) Reagent. 1,NH4SCN, CC14
Scheme 2 2 6
0(141 1 R = Ph, Me, o r Bu
n = l or 2 Reagent
I,
RNHOH
Scheme 227
($7
(%;
___) I , I1
( 1 1 1 *
(-J NOH
(144) Reagents
I,
Me3Al, n-C6HIL,
-8OoC,
11,
H20
Scheme 2 2 8
R =Me, or CH2Ph R e a g e n t s : i, R N H O H a q ,
11,
R'I, M e 2 C 0 ,
( E and Z ) 111,
NaHC03
S c h e m e 229
377
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
(139), (Scheme 223) has been used to resolve (+)-mecamylamine via the readily separable urea diastereoisomers.516
( E l - and (~)-2-Buten-1,4-diyldithiocyanateshave been prepared selectively (Scheme 224) :511 elimination performed on the (Z)-isomer affords (E)-1,3-butadienylthiocyanate which functions as a Diels-Alder diene if ethanol is used to trap the resultant thiocarbamate. The reaction of 5-methylthiolanium fluorosulphate with thiocyanate ion gives mainly 4- (methylthio)butyl thiocyanate,512 a result consistent with an hypothesis for the biogenesis of the latter;
the isothiocyanate has also been prepared (Scheme 225).
N-Alkyl(ary1)-N-isothiocyanato-carboxamides were prepared by
reacting the corresponding 2-chloroacetamides with potassium thiocyanate.513
Imidoyl isothiocyanates ( 1 4 0 ) were prepared by
reacting isocyanides with sulphenyl thiocyanates, or by treating imino chlorosulphides with ammonium thiocyanate (Scheme 226) 514
.
17
Nitrones
Nitrones of the type ( 1 4 1 ) were prepared by the reaction of the corresponding hydroxymethylene compounds with hydroxylamines (Scheme 227) .515
With the exception of the g-phenyl nitrone derived from
indanone, nitrones ( 1 4 1 ) were found to exist in the enolic form. Sterically unhindered and certain moderately hindered a-chloronitroso compounds (142) react with trimethylaluminium to give the methyl nitrones (143) (Scheme 228) .516 Relatively hindered a-chloronitroso compounds
such as ( 1 4 4 ) can undergo fragmentation followed by ring closure, in an overall sequence which leads to a ring expansion (Scheme 228).516 A nitrone obtained from an N-hydroxytryptophan ester and methyl orthoformate afforded a route to 6-carbolines via nitrone
cycloaddition.517 Nitrones were prepared by the electrochemical oxidation of N-hydroxy secondary amines using a supporting electrolyte such as
sodium iodide.518 Thioimidate N-oxides (nitrones of thio esters) were prepared by S-alkylation of 3-alkylthiohydroxamic acids with alkyl iodides,
-
followed by treatment of the resulting hydroiodide salts with base (Scheme 229) . 5 1 9
378
General and Synthetic Methods
18
Nitrates and Nitrites
A substituted 5-formyl-3-hydroxy-2~-l-benzopyranunderwent smooth
0-nitration at C-3 with fuming nitric acid, and was subsequently
-
converted into the 5-hydroxy derivative of the antihypertensive agent nipradilol. 520 References 1. 2. 3. 4. 5. 6. 7.
8. 9. 10.
11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
A.Nose and T.Kudo, Chem. Pharm. Bull., 1986, 34, 3905. H.Suzuki and Y.Hanazaki, Chem. Lett., 1986, 549. T.E.Nickson, J. Org. Chem., 1986, 2,3903. J. Org. Chem., 1986, 2,4294. D.H.Lloyd and D.E.Nichols, ______ S.Nakatsuka, T.Masuda, O.Asano, T.Teramae and T.Goto, Tetrahedron Lett., 1986, 27, 4327. F.J.Weiberth and S.S.Hall,J. Org. Chem., 1986, 51, 5338. J.Bergman, A.Brynolf, and E.Vuorinen, Tetrahedron, 1986, 42, 3689. J.Sepio1, Tetrahedron, 1986, 42, 609. S.N.Maiti, M.P.Singh, and R.GXicetich, Tetrahedron Lett., 1986, 27, 1423. Y-Kawahata, S.Takatsuto, N.Ikekawa, M.Murata, and S.Omura, Chem. Pharm. Bull., 1986, 34, 3102. S.C.Shim, K.N.Choi, and Y.K.Yeo, Chem. Lett., 1986, 1149. R.A.Abramovitch, M.M.Cooper, R.Jeyaraman, and G.Rusek, Tetrahedron Lett.. 1986., 27.. 3705. S.Mori, T-Aoyama, and T.Shioriri, Chem. Pharm. Bull., 1986, 2, 1524. Y.Ueda and V.Vinet, Can. J. Chem., 1986, 64, 2184. A.R.Katritzky and K.S.Laurenzo, J. Org. Chem., 1986, 51, 5039. K.Kohda, K.Baba, and Y.Kawazoe, Chem. Pharm. Bull., 1986, 34. 2298. B.Langlois and G.Soula, Bull. SOC. Chim. Fr., 1986, 925. S.Mori, T.Aoyama, and T.Shioiri, Tetrahedron Lett., 1986, 27, 6111. S.Yamada, Y.Nakagawa, O.Watabiki, S.Suzuki, and M.Ohashi, Chem. Lett., 1986, 361. ___ H.Tondys and H.C.van der Plas, J.Heterocyc1. Chem., 1986, 23, 621. H.Sladowska, A.van Veldhuizen, and H.C.van der Plas, __ J. Heterocycl. Chem., 1986, 23, 843.
22. W.Wiehl and A.W.Frahm, Chem. Ber., 1986, 119, 2668. 23. R.A.Rampulla and R.K.Russel1, Synth. C o m m u n . , 1986, 16, 1229. 24. D.Enders, H-Schubert, and C.Nuebling, Angew. Chem., Int. Ed. Enql., 1986, 25, 1109 25. X L a z b i n andG.F.Koser, J. Org. Chem., 1986, 51, 2669. 26. F.A.Davis, M.A.Giangiordano, and W.E.Starner, Tetrahedron Lett., 1986, 27, 3957. 27 - M.J.Pulwer and T.M.Balthazor, Synth. Commun., 1986, 16, 733. 28. S.Itsuno, K.Tanaka, and K.Ito, Chem. Lett., 1986, 1 1 B . 29. P.Sulmon, N.De Kimpe, and N.Schamp, J. Chem.Soc., Chem. Commun., 1986, 1677. 30. C.Betancor, R.Carrau, C.G.Francisco, and E.Suygrez, Tetrahedron Lett., 1986, 27, 4783. ___ 31. R.G.Shea, J.N.Fitzner, J.E.Fankhauser, A.Spaltenstein, P.A.Carpino, R.M.Peevey, D.V.Pratt, B.J.Tenge, and P.B.Hopkins, J. Org. Chem., 1986, 51, 5243.
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
379
H.C.Brown, K.-W.Kim, T.E.Cole, and B.Singararn, J. Am. Chem. 1986, 108, 6761. J.yulzer and C.Brand, Tetrahedron, 1986, 42, 5961. E.Slusarska and A.Zwierzak, Liebigs Ann. Chem., 1986, 402. Y.Murakami, Y.Hisaeda, J.Kikuchi, T.Ohno, M.Suzuki, and Y.Matsuda, Chem Lett., 1986, 727. 36. R.Herrmann, G.Huebener, F.Siglmueller, and I.Ugi, Leibiqs Ann. 1986, 251. 37. F.Siglmueller, R.Herrmann, and I.Ugi, Tetrahedron, 1986, 42, 5931. 38. L.E.Overman, M.E.Okazaki, and P. Mishra, Tetrahedron Lett., 1986, 4391. 39. F.Guibe, O.Danqles, and G.Balavoine, Tetrahedron Lett., 1986, 27, 2365. 40. J.-P.Wolf and H.Pfander, Helv. Chim. Acta, 1986, 69, 1498. B.Ohtani, H.Osaki, S.Nishimoto, and T.Kagiya, J. Am. Chem. SOC., 41. 1986, 108, 308. 5943. 42. J . F . M a Z e k and C.J.Burrows, Tetrahedron Lett., 1986, 43. M.Niitsu and K.Samejima, Chem. Pharm. Bull., 1986, 2,1032. 44. M.Somei, Chem. Pharm. Bull., 1986, 2,4109. 45. L.H.Helberg, C.Beeson, and R. Somanathan, Tetrahedron Lett., 1986, 27, 3955. 46. M-Mladenova, Synth. Commun., 1986, 16, 1089. 47. H.Takeuchi and K-Takano, J. Chem. SOC., Perkin Trans. 1, 1986, 611. 48. Y-Kawada, H.Yamazaki, G.Koga, S.Murata, and H.Iwamura, J. Org. E., 1986, 1472. 49. T.W.Bentley, D.J.Richards, and M.G.Hutchings, Tetrahedron Lett., 1986, 27, 5261. 50. K-Kobayashi, T.Okamoto, T.Oida, and S.Tanimoto, Chem. Lett., 1986, 2031. 51. Y.Yamamoto, S.Nishii, K.Maruyama, T.Komatsu, and W.Ito, J. Am. Chem. SOC., 1986, 108, 7778. 52. M.B.Eleveld, H.Hogeveen, and E.P.Schudde, J. Org. Chem., 1986, 51, 3635. 53. S.K.Manda1 and K.Nag, J. Org. Chem., 1986, 51, 3900. 54. A.Nose and T.Kudo, Chem. Pharm. Bull., 1986,4, 4817. 55. S.C.Yorke, J.W.Blunt, M.H.G.Munro, J.C.Cook, and K.L.Rinehart,Jr., Aust. J . Chem., 1986, 39, 447. 56. B.P.Cho, V.K.Chadha, G.C.Le Breton, and KL.Venton, J. Org. Chem., 1986, 51, 4279. 57. G.W.Kabalka, R.S.Varma, Y.-Z.Gai, and R.M.Baldwin, Tetrahedron ___ Lett., 1986, 27, 3843. 58. J.P.Guthrie, J.Cossar, and B.A.Dawson, Can. J. Chem., 1986, 64, 2456. 59. P.Beak, A.Basha, B.Kokko, and D.Loo, J. Am. Chem. S O C . , 1986, 108, 6016. __ 60. T.Kusumoto, T.Hiyama, and K.Ogata, Tetrahedron Lett., 1986, 27, 4197. 61. K.Ikeda, K.Achiwa, and M.Sekiya, Chem. Pharm. Bull., 1986, 34, 1579. 62. H.Kinoshita, K.Inomata, M.Hatashi, T.Kondoh, and H.Kotake, Chem. Lett., 1986, 1033. 63. M.Hashimoto, Y.Eda, Y.Osanai, T.Iwai, and S.Aoki, Chem. Lett., 1986, 893. 64. D.H.R.Barton, J.-P.Finet, and J.Khamsi, Tetrahedron Lett., 1986, 27, 3615. 65. P.DeShong, J.M.Leginus, and S.W.Lander, Jr., J. Org. Chem., 1986, ll_, 574. 66. L.Wei, A.Bel1, S.Warner, I.D.Williams, and S.J.Lippard, J. A m . Chem. SOC., 1986, 108, 8302. 32.
___ SOC.,
33. 34. 35.
m.,
z,
380
General and Synthetic Methods
67.
A.Spaltenstein, P.A.Carpino, and P.B.Hopkins, Tetrahedron Lett., 1986, 27, 147. 68. B.SchoenenberqE, A-Brossi, C.Georqe, and J.L.Flippen-Anderson, Helv. Chim. Acta, 1986, 69, 283. 69. S.M.Weinreb, D.M.Demko, and T.A.Lessen, Tetrahedron Lett., 1986, 27, 2099. 70. T-Hamada, A.Nishida, and O.Yonemitsu, J. Am. Chem. S O C . , 1986, 108, 140. 71. D.Heyer and J.-M.Lehn, Tetrahedron Lett., 1986, 27, 5869. 72. R.Schneider, A.Riesen, and T.A.Kaden, Helv. ChimTActa, 1986, 69, 53. 73. K S t u e t z , A.Georqopoulos, W.Granitzer, G-Petranyi, and D.Berney, J. Med. Chem., 1986, 2,112. 74. K.Haqa, K.Iwaya, and R.Kaneko, Bull. Chem. SOC. Jpn., 1986, 2, 803. 75. J.T.GuptGn, M.A.M.Moebus, and T.Buck, Synth. Commun., 1986, 16, 1561. 76. J.T.Gupton, J.Coury, M.Moebus, and S.Fitzwater, Synth. Commuq., 1986, 16, 1575. 77. M.S.Cooper and H-Heaney, Tetrahedron Lett., 1986, 27, 5011. 78. P.A.Grieco and W.F.Fobare, Tetrahedron Lett., 1 9 8 6 7 2 7 , 5067. 79. H.-U.Reissiq and H.Lorey, J. Chem. SOC., Chem. Commun., 1986, 269. Chem., 1986, 80. T.Fuchiqami, T.Sato, and T.Nonaka, J.Orq. 366. 81. L.A.Blanchard and J.A.Schneider, J. Orq. Chem., 1986, 1372. 82. Y.Nakatsuji, T.Kikui, I.Ikeda, and M.Okahara, Bull. Chem. S O C . Jpn., 1986, 59, 315. 83. G.-X.He, A.Abe, T.Ikeda, F.Wada, K.Kikukawa and T-Matsuda, Bull. Chem. S O C . Jpn., 1986, 2,674. 84. H.Tsukube, K.Takaqi, T-Hiqashiyama, T.Iwachido, and N.Hayama, J. Chem. SOC., Perkin Trans. 1 , 1986, 1033. 85. P.Depreux and A-Marcinal-Lefebvre, Can. J. Chem., 1986, 64, 626. 86. K.-Y.Law and F.C.Bailey, Can. J. Chem., 1986, 64, 2267. 87. B.S.Orlek, Tetrahedron Lett., 1986, 27, 1699. 88. E.J.Corey, R.Naef, and F.J.Hannon, J. Am. Chem. S O C . , 1986, 108, 7114. 89. T.Alfheim, S.Buden, J.Dale, and K.D.Krautwurst, Acta Chem. Scand., Ser. B . , 1986, 40, 40. 90. K.Saiqo, N.Kubota, S-Takebayashi, and M-Haseqawa, Bull. Chem. SOC. Jpn., 1986, 59, 931. 91. J.Barluenqa, H. C z r v o , B.Olano, S.Fustero, and V.Gotor, Synthesis, 1986, 469. 92. T.Koqa, Y.Noqami, N.Toh, and K.Nishimura, Synth. Commun., 1986, 16, 195. 93. R.B.Weisenfeld, J. Orq. Chem., 1986, 51, 2434. 94. K.Saiqo, R.-J.Lin, M.Kubo, A.Youda andM.Haseqawa, Chem. Lett., 1986, 519. 95. D.J.Cram, S.P.Ho, C.B.Knobler, E.Maverick, and K.N.Trueblood, J. Am. Chem. SOC., 1986, 108, 2989. 96. D.J.Cram and S.P.Ho, J. Am. Chem. SOC., 1986, 108, 2998. 97. A.Carroy, C.R.Langick, J.-M.Lehn, K.E.Matthes, and D.Parker, Helv. Chim Acta, 1986, 69, 580. 98. K.Hiraki, J.Tsutsumida, and Y.Fuchita, Chem.Lett., 1986 , 337. 99. S.Buoen and J.Dale, Acta Chem. Scand., Ser.B, 1986, 40, 141. 100. M.Iwata and H.Kuzuhara, Bull. Chem. S O C . Jpn., 1986, 59 , 1031. 101. T.Koqa, Y.Noqami, and S.Yamanaka, Synthesis., 1986, 461 102. A-Riessen, M.Zehnder, and T.A.Kaden, Helv. Chim. Acta, 1986, 69, 2067. 103. A.Reissen, M.Zehnder, and T.A.Kaden, Helv. Chim. Acta, 1986, 69, - 2074.
s, z,
~
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
381
104. M.Studer and T.A.Kaden, Helv. Chim. Acta, 1986, 69, 2081. 105. A.E.Martel1, R.J.Motekaitis, E.T.Clarke, and J.J-.Tarrison, Can. J. Chem., 1986, 64, 449. 106. K.F.Dancey, D.E.Gnton, and S.MOSS, Synth. COrnmUn., 1986, 16, 795 * 107. M-W-Hosseiniand J.-M.Lehn, Helv. Chim. Acta, '1986, 69, 587. 108. H.-J.Schneider and A-Junker, Chem.Ber., 1986, 119, 2815. 109. G.Beinert and M.A.Winnik, Can. J. Chem., 1986, 64, 1743. 110. M.Lang, J.-P.Schoeni, C.Pont, and J.-P.Fleury, Helv. Chim. Acta, 1986, 69, 793. 111. s n g , A.LaGoix, C.Pont, and J.-P.Fleury, Helv. Chim. Acta, 1986, 69, 1025. 112. J.BarlGnga, J.Joglar, S.Fustero, and V.Gotor, J. Chem. SOC. , Chem. Commun., 1986, 361. 113. M.Chu, P.-L.Wu, S.Givre, and F.W.Fowler, Tetrahedron Lett., 1986, 27, 461. 114. Y.Z.Hu=g and Q.Zhou, Tetrahedron Lett., 1986, 27, 2397. 115. P.F.Schuda, C.B.Ebner, and T.M.Morgan, Tetrahedron Lett., 1986, 27, 2567. 116. A.R.Katritzky, D.L.Ostercamp, and T.I.Yousaf, Tetrahedron, 1986, 42, 5729. 117. M.Cariou, R.Carlier, and J.Simonet, Bull. S O C . Chim. Fr., 1986, 781. 118. A.J6nczyk and Z.Owczarczyk, Synthesis, 1986, 297. 119. L.Rene, J.Poncet, and G.AUZOU, Synthesis, 1986, 419. 120. J.Barluenga, F.Aznar, and R.Liz, J. Chem. SOC., Chem. Commun., 1986, 1180. 121. J-Barluenga, F.Aznar, R.Liz, and C.Postigo, J. Chem. SOC., Chem. Commun., 1986, 1465. 122. R.L.Snowden and M.Wuest, Tetrahedron Lett., 1986, 27, 699. 123. R.L.Snowden and M.Wuest. Tetrahedron Lett.. 1986. ~, 27. 703. 124. J.Barluenga, F.Aznar, R.Liz, and M.-P.Caba1, synthesis, 1986, 960. 125. T.Tokumitsu, Bull. Chem. SOC. Jpn., 1986, 2,3871. 126. G.Stork, C.S.Shiner, C.-W.Cheng, and R.L.Polt, J. Am. Chem. __ S O C . , 1986, 108, 304. 127. F.Plenat, A.Bennamara, L-Chiche, and H.Christo1, Phosphorus Sulfur, 1986, 26, 39. 128. T.Gajda and A.Gierzak, Liebigs Ann. Chem., 1986, 992. 129. H.Braun, K.Klier, G.Kresze, M-Sabuni, O.Werbitzky, and J.Winkler, Liebigs Ann. Chem., 1986, 1360. 130. Y.Ito, T.Matsuura, S.Nishimura, and M.Ishikawa, Tetrahedron Lett., 1986, 27, 3261. 131. D.Faul and G.=mbert, Liebigs Ann. Chem., 1986, 1466. 132. L.F.Tietze and E.VOSS, Tetrahedron Lett., 1986, 27, 6181. 133. M.Hirama, 1-Nishizaki, T.Shigemoto, and S.Itc, JTChem. SOC., Chem. Commun., 1986, 393. 134. K-Narasaka, Y.Ukaji, and S.Yamazaki, Bull. Chem. SOC. Jpn., 1986. 59. 525. 135. R - J u l i G , T-Herzig, B.Bernet, and A.Vasella, Helv. Chim. Acta, 1986, 69, 368. 136. R.K.Atkins, J.Frazier, L.L.Moore, and L.O.Weige1, Tetrahedron Lett., 1986, 27, 2451. 137. D.A.Evans and A.E.Weber, J. Am. Chem. S O C . , 1986, 108, 6757. 138. Y.Ito, M.Sawamura, and T-Hayashi, J. Am. Chem. SOC., 1986, 108, 6405. 139. R.M.Giuliano, T.W.Deisenroth, and W.C.Frank, J. Org. Chem., 1986, 2304. 1 4 0 . A.Bongini, G.Cardillo, M.Orena, S-Sandri and C.Tomasini, JChem. SOC., Perkin Trans. 1, 1986, 1339. 141. A-Bongini, G.Cardillo, M.Orena, S-Sandri, and C.Tomasini, JChem. SOC., Perkin Trans. 1, 1986, 1345. ~
I
.
s,
382
General and Synthetic Methods
142. T.Hino, K.Nakakyama, M.Taniguchi, and M.Nakagawa, J. Chem. SOC., Perkin Trans. 1 , 1986, 1687. 143. K.S.Bruzik, J. Chem. SOC., Chem. Commun., 1986, 329. 144. T.Shono, Y.Matsumura, S.Katoh, and Y.Matsumoto, Tetrahedron Lett., 1986, 27, 6083. 145. X S a m m e s andD.Thetford, Tetrahedron Lett., 1986, 27, 2275. 146. R.M.Coates and C.H.Cummins, J. Org. Chem., 1986, X I 1383. 147. L.R.Krepski, K.M.Jensen, S.M.Heilmann, and J.K.Rasmussen, Synthesis, 1986, 301. 148. D.A.Claremon, P.K.Lumma, and B.T.Phillips, J. Am. Chem. SOC., 1986, 108, 8265. 149. U . S c h o n k o p f , U.Busse, R.Lonsky, and R.Hinrichs, Liebigs Ann. Chem., 1986, 2150. 150. U.Schoellkopf, D.Pettiq, and U.Busse, Synthesis, 1986, 737. 151. U.Schoellkopf, M.Hauptreif, J.Dippe1, M.Nieger, and E.Eqert, Angew. Chem., Int. Ed. Engi., 1986, 25, 192. 152. T.Wakamiya, Y.Oda, H.Fujita, and T.Shiba, Tetrahedron Lett., 1986, 27, 2143. 153. B.H.LiEhutz, B.Huff, and W.Vaccaro, Tetrahedron Lett., 1986, 27, 4241. 154. T.Weber, R.Aeschimann, T.Maetzke, and D.Seebach, Helv. Chim. el1986, 69, 1365. 155. A.Dur;ault, C.Greck, and J.C.Depezay, Tetrahedron Lett., 1986, 27, 4157. 156. S.Cardani, L.Prati, and 0-Tinti, Synthesis, 1986, 1032. 157. W.Shengde, Z.Chanqyou, and J.Yaozhong, Synth. Commun., 1986, 16, 1479. 158. Kbppolzer, R.Pedrosa, and R.Moretti, Tetrahedron Lett. , 1986, 27, 831. 159. KL-Castehano, S.Horne, R-Billedeau, and A.Krantz, TetrahedrE Lett., 1986, 27, 2435. 160. J.Mulzer, A-AKermann, B.Schubert, and C.Seilz, J_Orq. Chem., 1986, 51, 5294. 161. S.Sawada, T.Nakayama, N.Esaki, H.Tanaka, K.Soda, and R.K.Hil1, J. Org. Chem., 1986, 51, 3384. 162. A.J.Ozinskas and G.A.Gsentha1, J. Org. Chem., 1986, X I 5047. 163. R.Labia and C.Morin, J. Org. Chem., 1986, 51, 249. 164. A.K.Saksena, R.G.Lovey, V.M.GirijavallabhaK A.K.Ganguly, and A.T.McPhai1, J. Org. Chem., 1986, 51, 5024. 165. F.Effenberger, U.Burkard, and J.Winfahrt, Liebigs Ann. Chem., 1986, 314. 166. F.Effenberqer and U.Burkard, Liebigs Ann. Chem., 1986, 334. 167. T.Seethaler and G.Simchen, Synthesis, 1986, 390. 168. W.Oppolzer and R.Moretti, Helv. Chim. Acta, 1986, 69, 1923. 169. S.Ikegami, T.Hayama, T.Katsuki, and M.Y=guchi, Tetrahedron Lett., 1986, 2,3403. 170. a l m e s , J.Daunis, R-Jacquier, G.Nkusi, J.Verducci, and P.Viallefont, Tetrahedron Lett., 1986, 27, 4303. 171. C.Gennari, L.Colombo, and G.Bertolini, J. Am. Chem. SOC., 1986, 108, 6394. 172. D.A.Evans, T.C.Britton, R.L.Dorow, and J.F.Dellaria, J. Am. Chem. SOC., 1986, 108, 6395. 173. L.A.Trimble and J.C.Vederas, J. Am. Chem. SOC., 1986, 108, 6397. 174. T.Hvidt, O.R.Martin, and W.A.Szarek, rztrahedron Lett., 1986, 27, 3807. 175. K E - W a l k e r , C.Matheny, C.B.Storm, and H.Hayden, J. Org. Chem., 1986, 51, 1175. 176. A.S.DuEa, M.B.Giles, and J.C.Williams, J. Chem. SOC., Perkin Trans. 1 , 1986, 1655. 177. E.W.Logusch, Tetrahedron Lett., 1986, 27, 5935. J. Org. Ch?., 1986, X I 102. 178. W.H.Pirkle and T.C.Pochapsky, ______
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
383
179. J.Kemya, A.A.NatuL and V.N.Gogte, Chem Ind., 1986, 243. 180. E.G6mez, C.Avendano, and A.McKillop, Tetrahedron, 1986, 42, 2625. 181. D-Ferroud, J.P.Genet, and R.Kiolle, Tetrahedron Lett., 1986, 27. 23. 182. J.P.Genet, D.Ferroud, S.Juge, and J.R.Montes, Tetrahedron Lett., 1986, 27, 4573. 183. B.I.Glaenzer, K.Faber, and H.Grienq1, Tetrahedron Lett, 1986, 27. 4243. 184. E T a n i , E.Taniqawa, Y.Tatsuno, and S.Otsuka, Chem. Lett., 1986, 737. 185. 1.Malassa and D-Matthies, Liebigs Ann. Chem., 1986, 1133. 186. S.Ram and R.E.Ehrenkaufer, Synthesis, 1986, 133. 187. J.Ackrel1, J.M.Muchowski, E.Galeazzi, and A.Guzman, J. Orq. Chem., 1986, 51, 3374. 188. m t o h , Y.KaGko, K.Sakata, and K.Yamakawa, Bull. Chem. SOC. Jpn., 1986, 59, 457. 189. G o c h i n , O.=bot, J.Dunoques, and F.Duboudin, Synthesis, 1986, 667. 190. J.-B.Verlha and J.-P.Quintard, Tetrahedron Lett., 1986, 27, 2361. 191. T.W.Bel1 and A.Firestone, J. Am. Chem. SOC., 1986, 108, 8109. 192. R.H.Boutin and H-Rapoport, J. Orq. Chem., 1986, 51, 5320. 192. R.Tamura, D-Oda, and H. Kurokawa, Tetrahedron Lett., 1986, 27, 5759. 194. B.Garrigues and M.Lazraq, Tetrahedron Lett., 1986, 2 7 , 1685. 195. J.d'Angelo and J.Maddaluno,J. Am. Chem. SOC., 1986,108, 8112. 196. N.Yamasaki, M. Murakami, and T.Mukaiyama, Chem. Lett., 1986, 1013. 197. C.Fuganti, P.Grasselli, and L-Malpezzi, J. Org. Chem., 1986, 51, 1126. 198. P.Renaud and D.Seebach, Synthesis, 1986, 424. 199. H.Stamm and R.Weiss, Synthesis, 1986, 392. 200. H.Stamm and R.Weiss, Synthesis, 1986, 395. 201. Y.H.Paik and P.Dowd, J. Orq. Chem., 1986, 51, 2910. 202. P.Bey, F.Gerhart, and M.Junq, J. Org. Chem., 1986, 51, 2835. 203. C.Herdeis, Synthesis. 1986, 232. 204. Y.M.Choi, N.Kucharczyk, and R.D.Sofia, Tetrahedron, 1986, 42, 6399. 205. S.M.Weinreb, J.A.Gainor, and R.P.Joyce, Bull. SOC. Chim. Belg., 1986, 95, 1021. 206. K.Mai and G.Pati1, Synth. Commun., 1986, 16, 1823. 207. I.S.Blaqbrouqh, N.E.Mackenzie, C.Ortiz, and A.I.Scott, Tetrahedron Lett., 1986, 27, 1251. 208. J.Symes and T.A.Modro, Can. J. C h s . , 1986, 64, 1702. 209. S.Antebi and H.Alper, Can. J. Chem., 1986, 64, 2010. 210. P.Beak and K.D.Wilson, J. Orq. Chem., 1986, 51, 4627. 211. N.De Kimpe, P.Sulmon, L.Mo&ns, N.Schamp, J.-KDeclercq, and M.Van Meerssche, J. Orq. Chem., 1986, 51, 3839. 212. M.Iwata and H.Kuzuhara, Chem. Lett., 1986, 951. 213. A.P.Johnson, R.W.A.Luke, and R.W.Steele, J. Chem. S O C . , Chem. Commun., 1986, 1658. Can. J. Chem., 1986, 64, 2475. 214. E.Piers and B.W.A.Yeunq, ______ 215. M.Moriyasu, A.Kato, and Y.Hashimoto, Bull. Chem. SOC. Jpn., 1986, 59, 939. 216. M.Egli
General and Synthetic Methods
384
220. C.Cativiela, M.D.Diaz de Villegas, and E.Melendez, Tetrahedron, 1986, 42, 583. 221. G.J.Hanson, J.S.BarG, and T.Lindberg, Tetrahedron Lett., 1986, 27, 3511. 222. L.Grehn, U.Ragnarsson, and R.Datema, Acta Chern. Scand., Ser. B. 1986, 40, 145. 223. Y.Endo,K.Namikawa, and K.Shudo, Tetrahedron Lett., 1986, 27, 4209. 224. P.M.Manoury, J.L.Binet, A.P.Dumas, F.LefGvre-Borg, and I.Cavero, J.Med. Chem., 1986, 29, 19. 225. R.A.Pasca1, Jr., J.Sperge1, and D. Van Engen, Tetrahedron Lett., 1986, 27, 4099. 226. m u m b e r g e r and A-Vasella, Helv. Chim. Acta, 1986, 69, 1205. 227 T.Mandai, T.Moriyama, K.Ttsujimoto, M.Kawada, and J.Otera, Tetrahedron Lett., 1986, 27, 603. 228. H.Hiri, H.Wakbayashi, and M.Komiyama, B u l l . Chem. SOC. Jpn., 1986, 59, 545. 229. C.M.Jensen and W.C.Trogler, J. Am. Chem. S O C . , 1986, 108,723. 230. F.M.Hauser, S.R.Ellenberger, J.P.Glusker, C.J.Smart, and H.L.Carrel1, J. Org. Chem., 1986, 2,50. 231. H.Hoberg and E.Hernandez, J. Chem. SOC., Chem. Commun., 1986, 544. 232. F.Ozawa, M.Nakano, I.Aoyama, T.Yamamoto, and A.Yamamot0, J. Chem. SOC., Chem. Commun., 1986, 382. 233. A.Toshimitsu, G-Hayashi, K-Terao, and S.Uemura, J. Chem. S O C . , Perkin Trans. 1, 1986, 343. 234. Y.Kita, S.Akai, N.Ajimura, M.Yoshigi, T.Tsugoshi, H.Yasuda, and 4150. Y.Tamura, J. Org. Chem., 1986, 235. O.Piccolo, L.Filippini, L.Tinucci, E.Valoti, and A.Citterio, Tetrahedron, 1986, 42, 885. 236. J.M.Shin and Y.H.Ki6 Tetrahedron Lett., 1986, 27, 1921. 231. K.U.K.G.Nicholas and K.Vaughan, Can. J. Chem., 1986, 64, 799. 238. L.Grehn, K.Gunnarsson, and U.Ragnarsson, Acta Chem. S G n d . , Ser. B, 1986, 40, 745. 415. 239. F . O z a w C H.Yanagihara, and A.Yamamoto, J. O r g . Chem., 1986, 240. J.A.Lowe, 111, Synth. Commun., 1986, 16, 541. 241. J.Altman, N.Shoef, M.Wilchek, and A.WGshawsky, I s r . J. Chem., 1986, 59, 29. 242. CH.Hishmat, A.H.Abd-El Rahman, N.M.A.El-Ebrashi, and M.M.F.Ismai1, Chem. Ind., 1986, 142. 243. J.Dost, M.Hesche1, and J.Stein, J . Prakt. Chem., 1986, 328, 551. 244. N.Kurokawa and Y.Ohfune, J. Am. Chem. S O C . , 1986, 108, 6043. 245. M.Tamura, J.Jacyno, and C.H.Stammer, Tetrahedron Lett., 1986, 27, 5435. 246. KE.Ramer, R.N.Moore, and J.C.Vederas, Can. J. Chem., 1986, 64, 706. 247. H.Eckert and C.Seide1, Angew. Chem., Int. Ed. Engl., 1986, 25, 159. 248. P.Wipf and H.Heirngartner, E v . Chim. Acta, 1986, 69, 1153. 249. G.R.Petit and P.S.Nelson, J. Org. Chem., 1986, 1282. 250. H.Iida, K.Fukuhara, M.Machiba, and T.Kikuchi, Tetrahedron Lett., 1986, 27, 207. 251. m s s l e r , M.Kuehn, and T-Loeschner, Liebigs Ann. Chem., 1986, 21. 252. U.Schmidt, A-Lieberknecht, H.Griesser, R.Utz, T.Beuttler, and F-Bartkowiak, Synthesis, 1986, 361. 253. H.Kunz and H.-J.Lasowski, Angew. Chem., Int. Ed. Engl., 1986, 25, 110. 254. FA.Bartlett and F.Acher, Bull. SOC. Chim. Fr., 1986, 771. 255. G.R.Petit and P.S.Nelson, Can. J. Chem., 1986, 64, 2097. 256. S.Murahashi, T.Naota, and E.Saito, J.-Am. Chem. S O C . , 1986, 108, 7846.
z,
x,
z,
~
5: Amines. Nitriles, and Other Nitrogen-containing Functional Groups
385
257. Y.Morimoto, Y.FuJiwara, H.Taniguchi, Y.Hori, and Y.Nagano, Tetrahedron Lett., 1986, 27, 1809. 258. T.Yoshida, N.Kambe, S.Murai, and N.Sonoda, Tetrahedron Lett., 1986, 27, 3037. 259. P.K.SuS;famanian and R.W.Woodard, Synth. Commun., 1986, 16, 337. 260. M.T.Clark, R.A.Coburn, R.T.Evans, and R.J.Genco, J . MedTChem., 1986, 29, 25. 261. K.YoshGo, T.Kohno, T.Uno, T.Morita, and G.Tsukamoto, J. Med. Chem., 1986, 29, 820. 262. S a t a and H.Kuzuhara, Chem. Lett., 1986, 369. 263. R.Nomura, T.Wada, Y.Yamada, and H.Matsuda, Chem. Lett., 1986, 1901. 264. S.P.Joseph and D.N.Dhar, Tetrahedron, 1986, 42, 5979. 265. O.Attanasi, P.Filippone, A.Mei, and F.Serra-=netti, Synth. Commun., 1986, 16, 343. 266. S.Kim and S.Kim,J. Chem. S O C . , Chem. Commun., 1986, 719. 267. Y.M.Goo and Y.B.Lee, J. Chem. S O C . , Chem. Commun., 1986, 1247. 268. S-Shinkai, S.Nakamura, O.Manabe, T.Yamada, N.Nakashima, and T.Kunitake, Chem. Lett., 1986, 49. 269. M.Era, S.Hayashi, T.Tsutsui, S.Saito, M.Shimomura, N.Nakashima, and T.Kunitake, Chem. Lett., 1986, 53. 270. R.D.Gless,Jr., Synth. Commun., 1986, 16, 633. 271. C.Jenny and H-Heimgartner, Helv. Chim. Acta, 1986, 69, 174. 272. T.Jagodzihski, E.Jagodzifiska, and Z.Zab%ofiski, Tetrahedron, 1986, 42, 3683. 273. L.J.J.=onowski and W.A.Szarek, Can. J. Chem., 1986, 64, 1620. 274. C.Jenny and H.Heimgartner, Helv. Chim. Acta, 1986, 69,374. 275. 0.E.Jensen and A-Senning, Tetrahedron, 1986, 42, 6555. 276. J.E.Mills, Synthesis, 1986, 482. 277. J.L.LaMattina and C.J.Mularski, J. Org. Chem., 1986, 51, 413. 278. ~.D.Robbinsand J.R.Nea1, Synth. Commun., 1986, 5, 891. 279. H.Takahata, K.Yamabe, and T.Yamazaki, Synthesis, 1986, 1063. 280. J.H.Hillhouse, I.A.Blair, and L.Field, Phosphorus Sulfur, 1986, 26. 169. 281. =Schmidt and D.Weller, Tetrahedron Lett. , 1986, 27, 3494. 282. H . J . K ~ and ~ y.~.Kim, Synthesis, 1986, 970. 283. G.Bram, A.Loupy, and M.P&doussant, Tetrahedron Lett., 1986, 27, 4171. 284. N.Chatani and T.Hanafusa, J . Org. Chem., 1986, 51, 4714. 285. C.G.Krespan, J. Org. Chem., 1986, 51, 332. 286. H.-J.Liu and H.Wynn, Can. J. Chem., 1986, 64, 649. 287. H . - J . L ~and ~ ~ . W y n n ,Can. J. Chem., 1986, 64, 658. 288. T.Kurihara, M.Kanakawa, S.Harusawa, and R.Yoneda, Chem. Pharm. Bull., 1986, 34, 4545. 289. e m t r u p , S.Fischer, H.-M.Berstermann, M.Kuzaj, H.Lueersen, and K.Burger, Angew. Chem. Int. Ed. Engl., 1 9 8 6 , g , 85. 290. K.Mai and G.Pati1, Tetrahedron Lett., 1986, 27, 2203. 1986, 27, 291. B.Rigo, C.Lespagnol,etrahedronLett., 347. 292. S.Kim and K.Y.Yi, Tetrahedron Lett., 1986, 27, 1925. 293. K.Mai and G.Patil, Synthesis, 1986, 1037. 294. I.Minami, M.Yuhara, I.Shimizu, and J.Tsuji, J. Chem. SOC., Chem. Commun., 1986, 118. 295. M-Kimura, S-Matsubara, Y.Sawaki, and H.Iwamura, Tetrahedron Lett., 1986, 27, 4177. 296. N.Chatani, T.Takeyasu, and T.Hanafusa, Tetrahedron Lett., 1986, 27, 1841. 297. H.Uno, S.Fujiki, and H.Suzuki, Bull. Chem. Soc. Jpn., 1986, 59, 1267. 298. U.Hertenstein, S.Huenig, H.Reichelt, and R.Schaller, Chem. Ber., 1986, 119, 699. 299. n i s c h e r and S.Huenig, Chem. Ber., 1986, 119, 2590. ~
General and Synthetic Methods
386
300. K.Fischer and S-Huenig, Chem. Ber., 1986, 119, 3344. 301. S.Huenig and H.Reichelt, Chem. Ber., 1986, 119, 1772. 302. O.S.Andel1, J.-E-Baeckvall, and C. Moberg, Acta Chem. Scand., Ser. B , 1986, 40, 184. 303. K.Peseke, M.Michalik, and U.Schoenhusen, J. Prakt. Chem., 1986, 328, 856. 304. L.R.Krepski, K.M.Jensen, S.M.Heilmann, J.K.Rasmussen, and L.E.Lynch, Synth. Commun., 1986, 16, 617. 305. A.Alberola, A.M.Gonzalez, B.Gonzalez, M.A.Laguna, and F.J.Pulido., Tetrahedron Lett., 1986, 27, 2027. 306. H.Miyake and K.Yamamura, Tetrahedron Lett., 1986,. 27, 3025. 307. H.M.R.Hoffmann, K.Giese1, R.Lies, and Z.M.Ismai1, Synthesis, 1986, 548. 308. A.J.Fatiadi, Synthesis, 1986, 249. 309. R.Neidlein and R.Leidholdt, Chem. Ber., 1986, 119, 844. 310. K.Nakasuji, M.Nakatsuka, H.Yamochi, 1-Murata, S.Harada, N.Kasai, K.Yamamura, J.Tanaka, G.Saito, T.Enoki, and H.Inokuchi, Bull. Chem. S O C . Jpn., 1986, 2,207. 311. T.Kurihara, M.Miki, K-Santo, S-Harusawa, and R.Yoneda, Chem. Pharm. Bull.. 1986., 34. . 4620. 312. K-Shibata, Y.Saito, K.Urano, and M.Matsui, Bull. Chem. SOC. Jpn., 1986, 59, 3323. 313. H.Pellissicr,A.Meou, and G.Gil, Tetrahedron Lett., 1986, 2979. 314. H.Pellissier, A.Meou, and G.Gil, Tetrahedron Lett., 1986, 27, 3505. 315. P.Lorencak, G-Raabe, J.J.Radziszewski, and C-Wentrup, J. Chem. SOC., Chem. Commun., 1986, 916. 316. H.Moser. A-Fliri, A.Steiger, G.Costello, J-Schreiber, and A-Eschenmoser, Helv. Chim. Acta., 1986, 69, 1224. 317. R.Yoneda, K.Santo, S.Harusawa, and T.Kurihara, Synthesis, 1986, 1054. 318. Y-Kobayashi, S.Asada, I.Watanabe, H.Hayashi, Y. Motoo, and S.Inoue, Bull. Chem. SOC. Jpn., 1986, 2,893. 319. Y.Kobayashi, H.Hayashi, K.Miyaji, and S.Inoue, _ Chem. Lett., _ _ _ ~ 1986, 931. 320. J.Nokami, T.Mandai, A-Nishimura, T-Takeda, S.Wakabayashi, and N.Kunieda, Tetrahedron Lett., 1986, 27, 5109. 321. L.Khamliche and A.Robert, Tetrahedron Lett., 1986, 27, 5491. 322. G.I.Nikishin, E-1-Troyansky,V.V.Misintsev, A.N.Molokanov, and Y.N.Ogibin, Tetrahedron Lett., 1986, 27, 4215. 323. T.Kurihara, M.Miki, R.Yoneda, and S.H=usawa, Chem. Pharm. Bull., 1986, 34, 2747. 324. H.Haerle and TC.Jochims, Chem. Ber., 1986, 119, 1400. 325. N.V.Nquyen, K.Chow, J.O.Karlsson, R.Doedens, and H.W.Moore, J. Org. Chem., 1986, I, 419. 326. R.A.Russel1 and B.A.Pilley, Synth. Commun., 1986, 2,425. 327 S.Yamaguchi, T.Hanafusa, T.Tanaka, M.Sawada, K.Kondo, M.Irie, H.Tatemitsu, Y.Sakata, and S.Misumi, Tetrahedron Lett., 1986, 27, 2411. 328. K.Kobayashi and C.L.Gajure1, J. Chem. SOC., Chem. Commun., 1986, 1779. 329. T-Amano, K.Yoshikawa, T.Sano, Y.Ohuchi, M.Shiono, M.Ishiquro, and Y.Fujita, Synth. Commun., 1986, 16, 499. 330. J.Mauqer and A.Robert, J. Chem. SOC., Chem Commun., 1986, 395. 331. N.De Kimpe, P.Sulmon, and N.Schamp, Bull. SOC. Chim. Belg., 95, 567. 332. N.Chatani, and T.Hanafusa, Tetrahedron Lett., 1986, 27, 4201. 333. I.Saito, Y.-H.Kuo, and T.Matsuura, Tetrahedron Lett., 1986, 27,
z,
I
~~
~
5: Amines, Niiriles, and Other Nitrogen-containing Functional Groups
387
334. R.Bossio, S.Marcaccini and R.Pepino, Tetrahedron L e t t . , 1986, 27, 4643. 335. T W - M u r r a y , N.D.Murray, and R.G.Reid, J. Chem. SOC., Chem. Commun., 1986, 1230. 336. D.P.Matthews, J.P.Whitten, and J.R.McCarthy, J. Org. Chem., 1986, 51. 3228. 337. K.Anzaiand J.Uzawa, Can. J. Chem., 1986, 64, 2109. 338. T.Kato, E.Arakawa, S.Ogawa, Y.Suzumara, andT.Kato, Chem. Pharm. Bull., 1986, 34, 3635. 339. D.A.Evans, C.R.Illiq,and J.C.Saddler, J. Am. Chem. Soc., 1986, 108, 2478. __ 340. G.Boche, M.Marsch, and K.Harms, Angew. Chem., Int. Ed. Engl., 1986, 11, 373. 341. A.F.Hegarty and I.Cunningham, J. Chem. SOC., Chem. Commun., 1986, 1196. 342. P.G.Gassman and L.M.Haberman, J. Org. Chem., 1986, 51, 5010. 343. M.Westlinq, L.Smith, and T.Livinghouse, J. Org. Chem., 1986, 51, 1159. 344. rC.Brouwer and A.M.van Leusen, Synth. Commun., 1986, 16, 865. 345. A.J.Bloom and J.M.Mellor, Tetrahedron Lett., 1986, 2 7 , 8 7 3 . 346. A.J.Bloom, M.Fleischmann, and J.M.Mellor, J. Chem. SOC., Perkin Trans. l . , 1986, 79. 347. S.Jew, H.Kim, Y.Cho, and C.Cook, Chem. Lett., 1986, 1747. 348. K.Fuji, M.Node, H.Naqasawa, Y.Naniwa, and S.Terada, J . Am. Chem. SOC., 1986, 108, 3855. 349. A.G.M.Barrett, G.G=aboski, and M.A.Russel1, J. Org. Chem., 1986, 51, 1012. 350. R.Tamu&, M.Sato, and D.Oda, J. Org. Chem., 1986, 51, 4368. 351. R.Tamura, Y.Kai, M.Kakihana, K.Hayashi, M.Tsuji, Txakamura, and D.Oda, J. Org. Chem., 1986, 51, 4375. 352. S.Torii, T.Inokuchi, R.Oi, K-Kondo, and T.Kobayashi, J . Org. Chem., 1986, 51, 254. 353. =.M&lot, F.Texier-Boullet, and A.Foucaud, Tetrahedron Lett., 1986, 27, 493. 354. H.StacFand M.Hesse, Helv. Chim. Acta., 1986, 2,85. 355. M.J.Gray, M.P.Hartshorn and J.Vaughan, Aust. J. Chem., 1986, 39, 59. 356. T C r o m b i e and B.S.Roughley, Tetrahedron, 1986, 42, 3147. 357. H.Feqer and G.Simchen, Liebigs Ann. Chem. 1986, 428. 358. H.Feger and G.Simchen, Liebiqs Ann. Chem., 1986, 1456. 359. Y.Takeuchi, M.Asahina, A.Murayama, K.Hori, and T-Koizumi, J. Org. Chem., 1986, 2,955. 360. G.Rosini, E.Marotta, R.Ballini, and M.Petrini, Synthesis, 1986, 237. 361. R.Oehrlein, W.Schwab, R.Ehrler, and V.Jaeqer, Synthesis, 1986, 535. 362. R-Ballini and M.Petrini, Synth. Commun., 1986, 16, 1781. 363. S.I.Al-Khalil, W.R.Bowman, and M.C.R.Symons, J . Chem. S o c . , Perkin Trans. 1, 1986, 555. 364. M.Delgado, L.Echeqoyen, V.J.Gatto, D.A.Gustowski, and G.W.Goke1, J . Am. Chem. SOC., 1986, 108, 4135. 365. N.Ono, A.Kamimura, and A.Kaji, J. Org. Chem., 1986, 51, 2139. 366. G.Balina, P.Kesler, J.Petre, D.Pham, and A.Vollmar, J. Org. Chem., 1986, 51, 3811. 367. m l g e r , P.Dzerseman, and R.Royer, Bull. SOC. Chim. F r . , 1986, 807. 368. D.Beer, J.H.Bieri, I.Macher, R.Prewo, and A.Vasella, Helv. Chim. Acta, 1986, 69, 1172. 369. J.Boileau, E.WimmeK M.Carai1, and R.Gallo, Bull. SOC. Chim. Fr., 1986, 465. 370. X K i m u r a , H.Kobayashi, 0-Miyahara, and O.Mitsunobu, Bull. Chem. S O C . Jpn., 1986, 59, 869-
388
General and Synthetic Methods
371. D.Gaude, R.Le Goaller, and J.L.Pierre, Synth. Commun., 1986, 16, 63. 372. K T a p i a , G.Torres, and J.A.Valderrama, Synth. Commun., 1986, 16, 681. 373. KL.Atkins and W.S.Wilson J. Org. Chem., 1986, 2,2572. 374. R.L.Atkins, R.A.Hollins, and W.S.Wilson, J. Org. Chem., 1986, 51, 3261. 375. Y K e u m i , T.Morita, K.Teramoto, H.Takahashi, H.Yamamoto, K.Ikeno, M.Hanaki, T.Inagaki, and H.Kitajima, J. Orq. Chem., 1986, U,, 3439. 376. A.Fischer, D.L.Fyles, G.N.Henderson, and S.R.Mahasay, Can. J. Chem., 1986, 64, 1764. ___ 377. G.W.Bushnel1, A.Fischer, G.N.Henderson and S.R.Mahasay, Can. J. Chem., 1986, 64, 2382. 378. s u s s e l , M.Lemaire, A.Guy, and J.P.Guett6, Tetrahedron Lett., 1986, 27, 27. 379. H.M.Chawla, R.S.Mitta1, and C.J.Johny, Synth. Commun., 1986, 16, 949. 380. TRodenburg, R.Brandsma, C.Tinte1, J.van Thuijl, J.Luqtenburg, and J.Cornelisse, Recl. Trav. Chim-Pays-Bas., 1986, 105, 156. 381. B.Zielinska, J.Arey, R.Atkinson, T-Ramdahl, A.M.Winer and J.N.Pitts, Jr., J. Am. Chem. SOC., 1986, 108, 4126. 382. J.A.S.CaValeir0, M.G.P.M.S.Neves, M.J.E.Hewlins, and A.H.Jackson, J. Chem. SOC., Perkin Trans. 1 , 1986, 575. Tetrahedron Lett., 1986, 283. R.W.Murray, R.Jeyaraman, and L.Mohan, 27, 2335. 384. zR.Fishwick, D.K.Rowles, and C.J.M.Stirling, J. Chem. SOC., Perkin Trans. l., 1986, 1171. 385. N.Ono and A.Kaji, Synthesis, 1986, 693. 386. H.Stack and M.Hesse, Helv. Chim. Acta., 1986, 69, 1614. 387. U.Braendli, M.Eyer, and D.Seebach, Chem. Ber., 1986, 119, 575. 388. A.Amrollah-Madjdabadi, R.Beugelmans, and A.Lechevallier, Synthesis., 1986, 828. 389. S.L.Abidi, J. Org. Chem., 1986, 51, 2687. 390. G.Buechi, G.C.M.Lee, D.Yang, and S.R.Tannenbaum, J. A m . Chem. S O C . , 1986, E l 4115. 391. J.W.Lown and R.R.Koganty, J. Am. Chem. SOC., 1986, 108, 3811. J. Med. Chem., 1986, 29, 392. G.M.Singer, A.W.Andrews, and S.Guo, 40. 393. M.Miyahara, and M-Miyahara, Chem. Pharm. Bull., 1986, 2,980. 394. 0.Meth-Cohn and G.van Vuuren, J. Chem SOC., Perkin Trans. 1 , 1986, 245. 395. R.F.Smith, L.A.Olson, W.J.Ryan, K.J.Coffman, J.M.Galante, T.S.Wojdan, P.A.Mallardi, and T.P.Eckert, Synth. Commun., 1986, 16, 585. 396. K C - B r o w n and J.A.Wei1, Can. J. Chem., 1986, 64, 1836. 397. M.T.Reetz and J.Rheinheimer, J. Org. Chem., 1 B 6 , 51, 5465. 398. M.Negareche, Y.Badrudin, Y.Berchadsky, A.Friedmann, and P.Tordo, J. Org. Chem., 1986, 2,342. 399. T.Mitsuhashi, J. Am. Chem. Soc., 1986, E l 2400. 400. B.Zimmermann, H.Lerche, and T.Severini, Chem. Ber., 1986, g , 2848. 401. F.Ishibashi, T.Nashima, J.Nishino, I.Kobayashi, Y.Ichihara, Y.Kitagawa, S.Sasaki, M.Yoshikawa, A-Matsuoka, and K.Yamamoto, Bull. Chem. SOC. Jpn., 1986, 59, 73. 402. J.C.Caille, M.Farnier, and R.Zilard, can. J. Chem., 1986, 64, 824. 403. J.C.Caille, M.Farnier, R-Guilard, A.Aubry, and C.Lecomte, J. Chem., 1986, 64, 824. 404. A.Alemaqna, C.Baldoli, E.Licandro, S.Maiorana, and A-Papagni, Tetrahedron, 1986, 42, 5397. _I______
can.
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
389
405. T.Tezuka, T.Otsuka, P.-C.Wanq, and M.Murata, Tetrahedron Lett., 1986, 27, 3627. 406. D.EndeE, K.Papadopoulos, and B.E.M.Rendenbach, Tetrahedron Lett., 1986, 27, 3491. 407. D.Enders and XE.M.Rendenbach, Tetrahedron, 1986, 42, 2235. 408. M.Fujita, H.Oishi, and T.Hiyama, Chem. Lett., 1986,837. 409. D.Dhanak, C.B.Reese, S.Romana, and G.Zappia, J. Chem. SOC., Chem. Commun., 1986, 903. 410. D.Geffken, Chem. Ber., 1986, 119, 744. 411. A.Padwa and K.F.Koehler, J. Chem. S O C . , Chem. Commun., 1986, 789. 412. G.Kresse, A.Vasella, H.Felber, A.Ritter, and B.Ascher1, Recl. Trav. Chim. Pays-Bays., 1986, *, 295. 413. R.Nordmann and P.Gull, Helv. Chim. Acta, 1986, 69, 246. 414. K.Yanada, T.Naqano, a n d M . H i r o b e , h e d r o n Lett., 1986, 21, 5113. 415. G.Goto, K-Kawakita, T.Okutani, and T.Miki, Chem. Pharm. Bull., 1986, 34, 3202. 416. J.J.EiGh and R.Sanchez, J. Orq. Chem., 1986, 51, 1848. 417. M-Kosuqi, T.Oqata, H.Tamura, H.Sano, and T.Mig=a, $hem. Lett., 1986, 1197. 418. M.Kosuqi, M.Koshiba, A.Atoh, H.Sano, and T.Miqita, Bull. Chem. S O C . Jpn., 1986, 59, 677. 419. D.R.Boyd, K.M.McC=be,and N.D.Sharma, J. Chem. S O C . , Perkin Trans. 1 , 1986, 867. 420. M.Vaultier, P.H.Lambert, and R.Carrie, Bull. SOC. Chim. Fr., 1986, 83. 421. D.H.R.Barton, W.B.Motherwel1, E.S.Simon, and S.Z.Zard, J. Chem. S O C . , Perkin Trans. 1, 1986, 2243. 422. N.Ikota, H.Sakai, H.Shibata, and K.Koga, Chem. Pharm. Bull., 1986. , 34.. 1050. 423. J.C.McEtosh and P.Mishra, Can. J. Chem., 1986, 64, 726. 424. R.Breslow and M.P.Mehta, J. Am. Chem. SOC., 1986,108, 2485. 425. R.Breslow and M.P.Mehta, J. A m . Chem. SOC., 1986, 108, 6417. 426. R.Breslow and M.P.Mehta, J. Am. Chem. S O C . , 1986, 108, 6418. 427. J-Barluenga, J.Jardon, and V.Gotor, J. Chem. Res. (S), 1986, 218. 428. N-DeKimpe, Z.Yao, and N.Schamp, Tetrahedron Lett., 1986, 27, ~
1707.
429. D.J.Goldsmith and J.J.Soria, Tetrahedron Lett., 1986, 3, 4701. 430. Y-Yamaoto, Y. Morita, and K.Minami, Chem. Pharm. Bull., 1986, 34, 1980. 431. D-Armesto, M.J.Ortiz, and R.Perez-Ossorio, J. Chem. S O C . , Perkin Trans. 1, 1986, 2021. 432. J.Barluenqa, F.J.Gonzalez, S.Fustero, and V.Gotor, J. Chem. S O C . , Chem. Commun., 1986, 1179. 433. C.T.Gokou, M.Chehna, J.-P.Pradere, G.Duquay, and L.Toupet, Phosphorus Sulfur, 1986, 27, 327. 434. H.Dietrich, W.Mahdi, and K K n o r r , J. Am. Chem. Soc., 1986, 108, 2462. 435. R.A.Wanat, D.B.Collum, G-Van Duyne, J.Clardy, and R.T.DePue, JAm. Chem. SOC., 1986, 108, 3415. 436. D.Armest0, W.H.Horspoo1, J.-A.F.Martin, and R.Perez-Ossorio, JChem. Res. (S), 1986, 46. 437. C.-P.Chen, C.Shih, and J.S.Swenton, Tetrahedron Lett., 1986, 27, 1891. 438. XAumueller and S.Aueniq, Liebigs Ann. Chem., 1986, 142. 439. R.Carrau, r.Freire, R.Hernandez, and E.Suarez, Synthesis, 1986, 1055. 440. C.A.Maryanoff, R.C.Stanzione, and J.N.Plampin, Phosphorus Sulfur, 1986, 27, 221.
390
General and Synthetic Methods
441. D.J.Buurman and H.C.van der Plas, J. Heterocycl. Chem., 1986, 23, 1015. 442. E F e i t h , H.-M.Weber, and G.Maas, Chem. Ber., 1986, 119, 3276. 443. B.L.Feringa and J.F.G.A.Jansen, Tetrahedron Lett., 1986, 27, 507. 444. L.Capuano, W.Hel1, and C.Wamprecht, Leibigs Ann. Chem., 198 132. 445. P-Mstyus, G.ZGlyoni, G.Eckhardt, and H.Wamhoff, Chem. Ber. , 1986, 119, 943. 446. W.Walter and C.R.Saha, Chem. Ber, 1986, 119, 1095. 447. A.R.Katritzky, T.I.Yousaf, and B.C.Chen, Tetrahedron, 1986, 623. 448. P.Sulmon, N.De Kimpe, R.Verh6, L.De Buyck, and N.Schamp, Synthesis, 1986, 192. 449. T.Shrader, R.Kober, and W.Steglich, Synthesis, 1986, 372. 450. O.Tsuge, K.Ueno, S.Kanemasa, and K.Yorozu, Bull. Chem. SOC. Jpn., 1986, 59, 1809. 451. Jahangir, D.KMacLean, M.A.Brook, and H.L.Holland, J. Chem. SOC., Chem. Commun., 1986, 1608. 452. Y.Ito, T.Bando, T.Matsuura, and M.Ishikawa, J. Chem. SOC., Chem. Commun., 1986, 980. 453. G.Wulff, B.Heide, and G.Helfmeier, J. Am. Chem. S O C . , 1986, 108. 1089. 454. =.Beer, J. Chem. SOC., Chem. Commun., 1986, 1678. 455. R.Kupfer and E.-U.Wuerthwein, Chem. Ber., 1986, 119, 857. 456. E.-U-Wuerthwein and R.Kupfer, Chem. Ber., 1986, 119, 1557. 457. G.Heilig and W.Luettke, Chem. Ber., 1986, 119, 3102. 458. I.Parikh, H.Hilpert, K.Hermann, and A.S.Dreiding, Helv. Chim. 1986, 69, 1588. 459. D.Marji, H.TGhtoush, and J.Ibrahim, Tetrahedron, 1986, 42, 4517. 460. R.L.Beddoes, O.S.Mills, and F.Stansfield, J. Chem. Soc., Perkin Trans. l., 1986, 619. 461. W.P.Gessner, B-Venugopalan, A.Brossi, A.R.Jurgens, and C.D.Hufford, Can. J. Chem., 1986, 64, 2196. 462. K.Lempert, J.Fetter, J.Nyitrai, F.Bertha, and J.Mdller, JChem. SOC., Perkin Trans. 1 , 1986, 269. 463. R.Lux, A.Schwoebe1, and G.Kresze, Liebigs Ann. Chem. 1986, 32. 464. P.J.S.S.van Eijk, D.N.Reinhoudt, S.Harkema, and R.Visser, Recl. Trav. Chim.Pays-Bays., 1986, 105, 103. 465. J.Lub, M.L.Beekes and Th.J.de Boer, Recl. Trav. Chim. Pays-Bays., 1986, 105, 161. 466. R.S.Varma, M.Varma, and G.W.Kabalka, Synth. Commun., 1986, 14, 91. 467. A.Citterio and L.Filippini, Synthesis., 1986, 473. 468. L.B.Volodarsky and A.Y.Tikhonov, Synthesis, 1986, 704. 469. A.C.Pratt and Q.Abdu1-Majid, J. Chem. S O C . , Perkin Trans. 1 , 1986, 1691. 470. C.J.Peake and J.H.Strickland, Synth. Commun., 1986, 16, 763. 471. J.Goerdeler and W.Eqgers, Chem. Ber., 1986, 119, 3 7 3 r 472. Y.H.Kim, K.Kim, and S.B.Shim, Tetrahedron Lett., 1986, 27, 4749. 473. D.Sinou and M.Emziane, Tetrahedron Lett., 1986, 27, 4423. 474. S.Tomoda, Y.Matsumoto, Y.Takeuchi, and Y.Nomura, Chem. Lett., 1986, 1193. 475. M.Onaka, K-Sugita, and Y.Izumi, Chem. Lett., 1986, 1327. 476. H.B.Mereyala and B.Frei, Helv. Chim. Acta, 1986, 69, 415. 477. S.Tomoda, Y.Matsumoto, Y.Takeuchi, and Y.Nomura, Bull. Chem. S O C . Jpn., 1986, 2,3283. 478. T.Hudlicky, J.O.Frazier, G.Seoane, M.Tiedje, A.Seoane, L.D.Kwart, and C.Bea1, J. Am. Chem. SOC., 1986, 108, 3755.
s,
5: Amines, Nirriles, and Other Nitrogen-containing Functional Groups
39 1
479. S.Murahashi, Y.Tanigawa, Y.Imada, and Y.Taniquchi, Tetrahedron Lett., 1986, 27, 227. 480. A.Hassner and J.Keogh, J. O r q . Chem., 1986, 51, 2767. 481. A.Jeqanathan, S.K.Richardson, R.S.Mani, B.E.Haley, and D.S.Watt, J. Orq. Chem., 1986, 51, 5362. 482. S.Kusumoto, K.Sakai, and T.Shiba, Bull. Chem. SOC. Jpn., 1986, 59, 1296. 483 D.F.Taber, R.E.Ruckle, and M.J.Hennessy, J. Org. Chem., 1986, 5 1 , 4077. 484. R.Faqhih, F.C.Escribano, S.Castillon, J.Garcia, G.Lukacs, A.Olesker, and T.T.Thang, J. Org. Chem., 1986, 51, 4558. 485. S.Sivasubramanian, S.Aravind, L.T.Kumarasingh, and N.Arumuqam, J . Org. Chem., 1986, 51, 1985. 486. A.Gieren C.-P.Kaerlein, and T.Huebner, Tetrahedron, 1986, 42, 427. 487. A.Hassner and M.Stern, Anqew. Chem., Int. Ed. Enql., 1986, 25, 478. 488. A.Nishinaga, S.Yamazaki, and T.Matsuura, Chem. Lett., 1986, 505. 489. T.Tezuka, S.Ando, and T.Wada, Chem. Lett., 1986, 1667. 490. M.C.Pirrunq and J.A.Werner, J. Am. Chem. SOC., 1986, 108, 6060. 491. E.J.Roskamp and C.R.Johnson, J. Am. Chem. SOC., 1986, 108, 6062. 492. U-Burger and D.Zellweqer, Helv. Chim. Acta., 1986, 69, 676. 493. R.Heckendorn, Bull. S O C . Chim. Belg., 1986, 95, 921, 494. W.Bernloehr, M.A.Flamm-ter Meer, J.H.Kaiser, M.Schmitte1, H.-D.Beckhaus, and C.Ruechardt, Chem. Ber., 1986, 119, 1911. 495. J.E.Baldwin, R.M.Adlinqton, J.C.Bottaro, J.N.Kolhe, M.W.D.Perry, and A.U.Jain, Tetrahedron, 1986, 42, 4223. 496. J.E.Baldwin, R.M.Adlington, J.C.Bottaro, J.N.Kolhe, I.M.Newinqton, and M.W.D.Perry, Tetrahedron, 1986, 42, 4235. 497. J.E.Baldwin, R.M.Adlington, I.M.Newington, J. Chern. SOC., Chem. Commun., 1986, 176. 498. J.C.Stowel1 and C.M.Lau, J. Orq. Chem., 1986, 51, 1614. 499. H.Gstach and J.G.Schant1, Synth. Commun., 1986716, 741. 500. R.D.Sinqer, K.Vauqhan, and-can. J. C G m . , 1986, 64, 1567. 501. A.Ueno, F.Moriwaki, T.Osa, F-Hamada, and K.Murai, Bull. Chem. SOC. Jpn., 1986, 59, 465. 502. W.Kirmse, J.Rode, and K.Rode, Chem. Ber., 1986, 119, 3672. 503. W.Kirmse and J.Rode, Chem. Ber., 1986, 119, 3 6 9 4 7 504. W.Thie1, R.Mayer, E.-A.Jauer, H.Modrow, and H.Dost, J . Prakt. Chem., 1986, 328, 497. 505. K.A.Bello and J.Griffiths, J. Chem. S O C . , Chem. Commun., 1986, 1639. 506. A.Albini, E.Fasani, M.Moroni, and S.Pietra, J. Org. Chem., 1986, 51, 88. 507. B.Akte=es and J.C.Jochims, Chem. Ber., 1986, 119, 83. 508. D.N.Dhar and K.S.K.Murthy, Synthesis, 1986, 437. 509. A.N.Pudovik, I.V.Konovalova, and L.A.Burnaeva, Synthesis, 1986, 793. 510. B.Schoenenberger and A.Brossi, Helv. Chim. Acta., 1986, 69, 1486. 511. S.Huber, P.Stamouli, T.Jenny, and R-Neier, Helv. Chim. Acta, 1986, 69, 1898. 512. M.N.BeG and V.K.Sinqh, Can. J. Chem., 1986, 64, 940. 513. A.Vass and G.Szalontai, Synthesis, 1986, 817. 514. G.More1, E.Marchand, C.Haquin, and A.Fourcaud, J. Orq. Chem., 1986, 51, 4043. 515. H.G.Aurich, 0-Bubenheim, and M.Schmidt, Chem. Ber., 1986, 119, ?-7T,-
L 1 3 D .
392
General and Synthetic Methods
516. J.Lub, M.L.Beekes and Th.J.de Boer, Recl. Trav. Chim. Pays-Bays., 1986, 105, 22. 517. R.Plate, P.H.H.Hermkens, J.M.M.Smits, and H.C.J.Ottenheijm, J. O r g . Chem., 1986, 51, 309. 518. T.Shono, Y.Matsumuz, and K.Inoue, J. O r g . Chem., 1986, %, 549. 519. R.M.Coates and S.J.Firsan, J. O r g . Chem., 1986, 51, 5198. 520. T-Akashi, K.Kawamura, M-Shiratsuchi, and H.Ishihama, Chem. Pharm. B u l l . , 1986, 2,2024. ___I_-
6 Organometallics in Synthesis BY S.E. THOMAS AND T. GALLAGHER Part I: 1
The Transition Elements
Introduction
This report follows the format of previous years and once again, due to the limitations of space, it is selective. Two books covering general organotransition metal chemistry' l 2 and one discussing the use of organo-titanium reagents in organic synthesis3 have been published. Subjects of review articles include allylic oxidation of alkenes using metal complexes,
lanthanides in organic synthesis,! I
transition metal catalysis in organotin chemistry, zirconium-based catalysts in organic synthesis,
homogeneous
new general
synthetic methods involving ~-allylpalladiurncomplexes as
*
intermediates and neutral reaction conditions,
and palladium-
catalysed (3 + 2 ) cycloaddition approaches to five-membered rings. 9 2
Reduction
The first example of a homogeneous metal-catalysed desulphurization of thiiranes to alkenes has been reported (Scheme 1) . l o The reaction is mild, stereospecific, and applicable to thiiranes bearing alkyl, aryl, alkoxy, and ethoxycarbonyl substituents. Selective reduction of the carbonyl group of benzylideneacetone has been achieved with an iridium catalyst (Scheme 2) .ll This represents the first highly selective catalytic hydrogenation of the carbonyl group of an a,B-unsaturated ketone. Aryl alkyl ketones and aromatic aldehydes react with hydrogen under mild conditions in the presence of catalytic quantities of the dimer of chloro(hexa-ll5-diene)rhodiurn(I) and B-cyclodextrin to give hydrocarbons (Scheme 3) .I2
The reaction can tolerate the
presence of a variety of functional groups. A new preparative method for allenes has appeared (Scheme 4) .13 Several alk-2-ynyl carbonates (prepared by nucleophilic addition of magnesium and lithium acetylides to ketones or aldehydes followed by quenching with methyl chloroformate) were selectively hydrogenolysed with ammomium formate under palladium catalysis to give allenes in good yields.
393
General and Synthetic Methods
394
70 O l e Scheme 1
Ph 2
0 96
'lo
+ cat [ I r ( c o d ) ( O M e ) 2 1 2 , c a t . P E t P h 2
Ph
100 " C ,
Ph
3 0 o t m . H2
2
'lo
+
Scheme 2
R'
R' ( 54-1OO0/o)
R' = H, Me, OMe, OH, NMe20r OCOMe, Reagent:
i , cat
[1,5-HDRhCll2,
cat
R = H or a l k y l
cyclodextrin,
Scheme
3
1 atm
H2
"
395
6: Organometallicsin Synthesis
(66-8 7.10) R’
= H or a l k y l ;
R = alkyl or
aryl
R e a g e n t i , c a t P d Z ( d lb e n z y l i d e n e a c e t o n e ) , CHC13,
Scheme
I
ON
PPh,
I
Re
,’f
’\\
ON’
PPh3
CH3
D
(e.e.
H
1,
IV,
I
t---------
PPh,
H R D
HPF6Et20, -78’C,
11,
- 7 8 “ C , 1 1 1 , [(?5-C5H5)Re(NO)(PPh3)(CD0)1,
Scheme
5
0
p ‘i’ II
Rf
I
0
R
R ( S8-9So/o) Rf
Reagent.
I ,
cot
*o
H
RCHO,
CF3 C O Z H
0
,N,,/r, I
Ill
I V
> 97 -98’1.)
Reagents:
\
Q
-
“XoH
HCO2NH4
4
,/p, I
PBu”,,
cot
= fluoroalkyl,
P d ( P P h 3 ) 2 C 1 2 , Bun3N,
R = CI, Me or HCOZH, D M F
Scheme 6
OM^
396
General and Synthetic Methods
H R
R
117 o r
2=<;
11"
H, a l k y l , P h , C 0 2 M e , OR or O S i M e 3
=
, 0 s O 4 , CHZC12, r t . , 2 - 2 4 h uNMe2
I'
( Yields
59 - 7 5 "I.,
e e . 3 4 - 8 6 '/*I
,
1')
(Yields 1,5-95'/.,
OSO~C , H2CI2, - 7 8 ° C or
- lOO"C,
e e 35-90"/01
Scheme 7
n = 3 , 4 or Reagent
1,
5
40"/i, H 2 0 2 .
cat
Na2WOL, 2H20,
cat
Scheme 6
H3P04
6h
6: Organometallics in Synthesis
397
OH
0
*
I
HO
HO R’ R’
R ’ R’
( C o n v e r s i o n 86-100°/.; Se L e c t i v i t y 9 6 - 99
R’ Reagent
I,
= H or a l k y l ;
ButOOH,
cat
R 2 = alkyl
[ M O ( C O ) ~ ] , cat
cetylpyridinium chloride
Scheme 9
ILo
I
__r
(98’10) Reagent
’
I,
cyclohexanone,
cat
( ~ I ~ - C , H ~Z )~ rHZ
S c h e m e 10
( Yield
77%;
ee. 87%)
H
Reagent
I,
cat
Pd(PPh3I4,
$&:;:; ti
Scheme 11
)
398
General and Synthetic Methods
The optically active rhenium Lewis acid [ (Y5-C5H5)Re(NO)(PPh3)1' selectively binds one enantioface of several aldehydes (Scheme 5) . I 4 Stereospecific nucleophilic attack by a deuteride source followed by acidic work-up led to deuterated primary alcohols in 97-98% e.e. A useful synthetic method for converting phenols into arenes
has been reported (Scheme 6) . I 5 Phenyl f luoroalkanesulphonates, readily available from the corresponding phenols, react with tributylammonium formate in the presence of catalytic amounts of palladium to give arenes in good yields. 3
Oxidation
The original report on the titanium-catalysed asymmetric epoxidation of allylic alcohols (Sharpless system) prescribed stoichiometric amounts of the titanium tartrate 'catalyst' in the general procedure and many applications of this asymmetric epoxidation have been carried out using stoichiometric or near-stoichiometric amounts of the catalyst. Sharpless has reported the first general procedure for the asymmetric epoxidation of allylic alcohols using catalytic
(
Two new optically active diamines have been used in the asymmetric osmium tetroxide oxidation of alkenes to vicinal diols (Scheme 7) The first preparative procedure for the oxidative cleavage of 1,2-diols to carboxylic acids using hydrogen peroxide has been reported (Scheme 8) . I 9 The method requires catalytic amounts of tungstate and phosphate ions and is performed under acidic conditions. It has been successfully applied to water-insoluble 1,2-diols using a phase-transfer agent. The hexacarbonylmolybdenum/cetylpyridinium chloride/t-butyl hydroperoxide system has been shown to oxidize secondary alcohols in a highly selective manner in the presence of primary alcohols (Scheme 9) . 2 0 The zirconocene complex [ Y5-C5H5) 2ZrH2] catalyses an Oppenauer-type oxidation of alcohols in the presence of an appropriate hydrogen acceptor. On oxidation of diols containing two primary alcohols, and of diols containing two secondary alcohol groups, one of the alcohol groups is selectively oxidized to form hydroxy-aldehydes and hydroxy-ketones respectively. This system selectively oxidizes primary alcohols in the presence of secondary alcohols (Scheme 10).2 1
6: Organometallics in Synthesis
399
Scheme 12
(65 ‘M Scheme
13
S c h e m e 14
400
General and Synthetic Methods
-
Q
I
a I Fe
q-P
L
-
I
I
IV
Fe'
Fe
h
Reagents
I,
FeC13,
11,
H-,
III,
PhCH2MgBr,
IV,
Ph3C+,
v,
CN-,
VI,
FeCL3
S c h e m e 15
+
CO,M e
(e.e.5 0 "/.> Reagents
I,
( s ) - P h S ( 0 ) ( N T s ) C H 2 C 0 2 M eI
base,
S c h e m e 16
11,
Na/Hg
401
6: Organornetallies in Synthesis
4 Isomerizations and Rearrangements
An optically active allylic sulphone has been generated
via
a
palladium-catalysed sulphinate-sulphone rearrangement performed in the presence of a chiral phosphine ligand (Scheme 11) .22 Alkenes silylated at a remote carbon atom have been converted The
into allylsilanes using an iridium catalyst (Scheme 12) . 2 3
silyl group controls the isomerization of the double bond and good regioselectivity results. The first palladium(I1)-catalysed Claisen rearrangement has been reported (Scheme 13) .24
The vinyl ether double bond must be
heavily substituted in order to prevent poisoning of the catalyst and this imposes stringent structural demands on potential substrates.
5
Carbon-Carbon Bond-forming Reactions
via Orqanometallic Electrophilies. - Functionalization of unsaturated hydrocarbons by nucleophilic attack on their metal complexes continues to receive attention. Sequential double nucleophilic addition to a cationic cobalt complex of butadiene results in regiospecific 1,4-difunctionalization of butadiene (Scheme 14) .25 It is of note that it is unnecessary to reactivate this system before addition of the second nucleophile. Benzene has been converted into a disubstituted cyclohexadiene __ via
a route which involves three nucleophilic additions to a metal
complex with reactivation being necessary before the third addition (Scheme 15) .26
The first nucleophile unfortunately appears to be
restricted to hydride. lactonic A cycloheptenonc precursor to the (+)-Preloq-Djerassi
acid has been synthesized stereoselectively from cyclohepta-1, 3-diene using a nucleophilic addition-reactivation-nucleophilic addition sequence on iron complexes to introduce the required stereochemistry.27 A nucleophil ic addition-reactivation-nucleophi 1 ic addition sequence has also been used to produce disubstituted cycloheptadiene manganese complexes. 2 8 Enolates of an optically active sulphoximinyl ester derivative react preferentially with one of the two terminal carbon atoms of a symmetrical dienyliron system (Scheme 16) . 2 9 This represents the first example of chiral recognition during enolate addition to dienyliron complexes. An optically active metal complex of a simple alkene has been
402
General and Synthetic Methods
FP+
FP+
F p + = I(q5-C,H5)Fe(C0)21+ Reogents
I,
(R,R)-butane-2,3-d1ol,
v, N o B H q ,
VI,
11,
LiM eCuCN,
HBF4. OEt2
Scheme 17
Cyclocolorenone
Reagents
I,
CeIV;
11,
H g l I , H2SOL
Scheme 18
111,
CF3SO3S1Me3.
IV,
M eOH ,
6: Organometallics in Synthesis
403
TMS
0 S c h e m e 19
cat.
R2y + cos
Pd(PPh3I4
SR' S R'
R'
=
(>95%)
Me o r C H Z O M e ;
Rz
z
H, M e o r P h
S c h e m e 20
R
+ OAc
i
i I iii
-R
NH2
(59- 91
Reagents:
I,
cat
Pd(PPh3I4, NaN3,
11,
Scheme
PPh3;
21
111,
O/O)
NaOH/H20
General and Synthetic Methods
404
0 0-
c a t Pd(PPh3)&, c a t PPh3
&A (Yield 47'1.; e e loo"/.)
-
Scheme 2 2
RD
R
O
H
R
= CH,CH ( N H A c ) C 0 2 M e or C H ( N H A c ) C 0 2 M e
+ M' n ( C 0 ) 3 Scheme 2 3
Cr (COI3
Reagents
I,
LiCMe2CN,
iiI
CF3C02H
Scheme 24
DOQ
405
6: Organometallics in Synthesis
prepared for the first time via - a route which involves regioselective addition of LiMeCuCN to an optically active dihydrodioxin-iron complex (Scheme 17) 30 Stabilization of a positive charge adjacent to cobalt alkyne complexes has been exploited in a synthesis of the guiane sesquiterpene cyclocolorenone,3 1 and in an approach to the
.
fusicoccin class of diterpenes. 3 2
The cyclocolorenone synthesis
involves addition of a silyl enol ether to a cationic cobalt complex followed by regiospecific hydration and cyclization (Scheme 18).
A
Lewis acid mediated intramolecular addition of an allylic silane to an allyloxy-acetal and an internal Pauson-Khand reaction are the key steps in the approach to the fusicoccins (Scheme 19). Palladium-catalysed allylation has again been the subject of numerous reports. O f note is the use of 9-ally1 5-alklyl dithiocarbonate substrates which results in the production of allyl alkyl sulphides (Scheme 2 0 ) .3 3 These substrates circumvent catalyst poisoning problems normally associated with catalytic allylation of sulphur nucleophiles by generating the nucleophile __ situ
at a concentration which is never higher than that of the T-ally1 intermediate. The azide anion has been used as the nucleophile in palladiumcatalysed allylations for the first time. The allyl azides produced are versatile synthetic intermediates; for example, they can be readily converted into allylamines (Scheme 21) . 3 4 An intramolecular palladium-catalysed allylation reaction has been used to produce 2-allylcyclohexanone in almost 100% optical yield (Scheme 2 2 ) . 3 5 Diary1 ethers have been prepared from tyrosine and 4-hydroxyphenylglycine by nucleophilic addition of their anions to a (ch1orobenzene)manganese cation (Scheme 23) .3 6
No detectable
racemization of the amino-acids occurred under the conditions used in this reaction which are mild in comparison to those employed in other methods available for the synthesis of diary1 ethers. It has been reported that addition of 2-lithioisobutyronitrile to p-chlorotoluenetricarbonylchromium followed by protonation leads to the production of m-2-cyanopropan-2-yltoluenetricarbonylchromium (Scheme 24) . 3 7 This represents the first example of cine-substituion of arenetricarbonylchromium complexes. Addition of carbanions to (alky1benzene)tricarbonylchromium
~
complexes occurs predominantly in the =-position. Introduction of an alcohol group into the alkyl side chain, however, leads to chelation-controlled nucleophilic addition of carbanions to the
General and Synthetic Methods
406
woH, 2RLi
-pj
R-Li
-C r
W IO '
I
cr
Cr
(COl3
(CO),
R
& I 2Cr (COI3 17 - 4 8 "10
Scheme 2 5
Meo 0
Scheme 2 6
' I
11
Me
.\
, ph>>
TiH M ;2e< :
I
Me
I
-
H
OH
iii
R'
CH3
SO, R
S02R
(Yield 75-96%
e.e.79-90 1
Reagents:
I,
TiMe4,
11,
Me2CHOH,
ill,
R'CHO
S c h e m e 27
407
6: Organornetallies in Synthesis
I I
I
RMgBr
R'COR
(61-89"/0)
Reagents
VCI3,
I ,
R'COCI
11,
S c h e m e 28
M = L i or M g B r
Reagents:
I,
VCI3,
11,
R'CHO
Scheme
29
tLH R
( Y i e l d 7 3 - 90%; R
e.e. 85
= Et, B u n or B u ' O C H 2
I
I I
Reagent
I,
RLI,
Cur,
ph+~-'\
I
OH
1
S c h e m e 30
- 92 'lo l
General and Synthetic Methods
408
+ ,
0@OCPh3 I
Wocph3 'r I
0
5
o2
R2
O y ! ,
( Y i e l d 60-98'1'
;
e.e. 81 - 95 '1' 1
Reagents
R'MgCI,
I
( Y i e l d 7 5 - 91 'I.;
e.e. 77 - 9 4 '1. 1
CuBr.SMe2, THF, - 2 3 ' ~ ; I I , c ~ n c HCI, MeOH,ili,
KOH
S c h e m e 31
xR\
1
Reagent
I,
ycu, BF3,
PBu3
Scheme
32
6: Organornetallics in Synthesis
409
R'
+
aNyS+c02R3 R4MgBr
' s
.-. C u B r , T H F
R2
Scheme 33
R
Reagents
OMe
OMe
OMe
OMe
= C 0 2 M e or S i M e 3
I,
B u L i , THF, - 7 8 " C , 1 h ,
11,
ClCO Me, - 7 8 " C ,
Scheme 34
2
111,
Me3SiCL, - 7 8 " C
General and Synthetic Methods
410
ortho-position and subsequent formation of ortho-substituted
toluenetricarbonylchromium complexes (Scheme 25) .38
The structure
of the unusual ~6-5-methylene-cyclohexa-l, 3-diene intermediate was confirmed by X-ray crystal structure analysis. Rhodium carbenoid cyclizations have been used to synthesize seven-membered ring ethers in good yield (Scheme 26) . 3 9
The
substrates for this reaction were prepared in three steps from methyl acetoacetate. via Organometallic Nucleophiles - Addition of MeLi or MeMgCl to an ethereal solution of TiC14 at -78 " C followed by warming to -50 or -30 " C leads to the production of MeTiC13.
This reagent adds selectively to ketones in the presence of nitro, cyano, and ester
groups, a process which is inefficient or impossible using MeLi, MeMgC1, or MeTi(OCHMe2) .40
An optically active methyltitanium
reagent derived from TiMe4 and norephedrine has been used to deliver a methyl group stereoselectively to aromatic aldehydes (Scheme 27) . 41 Organovanadium reagents have been used to effect two useful transformations.
Alkylvanadium complexes, formed from Grignard
reagents and VC13, convert acid chlorides into ketones in high yield (Scheme 28) ,42 and vanadium acetylides, formed from acetylenic Grignard or lithium compounds and VC13, react with aldehydes to give a,B-acetylenic ketones via oxidative nucleophilic addition (Scheme 29).43 Enantioselective conjugate addition to a,B-unsaturated carbonyl compounds has been performed using two alternative strategies.
The possibility of achieving useful
enantioselectivies in the presence of a simple chiral controller ligand has been demonstrated for the first time (Scheme 30) .44 This reaction is strongly dependent, however, on the purity of the organolithium reagent used. ( ~ ) - v - T r i t y l o x y m e t h y l - u - b u t y r o l a c t a m serves as an efficient
chiral auxiliary in the conjugate addition reactions of the imides it forms with a , B-unsaturated carboxylic acids (Scheme 3 1 ) , 45 and conjugate addition of a 1-alkenylcopper reagent to the a , B-unsaturated ester of a chiral auxiliary alcohol has been employed in an enantioselective synthesis of California Red Scale pheromone (Scheme 32) .46 The reqioselectivity normally observed in the nucleophilic addition of organocopper reagents to a,B-unsaturated esters has been changed by the introduction of a leaving group in the y-position (Scheme 33) .47
a-Addition occurs cleanly leading to the
production of a-alkylated B,v-unsaturated esters.
41 1
6: Organometallics in Synthesis
Me
Cr KO),
Cr (CO),
\
Ph
( R 100% e.e.)
Cr (CO),
(R
R
>' 95 '1. e.e.)
= M e or E t
Reagents
1,
PhCHZNH2,
11,
LDA,
111,
R X ,
i v , H',hv
Scheme 35
Ph
General and Synthetic Methods
412
11,
IV
OMe
OMe
OMe
OMe
S i Me,
Reagents
I,
Cr(COI6,
11,
SiMe,
Bu”L1,
III,
Me3SICI,
IV,
S c h e m e 36
Mel,
V,
Bun4NF3H20,
VI,
02
413
6: Organometallics in Synthesis
( Y i e l d s 81 - 9 4 ‘I.;
d.e.
Reagents.
I,
Bu”LI,
11,
R2X
Scheme
37
Me1 +
Scheme
38
> 98%)
414
General and Synthetic Methods
r
1
I , I1
3 R , 4s
Reagents
I, P h C H Z N H L i ,
Me],
11,
111,
Br2
Scheme 39
- ***pJ3
I
I
I
ON
Re
I1
___._)
O N ,Rc, T P h 3
0 H--
Ph
Ph
H
Ph
(d.e. 9 6 *lo 1 Reagents
I, LI
N(SIMe3l2,
11,
Meoso2cF3
S c h e m e 40
6: Organometallics in Synthesis
415
Lithiation of tricarbonyl(fluoroanisole)chromium(O) complexes occurs exclusively ortho to the fluorine atom in contrast to lithiation of the uncomplexed arenes which occurs ortho to the oxygen atom (Scheme 3 4 ) . 4 8 This reactivity, in combination with nucleophilic displacement of the fluorine by amines, has been exploited in the totally regiocontrolled synthesis of a range of 1 ,2,3- , 1 ,2 ,4- , and 1,2,3 ,4 ,5-pol ysubs tituted arenes .4 9 Chiral benzylic amines have been synthesized from an optically y a stereoselective pure arene tricarbonyl chromium complex & 50 deprotonation/alkylation step (Scheme 3 5 ) . A stereoselective synthesis of (-)-(8R)-methylcanadine has been reported (Scheme 36) .51 This was achieved by regioselective complexation of the dimethoxyarene ring of (-)-canadine to tricarbonylchromium, protection of the C-11 position, stereoselective substitution at C-8, deprotection, and decomplexation. The high degree of stereochemical control afforded by the chiral auxiliary [ ( h5-C5H5)Fe (CO)(PPh3)3 has been studied further. It has been demonstrated that dienolates derived from [ q5-C H Fe (CO) (PPh3)COCH=CHCH2R'] can be regio- and stereo 5 5 selectively alkylated at the a-position to give a-substituted E-D, y-unsaturated acyl complexes (Scheme 37) .52
z-
A conformational analysis of the complex [ ( G-C5Hs)Fe (CO)(PPh3) COMel based on extended Hilckel and ab initio SCF MO calculations has been performeds3 and the results of this analysis have been used to improve the stereochemical control of the alkylation of enolates derived from [ R5-C5H5)Fe (CO)(PPh3)COCH2R] to 200 :1. 5 4 The enolate 5 [ ( R-C5H5) Fe (CO)(PPh3)C(CH2)0-1 has been trapped in its enol form using oxophilic [(45-C H ZrCl21, and in its keto form using carbophilic [Au (PPh3)C?l Addition of nucleophiles to a-alkyl-a, 0-unsaturated acyl ligands attached to [ ( q5-C5H5)Fe (CO)(PPh3)] has been shown to generate E-enolates which on alkylation produce quaternary carbon centres stereoselectively (Scheme 38) ,56 and stereocontrolled tandem Michael addition/alkylation reactions of a , 0-unsaturated acyl liqands bound to [ (q5-C5H5)Fe (CO) (PPh3)1 have been exploited in asymmetric syntheses of 8-lactams (Scheme 39) .57,58 Metal systems analogous to [ ( <-CsHs) Fe (CO)(PPh3)1 have been synthesized and their stereocontrol over alkylation reactions investigated. The rhenium-based moiety [ ( $-C5Hs)Re (NO)(PPh3)1
55*
(Scheme 4 0 ) 59 and the molybdenum-based fragment [{hydridotris(3,5-dimethylpyrazolyl)borate]Mo
(CO){ P (0Ph)3 j ] 60 both exert good
416
General and Synthetic Methods
( O v e r a l l yield 7 2 ' L ) Reogents
I,
MeCOCI/AIC13,
11,
MeCOCI,
111,
H Z O Z , N o O H , iv, N a O M e
S c h e m e 41
Me3S'YMgBr +7 Ph
Br
I
Me3six H
Ph
(Yieid 6 3 % ; e.e. 85 "10 1
Scheme
42
417
6: Organometallics in Synthesis
R'-
OTf
=
R2 =
Reagents
I, 11,
e n o l t r i f l a t e s , p r e p a r e d from steroidal ketones Ph, CMe3, SiMe3, C 0 2 E t , CH(OEt1,
cat
Pd ( P P h 3 ) 2 ( 0 A c ) 2 , Bun3N,
cat
P d ( P P h 3 ) 2 ( 0 A c ) 2 , cat
OMF, 6 0 ° C
0 Me
/iC02Me +
0
L
90 "I0 I,
cat
Pd(OAc),,
cat
0 5 - 1 h;
C u l , E t Z N H a DMF, r t , 1 - 1 5 h
Scheme 43
Reagents
orC (OH)Me2
PPh3, E t 3 N ,
[I,
S c h e m e 44
HCI
General and Synthetic Methods
418
n
\OBn
J
c a t [Pd(PPh3)Ll
NaOEt
n
OH
OBn
(+)-Tri sporol B
S c h e m e 45
a
frMS +
cat.[Pd(PPh3I4 1
0
0 S c h e m e 46
Scheme 47
(81
o/o)
6: Organometallics in Synthesis
419
Me,Si
+
i
R*o H
R R = a l k y l or v i n y l (71 Reagent.
cot
1,
Pd(OAcIZ,
cat
Bun3SnOAc,
cat
- 94 'Ir )
PPh3
S c he m e 48
Me3Si +OAC
R3
+
I
___)
&
R3*
R1
R2
R2 71 - 0 7
R'
R'
'10
58
- 100 '/o
= H or COzMe
R 2 = C0,Me
or C0,Et
R3 = H or Me
Reagents
I,
cat
Pd(OAc),,
P(OPr')3,
11,
F l a s h v a c u u m t h e r m o l y s l s , 530-755°C
S c h e m e 49
General and Synthetic Methods
420
stereochemical control over deprotonation/alkylation sequences. 2,4-Diene-1,6-diones have been synthesized from dienetricarbonyliron complexes in good yield
via
a route involving
two Friedel-Crafts acylation steps (Scheme 41) . 6 1 f 62 via Coupling and Cycloaddition Reactions - Optically active allysilanes have been prepared by a cross-coupling reaction catalysed by an optically active ferrocenylphosphine-palladium 63 complex (Scheme 42). 2-Ethoxycarbonylethylzinc iodide has been shown to couple with aryl and vinyl iodides under palladium catalysis to produce ethyl 3-arylpropionates and ethyl pent-4-enoates respectively in good yield.
Similar coupling reactions also occur with
3-ethoxycarbonylpropylzinc iodide. 64 A new route to conjugated enynes has been reported which involves cross-coupling of enol triflates with 1-alkynes in the presence of base and a palladium catalyst (Scheme 43) .65
Addition
of copper(1) iodide as a cocatalyst allows the reaction temperature to be reduced to ambient. Palladium-catalysed coupling reactions have been employed in two notable syntheses. A 5-halogenopyrimidine reacts with methyl acrylate in the presence of a palladium catalyst to give a methyl acrylate. (El-B-pyrimidinyl
Treatment with acid leads to ( E ) - 0 - ( 2 ,
4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)acrylic
acid, a
fermentation product of Streptomyces sparsogenes which exhibits anticancer activity (Scheme 44) . 66
A stereoselective
palladium-catalysed coupling of a 1-alkenylborane and a 1-halogenoalkene was the key step in a stereo- specific synthesis of (2)-Trisporol B (Scheme 45) .67 The use of trimethylenemethane in [3+21 cycloaddition reactions has been developed extensively.
Cycloadditions using
methyl l-(trimethylsilyl)-2-[(trimethylsilyl)methyl]~rop-l-en-3-yl carbonate as the trimethylenemethane precursor produce carboxylated adducts (Scheme 46) . 6 8
Reaction of trimethyl.enemethane with
imines results in the synthesis of 4-methylenepyrrolidines (Scheme 47) .69 This represents the first metal-catalysed addition of trimethylenemethane to a carbon-nitrogen double bond.
It has been
demonstrated that trimethylenemethane can be added to aldehydes to give
methylenetetrahydrofurans provided that a tin cocatalyst is
added to the reaction mixture (Scheme 48.) 7 0
Trimethylenemethane
also adds to masked acetylenes to produce 4-methylenecyclopent-lenes (Scheme 49) .71 Several novel Dicls-Alder cycloadditions involving transition
6: Organometallics in Synthesis
42 1
COZH Reagents
1,
Z n C I 2 , CH2C12,
11,
(NH4lZ Ce(N03)6
(25)
S c h e m e SO
co I ‘co Scheme 51
(c.e. 6 4 - 9 1 */. 1 R =
H
or a l k y l
Scheme 5 2
General and Synthetic Methods
422
QfLoy H
H ___) I
OH
H
I
H
Ph,P
H’
*aTLoy -I
0
MeC0,
p
P
/o
0 HC
h
0 (2)-
Phyllanthocin
Ph,P
R e a g e n t s i,m- ( P h 2 P)C6HLC02H, dlcyclohexylcarbodllmlde, 4 - p y r r o l l d l n o p y r I d l n e , 11,
cat [ ( C O D ) R h O A c
Iz,
1 1
CO/H2
S c h e m e 53
423
6: Organometallics in Synthesis
G9I
I
. Me3P’ A
l i
, ‘F
R
co
R=Me
=
...
Ill
I
M I
A
R = Et
R=Et Ill
R = Pr”
R = Pr”
0
Reagents
I,
L I A L H L , or N a B H 4 , i i , C O / A g + ,
Scheme
111,
BH3.THF,
54
iv,
Br2/H20
1 I
General and Synthetic Methods
424
I
I
'Fe
oc'
Fe-OMe
__)__)
I 'co
oc'/
co
F;=CH,
oc'/
co
co
J
11, I l l
-IV
M e 0 uOMe
Fe
/'
T O M " '
0
~
OC c o
Reagents
I , FIEF4,
11,
CO.
111,
MeOH,
IV,
Cel", MeOH, CO
Scheme 55
ppNEt2 NHAc
NHAc
X = I orBr R' = H o r Ph R 2 = Me, P h or C02H R e a g e n t s I , c o t [ P d C 1 2 ( P M e P h 2 ) 2 ] ,Et2NH, C O ( 2 5 - 5 6 a t m ) , v, HCI
Scheme 56
11,
HCI,
III,
OH-,
IV,
R'CH2COR2,
6: Organometallics in Synthesis
425
I , I1
Et
‘NHEt2
0
Reagents
I,
P d C 12 (Me CN) 2, E t 2 N H ,
11,
CO,
111,
CO, p i p e r l d l n e .
IV,
5102
Scheme 5 7
R =
0 alkyl
Reagents
iron carbonyls,
I,
11,
AIC13,C0,
111,
CO
S c h e m e 58
R’NH OH
I
R’N
v
R2
(77- 95 ‘Id
R1 = alkyl R2 =
H , M e o r Ph
R e a g e n t : 1,cat
PdC12, CuCt2, N a O A c , C 0 ( 3 a t r n ) , M eOCH2CH2 0M e
Scheme 59
General and Synthetic Methods
426
RCHO
Reagents
cat
I,
( 5 1 - 86"lo)
[ P t C 1 2 ( P P h 3 ) 2 1 , K 2 C 0 3 , C O ( 5 0 kg c r n - ? ) ,
dioxane;
11,
cat
H 2 ( 5 0 kg crn-z),
[ P t C 1 2 ( P P h 3 ) 2 1 , K2CO3, MeOH, CO ( 7 0 kg c rn-2 ),
dioxane
Scheme
60
,OMe
\
MeO,
(90 o/o)
Prot hrac a r c in Reagent
I,
cat
P d ( O A c ) 2 , P P h 3 , B u n 3 N , CO ( 5 a t m ) , t o l u e n e
Scheme 61 R'
R2 I
R1-~.+-H
___.___)
OC02Me
R'
C02Me
= H o r C7H,5
R 2 = H, C7H,5, Ph o r P r ' Reagent
I,
cat
P d Z ( d i b e n t y l r d e n e a c e t o n e ) 3 . C H C L 3 , c o t PPh3, C O ( 5 - 3 0 a t m ) , MeOH
Scheme 6 2
421
6: Organometallics in Synthesis
metals have been reported. An asymmetric Diels-Alder reaction was carried out using ( 5 )- ( + ) - [y5-C5H5)Fe (CO)(PPh3)COCH=CH2] as a chiral acrylate dienophile equivalent and cyclopentadiene and resulted in the production of (25)- ( - ) -bicycle L2.2.11 h e p t - 5 - e n e - 2 - e - carboxylic acid in high optical purity (Scheme 50) .72
Diels-Alder reactions have also been performed on
(Qlacryloyl) (2-cyclopentadienyl)dicarbonyliron (11) systems and (ferra-O-diketonato)BF2 complexes (Scheme 51) .73'74 Dienophiles prepared from a,B-unsaturated acids and 1,3-oxazolidin-2-one react with cyclopentadiene in the presence of catalytic amounts of a chiral alkoxytitanium(1V) complex and molecular sieves to give optically active adducts (Scheme 52) . 7 5 via Carbonylation Reactions. - The temporary incorporation of a co-ordinating phosphine into a tetracyclic phyllanthocin precursor has been used to direct [(COD)RhOAcI2-catalysed hydroformylation to In contrast undirected the desired C-3 position (Scheme 53) . 7 6 hydroformylation resulted in products formylated at C-3 and C-4 and many uncharacterized by-products. Pentanoic acid has been synthesized using carbon monoxide as 77 the sole carbon source (Scheme 5 4 ) . It has been reported that the (<-C5H5)Fe(C0)2 moiety can be used as a template for converting three CO groups into the C3 skeleton of dimethyl malonate (Scheme 55) .78 Recently developed palladium-catalysed double carbonylation reactions provide a convenient method for introducing two reactive carbonyl groups into organic substrates. This reactivity has been exploited in syntheses of isatin and quinoline derivatives (Scheme 56) . 7 9 The first example of double carbonylation of a simple alkene has been reported. But-1-ene was converted into a 0 , y -unsaturated a-keto-amide via an aminopalladation reaction (Scheme 57) .8 o The bicyclo[3.2.lloctane carbon skeleton, an important structural unit found in various types of terpenoid natural products, has been synthesized from cyclohexa-lI3-dienes using a route which involves two carbonylation steps (Scheme 58) .81 A palladium-catalysed carbonylation of B-aminoethanols has been used to prepare oxazolidinones under mild conditions (Scheme 59) . 8 2 With stoichiometric quantities of palladium, double carbon monoxide incorporation occurs to give morpholinediones. Organic iodides with B-hydrogen atoms can be carbonylated under platinum catalysis (Scheme 60) . 8 3
The enhanced stability of
platinum-hydrogen bonds with respect to palladium-hydrogen bonds
General and Synthetic Methods
428
R'
I Ill
NMe2
(CO 1,Fe
+
I n7
-I
4
K-
R =
H,alkyl
or
R'
R'
C02Me
Scheme
63
P h 3 S n (CO)3Co
Me0
Bun3Sn
Reagents
3
I,
BunLi,
11,
Ph3SnCo(CO)4,
III,
Me30+BFL-,
Scheme
64
IV,
Me-=-Me,
v, M e 3 S i I
429
6: Organometallics in Synthesis
RCHO
+
CNCH,C02Me
Ii ( Y i e l d 89 -100%; trans : cis
80 : 20 - 1OO:O - 97 '1. )
e . e . ( t r a n s1 7 2
R
= alkyl, vinyl
or a r y l
Scheme 65
430
General and Synthetic Methods
&AOEt H
H
R e a g e n t s : i, c a t
1 8 V ;
ii, 1 Z e q u i v [ c h l o r o ( p y r i d i n o ) bis
( d i r n e t h y ( g l y o x i r n a t o ) c o b a 1 1 (111)].-1
Scheme 66
8 V
I
III,
hv, 0 2 ,
IV,
NaBHq
-
6: Organometallics in Synthesis
43 1
R’
WCHO I
V N A C HO z R 2
I
+
Fe
H,N
I
COzR2
R1
W N A C H0 2 R z
1
+
Fe
Reagents
I, I I,
H2, Na2C03,
cat
RN ;
f
CO,H
L
p a l l a d i u m (11) p h t h a l o c y a n i n e ,
d I c yc l o h e x yL c a r b o d I i m i d e
Scheme 6 7
General and Synthetic Methods
432
avoids the 6-elimination problems encountered in palladium-catalysed carbonylation of iodides with O-hydrogens. Insertion of carbon monoxide into aryl halides prepared by condensation of ortho-halogenoanilines with 4-hydroxyproline derivatives leads to the lI4-benzodiazepine skeleton.
This
methodolgy has been applied to the first synthesis of prothracarcin, a compound active against Gram-positve and Gram-negative bacteria and murine tumours (Scheme 61) . 8 4 Allene carboxylates have been synthesized from propargylic carbonates using a palladium-catalysed decarboxylation-carbonylation reaction (Scheme 62) . 8 5 Alkynes react with [(dimethylamino)phenylmethylidene] tetracarbonyliron(0) with incorporation of CO to give
5- (dimethylamino)furans as the major products (Scheme 63) .86
The
product distribution is CO-pressure-dependent and
6-(dimethylamino)-a-pyrones are produced at. higher CO pressure. 2-Alkoxyfurans are formed when alkynes are reacted with (methoxyalkylidene)(triphenylstannyl)tricarbonylcobalt(O) complexes.
This reactivity has been exploited in a synthesis of
bovolide (Scheme 64) . 8 7 6 Miscellaneous Reactions It has been reported that a chiral ferrocenylphosphine-gold(1) complex catalyses the asymmetric aldol reaction of an isocyanoacetate with aldehydes (Scheme 65) . 8 8
The optically active
5-alkyl-2-oxazoline-4-carboxylates produced are readily converted into optically active B-hydroxyamino-acids. Radical cyclizations in the presence of cobalt(1) species lead to alkylcobalt (111) complexes which undergo 1 ,2-elimination of H-Co to produce alkenes.
Alternatively, oxidation of the cobalt(II1)
species produces alcohols. 8 9
This methodology has been successfully
applied to the synthesis of functionalized butyrolactones, benzofurans, indoles, and benzopyrans (Scheme 66) . 8 9 ’ The ferrocenylmethyl group has been used to mask peptide bonds (Scheme 67) .91
Intermediates containing this group are readily
purified due to their high lipophilicity and strong yellow colour. References 1
A Yamamoto, ‘Organotransition Metal Chemistry: Fundamental Concepts and Applications‘, Wiley - Interscience, Chichester, 1986.
6: Organometallics in Synthesis
433
2
A W Parkins and R C Poller, 'An Introduction to Organometallic
3
M T Reetz, 'Orqanotitanium Reagents in Organic Synthesis',
4
J Muzart, Bull.Soc.Chim.Fr., 1986, 65.
5
H B Kaqan and J L Namy, Tetrahedron, 1986,
6 7
T N Mitchell, J.Orqanomet.Chem., 1986, 304, 1. U M Dzhemilev, 0 S Vostrikova, and G A Tolstikov,
Chemistry', Macmillan, Basinqstoke, 1986. Springer-Verlag, Berlin, 1986. ~
J.Orqanomet.Chem., 1986,
42, 6573.
304, 17. 42, 4361.
8
J Tsuji, Tetrahedron, 1986,
9
B M Trost, Angew.Chem., Int.Ed.Enql., 1986,
25, 1. 27, 3573.
1 0 S Calet and H Alper, Tetrahedron Lett., 1986,
11 E Farnetti, M Pesce, J Kaspar, R Spoqliarich, and M Graziani,
J.Chem.Soc., Chem.Commun., 1986, 746. 12 H A Zahalka and H Alper, Orqanometallics, 1986,
5,
1909.
13 J Tsuji, T Sugiura, M Yuhara, and I Minami, J.Chem.Soc., ChemL Commun., 1986, 922. 14 J M Fernhdez, K Emerson, R H Larsen, and J A Gladysz, J.Am.Chem.Soc., 1986, 108, 8268. 15 Q-Y Chen, Y-B He, and 2-Y Yang, J.Chem.Soc., Chem.Commun., 1986, 1452. 16 R M Hanson and K B Sharpless, J.Org.Chem., 1986,
51,
17 M Tokles and J K Snyder, Tetrahedron Lett., 1986,
1922.
27, 3951.
18 T Yamada and K Narasaka, Chem.Lett., 1986, 131. 19 C Venture110 and M Ricci, J.Org.Chem., 1986,
El
1599.
20 K Yamawaki, T Yoshida, T Suda, Y Ishii, and M Oqawa, Synthesis, 1986, 59. 21 T Nakano, T Terada, Y Ishii, and M Ogawa, Synthesis, 1986, 714. 22 K Hiroi and K Makino, Chem.Lett., 1986, 617. 23 I Matsuda, T Kato, 27, 5747. -
S
Sato, and Y Izumi, Tetrahedron Lett., 1986,
24 J L van der Baan and F Bickelhaupt, Tetrahedron Lett., 1986, 27, 6267. 25 L S Barinelli, K Tao, and K M Nicholas, Orqanometallics, 1986, 2 , 588. 26 D Mandon, L Toupet, and D Astruc, J.Am.Chem.Soc.,
1986,
108,
1320. 27 A J Pearson and H S Bansal, Tetrahedron Lett., 1986, 2,283. 28 E D Honiq and D A Sweigart, J.Chem.Soc., Chem.Commun., 1986, 691. 29 A J Pearson and J Yoon, J.Chem.Soc., Chem.Commun., 1986, 1467. 30 M Rosenblum, M M Turnbull, and B M Foxman, Organometallics, 1986, 5, 1062.
434
General and Synthetic Methods
27
31 M Saha, B Bagby, and K M Nicholas, Tetrahedron Lett., 1986, 915; M Saha, S Muchmore, D van der Helm, and K M Nicholas,
J.Org.Chem., 1986, 51, 1960. 32 S L Schreiber, T Sammakia, and W E Crowe, J.Am.Chem.Soc., 1986, 108, 3128. 33 P R Auburn, J Whelan, and B Bosnich, J.Chem.Soc., Chem.Commun.,
1986, 146. 34 S - I Murahashi, Y Tanigawa, Y Imada, and Y Taniguchi, Tetrahedron Lett. , 1986, 27, 227. 35 K Hiroi, K Suya, and S Sato, J.Chem.Soc., Chem.Commun., 1986, 469. 36 A K Pearson, P R Bruhn, and S-Y
HSU, J.Org.Che&,
37 F Rose-Munch, E Rose, and A Semra, J.Chem.Soc.,
1986,
2,2137.
Chem.Commun.,
1986,1551. 38 J Blagg, S G Davies, C L Goodfellow, and K H Sutton, J.Chem.Soc., Chem.Commun., 1986, 1283. 39 J C Heslin, C J Moody, A M Z Slawin, and D J Williams, Tetrahedron Lett., 1986,
27, 1403.
40 M T Reetz, S H Kyung, and M Htlllmann, Tetrahedron, 1986, 42, 2931. 41 M T Reetz, T Kukenhbhner, and P Weinig, Tetrahedron Lett., 1986, 27, 5711. 42 T Hirao, D Misu, K Yao, and T Agawa, Tetrahedron Lett., 1986, 929. 43 T Hirao, D Misu, and T Agawa, Tetrahedron Lett., 1986,
27,
27, 933. 108,
44 E J Corey, R Naef, and F J Hannon, J.Am.Chem.Soc., 1986, 7114.
45 K Tomioka, T Suenaga, and K Koga, Tetrahedron Lett., 1986, 369. 46 W Oppolzer and 'T Stevenson, Tetrahedron Lett., 1986,
27,
27, 1139.
47 V Cal6, L Lopez, and G Pesce, J.Chem.Soc., Chem.Commun., 1986, 1252. 48 J P Gilday and D A Widdowson, J.Chem.Soc., Chem.Commun., 1986, 1235. 49 J P Gilday and D A Widdowson, Tetrahedron Lett., 1986,
27, 5525. 27,
50 A Solladie-Cavallo and D Farkhani, Tetrahedron Lett., 1986,
1331. 51 J Blagg and S G Davies, J.Chem.Soc., Chem.Commum., 1986, 492. 52 S G Davies, R J C Easton, A Gonzalez, S C Preston, K H Sutton, and J C Walker, Tetrahedron, 1986, 42, 3987. 53 S G Davies, J I Seeman, and I H Williams, Tetrahedron Lett.,
1986,
27, 619.
6: Organometallics in Synthesis
435
54 S L Brown, S G Davies, D F Foster, J I Seeman, and P Warner, Tetrahedron Lett.,
1986,
27, 623
55 I Weinstock, C Floriani, A Chiesi-Villa, and C Guastini, J.Am.Chem.Soc., 1986,
108, 8298.
56 S G Davies and J C Walker, J.Chem.Soc., Chem.Commun., 1986, 495. 57 S G Davies, I M Dordor-Hedgecock, K H Sutton, and J C Walker, Tetrahedron Lett., 1986,
27, 3787.
58 S G Davies, I M Dordor-Hedgecock, K H Sutton, J C Walker, R H Jones, and K Prout, Tetrahedron, 1986, 42, 5123. 59 P C Heah, A T Patton, and J A Gladysz, J.Am.Chem.Soc., 1986, 1185.
108,
60 C A Rusik, T L Tonker, and J L Templeton, J.Am.Chem.Soc., 1986, 108, __
4652.
61 M Franck-Neumann, M Sedrati, and M Mokhi, Angew.Chem., Int.Ed.EngL, 1986,
25, 1131.
62 M Franck-Neumann, M Sedrati, and M Mokhi, Tetrahedron Lett., 1986,
27, 3861.
63 T Hayashi, M Konishi, Y Okamoto, K Kabeta, and M Kumada, J.Org.Chem., 1986,
51,
3772.
64 Y Tamaru, H Ochiai, T Nakamura, and 2 Yoshida, Tetrahedron Lett., 1986,
27, 955.
65 S Cacchi, E Morera, and G Ortar, Synthesis, 1986, 320. 66 A Wada, J Yamamoto, T Hase, S Nagai, and S Kanatomo, Synthesis, 1986, 555. 67 N Miyaura, Y Satoh, S Hara, and A Suzuki, Bull.Chem.Soc.Jpn., 1986,
2,2029.
68 B M Trost, S M Miqnani, and T N Nanninga, J.Am.Chem.Soc., 1986, 108, 6051. 69 M D Jones and R D W Kemmitt, J.Chem.Soc., Chem.Commun., 1986,
1201. 70 B M Trost and S A King, Tetrahedron Lett., 1986,
27, 5971.
71 B M Trost, J M Balkovec, and S R Angle, Tetrahedron Lett., 1986, 27, 1445. 72 S G Davies and J C Walker, J.Chem.Soc., Chem.Commun., 1986, 609. 73 J W Herndon, J.Org.Chem., 1986,
s,2853.
74 P G Lenhert, C M Lukehart, and L Sacksteder, J.Am.Chem.Soc., 1986,
108,793.
75 K Narasaka, M Inoue, and 'T Yamada, Chem.Lett., 1986, 1967. 76 S D Burke and J E Cobb, Tetrahedron Lett., 1986,
27, 4237.
77 S L Brown and S G Davies, J.Chem.Soc., Chem.Commun., 1986, 84. 78 T W Bodnar, E J Crawford, and A R Cutler, Organometallics, 1986, 5, 947.
436
General and Synthetic Methods
79 F Ozawa, H Yanagihara, and A Yamamoto, J.Org.Chem., 1986,
2,
415 80 F Ozawa, M Nakano, I Aoyama, T Yamamoto, and A Yamamoto, J.Chem.Soc., Chem.Commun., 1986, 382. 81 P Eilbracht, R Jelitte, and P Trabold, Chem.Ber., 1986, 119, 169. 82 W Tam, J.Org.Chem., 1986, 51, 2976. 83 R Takeuchi, Y Tsuji, Y Watanabe, J.Chem.Soc., Chem.Commun., 1986, 351. 84 M Mori, Y Uozumi, M Kimura, and Y Ban, Tetrahedron, 1986, 42, 3193. 85 J Tsuji, T Sugiura, and I Minami, Tetrahedron Lett., 1986, 731.
27,
86 M F Semmelhack and J Park, Organornetall&, 1986, 2, 2550. 87 W D W u l f f , S R Gilbertson, and J P Springer, J.Am.Chem.Soc., 1986, 108, 520. 88 Y Ito, M Sawamura, and T Hayashi, J.Am.Chem.Soc., 1986,
108,
6405.
89 H Bhandal, G Pattenden, and J J Russell, Tetrahedron Lett., 1986, 27, 2299. 90 V F Patel, G Pattenden, and J J Russell, Tetrahedron Lett., 1986, 27, 2303. 91 H Eckert and C Seidel, Angew.Chem., Int.Ed.Engl., 1986,
2,159.
6: Organometallics in Synthesis
Part 11:
437
Main Group Elements By T. Gallagher
1 Group I
Selective Lithiation. - The importance of organolithium reagents continues to stimulate the development of new methods for their qeneration.
A range of useful lithiation reactions have been shown
to be accelerated by ultrasonic radication.
Of particular interest
is the reaction of the dibromide ( 1 ; X=Br) with lithium to give the monolithium derivative (1; X=Li).
This anion was trapped with
various electrophiles, but no products resulting from an 2-xylylene were observed.
The organolithiums derived from chloromethanes have
already found application in orqanoboron chemistry, but in an extension of these studies Matteson has examined the reactivity of (chloromethyl)lithium with aldehydes and ketones (Scheme 1 ) .
in
(Chloromethy1)lithium is thermally unstable but maybe qenerated __ situ
from chloroiodomethane and reacts wit!? carbonyl derivatives to
give either chlorohydrins or oxiranes, dependinq on the conditions used.2 This mode of reaction has been taken a stage further by Barluenga, and developed into an effective methylenylation procedure (Scheme 1 ) .
The intermediate alkoxide (2) may be metallated a
second time using lithium and the product, formulated as ( 3 ) , underqoes fragmentation on warming to provide the methylenylated Full details concerning the mechanistic and synthetic
product (4).3
aspects of the amination of organolithiums with g-methoxyhydroxylamine have appeared. Perhaps the most interestinq developments in the area of selective lithiations to appear this year have been concerned with the control of absolute stereochemistry. The application of chiral amide bases to the enantioselective deprotonation of epoxides was first described some years aqo by Whitesell and co-workers, but this year several qroups have reported on other aspects of these useful reaqents. Symmetrically substituted ketones (5; R=Me, CH2Ph) have been shown b y Simpkins to undergo an enantioselective deprotonation under kinetically controlled conditions to qive, after reaction with an electrophile (iodomethane, ally1 bromide or acetic anhydride), optically active ketones (6) or enol acetates (7) (Scheme 2).
The
ability of a number of bases to discriminate between the two prochiral protons present in (5) were evaluated and the most effective of those studied was the camphor derivative ( 8 ) ; deprotonation of (5; R=Me) proceeded in 74% enantiomeric excess
General and Synthetic Methods
438
(3) Reagents
l,MeLi,LiBr,THF,-78"C,
11,
R ' RC=O;
III,H+, I V , L I , - ~ O " C to - 2 0 ° C
Scheme 1
?Li
(5)
"b" (7)
Reagent S :
I,
R ~ N L I l:l , R ' X , ( R ' = o l l y l , m e t h y l ) ; iii
(8)
Li
Scheme 2
C H 3CO) 0
(4)
6: OrganometaIIics in Synthesis
4
MejSiCI
I
OL i
0
+
439
OSi Me3
(9) R
R
OLi
OSiMe3
X
Scheme 3 0
0
OL i
0
10 0
'C02Me
67%
...
Reagents: i , Me
111,
LI
Scheme 4
(1 5)
e.e.
cool to - 196"C,CO2parm to-80°C
General and Synthetic Methods
R
R
Reagents : I , l i t h i u m diisopropylamide ( L D A ) , - 70°C,then H 0
2
Scheme 5
H
R’
N
Nz-
i
R
R
.J:
N R’
Li+
ii
R (17)
XE (18)
RnE (19) Reagents:
6u”L) or L D A ; ii, electrophile(E+), ii;,CF 3 CO2 H , t h e n (COZH)2,H20; i v , EtSH, H + I,
Scheme 6
6: Organometallics in Synthesis (%
441
e.e.) usinq this base.
In a related study, Koga has examined
the ability of another series of chiral amide bases to effect the enantioselective deprotonation of 4-substituted cyclohexanones (Scheme 3) . 6
The lithium enolates (9) and (10) were trapped as their
trimethylsilyl derivatives and these products were obtained in 7-97% e.e. In this study the most promising base examined was the piperazine derivative ( 1 1 ) . Finally, Hoqeueen has examined the ability of lithium (5,s-)-a,a'-dimethyldibenzylamide ( 1 3 ) to resolve racemic 2 ,2 ,5-trimethylcyclohexanone (12).7 The enolate (14), which is presumably associated with protonated (13) (Seebach's 2" amine effect), may be reprotonated to give (12) in up to 46% e.e. or trapped with carbon dioxide followed by iodomethane to give (15) in
67% e.e. (Scheme 4).
This latter result, though very encouraging,
was only obtained under rather special conditions that involved cooling the enolate solution (in ether) in liquid nitrogen, then condensing C02 onto the top of this frozen mixture and finally allowing the whole system to warm to -80°C. These three reports will surely stimulate further work in this area, and it will be interesting to see whether a 'structure-activity' relationship can be developed for the chiral bases that have been prepared in terms of their possible substrates. The effect of temperature on the observed regioselectivity of deprotonation of fluoroacetone cyclohexylimine (16) has been examined.8 Although a fluoro substituent does not impose a major steric effect on the substrate, the electronic effect that it exerts must be substantial. At low temperatures ( - 8 0 ° C ) the preferred mode of enolisation is towards fluorine ( 9 6 : 4 ) , but at higher temperatures (-30°C) enolisation away from the electron-withdrawinq fluorine residue predominates (89:ll). Deprotonation of imines provides access to 2-azaallyl anions that are capable of undergoing a cyclisation reaction to appropriately substituted alkenes to qive pyrrolidines. An early limitation in this area was the need for activated anionophiles, but this has now overcome, at least within the confines of the intramolecular variant (Scheme 5) .9 This provides an elegant entry into fused pyrrolidines, and the cyclisation step shows a high level of stereoselectivity; furthermore the conditions employed tolerate a range of substituents. Other aspects of nitrogen-stabilised organolithiums have also been reported. Thus, deprotonations of aldehyde tert-butylhydrazones provides the anion (17) that functions effectively as an acyl anion (dl) reagent (Scheme 6 ) . l o A wide range of electrophiles have been
442
General and Synthetic Methods
I.
... 111,
ii
H
c AS02NMe2 SiMe3
I V
Jq
* E
R e a g e n t s . i , C I S02NMe2, Et3N, II B u n L I , t h e n M e 3 S i C L , (11, i3usLI, E', t h e n H 2 0 , IV,
2 k KOH, H 2 0
Scheme 7
(2 41 R e a g e n t s : i, Bu"Li, t h e n E+ ii , HC02H
Scheme 8
H (21 1
443
6: Organornetallicsin Synthesis
used (aldehydes, ketones, a,@-unsaturated esters and alkyl halides) and the initially-formed adducts
( 18;R1=But)
are first treated with
trifluoroacetic acid, to effect tautomerisation to the hydrazone, followed by mild acid hydrolysis.
The same research group has also
shown that adducts derived from trityl or diphenyl-4-pyridylmethyl hydrazones (18; R1=CPh3, C (4-pyridyl)Ph2) undergo facile homolytic decomposition to give the reduction products (19).
This latter
process may be applied to both aldehyde- and ketone-derived hydrazones.
11
Chiral oxazolines have been shown to serve us readily available auxiliaries for the functionalisation of unactivated secondary amines via the corresponding dipole-stabilised anion.
Reaction of e.g. (10)
with an alkyl halide provides, after removal of the chiral auxilary, the corresponding 2-substituted piperidine with a high degree of selectivity.
The directed metallation of aromatic substrates
continues to develop.
Full details on the use of !-trimethyl-
silylethoxpethyl) (SEM) pyrroles and indoles as a means of preparing the corresponding 2-substituted heterocycles have been p ~ b 1 i s h e d . l ~The SEM group not only acts as an efficient directing group, but also may be cleaved under very mild conditions (BunqNF, THF). The preparation of a series of 4-substituted imidazoles (21) by a combination of N-protection and temporary blocking of C - 2 has been reported in full (Scheme 7) .I4 Directed lithiations of alkoxy furans have potential in the synthesis of butenolides, and the tetramethyldiamidophosphate moiety has been successfully used to prepare 3-substituted furans (22). Acidic cleavage of the phosphorus residue then allows access to the corresponding 2-substituted butenolide (23), and the overall process becomes equivalent to using the anion (24) (Scheme 8). The ability of _N,N-dialkylamides to act as ortho-directing groups for metallation reactions is well precedented; however removal of this residue,*. hydrolysis of a tertiary amide,can be problematic and often limits the scope of the procedure. Commins has now shown that tertiary B-aminobenzamides e.g. (25) are not only capable of undergoing efficient ortho- lithiation, [ B u S L i / g , ~ ,, ~ g’ ’tetramethylethylenediamine (TMEDA), but also that cleavage of the amido group can subsequently be achieved using 6N-hydrochloric acid; conditions that fail for the corresponding g,N-dimethylamide.16 Snieckus however has effectively used N,N-dialkylbenzamides as orthodirectors in the regiospecific synthesis of naphthols and naphthaquinones via an anionic aromatic annelation process (Scheme 9).
M - - eR General and Synthetic Methods
444
CO-NEt2
RO
RO
1
(26)
(2 7) R e a g e n t s : i , L D A or M e L i ,
- 78°C
t o room t e m p e r a t u r e
Scheme 9
' Li
'N-SiMe3
PhCH=C=N
R
L''i
M e2 (28)
(29) Li M
Bu3Sn-NCO2Me
(30)
NCO
Li
H
(31)
R
R
F NHCO Me
OH Reagents
I
Bu"LI ( 2 equlvalents),THF, - 80°C t o
Scheme 10
-
3 0 ° C ; i i , R ' RCO
445
6: Organometallics in Synthesis
R
R NCO, L i Li
Reagents: i, B u n L i , then C O z ;
;;,
B u t L i ; iii, E+, then H+(-CO*)
Scheme 11
R
446
General and Synthetic Methods
Some mechanistic comment is made by the authors, who suggest a vinylbenzocyclobutane (27) as a possible intermediate based on the preferred conformation of the ally1 anion (26).17
Ultrasound has also found application in the selective ortho lithiation of the intermediate,=.
(28),produced in the addition of aryl lithiums to
amides (Bouveault reaction) .I8 Dianions, Alkeny1,and Alkynyl Anions. - Problems have often been encountered in attempts to carry out polylithiations of organic substrates.
Although di-, tri- and polyanionic species have been
characterised, the reaction of phenylacetonitrile and benzyldiethoxyphosphate (PhCH2P(0) (OEt)2) with two equivalents of lithium hexamethyldisilazide has been shown not to generate the corresponding general dianions.
Rather, using 13C-n.m.r.
spectroscopy, the species present has been shown to be a monoanion, complexed with a second molecule of base, and has been formulated, in the case of PhCH2CN, as (29).19
The aut-hors have coined the term
"Quadacs" (Quasi pigni.on Complexes) to cover this phenomenon. Tin-lithium exchange of the stannane (30) provides access to a novel d '
reagent (31) that has been used to prepare a series of
1,4-aminoalcohols (Scheme lo).
The C-metallation step is presumed to
involve a chelation-assisted metallation, since a number of related systems, e.g. (32) and (33), failed to undergo tin-lithium exchange. The free hydroxyl derivative (34) reacted smoothly to give the dianion (35), which was trapped by benzophenone in 80% yield.20 Further examples of the use of carbon dioxide as both a N-protecting group and for the stabilisation of a carbanion have appeared.
A series of substituted tetrahydroisoquinolines have been
prepared starting from the parent heterocyclef2' and the same concept has also been applied to the ring metallation of $-alkylanilines22 and to the functionalisation of 2-alkyl substituted indoles (Scheme 11) .23 The principal advantages of this methodology are the ease with which the 'protection' and 'deprotection' steps involving CO2 are achieved. The dianion/enolate complexes (36) generated from 6-hydroxy esters have been shown to react with alkyl halides in a highly selective fashion to give T n - (37) as the major product (Scheme 121, and this selectivity was improved by the addition of HMPA.
The
formation of a dianion species is crucial to the success of this process, and no selectivity was observed if the secondary hydroxyl function w a s silylated prior to depronation.
Lithium
6: Organometallics in Synthesis
R I
R'
syn
R
- ( 37)
anti- (37)
'90 Reagents
I,
10
Et2NLi,THF, HMPA, LiOS02CF3, -100°C: i i , R ' X
Scheme 12
R
bo +Rb OL i
i
R
R
R=Me,H
R
(38)
Reagents: i , L D A , HMPA , T H F ; i i , R ' X then
H+
Scheme 13
Reagents:
I,
L D A , H M P A , THF;
ii
ii, R"X,then ti+
Scheme 14
448
General and Synthetic Methods
Me
Me (40)
(41)
, Li
Li
Li
R'
SiMe, (4 3)
(42)
Reagents
I,
B u n L i , 6 u t O K , T M E D A , hexane, - 2 5 ° C . i i , L i B r ; ( PhCHO and P h S S P h )
ill, E
+
Scheme 15
x"
F
R
F
- xi ii
R
(44) R = a l k y l , aryl
F
(45)
Reagents: i , 6 u s L i , E t 2 0 , - 6 0 ° C ; ii, Bu"Li, E t Z 0 , 5 - 3 0 " C
Scheme 16
6: Organometallics in Synthesis
Reagents
: i,
449
But L i , hexane, room temperature
Scheme I7
d
OSO,
CF3
%Me3
ii I
Tb
6 Scheme 18
Li iv
7
‘ki net i; (50)
General and Synthetic Methods
450
trifluoromethanesulphonate was shown to be useful in accelerating enolate formation which was achieved at - ~ O O T . ~ ~ 4-Substituted 1,3-cyclohexanediones have been prepared by alkylation of the dianion (381, and monoalkylated products were obtained in 41- 78% yield (Scheme 1 3 ) .25 a-Ketoamides may also be deprotonated to give a dianion ( 3 9 ) , which then reacts with alkyl halides to give a-amido tertiary alcohols (Scheme 14).
In the case
of the proline-derived amide (40), the methylated product (41) was obtained in 75% diastereomeric excess.26
F u l l details have been
reported concerning both the reaction of dianions derived from @-diketones with lactones as a general r0ut.e into substituted spiroketals,27 and of the application of the dianion (42) to the stereoselective synthesis of substituted indoles.28 An improved procedure for the generation and selective trapping of 2,4’-dilithiophenylethyne (43) has been described.
Reaction of
(43)with electrophiles preferentially takes place at the aryl lithium site .2 9 This year has seen some interesting developments in the area of alkenyl anions, including the first direct metallation of ethene, which was achieved using a new mixed-based metallation system (Scheme 15). Lithioethene produced in this way was trapped in good yield by benzaldehyde and diphenyldisulphide. A series of di- and trifluorovinyl lithiums have been generated by either halogen-lithium exchange or direct deprotonation (Scheme 16).
Deprotonation of Z- (44) for example occurs at -100°C with
retention of configuration, but isomerisation of
z- (45) to the more
stable isomer, g- (45), takes place at - 3 0 ” c . ~ ~ The ability to control site selectivity in anion formation is central to the synthetic success of organolithium reagents. Stork has described the direct formation of the O-lithioenamines (47) and (49) based on the use of a chelating structure (Scheme 17). In the case of the cyclohexenyl derivative (46), no evidence for allylic deprotonisation was observed, and with the acyclic derivative (48) metallation B - with respect to nitrogen was the only process detected.32 This is in marked contrast to earlier work involving simple, nonchelatinq enamines, and is a valuable contribution to this special area. Regioselectivity in the context of substituted alkenyl anion has also been addressed.
It is known that the base-induced fragmentation of tosylhydrazones (Shapiro reaction) derived from a-substituted ketones leads predominantly to the “kinetic” (cf.ketone enolates)
45 1
6: Organometallics in Synthesis
R e a g e n t s : I , RMgX
(
2 equivalents) : ii, LI: iii, C02
Scheme 19
R-
-0Ts
-___---
R C ~ C - o
+
R---o-s,R;
(54) RCO, E t
Reagents.
I, MeLi ( 2 e q u i v a l e n t s ) , t i , L I tetramethylp~perldrdc , CH2BrZ, - 7 8 ' C ; I V , w a r m to room temperature, v, MeLl III,CISIR;,
Scheme 20
General and Synthetic Methods
452
(551
(56)
( f r o m RC0,Et)
Reagents
i , 1,3 - o r 1,L - c y c l o h e x a d l e n e , T H F , refiux; (CH,CO), 0 , I V , NaBHL,, MeOH
11,
CIS1Me3.then H+;
111
O A c / Ph (57)
68"lo
/\/\/OH 70 "lo
70 "1. Scheme 21
(58)
R' 59)
Reagents: i , N a H , D M F ; i i , R ' X
Scheme 22
(60) X = SPh (61) X = SO. Ph
6: Organometullics in Synthesis
453
alkenyl anion (50). Access to the isomeric "thermodynamic" alkenyl anion (51) may however be achieved via the corresponding alkenyl triflate, since Stille has demonstrated that alkenyl triflates may be readily converted to the corresponding alkenyl stannane (Scheme 18). Thus, depending on the conditions used to prepare the alkenyl triflates, both of the alkenyl lithiurns (50) and (51) may be prepared ~electively.~ A ~ 'one-pot' synthesis of a,@-unsaturated y-lactones has been achieved, based on the generation of the stabilised alkenyl anion (52) (Scheme 19) .34 The chemistry of alkynoates (53) has continued to develop this year, and two research groups have independently described how these anions may be silylated on oxygen to give ynol silyl ethers (54). Stang35 has exploited the reaction of alkynyl tosylates with methyl lithium to generate the desired alkynolate (53), and K ~ w a l s k ihas ~~ based his approach on methods developed earlier for the homologation of esters (Scheme 20). Furthermore, Stang has shown that silylation is a special case, in as much as reaction of (53) with EtjGeCl and Kowalski has however shown
Bu 3SnCl occurs on carbon and not oxygen.
that 0- to C-isomerisation of (54; R1=Me) occurs on warming to give a silyl ketene. substituents,-
This isomerisation can be slowed if bulky silyl R1=Pril are employed. Finally, as is the case with
more conventional silyl enol ethers, the ynol silyl ethers provide a convenient source of the corresponding enolate, Le. (54) may be converted back to (53). A general procedure for the preparation of aldehydes, alcohols and enol acetates has been reported that is based on the reductive homologation of esters (Scheme 21) .37 Electron-rich alkynolates (55) (prepared from RC02Et as shown in Scheme 22) may be reduced under strongly basic conditions by 1,3- or lI4-cyclohexadiene to afford the aldehyde enolate (561, which is readily transformed to the observed products.
The overall yields obtained in this procedure are good, as
shown for the transformations involving ethyl 3-phenylpropanoate (57). Sodium and Potassium. - A few reports have appeared focussing particularly on organometallic derivatives of sodium and potassium. The alkylation of a-formamido ketone enolates is a useful entry into substituted a-amino ketones (Scheme 22).38 Earlier work in this area used a very strong base ( L D A ) to generate the dianion corresponding to (58), but more mild conditions may be used. Reaction of (58) with NaH generates a monoanion which undergoes clean monoalkylation to give (59);
this species may subsequently be cleaved to provide the
454
General and Synthetic Methods
Scheme 23
Scheme 2 4
6: Organometallics in Synthesis
455
free aminoketone. Alkyl sodiums are stabilised in hexane solution by Mg(OCH2CH20Et)2, and the resulting 'reagent' has a well-defined A new synthesis of stoichiometry and moderate thermal stability3'. butyl potassium, a very potent metallating agent, has appeared. method, which is similar to the procedure used to prepare butyl
The
sodium, is based on the reaction of BunLi with potassium 40
tert-amylate.
Sulphur and Selenium-Stabilised Anions - As in previous years, anions stabilised by an adjacent sulphur, and to a lesser extent, a selenium residue have found extensive use in synthetic chemistry. A range of new methods have been developed forthe generation of these stabilised anions. As part of a larger programme directed towards the synthesis of the allamada and plumeria iridoids, Trost has reported on a new method 41 for the generation of enolates of a-phenylthiolactones (Scheme 2 3 ) . Attempts to effect an aldol-type condensation on the lithium enolates derived from both (60) and (61) failed, and this was attributed to problems associated with the enolisation conditions used and the unfavourable equilibrium associated with the condensation step. The bissulphenylation of lactones, as well as ketones, esters and nitriles, is well known, and Trost has shown that (62) undergoes cleavage in the presence of EtMgBr to give the enolate (63) that is efficiently trapped by acetaldehyde leading to (64). Further transformations of this product have been described, and the methodology has been extended to more complex lactones, e.g. (65), as well as to ketones/-. (66). The reductive cleavage of a C-S bond using lithium napthalenide or lithium 1-(dimethy1amino)naphthalenide is a useful method for generating organolithium reagents. Full details have appeared on the use of this procedure to prepare allylic anions, by cleavage of an all.ylic ~ u l p h i d e . ~ ~ Stereochemical and mechanistic aspects of the cyclisation of w-hydroxy thioacetals have been reported. Cohen had earlier observed that deprotonation of (67) led to the cyclopentanol derivative (691, and proposed that a carbenelike species (68) was involved. He has now examined a range of other substrates and, based on a detailed stereochemical study, a new mechanistic rationale has been presented that involves the displacement of PhS- from the lithiated thioacetal ( 7 0 ) by a hydride ion, followed by cyclisation (Scheme 24) .43 The direct double metallation of aromatic thioethers (71; X = H ) may be achieved using BunLi on the presence of TMEDA, and the resulting dianions (72; X=Li) have been
General and Synthetic Methods
456
(71) X =. H (72) X = Li
(74)X = H (76) X = L i SPh
[;FSph [I)-+ [:&OH
-.L+
Li
(77)
(78)
J."'
R
d; (79) Reagents
I,
Bu'LI,
dimethoxyethane ( D M E ) ; 1 1 , RCHO;
iii
~
MeOH, Hf
Scheme 25
(€31) Reagents
I * III
N - brornosuccinimide; E+ - 1 2 0 ° C
1 1 ,
But LI ( 2 equivalents) ,
Scheme 26
-
120° C ,
457
6: Organometallics in Synthesis
(82)
IV
Reagents i , L D A , H M P A , T H F ;i i , EC, i i i , E ' + ;
IV,
CuC12, C u O , H 2 0 , M e 2 C 0 ,
(83 1 Scheme 27
OH
a:Y
(84)
10 : 90 Scheme 28
458
General and Synthetic Methods
trapped with a variety of electrophiles.
With the isopropyi
derivatives (73) and (74), only dianions corresponding to (75) and (76) respectively have been trapped.44 A two step procedure for the elaboration of aldehydes to 2-substituted 3-phenylthiofurans (79) has been based on selective deprotonation of the substituted alkenyl sulphide (77). The formation of the alkenyl anion (78) is favoured over allylic deprotonation, and the procedure is straightforward with furans (79), which can be obtained in 56-69% yield (Scheme 25) .45 The stabilised dianion (80) can function as an equivalent of either a @ lithioacrylate (LiCH=CHC02R) or a @-lithiopropionate (LiCH2CH2C02R), and the reactivity of this readily available nucleophile towards oxiranes and oxetanes has been A useful entry to functionalised ketcne-S,S- acetals is based on the reaction of the alkenyl anion (81) with electrophiles (alkyl and silyl halides, aldehydes).
This anion was prepared by bromine-lithium
exchange using a readily available 2-bromoketene-S,S-acetal (Scheme 25) .47
Although (81) undergoes fragmentation at -78"C, it may be
trapped cleanly at -120°C.
Attempts continue to be made to define the
structural and electronic factors that determine the regioselectivity observed in the reaction between electrophiles and heteroatomstabilised allyl anions.
The question of whether a - or y-substituted
adducts are obtained is pertinent to the synthetic utility of these anions, and this year a number of interesting publications have addressed these issues.
The effect of steric bulk on the
site-selectivity of anions derived from ketene-S,S-acetals was first highlighted by Ziegler some years ago.
A Japanese research group has
now exploited the steric constraints imposed on the isopropyl derivative (82), and developed this reagent as an equivalent of the dianion (83).
The allyl ariion (82) shows a hiyh level of
y-selectivity in its reactions with a wide range of electrophiles, and following a second substitution hydrolysis of the ketene-S,S-acetal liberates the carboxyl function (Scheme 27) .48 Aldehydes are generally accepted to be 'soft' electrophiles towards allyl anions such as ( 8 2 ) , and usually lead to good yields of y-adducts.
However, with dithianyl derivatives,e_rg. (841, the exposed
nature of the a-site results in an increased level of reaction y & this site.
This may be suppressed if the normal lithium counterion is
replaced by cadmium.
The resulting orqanometallic complex gives
good levels of y-selectivity with aldehydes
(Scheme 28).
The same
authors have also studied the effect of added CdC12 to anions derived from a,@-unsaturated esters (85).49 The influence of an adjacent to
6: Organometallics in Synthesis
459
(88) X = STOI
(87)
( 8 9 ) X = SO.Tol
Me3Si
Y
Me3Si SPh
Li
R
(92)
(93)
P h S T O M e Li
(94)R = H (95)R = SiMe, OE t
Reagents: i , ( 9 4 ) , then Hf; i i , B u t O K a R X ; i i i , H + ,
Scheme 29
HZO, M e O H
General and Synthetic Methods
460
transition metal ligand on the reactivity of S-stabilised anions has been examined by comparing the anions (86) and (87).50 The diastereoselectivity exhibited by anions derived from (88)51 and (89)52 towards a wide range of chiral a-met.hy1-a-alkoxy- and a,@-dialkoxyaldehydes has been evaluated.
The nature of the solvents used and the
presence of other metal ions,e.g. Mg(II), Cu(I), Zn(I1) and Cd(II), can I__
have a substantial influence not only on the a:y selectivity observed, but also on the distribution of Cram vs anti-Cram products. Further advances within the area of nucleophilic carbohydrates have been reported by the Konstanz research group.
Treatment of the
glycal derivative (90) with LDA affords the lithiated species (91) which has been utilized in the synthesis of C-2 branched sugars.53
A
detailed analysis of steric and chelation effects on the stereoselectivity observed between a-lithiosulphinyl carbanions and aldehydes has appeared.54 This methodology has important applications in the stereocontrol led synthesis of complex tetrahydrofurans. 55 Additional features of the reactivity of [phenylthio(trimethylsilyl)methyl] lithium (92) have been reported.
Ager has compared the
reactivity of (92) towards a, B-unsaturated esters with other acyl anion equivalents based on sulphur.56 This anion also adds efficiently to activated alkenes (CH,=CRR1, R1=Ph, SR, C02Et, SiMe
3
)
to give the
silylated cyclopropanes (93).57 [Methoxy(phenylthio)methyl]lithium (94) and [methoxy(phenylthio)trimethylsilylmethyl]lithium
(95) react in a 1,2-sense with
a,@-unsaturated aldehydes and ketones to give Q,S-acetals and ketene-0,s-acetals respectively.58 Transformations of these synthetically useful products have been described, and the anion (94) plays a key role in a concise approach to functionalised y-ketoesters (96) (Scheme 29) .59 The lithio derivative (97) can be used as both a formyl and carboxyl acyl anion equivalent, and this species undergoes conjugate addition to a,B-unsaturated carbonyl groups to give 1,4-adducts in good yield.60
This versatile reagent has also been used to prepare
a-hydroxy aldehydes and ketones. The question of the extent to which oxygen stabilises a negative charge has been studied within the context of S-stabilised systems. Although 1,3-oxathiane (98) is deprotonated at C-2, a mode of reactivity that has been impressively exploited by Eliel, the corresponding sulphone (99) undergoes lithiation exclusively at C-4; this site is both kinetically and thermodynamically preferred. 62 Arguments surrounding the configuration of anions adjacent to
6: Organometallics in Synthesis
461
Li
Li
(104)
/iii
f SO2Ph Reagents
I
B u n L i, H M P A ,
11,
,then Me3SICI,
ill,
Me3StOS02CF3
Scheme 30
(10 7) R = al kyl ,halogen (109)
(108)
R = SPh,SiMeg,C02Me Scheme 31
(110 )
462
General and Synthetic Methods
I
(112)
R
(113) Recgents:
I ,
LDA ( u p to 5 equiv ), THF, -78"C,
11,
RX
Scheme 32
SMe
SMe Ar-CH
I
I
I
Ii
SMe
+
R'
I
Ar-C-R
I
'I1 IV
I
Ar-C-R
I
SMe
R'
I
1 1 1 ,A r -C-R
I
V
R"
SMe
(114) Reagents
I,
potassium diisopropylamide ( K D A )
, 11 , R X , ill ,
Scheme 33
Bu'LI ;I V
,
R' X , v
,
R" X
6: Organometallics in Synthesis
463
sulphones continue to be vented. Evidence based on C-H coupling constants, has now been presented that (loo), (101), and (102) are trigonal at the carbanionic centre; it had earlier been suggested that these anions were pyramidal at this carbon atom.63 The results of a theoretical study in this area have also been published.64 Lithiation of 2-benzenesulphonyl tetrahydropyran gives a synthetically flexible anion (103). This species has now been used to prepare 2-substituted dihydro- and tetrahydropyrans, as well as a series of spiroke ta 1 s . A new cyclopentannulation procedure has been described based on the lI4-addition of (104) to enones (Scheme 30). The precursor to (104) is easily prepared, and the compatibility of a range of enones to the reaction conditions has been established. 6 6 Although metallations of vinyl sulphones is a useful entry into the more highly substituted variants, there are problems associated with the level of stereospecificity observed. Anions such as (105) have been generated at - 9 0 ° C ,
by deprotonations of the corresponding
vinyl sulphone with MeLi, but they are configurationally unstable at temperatures above 6 0 ° C . The composition of the equilibrium mixture is then determined by the nature of R1 and R2. The use of (105) in the stereospecific synthesis of trisubstituted alkenyl sulphones is limited, since this anion only reacts with a very limited range of The metallation of 3-sulfolene as an electrophiles at < - 6 0 ° C . 6 7 entry into substituted buta-lI3-dienes was recently established. The same research group has extended this chemistry to include the 3-substituted derivatives (lob). Deprotonation of (106), with BunLi, leads to either ( 1 0 7 ) or ( 1 0 8 ) depending on the nature of R. Both of these anions however react with iodomethane at the position adjacent to the sulphone moiety leading to (109) and (110) respectively (Scheme 31) . 6 8 Polyanionic species stablized by sulphonyl residues have seen continued development in the last twelve months. y-Alkylation of (111) is possible only when both a'-protons have been removed to give a trianionic species. Interestingly when the isomeric ketosulphone was studied a dianionic intermediate was formed which was alkylated to give (112). A similar observation was made concerning ( 1 1 3 ) 6 9 (Scheme 32). Mesyltriflore (CF S02CH2S02Me) has been shown to be capable of 3 undergoing multiple metallation and can, by application of the Ramberg-Baeklund reaction, provide access to a range of substituted alkenes. The scope of these procrdures, together with relevant
General and Synthetic Methods
464
Li
PhSe
A, Li
Et
Reogents
I ,
P h M g B r , THF
Scheme 34
0 (122) B
r I ~
B
r
r
Ar&
Ary&Ar
0 (123) X=H (124)Xz I Reagents
I.
ArMgBr ( e x c e s s ) ,
11,
H'or
12
Scheme 35
6: Organometallics in Synthesis
465
mechanistic and stereochemical comment, have now appeared." A novel method for the qeminal dialkylation of carbonyl compounds which involves the stepwise reductive cleavage of a selenoketal has been outlined by Krief and co-~orkers.~' The scope of the process can best be illustrated starting with the benzaldehyde derivative (114). Deprotonation of this selenoacetal provides a stablized anion that can then be alkylated. Successive reductive cleavage of the remaining C-Se bonds then allows trialkyl residues to be introduced (Scheme 3 3 ) . The overall process can be formulated in terms of ArCHO to ArCR' R"' Finally, the dilithioderivative (115) of phenylselenoacetic acid has been used as a reagent for the synthesis of 5-substituted butenolides.
This has involved reaction of (115) with an oxirane,
followed by oxidative elimination of PhSeOH.12
2
Group I1
Beryllium, Maqnesium,and Calcium. - The toxic effects of beryllium salts and orqanoberyllium derivatives have limited the use of this element in synthetic laboratories. However a number of orqanoberyllium reagents (116-119) have been evaluated in terms of their ability to effect the asymmetric reduction of prochiral ketones. Secondary alcohols have been obtained in up to 42%e.e. using these derivatives .13 Oppolzer has continued to develop the magnesium-ene reaction, and has reported on the application of this useful cyclisation procedure to the synthesis of various terpenoids (c.2. (t)-chohol-A, ( 5 )-6-protoilludene, ( + ) -a-skytanthine) .74 The synthesis of the 3- and 4- pyridyl Griqnard reagents (120) and ( 1 2 1 ) has been achieved by reaction of the corresponding phenyl pyridyl sulphoxide with phenyl magnesium bromide (Scheme 34). The pyridyl Griqnards were trapped with aldehydes and ketones, and the same techniques have been successfully applied to the 4-quinolyl system.
''
The phosphonate derivative (122) 3as been prepared as an alternative source of the diethoxyphosphinyl carbanion, and the reactivity of the orqanomaqnesium reagent has been compared with the more commonly used orqanolithium species.76 An improved preparation of CH2(MqBr)2 has also been reported.77 Hart has extended his studies on the use of orqanomaqnesium reagents in the synthesis of (poly)aryls.78 The g-terphenyls (123) and (124) have been prepared by
General and Synthetic Methods
466
?Reagents
I ,
CH2=CH-CHHMgCI,
LDA ; ii , H f
Scheme 3 6
(1 26) Y = CO,R’, PO (OEt)2,S028ut,
SiMe3, S0.Bu‘ Reagents : i , Z n , THF, ultrasound, R C I C H , 45°C
Scheme 37
6: Organometallics in Synthesis
467
reaction of a lI2,3-trihalobenzene with an excess of an aryl Grignard (Scheme 35). Although the reaction of acyl chlorides or esters with RMgX is a useful method for preparing ketones, this reaction fails with e.9. CH2=CH-CH2MgC1. This highly reactive reagent tends to give high yields of the tertiary alcohol, even when the reaction is carried out at -78°C. An interesting development has now been described that overcomes that drawback (Scheme 36). When reaction is carried out in the presence of a powerful non-nucleophilic base e.9. LDA, deprotonation of the intermediate ketone (125) is facile and this prevents addition of a second equivalent of ally1 magnesium chloride. The intermediates can also be trapped with Me3SiC1, and N,PJ-dialkylamides may also be used as substrates under these conditions.” Other developments in this area include the use of magnesiumgraphite, generated from potassium-graphite (C8K) and magnesium chloride in tetrahydrofuran, for the pinacol coupling of aldehydes and ketones to give 1 ,2-di0ls.~’ The formation and rearrangement reactions of aryl substituted cyclobutylmethyl Grignards have been describedI8’ and magnesium metal in methanol solution has been used for the conjugate reduction of a , @-unsaturated esters.82 Ultrafine calcium particles have been used to prepare organocalcium halides from alkyl halides. Although this method overcomes some of the problems often associated with organocalciums, the limitation of this new procedure will be the availability of the purified calcium particles.83 Zinc and Mercury. - New methods for the preparation of reactive forms of zinc broaden the synthetic applications of this metal. The use of a Zn/Ag- graphite reagent, prepared from C8K and ZnC12/AgOCOCH3, allows the Reformatsky reaction to be carried out efficiently at low temperatures.84 The same reagent has in addition been shown to be more effective than Rieke zinc for the conversion of furanosyl and pyranosyl halides into glycols.85 A reductive McMurray-type dicarbonyl coupling of certain aryl and a,@-unsaturated carbonyl compounds to give alkenes may be accomplished using zinc in conjunction with Me3SiC1 .86 This reaction does not however proceed via a McMurray-type pinacol intermediate, which was demonstrated to be stable towards deoxygenation under the conditions used.
~
Knochel and Normant have demonstrated that functionalised allylzinc reagents undergo a regiospecific addition to terminal alkynes to give 1,4-dienes (126) in moderate to good yield (Scheme
General and Synthetic Methods
468
'q 'q
RCH=CH CH2ZnBr
e.g.MeSSMe
~
R
f
W
ZnBr
R'
(127) M=Li,MgX ,AIR';
' R'
then &Br
SMc
M
(128) Scheme 38
ZnI Et02C
(130)
Me
mMeMe p
OH
r - a ' - M e Y
e HgC I
Reagents
I , H ~ ( O C O C F ~ ) ~ , C H ~NaCl C I ~/ H , ~2 0~ , ~ 1 1~, L1AIH4
Scheme 39
?~V
OCO.CF3
,,
OH
OH
Me (135)
469
6: Organometallics in Synthesis
37) .87 The same research group has extended their studies in the area of mixed organometallic reagents. Variously substituted ally1 zinc reagents (RCH=CHCH2ZnBr) add to alkenyl lithium, magnesium or aluminium derivatives (127) to give the mixed germinal diorganometallic species (128). Each carbon-metal bond can then be used to functionalise the product further, by selective reaction with 88 a variety of electrophiles (Scheme 38). Reformatsky reagents react with allylic halides or acetates in the presence of a palladium (0)catalyst (Pd(Ph3PI4) to give y , 6-unsaturated esters.89 Coupling reactions of the useful organozinc reagents (129) and (130) have also been examined.
Once again, using a
palladium catalyst, (129) and (130) both undergo coupling with vinyl iodides and vinyl triflates. The coupling step is stereospecific in terms of the retention of alkene geometry, and aryl iodides have also been successfully employed in this sequence. The stereoselective coupling of polyf luoroalkenyl zincs have also been studied. The application of dialkylzincs in the area of asymmetric synthesis continues to receive attention. Noyori and co-workers have made a survey of chiral a-aminoalcohols capable of activating the addition of either Et2Zn or Me2Zn to aldehydes. The camphor-based ligand (131) appears to be very promising and good optical yields ( > 90%e.e.) have been observed.92 Many of the publications concerning organomercury derivatives have been full papers, describing, in detail, earlier preliminary reports. Factors affecting the diastereoselectivity observed in the protiodemercuration of a-mercurioesters (132) have been more clearly defined. Reduction of (132) using NaBH4 was earlier shown to give the threo-product (133), but the stereoselectivity (erythro vs threo) has been shown to be highly dependent on the amount of NaBH4 used. Other i hydride sources, e.g. NaBH3CN, LiA1H4, Bu2A1H, are also effective. 9 3 Studies relating to the nitratomercurati~n~~ and bromo (or iodo) mercurationg5 of alkenes have also been described. These represent useful methods for the functionalisation of C=C, and aspects of the mechanisms of these reactions have also been discussed. HgC12 in conjunction with I2 has also been shown to be a useful reagent for the direct and regiospecific synthesis of a-iodocarbonyl compounds from the parent aldehyde or ketone.96 Russell and co-workers have described the photostimulated reaction of both R2Hg and RHgCl with alkynes and electron-deficient alkenes.
Alkynes such as
P-SQ(Q=SO2Ph,I,SPh) undergo substitution rather than addition reaction with organomercurials.9 7
470
General and Synthetic Methods
pcq. K +
O X 0
100% e.e.
Q
-7+
COCH2P h
croH COCHzPh
89 "1, e e Reagents
( - ) - diisopinocampheylborane,( Ipc213H)then MeCHO , ii, H ~ o ~ / ~ H I ,
Scheme 40
47 1
6: Organometallics in Synthesis
An interesting development relating to the stereospecific oxyrnercuration of cyclopropanes has provided an entry into e.g. (134) or (135)148 possessing alternating hydroxyl and methyl residues (Scheme 39). This relies on a combination of the hydroxyl-directed cyclopropanation of an allylic alcohol, followed by a stereospecific o x y m e r c u r a t i o n l r e d u c t i o n sequence.98 3
Group I11
Boron. - As in previous years, organoboron chemistry has seen a considerable level of activity. Several review articles have appeared in 1986 that will be of use to organic chemists.
In addition to a
general review of recent aspects of boron in organic synthesisIg9 a discussion of chiral organoboranes has appeared. loo Brown has also produced a series of review articles that have been designed, "in the light of the flood of publications in the area, to make organoboron chemistry more available to practising chemists". These articles do, for the most part, focus on results from the author's own group, and Some interesting and unusual aspects of cover a range of areas."' organoboron chemistry have been illustrated by Corey in the stereospecific syntheses of
g-
and Z-y-bisabolene.
Reagent chemistry based on boron has seen some advances. Tetraethyldiboroxane, (Et2B)20, has been used to assist the cleavage of di-t-butylmethylsilyl ethers, and fl-bromobis(dimethylamino)borane (136) effects the ring-opening of terminal epoxides to give 1-bromo-2-alkanols.lo4 Reetz has used the optically active Lewis acid (137) as a catalyst in the enantioselective addition of silylenol ethers and of Me SiCN to aldehydes.lo5 3 Reducing agents, both boranes and borates, have already found widespread use in a variety of situations, but new reagents and advances in asymmetric reduction continue to be developed. A convenient new synthesis of potassium trisisoamylborohydride (KSia3BH) is based on the catalytic effect of (PriO)3B.106 The hexylchloroborane complex (137) has been compared to both thexylborane and diborane as a reducing agent towards a wide range of functional groups.lo7 Further details have appeared relating to the asymmetric reduction of dialkyl ketones using CR_,E) or (S,S)2,5-dimethylborolane (138). This reagent is unreactive towards terminal alkenes, so it was surprising that reduction of the isostruchiral carbonyl function is a facile process. Masamune has shown that the mesylate derivative (139) (generated from (138) and methanesulphonic acid) plays a key role.
General and Synthetic Methods
472
This species acts as a Lewis acid and in the absence of (1391, very low optical yields ( < 4% e.e.) were observed.The degree of asymmetric induction in the reduction step was also shown to be dependent on the concentration of (139). Computational studies relevant to the proposed transition state for the asymmetric reduction step have also been discussed.lo8 Chloroborane (140), known to reduce aralkyl and heteroaralkyl ketones, also reduces a-tertiary alkyl ketones in 84-96% e.e.lo9 These ketones, e.9. 2,2-dimethylcyclopentanone or 2,2-dimethylcyclohexanone, are in general unreactive towards the more
-
usual 'Alpineborane' reagent. The reducing properties of a series of 9-alkoxy-9-BBN derivatives, prepared from 9-BBN and a chiral alcohol
(3 (+)-menthol, ( - ) -isopinocampheol) followed by treatment with KH For instance, the glucofuranosyl have been briefly examined.'" in 7 8 - 1 0 0 % e.e. and derivative (141) reduces aralkyl ketones'" a-hydroxyesters have been obtained in up to 98% e.e. S y reduction of an a-ketoester112 with (141). A new method for the synthesis of methyl and dimethylborane has appeared,'13 and full details relating to the synthesis of triorganylboranes using a modified organometallic approach have been described. This involves the reaction of an alkyl/aryl/al lyl halide with magnesium in the presence of BF3.Et20, a process that is accelerated by ultrasonic irradiation. Studies relating to the stereoselective hydroboration of polyfunctional alkenes continue to appear. Various vinyl substituted pyridines, thiophenes and furans have been reacted with representative hydroborating agents, and further aspects of the hydroboration of cyclic dienes have been disclosed.'16 The asymmetric hydroboration of cyclic enol ethers and enamines (heterocyclic alkenes) provides access to the corresponding oxygenated heterocycles with good levels of optical purity (Scheme 40). Brown has also extended his studies concerning the use of (EJ-(1-substituted-1-alkeny1)boronic esters (142) to the stereoselective synthesis of lI2-disubstituted alkenes and the oxidation of (142) to give ketones.l18 The related vinyl dimethoxyboranes (143) have also been shown to be of value in the stereoselective synthesis of 5- and 3- disubstituted vinyl bromides. The generation of (143) involves the addition of either RIB(Br)H to a 1-bromo-1-alkyne (RCECBr) or Br2BH to an internal alkyne (RCZCR') . Some interesting developments concerning C-C bond formation using organoborane coupling reactions have been made. 9-Alkyl-9-BBN derivatives (144) react with aryl and benzyl halides in the presence of transition metal catalysts and carbon monoxide to give
473
6: Organometallics in Synthesis
/ 7 -
RCO. R ’
(144)
Ar-R Reagents
I
, 5 ‘I. PdCIz( PPh3)2, Zn ( a c a c ) * , THF, HMPA, CO, R’X , Pd, bis r ( diphenylphosphino) ferrocenyl C12, e i t h e r M e T B A r A r I
11,
Me
Scheme 41
‘0
(146)
?H
Me (148)
( 150)
Reagents : i , MeCHO, t h e n H20, OH
Scheme 42
474
General and Synthetic Methods
0
?H
OH
Scheme 4 3
'N-SR H
(157)
R
OH
(158)
Ryq?+ HO HO
Scheme 44
Me
6: Organometallics in Synthesis
475
unsymmetrical ketones, 120 and a palladium (11)-catalysed coupling reaction of (144) with aryl and 1-alkenyl halides has also been observed121 (Scheme 41). It has been known for some time that (144) will, in the presence of base, alkylate, or arylate (R=Ph) a-halo nitriles, esters and ketones. Brown has now extended this reaction to include the 9-alkenyl derivative (144; R=E-CH=CHR1) and this provides a useful entry into 6,y - unsaturated nitriles, esters and ketones. 122 Trisubstituted alkenes have been obtained by the palladium (11)catalysed coupling of (1-alkyl-1-a1kenyl)boronates (145) with aryl, alkenyl and allyl halides,123 and related methods have been used to achieve the stereospecific synthesis of (E,E) -;(E,Z) - and (Z,z) 1 ,3-dienes.124 Both Brown and Matteson have made substantial contributions concerning the one-carbon homologation of boronic esters .-e.g. (146) using either LiCH2C1 or LiCHC12. Both research groups have now reported additional progress in the area and new procedures have been developed with an emphasis on the in situ generation of the highly reactive halomethyl lithium reagents. 125 Limitations on space prevent a more detailed discussion of these improvements. The use of optically pure (146) to prepare chiral amines has also been described. Allylation of aldehydes and ketones and related electrophiles using allyldialkylboranes continues to stimulate interest, especially within the context of asymmetric synthesis.
All four possible
diastereomeric 6-methylhomoallyl alcohols corresponding to (149) and (150) may be prepared in a highly selective manner using either or E- crotyldiisopinocampheylboranes (147) and (148) and by controlling which enantiomer of a-pinene is used to prepare the chiral organoborane (Scheme 42) A related study has been reported by Roush who has used the diisopropyltartrate - modified (&)-crotylboronates (151) and their reactions with chiral aldehydes.128 The reactivity of the related Ipc2 derivatives A further extension of this area (152-154) has also been exarnined.12'
z-
involves functionalised allyl nucleophiles and a-heteroatom substituted allylboronates (155; X=Br, Cl, Me3Si, OMe, SR') add to aldehydes to give homoallyl alcohols (156), in which the (7,J-isomer predominates. These products have found synthetic applications (Scheme 43) and the factors controlling the 2-156): E-(156) isomer ratio have been studied.13' Very high levels of asymmetric inductions have been observed in the reaction of 9-allyl-9-BBN (144; R=CH2CH=CH2) with chiral imines131 and addition of a1 lylboronates to sulphenimides
476
-
General and Synthetic Methods
Br
I
7
Rw er
%GR,, R
(160) Reagents
i , A l , HC(OR')3,Et20,
-
8 0 ° C ; ii,Al,R"CH(OR')2,
Scheme 45
(162) R e a g e n t s : i, B u " L i ,
R X ; ii, B ~ i A I ~ ~ g ~ Ci i 3i , , - 7A8 ° Cl
Scheme 46
Et20
6: Organometallics in Synthesis
471
(163)
I
(165)
R (164)
SiMe3
-
/SiMe3
RI
DMF or HMPA
N i B r I, (168)
(169) Scheme 47
Reagents
I,
DIBAI; i i , M e L i
( 3 e q u i v a l e n t s ) , t h e n H + , III,H+
Scheme 48
478
General and Synthetic Methods
(157) gives the synthetically useful homollylsulphenamides (158).132 Chiral allenyl boronic esters (159) add efficiently to both aldehydes and 6-hydroxyketones with high levels of stereoselectivity/ stereospecificity (Scheme 44). Both ( + ) - and (-)-tartrates may be used to provide the enantiocomplementary products. 133 Aluminium and Thallium. - A new synthesis of triethylaluminium (as its diethyl etherate complex) has been achieved by ultrasonic irradiation of a suspension of aluminium and magnesium in an ether solution of bromoethane Organoboranes have been shown to be effective catalysts for the hydroalumination of alkenes; transition metal catalysts have previously been used to overcome the weak affinity of alanes towards alkenes. With either RB(OH)2 or R 3 B as the catalytic species, small amounts of water also enhance the rate of addition.135 Several new aspects of organoalane chemistry have been described this year. Orthoesters react with alanes, prepared from a variety of ally1 and propargyl halides, to give the corresponding B,y-unsaturated acetals (Scheme 45). Interestingly reactions involving acetals rather than ortho esters lead exclusively to the formation of allenic ethers (160) Allylic sulphones can be activated towards displacement by alkenylalanes using a Lewis acid (AlC1 ) .137 With e 2 (161) the 3
anion-stabilising effect of the sulphone can be used to introduce an additional alkyl substituent prior to A1CL3-catalysed displacement. The overall process can be considered in terms of the hypothetical equivalent ( 1 6 2 ) (Scheme 46). Tri-cis-myrtanylaluminium ( 1 6 3 ) can be prepared and has been shown to be effective for the asymmetric reduction of prochiral ketones; optical yields of 24-98% ee were obtained.73 Tri (isobutyl)aluminium has been used for the asymmetrisation of both meso- and racemic ketones, V J their chiral acetal derivatives (164) and (165).1 3 8 Diisobutylaluminium hydride (DIBAH) efficiently reduces a,a-unsaturated carbonyls in a 1,4-sense using methyl copper ( I ) as a catalyst. This reagent combination is highly selective and will not reduce saturated ketones and esters. Relatively little work has been published in the area of organothallium chemistry this year. Vinyl ketones have been shown to undergo efficient arylation, leading to 6-aryl ketones, when treated with ArTl(OCOCF3)2 in the presence of a catalytic amount of Li2PdC14. Tetrahydrofurans have been prepared by cyclisation of olefinic alcohols, and results relating to hydroxyterpenes have now
479
6: Organometallics in Synthesis
R
(173) R' = Ph (174) R' = Me
(171) R'= Ph (172) R'= Me
Si Ph Me2
4
Si PhMe2
SiPhMe,
SiPhMe2
'+iH;
+~CUI
&R
R
(176) Reagents i , ( P h M e 2 S I I 2 C U L L , THF, - 7 8 " C , R'COCI , cyclohexenone
ii,
electrophlle ( E ' ) ,
e.g.HC, R'X,
Scheme 49
PhMe2Si
, ,CO, H
O L ~ steps
Y Si Me, Ph
R
(177) PhMe2Si
OBn
R
(178) Reagents
i , Me2NCH(OMeI2, h e a t , i i , P h S O Z C l , p y r l d l n e , t i t , c o l l i d l n e , h e a t ( c l e a v a g e of
p - lactone) Scheme 50
General and Synthetic Methods
480
been described.14' 4
Group IV
Silicon.- There appears to be no diminution in the level of interest shown by organic chemists towards orqanosilanes, in terms of both their preparation and synthetic utility.
This section has been
divided into several parts for the convenience of the reader, but this division may on occasions appear to be arbitrary,since it is often difficult to make clear distinctions between the different types of orqanosilanes based simply on their reactivity. Allyl, Proparqyl, and Benzyl Silanes.
-
Several new procedures for the
preparation of allyl silanes have appeared.
Iridium (11) and rhodium (I) catalysts are effective in isomerising alkenes (166) to allyl
silanes (167). Yields are very good and high levels of usually obtained. 142
E-
( 1 6 7 ) are
Transition metal catalysts have been applied to
allyl silane synthesis in other ways.
The n-ally1 nickel complex
(168), which is readily prepared from 3-bromo-2-[trimethylsilyl)methyllpropene, reacts with alkyl halides to give the substituted allyl silanes (169) in 76-100% yield (Scheme 47)
The reduction of the
alkynylsilanes (170) provides a versatile entry into various orqanosilanes, including allylsilanes (Scheme 48).
The -Si(Me)2CH2C1
residue was incorporated into (170) to provide a higher level of selectivity in the hydroalumination step.
In hydrocarbon solvents
this is a consequence of chelation of -C1 to the aluminium centre. Vinyl silanes have also been prepared in this way.144 Optically active allyl silanes (171) and (172) have been prepared in up to 95% ee by cross-coupling of the Griqnard reagents (173) and (174) with alkenyl halides in the presence of a chiral ferrocenylphosphinepa 1 1 adium complex. The silyl-cupration of allenes has been shown to be a reliable source of both allyl and vinyl silanes (Scheme 49).
Simple alkyl-
substituted allenes lead predominantly to allyl silanes, while phenyl substitution on the allene, and allene itself, react to give vinyl silanes.
The intermediate organocopper
derivatives (175) and (176)
may also be trapped by alkyl and acyl halides, and enones to provide more highly functionalised 0 r g a n o s i 1 a n e s . l ~ ~Fleming has also described the use of diastereoselective aldol condensations of 0-silyl enolates, generated by addition of !PhMe2Si) CuLi to an a,B-unsaturated 2 ester, for the stereocontrolled synthesis of both g- and g-
48 1
6: Organometailics in Synthesis
f SiMe3 Me+;
0 \
CO.R
(179) R = M e (180) R = OMe Scheme 51
General and Synthetic Methods
482
SePh
R
0
SiMe, Rj+SePh
(181)
OH
Reagents
I,
RNH2, CF3C02H, HCHO, H20 ; R
= a l k y l , benzyl
Scheme 52
0
0
0
Scheme 53
6: Organometallics in Synthesis
483
allylsilanes (Scheme 5 0 ) . The level of diastereoselectivity observed in the aldol reaction was usually about 9:l and the major isomer (177) could be converted to either the E- or g- allylsilane. The isomeric enolate (178) was also available (see below) and provides a complementary reactivity.1 4 7 Electrophilic attack on allyl silanes represents one of their most commonly used modes of reaction. The relative reactivity of allyl silanes and alkenes towards diarylmethyl cations has been used to calculate the value of the 6- effect of a trimethylsilyl group. The introduction of a 8- SiMe3 residue increases the reactivity of an alkene towards Ph2CH by a factor of 30700, and the stabilising 8effect has been estimated at approximately 4.2 kcal mol-'. 148 Trost et al. have prepared the silyl-substituted trimethylenemethane precursors (179) and (180) In general the reactivity of these systems, in the presence of a palladium catalyst, parallels that observed with more straightforward trimethylenemethane complexes, but surprisingly, the nature of the oxygen substituent (R=Me or OMe) has a profound effect as illustrated (Scheme 51). Allyl silanes undergo a TiC14-catalysed addition to nitroalkenes to give y,6-unsaturated nitronates, which may be converted to ,6-unsaturated nitriles by reduction with low-valent titanium.l5O
y
The selenyl-substituted allylsilanes (181) react with acid chlorides (R'COCl) to give synthetically useful y-acylated vinylselenides (182) and a general cyclopentannelation procedure based on this conversion Nitrogen-containing heterocycles have been has been reported.15' prepared in aqueous solution by the addition of allyl silanes to simple iminium salts derived from primary amines (Scheme 52). Secondary amines react to give tertiary homoallylic amines (cf.(183)) but this is a slow reaction.152 Allyl silanes (184), derived from
,
6-ketoesters undergo a chelation controlled cyclisation using TiC14 (Scheme 53) This type of intramolecular chelation control promises to be a useful entry into stereodefined carbocycles. Majetich has published further on the intramolecular addition of an allyl silane to an enone, catalysed by fluoride ion.154 This also represents a useful cyclopentannelation method and the advantages of - catalysis over the use of Lewis acids have been discussed. F Cyclopentyl derivatives have been obtained using the functionalised allyl silane (185), which reacts with silyl enol ethers to give ultimately, a mixture of (186) and (187) (Scheme 5 4 ) The reactivity of the allylic anion derived from (188) has been examined. 156 Deprotonation with ButLi, followed by carboxymethylation
484
General and Synthetic Methods
Rao HO
@Y
SiMe2 Ph
R
(188) R = H (1901 R = C 0 2 M e
Reagents
'
i . R C H O , BF3.Et20, CH2C12
Scheme 5 5
Si Me3
(1931
MegSi
51me3
SiMeg (1941
LtAIHL, ___)
(1961
Scheme 56
(195)
R"
SiMej
6: Organometallics in Synthesis
485
leads predominantly to the y-adduct (189). This regioselectivity can, however, be reversed by the addition of Et3A1 to the lithium anion to give a- adduct (190).
A
wide range of electrophiles react with (190)
and this species may be regarded as an equivalent of anion (191). The electrochemical oxidation of allyl and benzyl silanes in the presence of an alcohol leads to the corresponding allyl/benzyl ethers. Aryl silanes are, however, inert under the conditions used. 157 Substituted oxygen heterocycles have been prepared by the reaction of * ~i
-siloxypropargylsilanes (192) with aliphatic and aromatic aldehydes (Scheme 55) .158
A related cyclisation of an alkenylsilane to an
oxonium ion is described in the next section.
The intramolecular
addition of allyl and propargyl silanes to enones using a Lewis acid (intramolecular Sakurai reaction) continues to be developed and further regiochemical studies have appeared. Vinyl, Alkynyl and Allenylsilanes. - Reference has already been made
A
to new syntheses of vinyl silanes in the previous
silver (I)-catalysed Heck-type arylation and heteroarylation of vinyl trimethylsilane and vinyltriethoxysilane has been achieved. 160
This
extends an earlier report in which desilylation to give styrenes was the predominant course when the reaction was carried out in the absence of Ag(1).
Vinyl silanes have also been prepared by the
reaction of alkenes with triethylsilane and a catalytic quantity of with allylic hydrogens tended to give mixtures of R U ~ ( C O ) ~ Alkenes ~. allyl and vinyl silanes.161 Silylated dienes have attracted some interest this year. Trost has described his attempts to prepare 2-(trimethylsilyl)buta-lI3-diene (193) by a Pd(0)-catalysed elimination of acetic acid from (194).162 It proved impossible to actually isolate (1931, since it readily dimerised under the reaction conditions to give (195). However, when the elimination
step was carried out in the presence of a suitable
dienophile,e.g. - vinyl ketone, diene (193) was efficiently trapped.
A
series of substituted 2-(trimethylsilyl)buta-l,3-dienes have been prepared by reduction of the readily available allenyl alcohols (196) (Scheme 56) .163
The vinylboranes (197) react with allyl halides and
1-halo-1-alkynes to give silylated 1,4-dienes (198) and enynes (199) in good yield.164
Vinyl boranes were known to couple with organic
halides in the presence of Cu(acac)2, but CuI proved to be a more effective catalyst in this study.
486
General and Synthetic Methods
+
wSiMe3
SiMej
'R'
SiMeg
(200)
Reagents: i. CIZnCEC-SiMe3.
Pd(Ph3P)&
Scheme 57
1
9
,R -
R
20
80 1
R -SiMe3 -%L
-R
' I
R
95 Reagents: i, 1 2 , SnClr, ( 3 equivalents) ; i i , I2 , AIC13( 0.2 equivalents)
Scheme 58
5
6: Organometallics in Synthesis
487
PhMe2Si
SiMe3
M
M = Li (202) M = MgBr
(201)
(203)
1 : 1 Mixture Reagents: i , TiClL
or
S n C I 4 , CH2C12 , - 2 O ' C
Scheme 59
...
I
SiMej
Reagents: i . Bu"Li. - 8 5 ° C ; ii, KH; i i i , BF3.Et20
Scheme 60
General and Synthetic Methods
488
Two new syntheses of 2,3-bis(trimethylsilyl)buta-lI3-diene (200) have been developed, and the reactivity of this diene in cycloaddition reactions was also e ~ a 1 u a t e d . l ~ ’ Silyl-cupration of alkenes is a useful route to vinylsilanes and the influence of the steric bulk of the silyl residue on the distribution of possible products has been investigated.166
The transition metal-catalysed silylboration of alkynes to give vinylsilanes has been achieved using (PhMe2SiBEt3)Li in the presence of methanol as a proton source.
This reaction has
been applied to the synthesis of vinylstannanes and the Kyoto research group has also described, in full papers, details of the silylzincatiori and silylalumination of alkynes as a highly stereoand regioselective entry into vinylsilanes.167 1-Silylalkynes have been obtained by a Pd(0)-catalysed coupling of trimethylsilylethynylzinc chloride with alkenyl halides (Scheme 57)
Interestingly,
E- bromoalkenes react preferentially when a E / j
mixture of isomers is used. Vinyl halides may be prepared by halogenation of vinylsilanes but Chan has shown that the stereoselectivity of the Lewis acid-promoted iododesilylation of terminal E-vinylsilanes to give Eor
2-
1-iodo-1-alkenes is highly sensitive to the amount of stannic
chloride used (Scheme 58).
This provides a useful, ‘tunable‘ entry to
these iodides and the process has been applied to the synthesis of two insect pheromones with defined
E/z isomeric ratios.16’
Vinyl anions derived from vinylsilanes have continued to develop as useful synthons.
The lithio derivative ( 2 0 1 1 , prepared by lithium-
bromine exchange shows an excellent level of stereointegrity if kept below 0°C and reacts with a wide range of electrophiles.
The
organomagnesium derivative (202) was also examined but this anion shows a higher propensity towards E/_Z_isomerisation.1 7 0 Configuration instability is a drawback to the use of anions such as (201) and (202) and Negishi has made a study of the structural and mechanistic The fluorinated features responsible for these isomerisations.17’ vinyl silane (203) has found applications in the synthesis of substituted chlorof luoroalkenes Cyclisations of vinyl silanes to oxonium ions, generated by the action of a Lewis acid on an acetal, provides a flexible route into unsaturated oxacycles (Scheme 59;
cf.
Scheme 55158),173 A high degree
99.5%) of stereospecificity was observed but mixtures were obtained in the case of medium-sized rings. Overman has also reviewed the use 174 of vinyl- and alkynylsilane-terminated cyclisations in synthesis. (>
Stereochemical aspects of the silicon-directed Nazarov
489
6: Organornetallics in Synthesis
/UORI*
PhMeZSi
R
P hMe2S i
= R' =
(2051 R '
M e ; R " = Li
(2061
Li
; R" =
(207)
Me
(2091
(2081
Reagents: i , RCu, EtAIC12 ; i i , LiOH,CH2N2 ; iii,HBFc,, m-CPBA
Scheme 61
0
(2101
0
(2121 Reagents: i, Bu"Li, -1OO'C ; ii, CIzCHOMe. -100°C
t o room temperature ;
iii. Bu*Li, TMEDA; i v , CH212 , Zn. AgOAc ; v.CrO3, p y
S c h e m e 62
General and Synthetic Methods
490
cyclisation have been investigated,17'
and some interesting
observations relating to the bulk of the silyl residue in these
'
processes have been made. 76 A stereocontrolled entry into congugated silylalkynes has been based on a combination of the highly diastereoselective (2,3)-Wittig rearrangement followed by the stereospecific fragmentation of the intermediate hydroxysilane (204) (Scheme 60) . 177 A Wittig rearrangement using vinylsilanes has also been used to prepare a key intermediate for leukotriene synthesis. 178 Other Silicon-containing Reagents.
-
Useful reviews of the chemistry
of silyl-substituted c y c l ~ p r o p a n e s land ~ ~ the application of a-silyl onium salts to the generation of reactive ylides18' have appeared. have already seen some applications of 6-silyl enolates to ally1
We
silane chemistry.147 Fleming has demonstrated methods of generating the isomeric enolates (205) and (206), together with their synthetic The influence of the 6-silyl applications in 6-lactam chemistry.18' group on the regiochemistry of enolization of ketone (207) has been studied. Deprotonation (LDA) is favoured away from the silyl residue and this is thought to be primarily a steric effect.182 Enantiomerically pure 6-silyl esters have been prepared by EtAlCl2promoted addition of organocuprates to the camphor derivative (208). Esters (209) were used to prepare chiral 8-hydroxyesters (Scheme 61) . la3 A silapinacol rearrangement of a , 6-dihydroxysilanes gives a-silyl aldehydes and ketones. The trimethylsilyl derivatives usually desilylate under these reaction conditions but the more stable ButMe2Si- analogues (210) have been isolated.184 a-Trimethylsilyl ketones react in good yield with electrophiles (Br2, PhSC1, PhSeBr) and ZnBr2 to give the a-bromo, a-phenylthio and a-phenylseleno ketones respectively. la5 Two useful syntheses of cyclopropyl acyl silanes have been reported (Scheme 62). In a process that involves lI2-silicon shift, cyclopropyl acyl silanes (211) may be prepared in moderate yield.186 Lewis or protic acid treatment of ( 2 1 1 ) leads to either acyclic acylsilanes or 2-trimethylsilyl-4,5-dihydrofurans. The alternative approach to these acylsilanes to appear this year is based187 on the cyclopropanation of the hydroxyallylsilane (212), the product of a (lI2)-Brook-type rearrangement. a-Trimethylsilyldiazoalkanes (213), prepared by alkylation of a-lithio-a-trimethylsilyldiazomethane, are readily oxidised by peracid to give acyl silanes.188 a-BromocyLsilanes (214) have been obtained from 1-trimethylsilyl-1-alkynes by
6: Organomerallics in Synthesis
49 1
MegSi SiMeg
R
0 (214)
(213)
0 R
~ ~ S i M e 3 R'
A
C
YOsiMe3 Rt
Prji/Prl
(216)
hR XR, I UR, /
'H
i
R
R
R
L
Scheme
63
OH
General and Synthetic Methods
492
0 MejSi
(217)
n
= 2,3,4
(218)
0
Ph
~c
-sI ?A co H I
R (220) R = Et or CH2Ph
(2191 Ph M e -S
I I
NH 2
R
E t or CHZPh
(221) R
E t 2Al
SnBu"3
AlEt2
(2221
(223) I
SnMeg
___)
SnMeg Reagents: i . Me3SnLi ( 2 equivalents), - 7 8 ° C
Scheme 64
493
6: Organometalks in Synthesis
hydroboration/oxidation followed by bromination of the intermediate borinate ester with N-bromosuccinimide.
Acetylenic acyl si lanes
(215) have proven to be a useful source of the otherwise relatively rare allenyl silyl ethers (216). I 9 * The synthetic utility of these reactive ethers has been explored but a lack of space here prevents further discussion. Directed hydrosilyation reactions have seen further advances this year. A number of 6-hydroxy ketones were reduced to &-1,3-diols by a process that presumably involves an intramolecular transfer of a hydrogen atom from silicon to the carbon group (Scheme 63) .Ig1 Diisopropylchlorosilane is an attractive reagent particularly in terms of its stability when compared to other dialkylchlorosilanen. The intramolecular hydrosilylation of allylic and homoallylic alcohols and the subsequent oxidative cleavage of the initially formed C-Si bond provides a regiocontrolled synthesis of 1,2- and 1,3-di0ls.~~~ The homoallylsilanes (217) undergo an efficient intramolecular acylation, using TiC14, to give 2-cyclopropylcycloalkanones (218).193 Triphenylsilane has been shown to be a useful reagent for the free-radical deoxygenation of secondary alcohols
via
their
acetates. Following on reports over recent years chlorotrimethylsilane has also been shown to accelerate the conjugate addition of both stoichiometric and 'catalytic' organocopper reagents.
The use of
HMPA or 4-dimethylaminopyridine ( D M A P ) is also beneficial under these circumstancesIg5. l3-Trimethy1si 1 ylethanesulphonyl chloride ( SES-C 1) (219) has been advocated as a new amine protecting group.lg6 It is readily prepared by the addition of sodium bisulphate to vinyl trimethylsilane, followed by reaction of the adduct with PC15. Sulphonamide deprotection is facile with CsF in DMF. The optically pure organosilanes (220) and (221) have been prepared €or use in determining the optical purities of alcohols or amines and carboxylic acids respectively.197 Tin and Lead. - New organtin derivatives that have been used to gain access to useful organolithium reagents by metal-metal exchange have already been described under "Group I". Despite the importance of this lithium-tin exchange, the mechanism of this process is still to be fully understood. Evidence has, however, been obtained for the discrete formation of unstable 'ate' complexs [ (R4SnR')-Lit] as intermediates. The Cu(1)-catalysed stannylalumination of 1-alkynes has been
General and Synthetic Methods
494
RXR'
R 20
SnMej
SnMe3
R-'
= - - CO.NMe2 &
R'X
Me3Sn
((2) - i s o m e r
not observed)
CO.NMe2
Reagents. i . Pd(Ph3P)4.(Me3Sn)2.THF: ii, h e a t . 75-90T.6-48h
Me3Sn
ec,
Scheme 65
C02Me
C02Me
SnMe3
SnMe? ( 227 1
(226) M
U
o
m
R
~ u " 3 ~ n
(€1
(228)
-
(229)
( Z )- (2291 OSi R3
I
0,
S~BU"~ (231 I
(230)
w -+Qp OSiMe3
OMe
Reagents: i,(Me0)2CHCH2CH2SnMe3(232), Me3SiOS02CF3 ( h e n TiCIL,
Scheme 66
11,
P D C , PY
495
6: Organometafficsin Synthesis
shown to be a reversible process, with the 1-stannylalkene (222) being the kinetically favoured regioisomer, but the 2-isomer (223) was thermodynamically more stable.
These intermediate alanes can also be
trapped by various electrophiles leading to a range of vinyl stannanes. lg9 The direct replacement of -SO2Ph from vinyl sulphones by BujnSn- under free-radical conditions leads to vinyl stannanes in 58-78% yield."' This follows on from an earlier observations by Julia that Bu3SnH effects the E / z isomerisation of vinylsulphones. 1,l-Distannyl-1-alkenes can be prepared from 1,l-dibromo-1-alkenes (Scheme 64). Temperature control is important for the success of this procedure and attempts to extend this to include 1,2-dibromo1-alkenes failed.201 A general synthesis of trisubstituted vinyl stannanes has been reported that is based on the use of the borane (224) as an effective equivalent of (225). An extension of this chemistry also makes tetrasubstituted alkenes available in a stereocontrolled fashion.202 Functionalised vinyl stannanes have been prepared by the Pd (0)-catalysed addition of (Me3Sn) to a , 6-acetylenic esters and amides and some interesting observations have been made concerning the distribution/stability of the possible products (Scheme 65). Piers has also explored some of the chemistry of these adducts and, for example, reaction of (226) (prepared according to Scheme 65) with MeLi leads to the cyclopentene (227) in 69%.203 The Petersen reaction has again been applied to the synthesis of vinyl stannanes this year204 and a high level of stereoselectivity has been observed in the addition of (Ph3Sn)3Zn to 1-alkynes, leading to vinyl stannanes.205 Following on from last year, the enophilic properties of (228) have been examined. The value of the resulting cycloadducts lies in the ability to manipulate the vinyl stannane moiety.206 The Barbier-type coupling of Bu3SnC1 with allylic halides is a useful entry into allyl stannanes and it has been shown that this reaction is accelerated by ultrasonic irradiati~n."~ Two isomeric B-stannyl enolates (229) have been used for the stereospecific synthesis of allyl stannanes in a fashion analogous to that developed for allyl silanes (cf.Scheme 50) .208 Addition of silylstannanes to enones leads to the useful silyl enol ethers (230), which are synthetically equivalent to the cyclohexanone a , 6-dianion (231).209 The bifunctional annulating reagent (232) has now been used, in conjunction with silyl enol ethers, to prepare spirocycles (Scheme 66) .155 The reaction of Me3SnCH2Li with esters (R'C02R') provides a
496
General and Synthetic Methods
0 &SnMeg
R'
ii0 (233)
( 2 3 4 ) X = OEt ( 2 3 5 ) X = NHAr
ljy
CO 2R
B u"3 S
Bu5Sn
n
n N R2
R *'
(2361
(237)
dNHPh __3
Sn B u " ~
R
(239)
'
(238)
//NPh
Nx R
Reagents : i, NBS or lead tetraacetate; ii, SnCIz
,
R
heat
Scheme 67
major OH
Reagents: i , R C O R ' , Pb, Bu"qBr.CISiMe3,DMF.
t h e n H'
Scheme 6 0
Scheme 69
minor
6: Organometallics in Synthesis
497
useful entry to methyl ketones. The initial adduct (233) is presumed to react with a second equivalent of Me3SnCH2Li, undergoing a second Li-Sn exchange, to give the enolate of the methyl ketone.
This
enolate was usually protonated on work-up but may also be trapped by aldehydes/ketones.210 Baldwin has shown that the methacrylyl moiety may be transferred under mild free radical conditions using ally1 stannane (234).211 This reagent, and the related derivative (235), have also been employed, as an equivalent to (236) to prepare a range of a-methylene-ylactones. 212 Stannanes (237) provide a versatile entry to cyclopentanoids, via the tin-directed Nazorov cyclisation,213 and (238) reacts with acid chlorides directly to give (g,~-dialkylaminomethyl)ketonesin good yields.214 Following their studies last year relating to the oxidative fragmentation of 6-stannyloximes, the same research group has now described a homolytic cyclisation of 6-stannylhydrazones (239). Using a range of oxidants, azocyclopropanes have been obtained, which can then be induced to undergo further rearrangement (Scheme 67) .215 A general synthesis of heterobiaryls has been achieved via the Pd (11)-catalysed coupling of aryl halides and heteroarylstannanes.216 Aryl stannanes have also been shown to undergo facile conversion to aryl fluorides on treatment with caesium f luorosulphate (CsS04F).217 Two useful reviews have appeared concerning aspects of transition metal catalysis in organotin chemistry. 218 The first examples of lead promoted Barbier-type reactions have appeared this year (Scheme 68).
Tetra-n-butylammonium bromide has
been shown to have a remarkable influence on the efficiency of these reactions.
Its role in unclear but the authors speculate that it is
probably involved in the generation of the active organolead species.219 Alk-1-ynyl lead triacetates (240) are prepared from lead ( I V ) acetate and alk-1-ynyltrimethylstannanes. Though unstable,(240) reacts as a alk-1-ynylcarbocation (RCZCB) equivalent with B-ketoesters to give (241) (Scheme 69) .220 5
Group V
Phosphorus. - Several developments have appeared this year in the area
of phosporus-based reagent chemistry.
A one-pot cyclopentannulation has
been achieved using 3-chloro-2-diethylphosphoryloxy-1-propene (Scheme 70).
(242)
This reagent was prepared in near quantitative yield by a
Perkov reaction involving 1 , 3-dichloroacetone and triethylphosphite.221
General and Synthetic Methods
498
( 242 1 i
Reagents: i, LDA: ii,(2&2),Pd(Ph3P)4(5 r n o l o / ~ ) ; i i i , l O %NaOH. H20. h e a t
Scheme 70
0
II
( E t 0)2P-OS02CF3
P h g k H ( 0 M c ) R 6FL
(243)
(244)
0
$: HO
R'
Reagents: i.SiButMe20S02CF3, PPh3; i i , Bu"Li.RCH0; iii,BunhNF, i v , R'CHO. Tic14
Scheme 71
(2471
(2461
0
(2481 X = CH2 (250) X = S
(251)
0
0-
II I (Et012PvS+\R
(249)
Ar H
_____+
11
(C F3COI20
Ar (252) Scheme 7 2
499
6: Organometallics in Synthesis
Methyl triphenylphosphonium tribromide (Ph3;MeBr3) has been utilized f the cleavage of 1,3-dithanes to give ketones.222 Nucleophilic displacements at carbon a to phosphorus can be problematic and phosphomethyl halides tend to only react with potent nucleophiles (RSand RSe-) Diethyl phosphonornethyl triflate (243) is readily prepared and uc of the triflate as a leaving group allows displacements to be effectec with a range of alcohol and amine n ~ c l e o p h i l e s . ~ Lithium ~~ diphenylphosphide (LiPPh2) is a useful reagent for the dehydroxylatior of a - h y d r o x y k e t o n e ~and ~ ~ ~diethoxytriphenylphosphorane (Ph30(OEt) he found use for the synthesis of aziridines by the cyclodehydration of B-aminoalcohols. 225 a-Alkoxyalkyl triphenylphosphonium tetraf luoroborates (244) are useful reagents for carbonyl homologation and may be prepared by the reaction of Ph3P with the corresponding acetal in the presence of a Lewis acid.
The method avoids the use of toxic
a-chloromethyl ethers.226 The B-functionalisation of enones can be achieved via the 'P-Si' reaction, leading to the phosphonium salt ( 2 4 5 ) . This and related species have found a number of useful synthetic applications.227 The reactivity of the stabilised ylid (246) towards aldehydes is enhanced by prior activation of the ylid by deprotonation of the 6-ketoester moiety with NaH.
High Z-selectivity is observed in the
Wittig reaction.228 Further details concerning the mechanism of the Wittiq reaction have appeared this year.229 Factors controlling the stereochemical outcome of the reaction between aldehydes and nonstabilised ylids have been discussed in light of the low temperaature n.m.r. detection of individual diastereomeric 1 ,2-oxaphosphetanes.230 Warren has described the application of the Horner-Wittiq reaction to the stereocontrolled synthesis of various unsaturated carboxylic acids. 2 3 1 The generation of 2-diphenylphosphinyl-l,3-butadiene (247) by the electrocyclic ring-opening of cyclobutene (246) occurs at 1 5 0 ° C and this diene undergoes the Diels-Alder cycloaddition with a wide range of dieneophiles.232 The two dithianyl derivatives (248) and ( 2 4 9 ) are useful for the synthesis of ketene-S,S-acetals. Both aldehydes and ketones react with (2481, but (249) shows selectivity, albeit in low yield, for aldehydes. The related derivative ( 2 5 0 ) is also described.223 a-Hydroxy phosphonic acids ( 2 5 1 ) are prepared by adsorbing a mixture of a ketone and a dialkylphosphite onto a y-aluminia/KF support.
under these conditions dialkylphoshites also
react with imines, lactones, nitriles and a,B-unsaturated esters and
General nnd Synthetic Methods
I
R
R
R
(2531 Reagents
I,
L D A . (Et0)2P(O)CI, then L D A , t i . l i t h i u m hexamethyldtsilazide(LHMDS),
then ButLi,
111,
(EtO)2P(O)CI
Scheme 7 3
0
0
II
II
pYc'R.
( E 012
R
(25LI R
= a l k y l , C I , SR"
+ HMPA.100 "C
R/\\c/
s\c
RTSiMe3 + S A Si Me3
'0MegSi-SA (257)
CI
-
(256)
CsF
(255)
Scheme 7 4
OH
SPh
Scheme 75
SPh
H2
6: Organometallics in Synthesis
50 1
reaction is effected in the absence of a solvent.234 phosphonates continues to stimulate interest.
The flexibility of
Cycloadducts resulting
from the 1,3-dipolarcycloaddition reactions of nitrile oxide (252) undergo smooth Wadsworth-Emmons reactions.23
The a-aryl phosphoryl
sulphides (252) have been prepared efficiently using a Pummerer-type
.
rearrangement of the corresponding sulphoxide (Scheme 72) 236 New routes to B-ketophosphonates have appeared based on base-promoted 0- to C-rearrangement of enol phosphonates,2 3 7 and the reaction238 of dianion (253) derived from an a-bromoketone (Scheme 73). Both routes offer significant advances in terms of the types of derivative that they made available.
Another general synthesis of
functionalised B-ketophosphonates (254) has been described.239
The
Peterson reaction has been applied to the synthesis of vinyl p h o ~ p h o n a t e s ~ ~and ' a number of other vinyl phosphorus derivatives have been obtained by the Pd(I1)-catalysed coupling of alkenyl bromides with H I Ph(0Et) P ( 0 )H or Me (OR)P (0) H.241 Ph2P (0)
A transition metal catalyst
(Ni(codI2) has been used to prepare allyl phosphonates from allyl acetates or carbonates and (3, Q-dialkylphosphonates. 242 n Antimony and Bismuth - Tri-n-butylstibine (Bu Sb) mediates the 3 olefination of carbonyl groups with a-bromoacetates (a "Sb-Wittig" reaction).
No base is required for this reaction to take place.243
Triphenylantimonyl dicarboxylates (Ph3Sb(0.C0.R)2) react with amines to give amides in good yield.244 Bismuth chemistry has seen another quite active period over the last twelve months.
For example, aldehydes undergo allylation with
allylic halides and a mixture of bismuth (111) chloride and either zinc or ion to give homoallylic alcohols.245 The oxidative cleavage of 1,2-diols using a catalytic bismuth system (Ph3Bi(l-10 mol%), NBS, K2C03, MeCN/H 0) proceeds by a different mechanism to that operating 2 with the use of stoichiometric Ph3BiC03.2 4 6 Barton has shown that aliphatic and aromatic amines and alcohols and phenols undergo O_-phenylation using Ph3Bi (0.C0.CH3) 6
and a copper catalyst.247
Group VI
Sulphur. - Useful reviews that have appeared this year include a discussion of the chemistry of a - c h l o r ~ s u l p h i d e sand ~ ~ ~ an overview of the preparation of sulphoxides by the oxidation of sulphides.249 Tertiary and benzylic nitro compounds have been converted to the corresponding sulphides using PhSSiMe
3'
250
502
General and Synthetic Methods
R
qsp. R+Rj
+
SPh
w SR y' a'
R'
(260) n = 1 - 3 ( 2 6 2 ) n = 1. R = H , R ' = SPh
(263)
R
_j,
NC
Reagents: I, PhSCI, then AgBF4
or
PhS' B F i or PhSOMe. then Me3SiOS02CF3 Scheme 76
X
-: (266) X = 0
(265) X
(2671 X = 02
(2681
(269)
503
6: Organometallics in Synthesis
Thioaldehydes continue to find synthetic applications. Full details of both the characterisation of thiopivaldehyde and the Diels-Alder reactions of a variety of other thioaldehydes have been 251 reported by Vedejs and coworkers. New methods have been developed for the generation of the reactive thiocarbonyl ylid (255) and the thioketene S-methylides (256), both of which depend on the fragmentation, by l o s s of disiloxane, of an appropriately substituted silylsulphoxide precursor.252 Fluoride-induced cleavage of chloromethyl (trimethylsilylmethyl)sulphide (257) provides an alternative route to (255)253 (Scheme 74). These reactive species were readily trapped by 1,3-dipolarophiles. Reduction of a-chlorosulphides with chromium(I1) chloride provides an (6-thioalkyl)chromium(III) reagent that is nucleophilic towards aldehydes to give O-hydroxysulphides in 48-88% yield. 254 The rearrangements of the related hydroxysulphides (258) have been shown by Warren to give ally1 sulphides, but with a degree of regioselectivity that is dependent on ring size (Scheme 75) .255 Oxidative fragmentation of the y-hydroxysulphides (259), using
N-chlorosuccinimide, occurs with ring opening, leading to the .-0x0-vinylsulphides
(260). This chemistry when applied to (261) gave
the ketene-S,S-acetal (262) albeit in only 14% yield.256 Thionium ions, generated from either an alkenyl sulphide and TiC14257 or by a Pummerer-type activation of a1 lyl sulphoxide,258 may be efficiently trapped by silyl enol ethers.
In the latter case the
thionium ion (263) is presumed to be involved and this species reacts with the nucleophilic enol ether exclusively at the y-site. New methods for the generation of episulphonium ions have been applied to the synthesis of carbocycles.
A series of conditions have
been devised for an efficient arene-alkene cyclisation, mediated by the episulphonium ion (264) (Scheme 76). Methylbenzenesulphenate (PhSOMe) in conjunction with a Lewis acid is an attractive system in that it avoids the use of silver(1) salts and does not require the aryl ring to be highly activated by alkoxy substitution.259
The cyclisation of alkenyl substituted N-tosyl anilines to give indoles or indolines has been carried out using [M~S(SMe)2BF4-,260 and a regiospecific synthesis of
E-
o r E-alkenylsulphides has been reported
based on the Ni(I1)-catalysed coupling of a Griqnard reagent with either E- or Z-l-bromo-2-(phenylthio)ethene. 261
cyc 1isation reactions involving the highly electron-deficient dienophiles (265-267) have
been investigated262 and a new asymmetric synthesis of cyclic
504
General and Synthetic Methods
Reagents: i , (Ar
p-MeCgH&), ArNa.4H20,HgC12. MeOH. ii, ArNa.4H20.12, MeOH ;
i i i , DBU; iv.CbHgN.MeCN; v.BunLi. t h e n R ' X , vi. m-CPBA,NaHCQ
Scheme 77
Arso2w SiMeg
'OR
(277)
Reagents: i.Br-SOzBr.
>OR
(278)
then Et3N; ii, ButOK
Scheme 70
6: Organometallics in Synthesis
OH
505
S02Ph
MeS&R. Ar02S
R
Mes)=Yso2Ar
R+ R'
R'
(280)
(282)
(281)
0
II
Ph-S-CHZLi
II
NSiMeg (283)
UR. dR
PhSe
pxAH (285)
-&
+
Reagents: i , (Me0)2P(O)CH2CO.R', NaH; ii, 30'/0 H202 , CH2CIz
Scheme 79
TeNa (2861
Reagents: i , ArTeBr; ii , RTeNa , heat
Scheme 80
506
General and Synthetic Methods
a-sulphinyl ketones, based on the use of an electrophiiic chirai sulphinate,has appeared.263 The participation of alkenyl sulphoxides in Michael and related additions continues to attract interest.264
Posner has reported on
the addition of ester and ketone enolates to enantiomerically pure (268) and (269).265 These Michael-type additions have also been the subject of a molecular modelling study, where both steric and electronic effects have been assessed;
the results of these calculations have been
compared to existing experimental results .266
A new synthesls of (269, n=l) and related derivatives is based on the carboxylation of the anion (270) with C02267 Chiral alkenyl carbamates, (272) and (273),269 sulphoxides (271)268 and .N-sulphinyl have been used as dienophiles and both systems show high levels of diastereoselectivity. There has been considerable activity surrounding alkenyl sulphones this year.
The 1- and 2- arylsulphonyl alkenes (274) and
(275) have been obtained by either the sulphonylmercuration or iodosulphisation o f 1-alkenes.
If allylic protons are present,
isomerisation to give allylic sulphones is facile.
a-Substituted
sulphones (276) are also available in an efficient manner (Scheme 77) .270
The silylated alkenyl sulphone (277) has been noted as an
equivalent of cation (278) in an approach to the bicyclomycin skeleton.271 a-Haloalkane sulphonyl bromides undergo free radical addition to alkenes to give adducts (279) that can be used for the ‘vinylogous Ramberg-Bsckland’ reaction (Scheme 78).
A series of polyenes, and
enones have been obtained in this way.272 The syn-hydroxy sulphones ( 2 8 0 ) are available in a highly ~
diastereoselective fashion by the zinc-promoted addition of 2-(phenylsulphony1)allylic halides to aldehydes.
The susceptibility
of (280) to conjugate addition reactions was also evaluated.273
Full
details relating to the stereoselective synthesis of sulphonylsubstituted 1 , 3 - and 1,4-dienes have been pub1 ished. 274 The addition of enamines to (phenylsu1phonyl)propadiene takes place at -50°C to qive allylic s ~ l p h o n e sand ~ ~ the ~ isomeric allylic sulphones, (281) and (282), may be equilibrated via a facile silica gel-catalysed 1,3-rearrangement.276 Functionalised sulphoximines have been prepared
the
silyl-protected organolithium derivative (283). This species reacts with a wide range of electrophiles and desilylation of the adducts
6: Organometallics in Synthesis
occurs on workup.277
507
The conjugate addition reactions to chiral
alkenyl sulphoximides occur with a level of asymmetric induction of up to 68% de but these results were sensitive to the reaction conditions used. 278 Ketene-S,S-acetals have been prepared by the Ni(I1)-catalysed displacement of 1,l-dibromo-1-alkenes with thiolates.
The same method
can also be applied to the synthesis of ketene-Se,Se-acetals.
The
limitations and scope of this procedure have been discussed.279
Other
approaches to ketene-S,S-acetals and related systems have appeared this year.280 Selenium and Tellurium. - Simple alkyl and aryl selenoaldehydes [RC(Se)H] have been generated by fluoride-induced cleavage of (284), and cycloadducts have been isolated.281
Elemental selenium catalyses
the reduction of aryl nitro groups to N-arylhydroxylamines282 and new aspects of NaSePh, relating to both its generation and nucleophilic properties have been described. 283 Hanessian has proposed the use of 3-phenylselenobutanal (285) as an efficient crotonaldehyde equivalent (Scheme 79);
when analogous
chemistry was applied to crotonaldehyde itself, low yields resulted.284
Further aspects of the use of PhSeCl for the
amidoselenation of alkenes have been described, including stereochemical features and the application of this methodology to bicycl ic 1ac tams. Livinghouse has extended his studies on episulphonium ions Scheme 76) to include the corresponding episelenonium ions.
(cf.
The
reagent of choice in this latter situation was
E- (phenylseleno)succinimide, combined with a suitable Lewis acid.286 The oxidative rearrangement of allylic selenides is a useful method for synthesising allylic amines. Recent developments, both in terms of improved procedures and synthetic applications, are documented.287 An extensive study of the reactions of vinyl selenoxides and selenones with nucleophiles has appeared.288
Selenoxides tend to
undergo vinylic displacement (with RS-, RO- etc) but selenones also undergo addition to the alkene residue to give a selenium-stabilised anion.
The precise fate of this latter intermediate depends on the
nature of the nucleophile used.
A new method for the resolution of
racemic selenoxides has been described.289 A useful review of tellurium reagents in organic synthesis underlines the growing interest in this area.290 The
508
General and Synthetic Methods
thiophene-tellurolate (286) is an especially useful nucleophile, readily generated in catalytic amounts from the corresponding ditelluride.
This species efficiently cleaves the 2,2,2-trichloro-
t-butyloxycarbonyl amine protecting group. 291
The related telluride (PhTeNa) reacts with a,a'-dichloro-9-xylenes to give Q-quinodimethanes and although this reaction should also be catalytic in tellurium, best results were observed with the use of two equivalents of PhTeNa.292 Telluride ion (Te2- ) is also a powerful nucleophile and reacts rapidly with chloromethyloxiranes to give allylic alcohols. 293 Alkenyl tellurides may be prepared via either an electrophilic O K nucleophilic tellurium species (Scheme 80) .294 may also be incorporated into this sequence.
Elemental tellurium The cross-linked
polystyrene tellurinic acid derivative (287) is a mild and selective reagent in conjunction with H202 for the epoxidation of alkenes. Interestingly, the nonpolymer bound form of (287) shows no activity, and possible reasons for this difference have been discussed.295
References P. Boudjouk, R. Sooriyakumaran and B. - H.Han. J.Org.Chem., 1986,51,2818. 2. K.M. Sadhu and D.S. Matteson, Tetrahedron Lett., 1986,1,795. 3. J.Barluenga, J.L.Fernandez-Simon, J.M.Concell6nI and M.Yus, J.Chem.Soc., Chem.Commun., 1986,1665. 4. P.Beak, A.Basha, B.Kokko, and D.K.Loo, J.Am. Chem., SOC., 1986, 108.6016 5. N.S.Simpkins, J.Chem.Soc., Chem.Commun., 1986,88. 6. R.Shirai, M.Tanaka, and K.Koga, J.Am.Chem.Soc., 1 9 8 6 , ~ , 5 5 4 3 . 7. (a) M.B.Eleveld, and H-Hogeveen, Tetrahendron Lett., 1 9 8 6 , z , 631; ( b ) H-Hogeveen, and W.M.P.E.Menge, p.2767. 8. J.T.Welch and K.W.Seper, J.Org.Chem., 1 9 8 6 , ~ , 1 1 9 . 9. W.H.Pearson, M.A.Waltess, and K.D.OsweL1, J.Am. Chem.Soc., 1986, 108,2769. 10. J.E.Baldwin, R.M.Adlington, J.C.Bottoro, J.N.Kolhe, M.W.D.Perry, and A.U.Jain, Tetrahedron 1986,42,4223; (b) J.E.Baldwin, R.M.Adlington, A.U.Jain, J.N.Kolhe and M.W.D.Perry, ibid p.4247. 11. J.E.Baldwin, R.M.Adlington, J.C.Bottoro, J.Kolhe, I.M.Newington, and M.W.D.Perry, Tetrahedron, 1986,42,4235. R.E.Gawley, G.Hart, M.Gokoechea-Pappas and A.L.Smith, 12. J.Org.Chem., 1986,51,3076. 13. M.P.Edwards, A.M.Doherty, S.V.Ley, and H.M.Organ, Tetrahedron, 1986.42.3723. . . 14. A.J.CSenter and D.J.Chadwick, Tetrahedron, 1986,42,2351. 15. J.H.Nasman, N-Kopola, and G.Pensar, Tetrahedron Lett., 1986,27, 1391. 16. D.L.Comins,and J.D.Brown, J.Org,Chem., 1986,=,3566. 17. M.P.Sibi, J.W.Dankwardt, and V.Snieckus, J.Org.Chem., 1 9 8 6 , ~ , 2 7 1 . 18. J.Einhorn and J.L.Luche, Tetrahedon Lett., 1986,2JI1791,1793. 19. P.J.Crowley, M.R.Leach, 0.Meth-Cohn and B.J.Wakefield, Tetrahedron Lett., 1 9 8 6 , ~ , 2 9 0 9 . 20. A.Sidani, and M.Vaultier, Tetrahedron Lett., 1986,27,857. 21. A.R.Katritzky and K-Akutagawa, Tetrahedron, 1986,%,2571. 1.
=,
~
509
6: Organometallics in Synthesis
22.
A.R.Katritzky, W.-Q. Fan, and K.Akutagawa, Tetrahedron, 1 9 8 6 ,
23. 24.
KR.Katritzky and K-Akutagawa, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 6 8 0 8 . (a) K.Narasaka and Y.Ukaji, Chemistry Lett., 1 9 8 6 , 8 1 7 (b) K.Narasaka, Y.Ukaji, and K.Watanabe, Chemistry Lett., 1 9 8 6 ,
25. 26. 27.
W.M.Berry, M.C.P.Dorey and L.Harwood, Synthesis, 1 9 8 6 , 4 7 6 . E.R.Koft and M.D.Williams, Tetrahedron Lett., 1 9 8 6 , 2 , 2 2 2 7 . (a) A.G.M. Barrett, R.A.E.Carr, M.A.W.Finch, J.-C.Florent, G-Richardson, and N.D.A.Walshe, J.Org.Chem., 1 9 8 6 , z l 4 2 5 4 . (b) S.V.Attwood, A.G.M.Barrett, R.A.E.Carr,and G.Richardson J.Chem.Soc., Chem.Commun., 1 9 8 6 , 4 7 9 . A.B.Smith 111, M.Visnik, J.N.Haseltine, and P.A.Sprengeler, Tetrahedron, 1 9 8 6 , 4 2 , 2 9 5 7 . ~ . F u r b e r ,R.J.K.Taylor, and S.C.Burford, J.Organomet.Chem., 1 9 8 6 ,
43,4027.
1755.
28. 29.
311,
C35.
~
30. 31. 32.
L-Brandsma, H.D.Verkruijsse, C.Schade, and P.von R. Schleyer, J.Chem.Soc., Chem.Commun., 1 9 8 6 , 2 6 0 . J.P.Gillet, R.Sauvetre arid J.F.Normant, Synthesis 1 9 8 6 , 3 5 5 . G.Stork, C.S.Schiner, C.-W.Cheng, and P.L.Polt, J.Am. Chem.Soc., 1986108,304.
33.
34.
W.D.Wulff, G.A.Paterson, W.E.Banta, K.-S.Chan, K.L.Faron, S.R.Gilbertson, R.W.Kaesler, D.C.Yang, and C.K.Murrary, J.Org. Chem., 1986,=,277. J.Barluenga, J.R.Fernandez, and M.Yus, J.Chem.Soc., Chem.Commun., 1986,1983.
35. 36.
(a) P.J.Stang and K.A.Roberts, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , (b) P.J.Stanq, M.Boehshar-id, - p.7832. C.J.Kowalski, G.S.Ha1, and M.S.Hague, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8
37. 38.
C.J.Kowalski, and M.S.Haque, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 1 3 2 5 . J.Ackrel1, J.M.Muchowski, E.Galeazzi, and A.Guzman,.Orq.Chem.,
39. 40.
C.G.Screttas and M.Micha-Screttas, J.Organomet. Chem., 1986,=,1. R.Pi, W-Bauer, B.Brix, C.Schade and P - v o n R. Schleyer, J.Organometa1. Chem., 1 9 8 6 , ~ , C 1 . (a) B.M.Trost, M.K.-T. Mao, J.M.Balkovec, and P.Buhlumayer, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 4 0 6 5 . (b) B.M.Trost, J.M.Balkovec, and M.K.-T.Mao, ibid., p . 4 9 7 4 . T.Cohen and B.S.Guo, Tetrahedron, 1 9 8 6 , g I 2 8 O 3 . R.H.Ritter and T.Cohen, J.Org.Chem., 1 9 8 6 , ~ , 3 7 1 8 . S.Cabiddis, C.Floris, and S.Melis, Tetrahedron Lett., 1986,=,
7125;
7127.
1986,2,3374.
41.
42. 43. 44.
4625. 45. 46. 47 48.
P.G.McDouga1, and Y.-I.Oh, Tetrahedron Lett., 1 9 8 6 , 2 7 , 1 3 9 . (a) N.C.Barua, and R.R.Schmidt, Chem.Ber., 1 9 8 6 , 1 1 9 , 2 0 6 6 . (b) N.C.Barua and R.R.Schmidt, Synthesis, 1 9 8 6 , 1 0 6 7 . A.R.Chamberlin. and H-Nguyen, J.Org.Chem., 1 9 8 6 , ~ , 9 4 0 . T.Fujisawa, K.Umezu, M.Suziki, and T.Sato, Chemistry Lett., 1 9 8 6
49. 50.
L.Bo, and A.G.Fallis, Tetrahedron Lett., 1 9 8 6 , z , 5 1 9 3 . M-Frank-Neuman, D. Martina, and M.-P.Heitz, J.Organomet.Chem.,
51.
R.Annunziata, M.Cinquini, F.Cozzi, L.Rainmondi, and S.Stefanelli, Tetrahedron, 1 9 8 6 , 4 2 , 5 4 4 3 , 5 4 5 1 . R.Annunziata, M.Cinquini, F.Cozzi, and L-Raimondi, J.Chem.Soc.Chem.Commun., 1 9 8 6 , 3 6 6 . R.R.Schmidt, and J.Kast, Tetrahedron Letters, 1 9 8 6 , 2 7 , 4 0 0 7 . D.R.Williams, J.G.Phillips,F.H.White, and J.C.Huffman, Tetrahedron 1 9 8 6 , g l 3 O 0 3 . D.R.Williams, and J.G.Phillips, Tetrahedron, 1 9 8 6 , 4 2 , 3 0 1 3 . D.J.Ager, and M.B.East, J.Org.Chem., 1 9 8 6 , z l 3 9 8 3 .
1675.
~
1986,=,59. 52. 53. 54. 55. 56.
510
General and Synthetic Methods
57. 58. 59. 60.
E.Schaumann, C.Friese, and C.Spanka, Synthesis 1986,1035. S-Hackett, and T.Livinghouse, J.Org.Chem., 1986.zl879. S-Hackett, and T-Livinghouse, J.Chem.Soc., Chem.Commun., 1986,75. K.Ogura, N.Yahata, M.Minoquchi, K.Ohtsuki, K.Takahashi, and H.Iida, J.Orq.Chem., 1 9 8 6 , ~ , 5 0 8 . 61 - K.Ogura, T.Tsuruda, K.Takahashi and H.Iida, Tetrahedron L e z , 1986,27,3665. 62. K.Fuji, Y.Usami, K.Sumi, M.Ueda, and K.Kajiwara, Chemistry Lett., 1986,1655. 63. A. Berlin, S.Bradamante, R. Ferraccidi I and G.A. Pagani, J.Chem.Soc., Chem.Commun., 1986,1191. 64. D.A.Bors and A.Streitwieser Jr., J.Am Chem SOC., 1 9 8 6 , ~ , 1 3 9 7 . 65. S.V.Ley, B.Lygo, F.Sternfeld, and A.Wonnacott, Tetrahedron, 1986,42,4333. 66. S.D.Lombaert, I.Nemery, B.Koekeus, J.C.Carretero, T.Kimme1, and L.Ghosez, Tetrahedron Lett., 1986,c,5099. 67. H-Kleijn, and P.Vermeer, J.Organomet.Chem., 1 9 8 6 , ~ , 1 . 68. Y.-T.Tao, C.-L.Liu, S.-J.Lee, and S.-S.P.Chou, J.Org.Chem., 1986, 51,4718. 69. P-T-Lansbury,C.J.Spaqnuo10 and E.L.Grimm, Tetrahedron Lett., 1986,=,2725. 70. J.B.Hendrickson, G.J.Boudreaux, and P.S.Palumbo, J.Am.Chem.Soc., 1986108,2358. 71. M . C l E m b e a u , and A.Krief, Tetrahedron Lett., 1986,~,1718,1723. 72. S.Hanessian, P.J.Hodges, P.J.Murrary, and S.P.Sahoo, J.Chem.Soc., Commun., 1986,754. 73. M-Falorni, L-Lardicci, C.Rosirii and C.Giacomelli, J.Org.Chem., 1986,51,2030. 74. (a) Wzppolzer and E.J.Jacobsen, Tetrahedron Lett., 1 9 8 6 , ~ , 1 1 4 1 ; (b) W.Oppolzer and A.F.Cunninqham, ibid, p.5467; (c) W.Oppolzer and A.Nakao, ibid., p.5471. 15. N.Furukawa, T.Shibutani, K.Matsumura, H-Fujihara, and S.Oae, Tetrahedron Lett., 1986,=,3899. 76. P.Coutrot, M.Youssefi - Tabrizi, and C.Grison, J.Orqanomet.Chem., 1986,316,13. 77. B.J.J.Van de Heisteeg, G.Schat, O.S.Akkerman,and F.Bickelhaupt, J.Organomet.Chem., 1986,%,1. 78. C.J.F.Du, H.Hart,and K.-K.D.Nq, J.Org.Chem., 1986,51,3162. 1986,El228.79. C.Ferr, and J.Galindo, Helv.Chim.Acta, 80. R.Csuk, A.Fbrstner, and H.Werdmann, J.Chem.Soc., Chem.Commun., 1986,1802. 81. E.A.Hil1, C.L.Harder, R.Wagner, D.Meh, and R.P.Bowman, J.Orqanomet.Chem, 1986,=,5. 1986,32409. 82. I.K.Youn, G.H.Yon,and C.S.Pak, Tetrahedron Lett, 83. K.Mochida, S.Ogura, and T.Yamanishi, Bull.Chem. SOC. Jpn., 1986,59,263?. 84. R.Csuk, A-Furstner, and H.Werdman, J.Chem.Soc., Chern.Commun., 1986,775. 85. R.Csuk, A.Fbrstner, B.I.Glanzer,and H.Werdman, J.Chem.Soc., Chem.Commun., 1986,1149. 86. A.K.Banerjee, M.C.Sulbaram de Carrasco, C.S.V.Frydrych-Houqe, and W.B.Motherwel1, J.Chem.Soc., Chem.Comun., 1986,1803. 87. P.Knoche1 and J.F.Normant, J.Organomet.Chem., 1986,309,l. 88. P.Knoche1 and J.F.Normant, Tetrahedron Lett., 1986,27,1039,1943,5727. 89. G.P.Boldrini, M.Menqolu, E.Taqliavini, C.Trombini, and A.Umani-Ronchi, Tetrahedron Lett., 1886,z,4223. 90. Y.Tamura, H.Ochrai, T.Nakmura, and Z.Yoshida, Tetrahedron Lett., 1986.27.955. ~.. , . 91. (a) Jy.Gillet, R.Sauvetre, and J.F.Normant, Synthesis, 1986,538. ~
6: Organometallics in Synthesis
92. 93. 94. 95. 96. 97.
98.
99. 100. 101.
5 11
(b) F.Tellier, R.Sauv$tre, and J.F.Normant,Tetrahedron Lett., 1986,27,3147. M.Kitamura, S.Suga, K.Kawai. and R.Noyori, J.Am.Chem.Soc., 1986,108,6071. F.H.Gouzoules, and R.A.Whitney, J.Org.Chem., 1986,xI2O24. A.J.Bloodworth, and P.N.Cooper, J.Chem.Soc., Chem.Commun., 1986,709. J.Barluenga, J.M.Martinez-Gallo,C.NaJera, and M.Yus, J.Chem.Research (S), 1986,274. J.Barluenga, J.M.Martinez-Gallo, C.NaJera, and M-Yus, Synthesis, 1986 I 678. (a) G.A.Russel1 and P.Ngoviwatchai, Tetrahedron Lett., 1986,27,3479. (b) G.A.Russel1, W.J.S.S.Hu, and R.K.Khanna, J.Org.Chem., 1986,51,5498. D.B.Collum, W.C.Stil1 and F.Mohamadi, J.Am.Chem.Soc., 1986,108,2094. G.W.Kabalka, J.Organomet. Chem., 1986,=,1. D.S.Matteson, Synthesis 1986,973. (a) A.Suziki, N.Miyaura, S.Abiko, M.Itoh, M.M. Midland, A.J.Sinclair, and H.C.Brown, J.Org.Chem., 1986,s,4507; (b) H.C.Brown and G.A.Molander, J.Org.Chem., X I p.4512. (c) H.C.Brown and K.K.Wang, =,p.4514. (d) H.C.Brown, D-Basavaiah, and N.G.Bhat, J.Orq.Chem., 4518. (e) J.A.Sikorski, N.G.Bhat, T.E.Cole, K.K.Wang, and H.C.Brown, ibid.4521. .~ E.J.Corey and W.L.Seibe1, Tetrahedron Lett., 1986,~,905,909. W.V.Dahlhoff, and K.M.Taba, Synthesis, 1986,561. T.W.Bel1, and J.A.Ciaccio, Tetrahedron Lett., 1 9 8 6 , ~ , 8 2 7 . M.T.Reetz, F.Kunisch, and P.Heitman, Tetrahedron Lett., 1986,27,4721. C.A.Brown and S.Krishnmurthy, J.Org.Chem., 1986,=,238. H.C.Brown, B.Nazer, J.S.Cha, and J.A..Sikorski, J.Org.Chem., 1986,xI5264. (a) T.Imai, T.Tamura, A.Yamamoto, T.Sato, T.A.Wollmann, R.M.Kennedy, and S.Masamune, J.Am.Chem.S~c.~1986,108,7402. (b) S.Masamune, R.M.Kennedy, J.S.Petersen, K.N.Houk,and Y.Wu, ibid, p.7404. R B r o w n , J-Chandrasekhoran and P.V.Ramachandran, J.Orq.Chem., 1986,51,3394. H.C.Brown, W.S.Park, and B.T.Cho, J.Org.Chem., 1986,51,3278. H.C.Brown, W.S.Park,and B.T.Cho, J.Org.Chem., 1986,51,1934. H.C.Brown, B.T.Cho, and W.S.Park, J.Org.Chem., 1986,%,3396. H.C.Brown, T.E.Cole, M.Screbnik and K.W.Kim, J.Org.Chem,, 1986,51,4925. H.C.Brown and U.S.Racherla, J.Org.Chem., 1986,%,427. H.C.Brown, J.V.N.V.Prasad, and S.-H.Zee, J.Org.Chem., 1986,=,439. H.C.Brown and K.S.Bhat, J.Orq.Chem., 1986,z,445. H.C.Brown and J.V.N.V.Prasad, J.Am.Chem.Soc., 1986,1_OJI2O49. (a) H.C.Brown, D.Basavaiah, S.U.Kulharni, H.D.Lee, E.Negishi, and J.J.Katz, J . O r g . C h e 5 1986,51,5270. (b) H.C.Brown, T.Imai, and N.G.Bhat, G Ip.5277. ( c ) H.C.Brown, H.D.Lee, and S.U.Kulkarni, P.5282. H.C.Brown, N.G.Bhat, and S.RaJagopalan, Synthesis, 1986,480. Y-Wakita, T.Yasunaga, Makita, and M.Kojima, J.Orqanomet.Chem., 1986,301,C7. N.Miyaura, T.Ishiyama, M.Ishikawa, and A.Suzuki, Tetrahedron Lett., 1986,27,6369.
x,
102. 103. 104. 105. 106. 107. 108.
109. 110. 111. 112. 113. 114. 115. 116. 117. 118.
119. 120.
121.
w,
General and Synthetic Methods
512
1 2 2 . H.C.Brown, N.G.Bhat, and J.B.Campbel1 Jr., J.Orq.Chem., 1986,51,3398. 1 2 3 . M.Satoh, N.Miyaura, and A.Suziki Chemistry Lett., 1 9 8 6 , 1 3 2 9 . 1 2 4 . (a) G.A.Molander and P.W.Zinke, Orqanometallics, 1 9 8 6 , ? , 2 1 6 1 .
(b) N.Miyaura, M.Satoh and A.Suziki, Tetrahedron Lett., 1986,27,3745. 125.
w,
(c) S.Hyuqa, S.Takinami, S.Hara, and A.Suziki p.977. (a) H.C.Brown and S.M.Sinqh, Orqanometallics, 1 9 8 6 , 5 , 9 9 4 , 9 9 8 . (b) H.C.Brown, S.M.Singh, and Pl.V.Ranqaishenvi, J.Org.Chem., 1986,51,3150.
(c) D-S-Matteson,K.M.Sadhu, and M.L.Peterson, J.Am.Chem. SOC., 1986,108,810.
(d) D.S.,Matteson and G.D.Hurst, O r q a n o m e t a l l i c s , l 9 8 6 , 5 , 1 4 6 5 . (el H.C.Brown, M.Srebnik, and T.E.Cole, N,p . 2 3 0 0 . 1 2 6 . H.C.Brown, K.-W.Kim. T.E.Cole and B.Sinqaram J.Am.Chem.Soc., 1986,108,6761. 1 2 7 . H.C.Brown and K.S.Bhat, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 2 9 3 , 5 9 1 9 . 1 2 8 . (a) W.R.Rousch, and R.L.Haterman, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 2 9 4 . W.R.Rousch, M.A,Adam, A.E.Walts, and D.J.Harris, p.3422. 1 2 9 . P.K.Jadhav, K.S.Bhat, P.T.Peruma1, and H.C.Brown, J.Orq.Chem., 19 8 6 ,5 2 , 4 3 2 . 1 3 0 . R.W.Hoffman and B.Landman, Chem.Ber., 1 9 8 6 , ~ , 1 0 3 9 . 1 3 1 . Y.Yamamoto, S.Nishii, K-Maruyama, T.Komatsu, and W.Ito, J.Am.Chem.Soc.. 1 9 8 6 , 1 0 8 , 7 7 7 8 . 1 3 2 . P.G.M.Wuts, and Y.W.J=, Tetrahedron Lett., 1 9 8 6 , ~ , 2 0 7 9 . 1 3 3 . (a) N.Ikeda, I.Arai, and H.Yamamoto, J.Am.Chem.Soc., 1986,108,483. ~
~
,
u,
I
(b) N.Ikeda, K.Omori, and H.Yamamoto, Tetrahedron Lett., 1986,2,1175. 1 3 4 . Y.-T.Lin, J.Orqanomet.Chem.,
1986,317,277.
135. K.Maruoka, H.Sano, K-Shinoda, S.Nokai,and H.Yamamoto, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 6 0 3 6 . 1 3 6 . (a) G.Picoton and P.Miqiniac, Chem. Ber., 1 9 8 6 , = , 1725. (b) F.Barbot and P.Miqiniac, J.Orqnomet Chem., 1 9 8 6 , = , 8 3 . 1 3 7 . B.M.Trost and M.R.Ghadiri, J.Am.Chem.Soc., 1 9 8 6 , 1 0 8 , 1 0 9 8 . 138. Y.Naruse and H.Yamamoto, Tetrahedron Lett., 1 9 8 6 , 2 7 , 1 3 6 3 . 1 3 9 . T.Tsuda, T.Hayashi, H.Satomi, 'l'.Kawamoto,and T.Saequa, J.Orq.Chem., 1 9 8 6 , = , 5 3 6 . 140. R.A.Kjonaas, J.Orq.Chem., 1 9 8 6 , = , 3 7 0 8 . 1 4 1 . H.M.C.Ferraz, and T.J.Brockson, Tetrahedron Lett., 1 9 8 6 , 2 7 , 8 1 1 1 4 2 . I.Matsuda, T.Kato, S.Sato, and Y.Izumi, Tetrahedron Lett., 1986,=,5742. 1 4 3 . G.A.Molander, and D.C.Shubert, Tetrahedron Lett., 1 9 8 6 , z l 7 8 7 . 1 4 4 . H-Shiragami, T-Kawamoto, K.Utimoto and H.Nozaki, Tetrahedron Lett., 1 9 8 6 , 1 , 5 8 9 . 1 4 5 . T.Hayashi, M.Konish, Y.Okamoto, K.Kabeta, and M.Kamada, J.Orq.Chem., 1 9 8 6 , = , 3 7 7 2 . 1 4 6 . I.Fleminq, and F.J.Pulido, J.Chem.Soc., Chcm.Commun., 1 9 8 6 , 1 0 1 0 . 1 4 7 . I.Fleminq, and A.K.Sarkar, J.Chem.Soc., Chem.Commun., 1 9 8 6 , 1 1 9 9 . 1 4 8 . H.Mavr and R.Pock. Tetrahedron, 1 9 8 6 . 4 2 . 4 2 1 1 . 1 4 9 . B.M.Trost, S .M.Mi$nani, and T.N.NannlG: J.Am.Chem.Soc., 1986,108,6051. 1 5 0 . H.Uno, S.FuJiki, and H.Suzuki, Bull.Chem.Soc.Jpn., 1 9 8 6 , = , 1 2 6 7 . 1 5 1 . (a) K.Hiroi and H.Sato, Chemistry Lett., 1 9 8 6 , 1 7 2 3 . (b) K.Hiroi, H.Sato, and K.Kotsuji, ibid, p . 7 4 3 . 1 5 2 . S.D.Larsen, P.A.Grieco, and W.A.Fobare,J.Am.Chem.Soc., 1986,108,3512. 1 5 3 . G.A.Molander and S.W.Andrews, Tetrahedron Lett., 1 9 8 6 , & 7 , 3 1 1 5 . 1 5 4 . G-Majetich, R.W.Desmond Jr., and J.J.Soria, J.Orq.Chem., 1986,51,1753.
513
6: Organometallics in Synthesis
155. T.V.Lee. K.A.Richardson, and D.A.Taylor, Tetrahedron Lett., 1986,27,5021 156. H.Uno, Bull.Chem.Soc.Jpn., 1986,2,2471. 157. J-Yoshida, T-Murata, and S.Isoe, Tetrahedron Lett., 1986,_?_1,3373. 158. J-Pornet, D-Damour, L-Miginiac, Tetrahedron 1986,42,2017. 159. D.Schinzer, J.Steffen, and S.Solyom, J.Chem.Soc., Chem.Commun., 1986 ,829. 160. K.Karabelas, and A.Hallberg, J.Org.Chem., 1986,=,5286. 161. Y.Seki, K.Takeshita, K. Kawamoto, S.Murai, and N.Sonoda, J.Org.Chem., 1986, 51, 3890. J.Org.Chem., 1986,=,3435. 162. B.M.Trost and S.MigGni, _______ 163. K.Wang, S.S.Nikam and M.M.Morcano, Tetrahedron Lett., 1 9 8 6 , z ,1123. 164. M.Hoshi, Y.Masunda, and A.Arase, Bull.Chem.Soc.Jpn, 1986,2,659. 165. P.J.Gorratt, and A.Tsotinis, Tetrahedron Lett., 1 9 8 6 , ~ , 2 7 6 1 . 166. H.-M.Chen and J.P.Oliver, J.Organomet.Chem., 1986,316,255. 167. (a) K.Nozai, K.Wakamatsu, T.Nonako, W-Tuckmantel, K.Oshima, and K.Utimoto, Tetrahedron Lett., 1986,27,2007. (b) K.Wakamatsu, T.Nonaka, Y.Okuda, W.Tuckmante1, K.Oshima, K.Utimoto, and H.Nozaki, Tetrahedron, 1986,42,4427. (c)W.Tuckmantel, K.Oshima, H-Nozaki, Chem.Ber., 1 9 8 6 , ~ , 1 5 8 1 . 168. B.P.Andreini, A.Carpita, and R.Rossi, Tetrahedron Lett., 1986,27,5533. 169. T.H.Chan, and K.Kaumoglo, Tetrahedron Lett., 1986,27,883. 170. G.L.Larson, E.Torres, C.B.Morales, and G.J.McGarvery, Organometallics, 1986,1,2274. 171. E.Negishi and T.Takahashi, J.Am.Chem.Soc., 1 9 8 6 , ~ , 3 4 0 2 . 172. S.Martin, R.SauvStre,and J.F.Normant, J.Organomet.Chem., 1986,303,317. 173. (a) L m v e r m a n , A.CastaReda and T.A.Blumenkopf, J.Am.Chem.Soc., 1986,108,1303. (b) L.E.Overman T.A.Blumenkopf, A.CastaZeda, and A.S.Thompson, _ ibid, _ p.3516. 174. T.A.Blumenkopf, and L.E.Overman, Chem.Rev., 1986,@,857. 175. S.E.Denmark, K.L.Harbermas, G.A.Hite and T.K.Jones, Tetrahedron, 1986,42,2821. 176. B.L.Chenard, C.M.van Zyl, and D.R.Sanderson, Tetrahedron Lett., 1986,27,2801. 177. K.Mikami, T.Maeda, and T.Nakai, Tetrahedron Lett., 1 9 8 6 , ~ , 4 1 8 9 . 178. A.D.Kay,G.Pattenden and S.M.Roberts, Tetrahedron Lett., 1986,27,2033. 179. L.A.Paquette, Chem-Rev., 1986,@,733. 180. (a) E.Vedejs and F.G.West, Chem.Rev., 1986,86,941; (b) O.Tsuge, S.Kanemasa,A.Hatada and K.Matsuda, Bull.Chem.Soc., Jpn., 1986,zl2537. 181. I.Fleming, and J.D.Kidburn, J.Chem.Soc., Chem.Commun., 1986,1198,305. 182. W.Engw1, I.Fleming, and R.H.Smithers, J.Chem.Soc., Perkin Trans., 1,1986,1637. 183. W.Oppolzer, R.J.Mills, W.Pachinger, and T.Stevenson, Helv. Chim. ___ Acta, 1986,69,1542. 184. R.F.Cunico, Tetrahedron Lett., 1986,27,4269. 185. (a) 1-Matsuda, and S.Sato, J.Organomet.Chem., 1986,=,47. ( b ) T.Benneche. M.L.Christiansen,and K. Undheim, Acta Chem.Scand., Ser.B., 1 9 8 6 , ~ , 7 0 0 . 186. (a) T.Nakujima, M.Tanabe, K.Ohno, M.Segi, and S.Suga, Chemistry Lett., 1986,177. p.181. (b) T-Nakujima, H.Miyayi, M.Segi, and S.Sato, 187. M.E. Scheller, and B.Frei, Helv.Chim.Acta., 1986,2,44. 188. T.Aoyama and T-Shioiri, Tetrahedron Lett., 1986,27,2005. 189. P.C.B.Paae and S.Rosentha1. Tetrahdron Lett., 1986.27.5421.
w,
5 14
General and Synthetic Methods
190. H.J.Reich, E.K.Eisenhart, R.E.Olson, and M.J.Kelly, J.Am.Chem.Soc., 1986, 108, 7791. 191. S.Anwar and A.P.Davis, J.Chem.Soc., Chem.Commun., 1986,831. 192. (a) K.Tamao, T.Tanaka, T.Nakajima, R.Sumiya, H.Arai, and Y.Ito, Tetrahedron Lett., 1986,3,3377. ( b ) K.Tamao, T.Nakajima, R.Sumiya, H.Arai, N-Hiquchi, and Y.Ito, J.Am.Chem.Soc., 1 9 8 6 , E , 6 0 9 0 . 193. Y.Hatanaka, I.Kuwajima, Tetrahedron Lett., 1986,2,219. 194. H.Sano, M.Oqata, and T.Migita, Chemistry Lett., 1986,77. 195. (a) E-Nakamura, S-Matsuzawa, Y.Horiguchi, and 1.Kawajima. Tetrahedron Lett., 1986,~,4025,4029,4933. (b) A-Alexakis, J.Berlan, and Y.Besace, Tetrahedron Lett., 1986,27,1047. 196. S.M.Weinreb, D.M.Demko, T.A.Lessen, and J.P.Demers, Tetrahedron Lett., 1986,2,2099. 197. D.Terunuma, M.Kato, M.Kamei, H.Uchida, S.Ueno, and H.Nohira, Bull.Chem.Soc.Jpn., 1 9 8 6 , ~ , 3 5 8 1 . 198. H.J.Reich and N.H.Phillips, J.Am.Chem.Soc., 1 9 8 6 , E I 2 1 O 2 . 199. S.Sharma, and A.C.Oehlschlaqer, Tetrahedron Lett., 1 9 8 6 , ~ , 6 1 6 1 . 200. Y.Watanabe, Y.Ueno, T.Araki, T.Endo, and M.Okawara. Tetrahedron Lett., 1 9 8 6 , Z l 2 1 5 . 201. T.N.Mitchel1, and W.Resman, Orqanometallics, 1986,2,1991. 202. K.H.Chu, and K.K.Wanq, J.Org.Chem., 1986,=,767. 203. E.Piers, and R.T.Skerlj, J.Chem.Soc., Chem.Commun., 1986,626. 204. (a) D.J.Aqer. G.E.Cooke, M.B.East, S.J.Mole, A.Rampersand, and N.J.Webb, Organometallics, 1986,5,1906. (b) A. Zapata, R.C.Fortou1 and A.C.Acuna, Synth.Commun., 1985,=,179. 205. T.Nanaka, Y.Okuda, S.Matusubora, K.Oshima, K.Utimoto, and H.Nozaki, J.Orq.Chem., 1986,=,4716. 206. M.Taddei and A.Mann, Tetrahedron Lett., 1986,z,2913. 207. Y.Naruta, Y.Nishiqaichi, and K.Maruyama, Chemistry Lett., 1986,1856. 208. I.Fleming, and M.Rowley, Tetrahedron Lett., 1986,27,5417. 209. B.L.Chenard, Tetrahedron Lett., 1986,Z,2805. 210. T.Sato, H-Matusuoka, T.Igarashi, and E.Murayama, Tetrahedron Lett., 1986,3,4339. 211. J.E.Baldwin, R.M.Adlington, D.J.Birch, J.A.Crawford and J.B.Sweeney, J.Chem.Soc., Chem.Commun., 1986,1339. 212. ( a ) J.E.Baldwin, R.M.Adlinqton, and J.B.Sweeney, Tetrahedron Lett., 1986,Z,5423. (b) K.Tanaka, H.Yoda, Y.Isobe, and A.Kaji, J.Org.Chem., 1986,51,1856. 213. M.R.Pee1, and C.R.Johnson, Tetrahedron Lett., 1986,27,5947. 214. J.-B.Verlhac, and J.-P.Quintard Tetrahedron Lett., 1986,27,2361. 215. H.Nishiyama, H.Arai, Y.Kanai, H.Kawashima, and K.Itoh, Tetrahedron Lett., 1986,Z,361. 216. T.R.Bailey, Tetrahedron Lett., 1986,21,4407. 217. M.R.Bryce, R.D.Chambers, S.T.Mullins, and A.Parkin, J.Chem.Soc., Chem.Commun., 1986,1623. 218. (a) T.N.Mitchel1, J.Orqanomet. Chem., 1 9 8 6 , ~ 4 - , 1 . (b) K.Kikukawa, H-Umekawa, T.Matsuda, ibid, 311, C44; 9 , l q n E 6 , g ,5 0 8 ; (c) J .K .St i1 le , Angew .C hemie , Ed.8 219. (a) H.Tanaka, T.Hamatani, S-Yamashita, and S.Torii, Chemistry Lett., 1986,1461; (b) H.Tanaka, S.Yamashita, T-Hamatani, Y.Ikemoto, and S.Torii, ibid p.1611. 220. X M o l o n e y , J.T.Pinhey, and E.G.Roche, Tetrahedron Lett., 1986.27.5025. . . 221 S.C.Wzch, J.-M. Assercq, and J.-P.Loh, Tetrahedron Lett., 1986,2,1115.
6: Organometallics in Synthesis
222 223 224. 225. 226. 227. 228. 229. 230. 231. 232. 233.
234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247.
248 -
249. 250. 251.
515
H.J.Crustau, A.Bazbouz, P.Morand, and E.Torreilles, Tetrahedron Lett., 1986, 2 , 2 9 6 5 . D.P.Phillion and S.S.Andrew, Tetrahedron Lett., 1986,g,1477. A.Leone.-Bay, J.Orq.Chem., 1986,2,2378. J.W.Kelly, N.L.Eskew and S.A.Evans Jr., J.Orq.Che% 1986,51,95. M.Tuckmante1, K.Oshima, and K.Utimoto,Tetrahedron Lett., 1986,27,5617. (a) A.P.Kozikowski, and S.H.Jung, J.Orq.Chem., 1 9 8 6 , ~ , 3 4 0 0 . , (b) ~ . ~ . K o z i k o w s kand i S.H.Jung, Tetrahedron Lett., 1986,2,3227 K.M.Pietrusiewicz and J.Monkiewicz, Tetrahedron Lett., 1986,2,739. N.S.Isaacs and O.H.Abed, Tetrahedron Lett., 1986,27,995,1209. B.E.Maryanoff, A.B.Reitz, M.S.Mutter, R.R.Inners,H.R.Almond Jr., R.R.Whittle and R.A.Olofson, J.Am.Chem.Soc., 1986,108,7664. (a) N.Greeves and S.Warren, Tetrahedron Lett., 1 9 8 6 , g l 2 5 9 . (b) D.Levin and S.Warren, *,p.2265. T-Minami, T.Chikuqo and T-Hanamoto, J.Orq.Chem., 1986,=,2210. (a) E-Juaristi, B.Gordillo, and L.Valle, Tetrahedron, 1986,42,1963; (b) E-Juaristi, L.Valle, B.A. Valenzuela, and M.A.Aquilar, J.Am.Chem.Soc., 1 9 8 6 , ~ , 2 0 0 0 . (a) D.Villemin and R.Racha, Tetrahedron Lett., 1986,27,1789. (b) B.Texier-Boullet, and M.Lequitte, ibid, p.3515. O.Tsuqe, S.Kanemasa, and H.Suga, Chemistry Lett., 1986,1983. I.K.Stamos, Tetrahedron Lett., 1 9 8 6 , ~ , 6 2 6 1 . G.B.Hammond, T.Caloqeropoulou,and D.F.Wienier, Tetrahedron Lett., 1 9 8 6 , Z l 4 26 5 ; P.Sampson, G.B.Hamond, and D.F.Wiemer, J.Org.Chem., 1986,=,4342. P.Courtrot and A-Ghribi, Synthesis, 1986,661,790. E.E.Aboujaude, S.Lietje, N.Collignon, M.P.Teulade, and Synthesis, 1986, 934. P-Savigniac, _____ (a) X. Yu and 2 . Li, Synthesis, 1986, 240; (b) Y.Xu, J.Xia, and H.Guo, ibid p.691. X.Lu and J.Zhu, Synthesis 1986,563. Y.Huanq, Y.Shen, and C.Chen, Tetrahedron Lett., 1 9 8 6 , z I 2 9 O 3 . R.Nomura, T.Wada, Y.Yamada and H.Matsuda, Chemistry Lett., 1986,1901. M.Wada, H.Ohki., and K.Akiba, Tetrahedron Lett., 1986,z,4771. D.H.R.Barton, K.-F.Finet, W.B.Motherwel1 and C.Pichon, Tetrahedron, 1986,42,5627. (a) D.H.R.Barton, J.-P. Finet, and C.Pichon, J.Chem.Soc., Chem.Commun., 1986,65; (b) D.H.R.Barton, J.-P.Finet, and J.Khamsi, Tetrahedron Lett., 1986,27,3615; (c) D.H.R.Barton, J.-P.Finet, J.Khamsi and C.Pichon, ibid, p.3619. (d) H-Brunner, U-Obermann, and P.Wimmer J.Orqanomet.Chem,, 1986,361,Cl. (a) B-M-Dilworth and M.A.McKervey, Tetrahedron, 1986,42,3731; See also Ib) J.P.Cronin, B.M.Dilworth, and M.A.McKervey, Tetrahedron Lett., 1986,27,757; (c) T.Harada, A.Karadawa,and A.Oku, J.Orq.Chem., 1986,=,842. ( a ) M.Madesclaire, Tetrahedron, 1986,42,5459. (b) €or the asymmetric oxidation of prochiral sulphides see T.Takata, and W.Ando, Bull.Chem.Soc.Jpn.,l986,~,1275. N.Ono, T.Yanai, and A.Kaji, J.Chem.Soc.,Chem.Comun., 1986,1040. (a) E.Vedejs,D.A.Perry, and R.G.Wilde, J.Am.Chem.Soc., 1986,108,2985; ( b ) E.Vedejs, T.H.Eberlein, D.J.Mazur, C.K.McClure, D.A.Perry, R.Ruqgeri, E.Schwartz, J.S.Stults, D.L.Varie, R.G.Wilde, and S.Wittenberqer, J.Orq.Chem., 1986,%,1556.
5 16
General and Synthetic Methods
252. (a) Y.Terao, M.Aono, I.Takahasi, and K.Achiwa, Chemistry Lett., 1986,2089. (a) M.Aono, C.Hyodo. Y.Tera0, and K . Achiwa, Tetrahedron Lett., 1986,27,4039. 253. A-Hasomi, Y.Matsuyama, and H.Sakurai, J.Chem.Soc., Chem.Commun., 1986,1073. 254. S.Nakatsukasa, K-Takai, and K.Utimoto, J.Org.Chem., 1986,zI5O44. 255. M.Hanaby, and S.Warren Tetrahedron Lett., 1986,27,765. 256. M.Yasumura, K.Takaki, T-Tamura, K.Negoro, Bull.Chem.Soc.Jpn., 1986,!39,317. 257. T.Takeda, Y.Kaneko, and T.Fujiwara, Tetrahedron Lett., 1986,27,3029. 258. R.Hunter and C.D.Simon, Tetrahedron Lett., 1986,27,1385. 259. (a) E.Edstrom, and T.Livinqhouse, J.Chem.Soc., Chem.Commun., 1986,279. (b) E.Edstron and T.Livinghouse, J.Am.Chem.Soc., 1 9 8 6 , ~ , 1 3 3 4 . 260. G.Capozzi, R-Ottana, and G.Romeo, Heterocycles, 1986,24,583. 261. J.Fiandanese, G.Miccoli, F.Naso, L.Ronzinici J.Organomet.Chem., 1986,312,343. 262. N.Ono, A.Kamimura, and A.KaJi, _______ J.Org.Chem., 1 9 8 6 , ~ , 2 1 3 9 . 263. K.Hiroi and N.Matsyama, Chemistry Lett., 1986,64. 264. S.T.Saenqchantara and T.W.Wallace, J.Chem.Soc., Chem.Commun, 1986,1592. 265. (a) G.H.Posner, and C.Switzer, J.Am.Chem.Soc., 1986, 3 , 1 2 3 9 . (b) G.H.Posner, M-Weitzerberg, T.G.Hamil1, E.Asirvatheu, H.Cun-Henq and J.Clardy, Tetrahedron, 1986,42,2919. 266. S.D.Khan, and W.J.Hehre, J.Am.Chem.Soc., 1986,108,7399. 267. R.A.Holton, and H.-B.Kim, Tetrahedron Lett., 1 9 8 6 , ~ , 2 1 9 1 . 268. H.Takayama, A.Iyobe and T-Koizumi, J.Chem.Soc., Chem.Commun., 1986,771. 269. (a) S.W.Remiszewski, J.Yang, and S.M.Weinreb, Tetrahedron Lett., 1986 , E l1853. (b) See also, J.K.Whitesel1, D.James, and J.F.Carpenter, J.Chem.Soc., Chem-Commun., 1985,1449. 270. (a) K.Inomada, T.Koayashi, S.Sasaoko, H.Kinoshita, and H.Kotake, Chemistry Lett., 1986,289. (b) K.Inomada, Y.Tanaka, S.Sasaoko, H.Kinoshita, and H.Kotake, ibid p.341. __ 271. I.M.Dawson, J.A.Gregory, R.B.Herbert, and P.G.Sammes, J.Chem.Soc., Chem. Commun., 1986,620. 272. E.Block, A.Aslam, V.Eswarakrishnan, K.Gebreyes, J.Hutchnson, R.Iyer, J.A.Laffitte, and A.Wal1, J.Am.Chem.Soc., 1986,108,4568. 273. P.Auvray, P.Knoche1, and J.F.Normant, Tetrahedron ,.tteL 1986,27,5091,5095. 274. (a) T.Cuvigny, C.Herve du Penhoat, and M-Julia Tetrahedron 1986,42,5321,5329. (b) C.Herve du Penhoat and M.Julia, Tetrahedron, 1986,42,4807. 275. K.Hayakawa, M-Takewaki, 1.Fujimoto and K-Kanematsu, J.Cg.Chem., 1986, 51,5100. 276. K . O g u r Z T.Iihama, S.Kinchi, T.Kajiki, O.Koshikawa, K.Takahashi and H.Iida, J.Orq.Chem., 19 8 6 , z l 7 0 O . 277. K.J.Hwang, J.Orq.Chem., 1986,%,99. 278. (a) S.G.Pyne, J.Chem.Soc., Chem.Commun., 1986,1686. (b) S.G.Pvne and S.L.Cha~man,ibid, p.1688. 279. H.J.Cristau. B.Chabaud. R.Labaudinie;e. and H.Christo1. J.0rg.Chem.i 1986,51,8?5. 280. (a) K.Ogura, K-Ohtsuki, T.Takahashi, H.Iida, Chemistry Lett., 1986,1597. J.Organomet.Chem., (b) J.Klaveness, F.Rise, and K.Undheim, __ 1986,303,189.
6: Organometallics in Synthesis
281.
(c) T.Okuyama, W.Fujiwara, and T.Fueno, Bull.Chem.Soc.Jpn., 1986,2,453. (a) G.A.Krafft and P.T.Meinke, J.Am.Chem.Soc., 1986,108,1314. (b) A.Ishii, R.Okazaki and N.Inamoto, Bull.Chem.Soc.Jpn., 1986.59.2529. K.Yanada, H.Yamaguchi, H.Mequri, and S-Uchida, J.Chem.Soc., Chem.Commun.,l986,1655. (a) S.V.Ley, I.A.O'Nei1, and C.M.R.Low, Tetrahedron, 1986, 42.5363. (b) M.J.Evers, L.E.Christiaens, and M.J.Renson J.Org.Chem., 1986,51,5196. S.Hanessian, P.J.Hodqes, S.P.Sahoo, and P.J.Roy Tetrahedron Lett., 1986,z,2949. (a) C.G.Francisco, E.I.Leon, J.A.Salazar, and E.Suarez, Tetrahedron Lett., 1986,27,2513. (b) A.Toshimistu, K.Terao, S.Uemura, J.Orq.Chem., 1 9 8 6 , ~ , 1 7 2 4 . E.D.Edstrom, and T.Livinghouse, Tetrahedron Lett., 1986,27,3483. (a) R.G.Shea, J.N.Fitzner, J.E.Fankhauser, A.Spaltenstein, P.A.Carpina, R.M.Peevey, D.V.Pratt, B.T.Tenge, and P.B.Hopkins, J.Org.Chem., 1986,%,5243. (b) A.Spaltenstein, P.A.Carpina, and P.B.Hopkins, Tetrahedron Lett., 1986,27,147. M.Tiecco, D.Chianelli, L.Testaferri, M.Tinqoli and D.Bortoli, Tetrahedron. 1986.42.4889. 4897. . . F.Toda, and K.Mori,J.Chem.Soc., Chem.Commun., 1986,1357. N.Petragnani and J.V.Comasseto, Synthesis 1986,l. M.V.Lakshmikanthan, Y.A.Jackson, R.J.Jones G.J. O'Malley, K.Ravichandran, and M.P.Cava, Tetrahedron Lett. I 1986,27,4687. N.Kambe, T.Tsukamoto, N.Miyoshi, S.Murai and N.Sonoda, Bull.Chem.Soc.Jpn., 1986,=,3013. G.Polson and D.C.Dittmer, Tetrahedron Lett., 1986,=,5579. M.J.Dabdoub, V.B.Dabdoub, J.V.Comasseto, and N.Petraqnani, J.Organomet.Chem., 1986,308,211. W.F.Bril1, J.Org.Chem., 1986,=,1149. r
282.
~~
283.
- r
284. 285. 286. 287.
288. 289. 290. 291. 292. 293. 294. 295.
517
~
7 Saturated Carbocyclic Ring Synthesis BY T.V. LEE
1
Three-membered Rings
General Methods. - A review of the preparati.on and chemistry of silyl substituted cyclopropanes, an area which has been unusually quiet during the period under review, will be of general interest.' Despite this, amongst the novel routes to cyclopropanes reported is one involving the treatment of an a-haloketone (1) with diiodomethane in the presence of samarium to form a cyclopropanol.' A cation radical chain cyclopropanation reaction has also been described using ethyl a-diazoacetate ( 2 1 , to give reasonable yields
of useful three-membered rings.3 A full account of the Lewis acid catalysed [2++4] polar cycloaddition react Lon of the methylthio chloride (3) with a 1,3-diene is of interest,4 as is a study of the stereochemical outcome of the cyclopropanation of allylic alcohols . 5 2
Four-membered Rings
Photochemical [ 2 + 2 1 cycloaddition still constitutes by far the most common way to prepare cyclobutanes, and has been applied to a relatively complex system (4) in a copper-catalysed route to robustadials, resulting in a structural revision of these molecules.6
The acetal (5) also gives good yields of the
photoadduct (6) which overcomes previous difficulties in which ester analogues of (5) failed to react.'
Importantly a chiral
version of the reaction has been developed with reasonable success. This utilizes the lactam (7) which, upon reaction with ethylene, gives an adduct with good diastereoselectivity, forming upon hydrolysis two isomeric cyclobutanes, the major one of which has been converted to (-)-grandis01 (Scheme 1) .8
A second means of
achieving a chiral photocycloaddition is to use the chiral spirocyclic enone (8) which has resulted in the synthesis of both Of these two methods, the former is
enantiomers of grandisol.'
better in terms of the diastereoselectivity of the photoaddition
518
7: Saturated Carbocyclic Ring Synthesis
OBr
-
0
+
519
Srn
CH,I,
.>p
Ar3N+ SbCls
H
C0,Et
+
b
CH2CL2, 0 *C
:
€to&
Me
CH3
(2)
Ar = Br-@
0
MesYMe + CI
BUi
i, SnC14
b ii, Et3N
-
BU'
CuOTf
HO
0
hV
hv
Ar*
0
520
General and Synthetic Methods
y---
yy-&
Me
0
H
a
HO (
Me
O
steps f---
Me0,C
- - Grandisol
Reagents:
i, C H 2 = C H 2 , h V ,
PhCOMe, - 7 8
'C;
Scheme 1
H
0
P
Me02C
Y
tie
+
O5
ii, H 2 S 0 4 , MeOH
Me
52 1
7: Saturated Carbocyclic Ring Synthesis
6Ph
SPh
Jr
+
4yPh 0
0(11 1
C02Bu'
J
7
+
-
Bun0
ZnBr2
- 78
C0,Bu'
BU'0,C
O C
7 2 '10
(12)
OH
I
FeSOq
b AcOH
(13)
fi
AlBN,
(1L)
ni
10% BujSnH
A,
dark
84 'lo
5 OIO
General and Synthetic Methods
522
NC;l + Scheme
2
Me EtCOAf
i,LDA .____)
HO
ii,
BJO-
CONMe
(15 OH
-
PhSO, PriNOC4:-
Li'
4-
Pr; NOC'
(16)
0
I1 -
+
PhSO,
0
PriNoCC0,Me
7: Saturated Carbocyclic Ring Synthesis
523
but the latter is a shorter synthesis.
An alternative to using
s u c h chiral auxiliaries in photoadditions is to use a chiral
ketene such as (9), althouqh the diastereoselectivity in this reaction is only modest. l o Two new interesting polar cyclization routes to cyclobutanes have appeared. The first of these utilizes a new reaction of an enone with the thioenol ether (10) under the influence of Lewis acid, in a stepwise process presumably involving an intermediate such as (11) . I 1
The second new method also uses an
enol ether but in a reaction with t-butylmethylenemalonate ( 1 2 ) . I 2 Finally, a fully detailed account of a substitutive spiroannulation route to cyclobutanones will be useful .I3
3
Five-membered Rings
General Methods. - Cycloaddition strategies to cyclopentanes are potentially valuable, and a timely review on the use of trimethylenemethane to partially achieve this aim is of interest.l4 Radical ring closures continue to be widely studied with an intriguing new way of generating radicals, for use in subequent ring closure, being described and involving the 6-fragmentation of a tertiary cyclohexyl radical, generated from the hydroperoxide (13).15
A full account of the use of radical ring closure in
bi,tri- and poly-cycle formation will be of interest to anyone wishing to make use of these reactions,16 as will be a mechanistic study17 and a related report upon some of the factors influencing five versus six-membered ring formation in these cyclizations.'* Further work upon the radical cyclization of allenic ketones under dissolving metal conditions to give mainly cyclopentanes has been described,"
as has the cyclization of the iodo-alkyne (14),
initiated by tin hydride. This process has also been extended to triquinane synthesis.*' The use of an homoallylic radical in a Michael addition to an electron deficient alkene followed by cyclization results in an alternative synthesis of cyclopentanes (Scheme 2) . 2 1
A clever application of known chemistry has been used in a route to iridoids and involves Michael addition to the diester (15) followed by Dieckmann condensation.2 2 An anionic cyclization-elimination route to cyclopentenes is of interest, and involves the reaction of the anion (16) with a Michael acceptor, followed by cyclization and elimination to the cyclopentene (17). 2 3
A further research group has utilized the concept of preparing
524
Me RC02Et
+
1 BrMg(CH2),CHMgBr
-
General and Synthetic Methods
R&,Me+ ,OH
Ho&Rs,Mc
Scheme 3
Reagents: i,
K, N H 3 (L), d O H , Me1 , ii, 03-Zn,
AcOH, Jones
Scheme 4
2,6 - Lutidine,
Me Me
(20)
HO (21
-20
1
'c 74 OIO
7: Saturated Carbocyclic Ring Synthesis
525
0 II 0 OCCF,
0
CH,CI,,
O'C
+ (22
1
78 'lo
- 0,C C F,
Me,Si 0,C
t
Si Me,
SiMe3
Me,Si
ii
I
OC0,Me
I
PdL,
Pd L,
(241
(23
1
iii
Hozc9 Me,Si 0,C
iv
R
EWG
I
Pd L,
Reagents: i. [ P d ( P P h 3 1 4 ] ; ii, MeJSiOCO,Me ( 2 5 1 ;
i i i , MeO-;
iv, R
-
Scheme 5
P
Reagents: i. MeCO2CH2CCH2SiMe3. Pd ( O A c 1 2 . ( P r ' 0 1 3 P - PhCH,,
Scheme 6
100 'C
~
~
~
526
General and Synthetic Methods
vicinal ester dianions for annulations by reacting them with a ~ r y l a t e s ,and ~ ~ by using a relatively conventional ring closure of the ylid (18) some useful optically active cyclopentenones have been prepared. 25
Further uses of the bis-Grignard reagents
1,5-bis(bromomagnesio)pentane and 1,6-bis-(bromomagnesio)hexane in reactions with esters to form cyclic products have been described, as shown in Scheme 3.26 An interesting new route to cyclopentanes involves a ring contraction of a cyclohexadienol ether such as (19) upon treatment with p-bromobenzenesulphonyl azide. 27
The ready availability of
compounds like (191, a Birch reduction, plus the fact that dienol ethers bearing a chiral group react with a high degree of diastereoselectivity makes this a potentially powerful route to 5-membered rings.
Birch reduction, ozonolysis, and decarboxylation
of indanones also constitutes a new preparation of substituted cyclopentenones (Scheme 4) .28 The Claisen reaction mediated ring contraction of macrocyclic lactones is a well known route to cyclopentanes and other size rings, and full details of this approach have now a ~ p e a r e d . ~ ’ A combination of asymmetric 1,4-addition and the magnesium-ene cyclization has resulted in an excellent synthesis of 6-necrodol (20).3 0
The magnesium-ene
reaction has also been used in the preparation of chiral Q- and and 6-skytanthine31 and in the synthesis of racemic c h o k 0 1 - A ~ ~ racemic 6-protoilludene.33 A cationic cyclopentannulation, leading to a synthesis of methylenomycin B , is of interest and involves acid treatment of the allenic alcohol (21) .34 A comprehensive account of the chemistry of cyclopropene ketals, including their use as 1,3-dipoles in the preparation of cyclopentenones, is of interest.35 The trapping of Pummerer reaction intermediates formed from sulphoxides, such as (22), by alkenes is the basis for a new synthesis of ~ y c l o p e n t a n o n e s . ~ ~ I n a useful extension of the chemistry of the palladium ( 0 ) complexed trimethylenemethane moiety, Trost has described the formation of (24) from the bis-silyl compound (23). Even in the presence of an enone this complex is alkylated with the carbonate (25) produced in the first step, and then a second zwitterion is formed for reaction with an enone in a [3+2] cycloaddition (Scheme 5) . 3 7 The same research group has described an approach to brefeldin-A which uses the above [3+2] cycloaddition strategy to generate three contiguous stereocentres of correct absolute and relative stereochemistry as shown in Scheme 6.38 A previously
521
7: Saturated Carbocyclic Ring Synthesis
+
= - - CH,
Me-
I
CO,(
BF,
CO),
(26)
(27
COAr’
Ar’
1
OH T i CI4
Y
*
SiMe,
Me,Si
I
%
g*
BugSnH
(30 1
(p CO, E t
45% Scheme 7
15%
528
General and Synthetic Methods
described donor-acceptor [3+21 annulation sequence has now been used in the preparation of racemic oplopanone.39 The useful rhodium catalysed intramolecular C-H insertion reaction of a-diazoketones to give cyclopentanes has now been described in
and rhodium chemistry has also been used in a
novel route to cyclopentenones which uses a rhodium carbonyl cluster catalysed hydrocarbonylation of enynes. 4 1 The cationic cobalt complex (26) serves as a precursor to lI4-diketones and so to cyclopentanones, by reaction with an enolate anion followed by decomplexation and alkyne hydration. 42
The application of this in
the synthesis of sesquiterpenes has also been described.43
A
mechanistic discussion of the cyclodimerization of enones such as n4-enone tricarbonyl iron complexes44 is valuable and (27) interesting as is the Lewis acid induced cyclization of the allylsilane (28) which provides a highly diastereoselective approach to cyclopentanes. 45
Finally in this section, the lithium-halide
exchanqe of the vinyl iodide (29) has been shown to result in ring closure to a cyclopentenone. 46 Fused Five-membered Rings. - As in the preparation of cyclopentanes, radical ring closures are playing an increasingly useful role in the synthesis of fused five-membered rings
for instance, a further
application of tandem radical cyclization in the synthesis of racemic silphiperfol-6-ene.47
A transannular radical cyclization
has been utilized in the preparation of linear triquinanes (Scheme
7), although the modest yields and lack of regiospecificity are currently limiting for this reaction.48
A combination of ester
enolate rearrangement-radical cyclization has been used to prepare fused cyclopentanes, albeit by use of a fairly lengthy sequence.49 1,3-Diyl trapping reactions have been shown to be of widespread use in the synthesis of cyclopentanes and a review of their use is most timely. 50 Three highly useful fused five-membered ring synthetic building blocks are bicyclo~3.3.0loct-l-ene-3-one, bicyclo[3.3.0loctane-3, 7-dione and bicyclo[3.3.0]oct-6-en-2-one and full details of convenient preparations of these molecules are genuinely useful. 5 1 r 5 2 t 5 3 Details of reactions involving the intramolecular addition of allylsilanes to Michael acceptors to give fused cyclopentanes have appeared,54 and a novel 'one-pot' annulating reagent (31) has been described, in which the two reactive centres are activated by one set of conditions.
Although currently lacking
529
7: Saturated Carbocyclic Ring Synthesis
BrMg
+
6 q % v Cu'Br
Me
w KH
ii (3L 1
(35
S ch eme 8
1
530
General and Synthetic Methods
(37
(36
Reagents: i , BuLi, THF,
HMPA;
1
ii, 10'Ie H C I . acetone
C0,Et CO,Et
TMSOTf, Et3N C6H6. 10 h
Me
Me (L3 1
Scheme 9
7: Saturated Carbocyclic Ring Synthesis
531
aSPh HCOZH, CF3C02H
60 'C,
(LL
24 h
1
60 'lo
cd-co2 H
(L51
OH
@* X
0 % R = H or Me X
= NMePh
or SMe
Scheme 10
532
General and Synthetic Methods
regiocontrol such reactions do in principle offer potential for rapid ring construction.55 A different allylsilane cyclization to cyclopentanes involves closure onto the alkyl cation (32).56 Silicon controlled Nazarov cyclizations have been established and a full account of this work, including further stereochemical details, has appeared;57
intriguingly the use of bulky silicon groups on
enones, such as (33), allows control of the reaction and gives a useful product in which the silyl group is retained.j8 Furthermore a tin-directed Nazarov cyclization has been reported so complementing the silicon chemistry.j9 Tandem reactions are currently very popular as seen in the section on radical cyclizations, and two more examples have been described.
Firstly, the combination of Claisen
rearrangement-vinylcyclopropane rearrangement has been applied to the synthesis of epi-isocomene,60 and secondly the use of a Michael reaction and carbene insertion in tandem leads to a new cyclopentene annulation (Scheme 8).
Thus, the addition of a carbon nucleophile
to an alkynyl-iodinium salt first forms an intermediate which breaks down to a carbene, which then undergoes C-H insertion.61 Oplopanone and analogues were the targets chosen to demonstrate a useful (2)-ethylidenecyclopentannulation sequence, illustrated by the conversion of (34) to (35) .62
The use of the dithiane ( 3 6 ) as an
equivalent for the synthon (37) permits a simple two step route to fused cyclopentanes as shown in Scheme 9.
The lack of regiocontrol
in the second step of this procedure is a weakness, but further studies may overcome this problem since the conversion of (39) to (38)
via a retro-aldol reaction should be possible.63
The reagent
(40) has been introduced as a new ‘one-pot’ cyclopentenone annulating reagent,64 whilst a further novel method uses the regioselective alkylation of allylic sulphides (41), via a-silylated intermediates;65 this latter method has been applied to a synthesis of dihydrojasrnone.66 Base treatment and Michael addition to the a,4-unsaturated ester of (42) to form a hydrindanone has been reported as a key step in a synthesis of racemic f a ~ c e t t i m i n e , ~ ’ and a novel base induced aldol cyclization of the keto-ester (43) constitutes the basis for a new approach to the capnellane diols.68 A hydrolytic ring closure of an enol thioether ketone (44) has also been described being the key step in a synthesis of (+)-pentalenene.69 Vinyl lithium species such as (45) have been shown to undergo a stereoselective cyclization to the ‘syn‘ hydrindane (46), after trapping with an
533
7: Saturated Carbocyclic Ring Synthesis
0 Q-
-
0
A
t
0
Hirsutene
hV
*
&o
0
Me H
0
0
Scheme 11
OMe
OMe
JJp
&OMe
HO
&
Reagents:
HO
i, C ~ C O ( C O ) ~xylene, , hv,
ii, A R - d e c a n e , 20 h
Scheme 12
534
General and Synthetic Methods
Me,Si 0
(L9
C02Me
-[ ;3;-"'] E t 3 N . 2 . 5 HF
1
(50
1
S i Me,
PhS
4
0 (52 1
( 51
+
OLi
PPh, I
OLi
6
4 ii,iii p
p
h
4 i ( 5 3 ) 44%
Scheme 13
overall
535
7: Saturated Carbocyclic Ring Synthesis
electrophile7'
whilst samarium iodide is recommended as an improved
reagent for cyclization of 2-(~-iodoalkyl)cyclohexanone ( 4 7 ) , although with variable stereoselectivity.71 Two related pieces of work giving rise to functionalized cyclopentanes have appeared, involving the intramolecular reaction of a heterodiene with an hetero substituted dienophile (Scheme Biomimetic cyclizations of germacrene derivatives, 10) . 7 2 r 7 3 induced via a bromonium ion, are well known and have now been applied to a synthesis of three naturally occurring ring fused cyclopentanes, oppositol , oplopanone, and aphanamol 74 Further applications of the 6-alkynone cyclization route to cyclopentenones involve the preparation of ( 2 )-methylenomycin B 7 5 r 7 6 and of (+)-isocomene.77 A full account of a transannulation route to
.
angular triquinanes has been described,78 as has a general approach to linearly fused triquinane natural products (Scheme 11) ." 4
Six-membered Rings
Diels-Alder Reactions. - It is very apparent that the year under review marks a sizeable decline in new descriptions of this reaction, especially as its intramolecular variant. However it is also clear that the intramolecular Diels-Alder reaction is now accepted as a powerful and important synthetic strategy. Although not normally included in this section the remarkable one-step formation of O-ring aromatic steroids from acyclic precursors, as shown in Scheme 12, deserves noting.80 The taxanes constitute a synthetic target curently being approached
via
an intramolecular
Diels-Alder reaction,with the diene (48) being useful for this8' and with a full account of previous studies with the same aims having appeared.82 Also of interest is a detailed description of this reaction as applied to the stereoselective synthesis of testosterone and a n d r ~ s t e r o n e . ~By ~ using the cyclopropane carboxylate (49) as a masked vinyl ketone it is possible to produce the triene ( 5 0 ) , E u , for use in intramolecular Diels-Alder reactions84 whilst a study of the effects on yield and stereochemistry of using N,N-dimethylaniline as solvent in these reactions has been reported.85 The use of a second diene so Such a diene will be systems, as will the
of the diene (51) permits the facile generation allowing a tandem reaction to be performed.86 of potential use in constructing polycyclic sulphoxide (52) which serves as a masked
equivalent to 3-methy1ene-ll4-butadiene.87
A further use of a
General and Synthetic Methods
536
Et0,C
b-
C02Et
i , LiN(SiMeg)2
ii, 2 x E t 0 2 C
Y Br
Scheme
EtO'
54 OIO
14
P=O \oE,
(54)
OSi Me,
0
(55 1
6 8 'to
bCHO 'x.3 . ..
+
I , II
92 'lo Reagents:
i , H,O+,
ii, CF3C02H
Scheme 15
7: Saturated Carbocyclic Ring Synthesis
531
A
H (56)
(57
Me/
0~
p
___) :
0 2"4
____)
H20
(59
1
OSi
+
T i C14
PhNHMe
(60
(61
O
Q
5H
1
General and Synthetic Methods
538
dienamine in the Diels-Alder reaction has also been demonstrated. 88 Other Syntheses of Six-membered Rings. - The use of multi-component, one-pot annulation sequences offers considerable synthetic scope as demonstrated by a new cyclohexanone forming reaction (Scheme 13). Thus reaction of an enolate anion, formed either by proton abstraction8’ or nucleophilic addition to an enone, with a Michael acceptor is followed by the addition of triethylboron plus vinyltriphenylphosphonium bromide to give, after Wittig reaction, the decalin (53) in good overall yield.
This and related three
component couplings have been designated as Michael-Michael-RingsClosure (MIMIRC) sequences, with the reaction shown in Scheme 14 being a further good example.” A closely related reaction uses the ester (54) to achieve a three component couplingg2 and a most timely review of such processes will be useful.93 A double Michael reaction of a,B-unsaturated ketones with silyloxydienes (55) using trityl perchlorate as catalyst also gives access to six-membered rings.94
By use of an enamine as a Michael
donor in a reaction with an a-formyl enone, as opposed to using an enolate anion, an existing cyclohexannulation has been expanded further as shown in Scheme 1 5 . ’ ~ A highly stereoselective intramolecular alkylation of an ester enolate leads to an essentially pure diastereoisomeric cyclohexane which will be of value in ~ y n t h e s i s . ’ ~Thus base treatment of (56) causes cyclization, presumably the conformation shown, to give the ester (57). The stereochemical outcome of the intramolecular cyclization of 8-ketoester enolate anions on enonesg7 and ynonesg8 to form six-membered and larger rings has also been studied. A new, but lengthy annulation sequence which controls three stereocentres has been developed, for which base treatment of the An exciting extension of the dienone ( 5 8 ) is the last step.” Robinson annelation involves an enantioselective example using chinchonium salt based phase transfer catalysis . l o o Although currently limited to the use of carvone an interesting new annulation involves an acid induced cyclization of the alkenyl bromide (59). I o 1 Cyclization of the vinylsilane (60) introduces a method for ring formation that permits the stereospecific generation of an exocyclic alkene102’103 whereas an intramolecular variant of a known reaction of homoallylsilanes gives access to a range of a-cyclopropyl ketones by Lewis acid treatment of an acyl choride such as (61).lo4
As part of a steroid synthesis the cyclization of
7: Saturated Carbocyclic Ring Synthesis
5 39
OSiMe, I
______)
%ph2!
OMe
OMe
phT%3 HO
( 65)
(66
I
OMe
1
8 5 'lo
(67)
OMe
General and Synthetic Methods
540
Ill
50 'C
Ho--% (68 )
Si Me, I
co ___)
@
H
85 %
70
82 %
(71)
q
C r C I 3 , LiAIH4
CHO
0r (72)
OH
54 1
7: Saturated Carbocyclic Ring Synthesis
the epoxystannane (62) has been reported.'05 The power of radical ring closure reactions is demonstrated most elegantly in a synthesis of isoamijiol, in which a whole range of carbon-carbon bond forming reactions are used including the cyclization of the ketone (63).Io6 Additionally, the use of a new substrate in radical cyclizations (64) allows access to both six and five-membered rings in a process which for success requires the halide to be on an s p 2 carbon.lo7
Furthermore a useful, and
surprisingly selective, radical cyclization involves a tin hydride reaction at the iodide (65).lo8 However, this reaction appears to be limited to a small number of substrates. Polyene Cyclizations. - This too is an area of decreasing activity but some interesting contributions have appeared. For instance the use of the binaphthol derivative (66) as a chiral Lewis acid permits the asymmetric cyclization of unsaturated aldehydes'"
whilst the
ability of a carboalkoxyallylsilane to successfully terminate a polyene cyclization, so giving a more useful end product, has been demonstrated.'" The use of a simple allylsilane to terminate the cyclization is well known and has been applied to synthesis of karahana ether, 'I1 labdadienoic acid, and isodrimenin. 5
Seven-membered, Medium, and Large Rings
The arene-olefin cycloaddition has been used in a synthesis of the pseudoguaianolide, rudmol lin. l 3 A combination of intramolecular Diels-Alder reaction and ozonolysis of the product (67) leads to a simple preparation of nine-membered rings114 as does the use of an oxy-Cope rearrangement on the vinylcyclobutanol (68), which was the key step in a synthesis of poitediol.'15 An important achievement is the synthesis of optically active fusicoccane, in which the key reaction is cyclization of the bis aldehyde (69) Ring closure of the cobalt complex propargyl derivative ( 7 0 ) , involving reaction 2 a cobalt stabilized carbocation gives access to eight-membered rings117 which are also the product of the nickel(0) catalysed [4+4]cycloaddition of the tetraene (71) .l18 An intramolecular Michael addition of a malonate on an enone or ynone forms nine-and ten-membered rings.
Furthermore the effect
of unsaturation on the intramolecular malonate displacement of primary halides to form eleven-to fourteen-membered rings has been
zr
542
General and Synthetic Methods
0
I
(73 1
i
OSiMe,
&
(7L1
89Y o Reagent: i, T i c $ - CH2CL2
Scheme 16
____) A1Cl3
@
CH(SEt),
\
& \
0
SE t
0
OSiMe3
d
___, i , ii
i- f 4 e C ()7L6 )S n M e 3 8 3 '10
Reagents. i, TMSOTf, TiCIL; i i , P D C
Scheme 17
7: Saturated Carbocyclic Ring Synthesis
543
reported.I2O Low valent chromium induced cyclization of w-bromo-farnesal (72) is the key step in a synthesis of racemic costunolide12' and a radical cyclization of the iodide (73) has been described
.
6
Ring Expansion Methods and Spiro-ring Compounds
A mechanistic study on the rhodium (I) catalysed ring expansion of 1-methylcyclopropylmethanol to 1-methylcyclobutanol is of interest,123 as are full details of the ring expansion of a cyclopropyl alcohol to cyclobutanone including the use of this reaction in the synthesis of various i r i d ~ i d s . ' ~ ~ 'A ~ring ~~ expansion strategy has been used to prepare spirocyclic compounds by a Lewis acid catalysed epoxy silyl ether rearrangement (Scheme 16) Lithium-halogen exchange of iodides such as (74) provide access to spirocyclic ketones127 whilst the continuing interest in the anti-tumour properties of fredericamycin A has prompted a number of synthetic reports upon it. Amongst these is an intramolecular acylation of thioacetal (75) to form the spirocyclic portion of the molecule. 128 An extremely simple way of preparing spirocyclic systems has been reported involving the reaction of the acetal (76) with the silyl enol ether of a carboxaldehyde (Scheme 17) .I2' References 1. 2. 3. 4.
5. 6.
8. 9. 10.
11.
12. 13. 14. 15. 16.
L.A.Paquette, Chem. Rev., 1986, 86, 733. T.Imamoto, T.Takeyama, and H . K o t C Tetrahedron Lett., 1986, 27, 3243 G.Stuffleberne, K.T.Lorenz, and N.L.Bauld, J. Am. Chem. SOC., 1986. 108. 4234. H.Ishibashi, M.Okada, H.Nakatani, M.Ikeda, and Y .Tamura, JChem. SOC., Perkin Trans 1, 1986, 1763. F-Mohamadi and W.C.Stil1, Tetrahedron Lett., 1986, 27, 893. K.La1, E.A.Zarak, W.J.Youngs, and R.G.Salomon, J. Am. Chem. SOC., 1986, 108, 1311. M.C.Pirrung and S.A.Thompson, Tetrahedron Lett., 1986, 27, 2703. A.I.Meyers and S.A.Fleming, J. Am. Chem. SOC., 1986, 108, 306. M.Demuth, A.Palomer, H-D Sluma, A.K.Dey, C.Krtlger, and Y.-H.Tsay, Anqew. Chem.. Int. Ed. Engl., 1986, 22, 1117. G.Fr'lter, U.Mllller, and W. Gtlnther, Helv. Chim. Acta, 1986, 69, 1858. T.Takeda, T.Fujii, K-Morita, and T.Fujiwara, Chem. Lett., 1986, 1311. M.R.Baar, P.Ballesteros and B.W.Roberts, Tetrahedron Lett., 1986, 27, 2083. B.M.TrGt, M.K.-T.Mao, I.M.Balkovec, and P.Buhlmayer, J. Am. Chem. SOC., 1986, 108, 4965. B.M.Trost, An ew. Chem., Int. Ed. Engl., 1986, 25, 1. Z-Cekovic a n d t t . , 1986727, 5981. A.L.Beckwith and D.H.Roberts, J. Am. Chem. SOC., 1986, 108, 5892.
544
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37 38. 39. 40. 41. 42. 43. 44. 45. 46.
General and Synthetic Methods
A.L.Beckwith and D.M.O'Shea, Tetrahedron Lett., 1986, 27, 4525. G.Stork and R.Mook, Jr., Tetrahedron Lett., 1986, 27, 4529. J.K.Crandal1 and M.Mualla, Tetrahedron Lett., 1986727, 2243. D.P.Curran, M.H.Chen, and D.Kim, J. Am. Chem. SOC., 1986, 108, 2489. Z.Cekovic and R.Saicic, Tetrahedron Lett., 1986, 27, 5893. M.Yamaguchi, K.Hasabe, S.Tanaka, and T.Minami, Tetrahedron Lett., 1986, 2,959. P.Beak and D.A.Burg, Tetrahedron Lett., 1986, 27, 5911. E.J.Corey, W.Su, and I.H.Houpis, Tetrahedron Lett., 1986, 27, 5951. H.J.Bestmann and T. Moenius, Angew Chem., Int. Ed. Engl., 1986, 25, 994. P.Cannone and M.Bernatchez, J. Org. Chem., 1986, 51, 2147. D.J.Goldsmith and J.J.Soria, Tetrahedron Lett., 1986, 27, 4701. C.J.Moody and J.Toczek, Tetrahedron Lett., 1986, 27, 5253. R.L.Funk, M.M.Abelman, and J.D.Munger, Jr., Tetrahedron, 1986, 42 , 2831. KOppolzer and P.Schneider, Helv. Chim. Acta, d1986, 63, 1817. W.Oppolzer and E.J.Jacobsen, Tetrahedron Lett., 1986, 27, 1141. W.Oppolzer and A.F.Cunningham, Tetrahedron Lett., 1986, 5467. W.Oppolzer and A.Nakao, Tetrahedron Lett., 1986, 27, 5471. M.A.Tius, D.P.Astrab, A.H.Fauq, J.B.Ouseet, and S.Trehan, Lm . Chem. SOC., 1986, *,3438. D.L.Boger and C.E.Brotherton, J. Am. Chem. SOC., 1986, 108, 6695. H.Ishibashi, S.Harada, M.Okada, M.Ikeda, K.Ishiyama, H-Yamashita, and Y.Tamura, Synthesis, 1986, 847. B.M.Trost, S.M.Mignani, and T.N.Nanninga, J. A m . Chem. SOC., 1986, 108, 6051. B . M . T r Z , J.Lynch, P.Renaut, and D.H.Steinman, J. Am. Chem, SOC., 1986, 108, 284. E-Piers and A.V.Gavai, Tetrahedron Lett., 1986, 27, 313. D.F.Taber and R.E.Ruckle, Jr., J. Am. Chem. SOC., 1986, 108, 7680. K.Doyama, T.Joh, S.Takahashi, and T.Shioharo, Tetrahedron Lett., 1986, 27, 4497. =ha, B.Bagby, and K.M.Nicholas, Tetrahedron Lett., 1986, 915. M.Saha, S.Muchmcre D. van der Helm, and K.M.Nichclas, J. Org. Chem., 1986, 51, 1960. =da and Y.asuji, Chem. Lett., 1986, 1631. G.A.Molander and S.W.Andrews, Tetrahedron Lett., 1986, 27, 3115. H.Sawada. M.Webb. A.T.Stol1. and E.Nesishi. TetrahedronLett.. 1986. _. 27: 2775. D.P.Curran and S.C.Kuo, J. Am. Chem. S s . , 1986, 108, 1106. J.D.Winkler and V . S r i d a r m SOC., 1986,108, 1708. J. Chem. SOC., Chem. Commun., A.Y.Mohammed and D.L.J.Clive, ___ 1986, 588. R.D.Little, Chem. Rev., 1986, 86, 875. S.K.Davidsen and C.H.Heathcock,Synthesis, 1986, 842. S.H.Bertz, J.M.Cook, A-Gawish, and U.Weiss, Org. Synth., 1986, 64, 27. S.Hashimoto, T.Shinoda, and S.I.Ikegami, Tetrahedron Lett., 1986, 27, 2885. G-Matjetich, R.W.Desmond, Jr., and J.J.Soria, J. Org. Chem., 1986, 11, 1753. T.V.Lee, K.A.Richardson, and D.A.Taylor, Tetrahedron Lett., 1986, 27, 5021. J.IpakGchi and G.Lauterbach, Angew Chem., Int. Ed. Eng., 1986, 25, 354. ~
z,
z,
'
~
47. 48. 49. 50. 51. 52. 53. 54. 55. 56.
~
545
7: Saturated Carbocyclic Ring Synthesis
57.
S.E.Denmark, K.L.Habermas, G.A.Hite, and T.K.Jones, Tetrahedron, 1986, 42, 2821. 58. B.L.Chenard, C.M. Van Zyl, and D.R.Sanderson, Tetrahedron Lett., 1986, 27, 2801. 59. =Peel and TR.Johnson, Tetrahedron Lett., 1986, 27, 5947. 60. T.Hudlicky, L.D.Kwart, M.M.Tiedje, B.C.Ranu, R.P.ShEt, J.O.Frazier, and H.L.Rigby, Synthesis, 1986, 716. 61. M Ochiai, M.Kunishima, Y.Nagao, K.FuJi, M.Shiro, and E.Fu]ita, J.Am. Chem., 1986, 108, 8281. 62. E.Piers and A.V.Govai, Tetrahedron Lett., 1986, 27, 313. 63. L.A.Paquette and D.R.St. Laurent, J. Orq. Chem., 1986, 21, 3861. 64. S.C.Welch, J.-M.Assercq, and J.P.Loh, Tetrahedron Lett., 1986, 27, 1115. 65. K.Hiroi, H.Sato, and K.Kotsuji, Chem. Lett., 1986, 743. 66. K-Hiroi and H. Sato, Chem. Lett., 1986, 1723. 67. C.H.Heathcock, K.M.Smith, and T.A.Blumenkopf, J. Am. Chem. SOC., 1986, 108, 5022. 68. M-Shibasaki, T.Mase, and S.I.Ikeqami, J. Am. Chem. SOC., 1986, 108, 2090. __ 69. D.H.Hua, J. Am. Chem. SOC., 1986, 108, 3835. 70. A.R.Chamberlain and S.H.Bloom, Tetrahedron Lett., 1986, 27, 551. 71. G.A.Molander and J.B.Etter, J. Orq. Chem., 1985, 51, 1778. 72. S.L.Schreiber, H.V.Meyers, and K.B.Wiberq, J. Am. Chem. SOC., 1986, 108, 8274. 73. S.E.Denmark and J.A.Sternberq, J. Am. Chem. S O C . , 1986, 108, 8277. 74. Y.Shizura, S.Yamaguchi, Y.Terada, and S.Yamamura, Tetrahedron Lett., 1986, 27, 57. 75. M.Koller, M . K G p f and A.S.Dreiding, Tetrahedron Lett., 3986, 27. 19. 76. M.Koller, M. Karpf, and A.S.Dreiding, Helv. Chim. Acta, 1986, 69, 560. 77. G.G.G.Manzardo, M.Karpf, and A.S.Dreiding, Helv. Chim. Acta, 1986, 69, 659. 78. G.Mehta and K.S.Rao, J. Am. Chem. Soc., 1986, 108, 8015. 79. G.Mehta, A.N.Murthy, D.S.Reddy, and A.V.Reddy, J. Am. Chem. S O C . , 1986, 1 2 , 3443. 80. S.H.Lecker, N.H.Nguyen, and K.P.C.Vollhardt, J. Am. Chem. SOC., 1986, 108, 856. 81. P.A.Brown and P.R.Jenkins, J. Chem. S O C . , Perkin Trans.1, 1986, 1303. 82. K.J.Shea, J.W.Gilman, C.D.Haffner, and T.K.Dougherty, J. Am. Chem. S O C . , 1986, 108, 4953. 83. M.Ihara, I.Sudow, K.Fukumoto, and T.Kametani, J. Chem. S O C . , Perkin Trans 1, 1986, 117. 84. R.Zschiesche, E.L.Grimm, and H.V.Reissiq, Anqew. Chem., Int. Ed. Enql., 1986, 25, 1086. 85. K.A.Parker and T.Fbal, Tetrahedron Lett., 1986, 27, 6291. 86. A.Hosomi, K.Otaka, and H.Sakurai, Tetrahedron Lett., 1986, 27, 2881. 87. E.Wada, N.Naqasaki, S-Kanemasa, and O.Tsuge, Chem. Lett., 1986, 1491. 88. R.L.Snowdon and M.Wust, Tetrahedron Lett., 1986, 27, 699. 89. G.H.Posner, S.-B.Lu, and E.Asirvatham, Tetrahedron Lett., 1986, 27, 659. 90. G.H.Posner and E.Asirvatham, Tetrahedron Lett., 1986, 27, 663. 91. G.H.Posner, S.B.Lu, E.Asirvatham, E.F.Silversmith, andE.M.Silverman, J. Am. Chem. SOC., 1986, 511. 92. T.Minami, K.Watanabe, and K.Hirakawa, Chem. Lett., 1986, 2027. 93. G.M.Posner, Chem. Rev., 1986, 86, 831. ~
=,
General and Synthetic Methods
546
94. 95. 96. 97. 98. 99 100.
T-Mukaiyama, Y.Sagawa, and S.Kobayashi, Chem. Lett., 1986, 1635. W.L.Meyer, M.J.Brannon, A.Merrit, an3 D.Seebach, Tetrahedron Lett., 1986, 27, 1449. K A h n , D . K i E M.W.Chun, and W.-K.Chnng, Tetrahedron Lett., 1986, 27, 943. G.Berthiaume , J . -F Lave1 lee and P .Deslongchamps , Tetrahedron Lett., 1986, 27, 5451. J.-F.Lavellee,G.Berthiaume, and P.Deslongchamps, Tetrahedron Lett.. 1986.. 27. . 5455. S K r a f f t , RX.Kennedy, and R.A.Holton, Tetrahedron Lett., 1986, 27, 2087. A.BhatGcharya, V.-H.Dollinq, E.J.J.Grabowski, S.Karady, K.M.Ryan, and L.M.Weinstock;.Angew. Chem. Int. Ed. Engi. , 1986. . 25.. 476. J.-P.GGson, J.-C.Jacquesy, and B.Renoux, Tetrahedron Lett., 1986, 27, 4461. E.J.Corey and W.L.Siebe1, Tetrahedron Lett., 1986, 27, 905. E.J.Corey and W.L.Siebe1, Tetrahedron Lett., 1986, 27, 909. Y.Hatanaka and I.Kuwajima, Tetrahedron Lett., 1986, 27, 719. D.N.Jones and M.R.Pee1, J. Chem. SOC., Chem. Commun., 1986, 216. G.Pattenden and G.M.Robertson, Tetrahedron L e z . , 1986, 27, 399. H.Urabe and I.Kuwajima, Tetrahedron Lett., 1986, 27, 1355. R.Tsang and B.Fraser-Reid, J. Am. Chem. SOC., 1986,108, 8102. S.Sakane, K.Muruoka, and M.Yamamoto, Tetrahedron, 1986, 42, 2203. W.S.Johnson, C.Newton, and S.D.Lindel1, Tetrahedron Lett., 1986, 27, 6027. R.J.Armstrong and L.Weiler, Can. J. Chem., 1986, 64, 584. R.J.Armstrong, F.L.Harris, and L.Weiler, Can. J. Chem., 1986, 64, 1002. P.A.Wender and K.Fisher, Tetrahedron Lett., 1986, 27, 1857. A.P.Kozikowski and S.H.Jung, Tetrahedron Lett., 1986, 27, 3227. R.C.Gradwood, R.M.Lett, and J.E.Wissinger, J. Am. ChemFSoc. 1986, 108, 6343. N.Kato, K.Nakanishi, and H-Takeshita, Bull. Chem. S O C . Jpn., 1986, 59, 1109. S.L.Schreiber, T.Sammakia, and W.E.Crowe, J. Am. Chem. SOC., 1986, 108, 3128. P.A.Wender and NC.Ihle, J. Am. Chem. SOC., 1986, 108, 4678. P.Deslongchamps and B.L.Roy, Can. J. Chem., 1986, 64, 2068. D.Brillon and P.Deslongchamps, Tetrahedron Lett., 1986, 27, 1131. H.Shibuya, K.Ohashi, K.Kawashima, K.Hori, N-Murakami, and I.Kitagawa, K.Hori, N.Murakami, and I.Kitagawa, Chem. Lett., 1986, 85. N.A.Porter, D.R.Magnin, and B.T.Wright, J. Am. Chem. SOC., 1986, 108, 2787. J.T.Burton and R.J.Puddephatt, Can. J. Chem., 1986, 64, 1890. B.M.Trost, M.K.-T.Mao, J.M.Balkovec, and P.Buhlmayer,J. Am. Chem. SOC., 1986, *,4965. B.M.Trost, J.M.Balkovec, and M.K.-T.Mao, J. Am. Chem. SOC., 1986, 108, 4974. K.Muruoka, M.Haregawa, and H.Yamamoto, J. Am. Chem. Soc., 1986, 108, 3827. T.Van der Does, G.W.Klumpp, and M.Schake1, Tetrahedron Lett., 1986, 27, 519. M. Brown and R.Veith, Tetrahedron Lett., 1986, 27, 179. T.V.Lee, K.A.Richardson, and D.A.Taylor, Tetrahedron Lett., 1986, 27, 5021.
.
I
I
101.
102. 103. 104. 105. 106. 107. 108. 109. 110.
111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129.
8 Saturated Heterocyclic Ring Synthesis BY K . COOPER AND P.J. WHITTLE
1 Oxygen-containing Heterocycles Three-membered Rings. - The addition of oxygen to double bonds remains the most common method for epoxide synthesis, and several new variations on that theme have appeared this year. Thus, alkenes
are converted into epoxides using a solution of elemental fluorine in an acetonitrile/water mixture with complete retention of olefin stereochemistry.' Prat and Lett have re-examined the use of tungstic acid catalysed epoxidation in an attempt to define the scope and synthetic utility of the process. They have shown that reactivity increases with the nucleophilicity of the double bond and that the reaction proceeds only marginally slower at neutral pH than under acidic conditions. With regard to stereochemical outcome the major isomer produced is identical to that produced by vanadate catalysed epoxidations (Scheme 1 ) and in general homoallylic alcohols give poorer stereoselectivity. High stereoselectivity is also given by the dibutyltin oxyperoxide mediated epoxidation of olefins, and in the epoxidation of dienes much higher regioselectivity is shown than by analogous methods: for example, the epoxide (2) is given exclusively on epoxidation of ( 1 ) .4
e.
a,@-Unsaturated ketones, esters, sulphones, are difficult to epoxidize and usually give uncontrolled mixtures of isomers when using the Weitz-Scheffer reaction (alkaline hydrogen peroxide). TWO new methods of epoxidizing such substrates have appeared this year. Glotter and Zviely have shown that the introduction of a neighbouring hydroxy-group allows the epoxidation of a,R-unsaturated ketones by the vanadium/t-butyl peroxide method. Chelation is thought to exert the stereocontrol giving, in general, syn-epoxidation (Scheme 2) . 5 On the other hand Meth-Cohn and his group have developed the use of lithium hydroperoxide in the epoxidation of a,@-unsaturated esters and sulphones. High stereoand regio-selectivity are observed, which is rationalized by 'chelate-locking' of the stereochemistry (Scheme 3 1 , and an encouraging amount of ( 1 9 - 5 5 % ) of enantioselectivity has been observed by incorporating homochiral alcohols into the esters. Further studies into improving the selectivity are underway. 547
General and Synthetic Methods
548
R'YYR3 H202
~
1 rnoI"/. H2WOL
R2
OH
R'F wR3
R'
+
major
Scheme 1
Scheme 2
Scheme 3
OH
minor
8: Saturated Heterocyclic Ring Synthesis
549
Scheme 4
(6)
(7)
OMe
Rbcc R3
0
.
HgO P -TSOH
550
General and Synthetic Methods
I
I
I
OH
(10)
Scheme 5
R2L
o-cl
R'
J
elimination
&
OEt
H Scheme 6
8: Saturated Heterocyclic Ring Synthesis
55 1
The well established Sharpless asymmetric epoxidation,
*
and
asymmetric epoxidation in general , have been reviewed. A new method for converting ketones and aldehydes into epoxides has been reported whereby the unstable chloromethyl-lithium is generated in the presence of the carbonyl compound (Scheme 4)
.'
The
method therefore depends on the rate of reaction of iodochloromethane with alkyl-lithium being faster than reaction of the carbonyl compound with the alkyl-lithium, but in general yields are high (65-99%). Five-membered Rings. - Tetrahydrofurans. Several methods for the synthesis of tetrahydrofurans by acid-catalysed cyclization have been described this year. Noda et al. have shown that the enediol derivatives (3) or (4) can be cyclized in the presence of acid for 1 hour to give the trans-substituted tetrahydrofurans (5) in good yield (52-99%). " L o n g e r reaction times generate the thermodynamically more stable tetrahydropyrans, also in good yield. Acid-catalysed cyclization of the allenic 6-keto-esters (6) or (8) in the presence of mercury(I1) oxide gives the products (7) and (9) respectively." In the absence of acid no reaction occurs. The nominally disfavoured cyclization of 3-alkenols to tetrahydrofurans can be accomplished by treatment of the alkenols with thallium(II1) acetate. The products are formed in a stereoselective manner giving acetoxy-substituted tetrahydrofurans at primary and secondary centres, and hydroxy-substituted tetrahydrofurans at tertiary centres.l 2 Thus, for example, isopulegol is converted into (10) in 80% yield. Radical-mediated reactions continue to be popular for the formation of heterocycles, and several additional methods for tetrahydrofuran synthesis using radicals have been published. Reductive cyclization using tri-n-butyltin hydride has been the most commonly used method, and Pezechk et al. have extended this methodology to the synthesis of the perhydrofuro[2,3,b]furans, as shown in Scheme 5.13 A reductive method has also been used for the cyclization of the vinyl ethers ( 1 1 ) to give substituted tetrahydrofurans.l4 In contrast to this methodology Pattenden's group has demonstrated that radical cyclization in the presence of cobalt(1) allows an oxidative work-up which can be adapted to give either an olefinic product or a hydroxy-substituted product (Scheme 6) .15 Stork's group has also extended the usefulness of radical cyclizations by capturing the intermediate radical in a carbon-carbon bond-forming reaction, and this is best illustrated by
552
General and Synthetic Methods
OE t
OEt
I
I
I I
J. 0
Si Me3 (13)
cz=2H
HO
OH
PGFZ,
(1 5 )
(16) R2
553
8: Saturated Heterocyclic Ring Synthesis
EU~OK ___)
EU~OH
Platyphyllide
(23)
b+
0
‘e-’
R’KR2
554
General and Synthetic Methods
their synthesis of (+)-PGF2,;16
the key step is the
tri-n-butyltin-mediated cyclization of (121, followed by in situ capture of the octenone (13) to give the product (14). Two research groups have simultaneously published on the synthesis of oxygen-containing five-membered rings via oxonium ylide generation and subsequent [2,31 sigmatropic rearrangement.
Thus,
Pirrung and Werner have shown that the keto-ester diazo-compounds (15) are converted into the heterocycles (16) using rhodium catalysis,l 7 whereas Roskamp and Johnson have used the diazo-ketones
(17) to generate the corresponding tetrahydrofuranones (18).I8 Yields are good in both cases and represent the first synthetically useful examples of the intramolecular oxonium ylide generation and rearrangement. Trost and his co-workers have extended their work on the addition of the 'trimethylenemethane' palladium complex to carbonyl compounds and shown that addition of 5 mole% of tri-n-butyltin acetate to the palladium-catalysed reaction of
trimethylsilylmethylallyl acetate with aldehydes gives high yields (>71%) of the desired tetrahydrofurans (19). I 9 Previously, only use of the trimethylstannylmethylallyl acetate had given efficient reaction with the inconvenience of difficult work-up and reagent preparation. The aldol products derived from addition of the diketones (20) to aldehydes can be converted into 2,3,5-tri.substituted tetrahydrofurans a reductive cyclization strategy employing triethylsilane in the presence of trityl perchlorate.2 o The
anti-aldol products give predominantly the 2,5-cis-products (211, whereas the syn-aldol product gives only the =-isomer. ~
Dihydrofurans. The previously published synthesis of dihydrofurans by silver-catalysed cyclization of the pallenic alcohols has been found to be applicable to the preparation of trimethylsilylsubstituted dihydrofurans. 2 1 The allenic ether (22) has been used in an intramolecular Diels-Alder reaction to generate the fused dihydrofuran ring system (23) as the key step in a synthesis of platyphyllide. 22
The reaction has general applicability.
[3+2]
Cycloaddition as an approach to dihydrofurans has been further extended by the discovery that electrochemical oxidation of lI3-diketones (24) in the presence of olefins gives fused 23 dihydrofurans in moderate to high yield (45-97%). Pattenden and his co-workers have extended their cobalt(1)mediated cyclization methodology (see earlier) to the synthesis of
8: Saturated Heterocyclic Ring Synthesis
555
\1““,
e l i mi n a t/o;i
ii, NaBH4 02
Scheme 7
OAc
OAc
(26)
Reagents.
I,
B u t O O H , H g O A c , ii, K B r , iii, B r 2 , N a B r , MeOH
I V ,
Ag02CCF3
Scheme 8
RIOfiO
i.j
TiX4
R2
R2
(27)
X
(28)
General and Synthetic Methods
556
R’
GR& ZnCIZ
A3
R3
&x (31)
ZnC12
Me
Me
Scheme 9
HgCl
R
Hg ( O A C ) ~ HCIOL
OH
0 R
(32)
i
NaBHL
pdoH
R
R
@
8: Saturated Heterocyclic Ring Synthesis
dihydrobenzofurans.24
557
Again, the intermediate organocobalt species
can be transformed to an olefin or hydroxy-substituted product (Scheme 7 ) . The spirobenzofuran ring system appears in several natural products, and Spanerello et al. have developed an intramolecular Michael cyclization for its synthesis.25 Thus, treatment of the phenol (25) with acid furnished a 4:l mixture of diastereoisomers where (26) predominated. Five-membered Rings Containing More than One Oxygen. B y combining the observation that 1-bromoalkyl t-butyl peroxides cyclize to give 1,2-dioxolanesI with the group's method of 1-bromoalkyl t-butyl peroxide synthesis from cyclopropanes, Bloodworth et all have now developed a general and practical synthesis of 1,2-dioxolanes from cyclopropanes (see Scheme 8), which avoids the need to use 98% 26 hydrogen peroxide. Six-membered Rings. -Tetrahydropyrans and Dihydropyrans. Little new work has appeared this year on general methods for the synthesis of tetrahydropyrans. However, Winstead et al. have provided an explanation for the Stapp synthesis of tetrahydropyrans, and in so doing have made considerable improvements in both the yields and the stereoselectivity of the reaction.27 Thus, the cis- and transacetals (27) and (29) cyclize in the presence of titanium tetrachloride at low temperature to give the cis- and transtetrahydropyrans (28) and (30) respectively with high stereoselectivity. Wasserman's research group has shown that the carbonyl epoxide rearrangement, which they have previously described using flash vacuum pyrolysis, may be conveniently carried out under acid catalysis giving a general and high-yielding method for the synthesis of the bicyclodioxoalkenes ( 3 1 ) ,28 which has been applied to an enantiospecific synthesis of the house mouse pheromone2' (see Scheme 9). Kitching et al. have described a new method for spiroacetal synthesis involving mercury-induced cyclization of dienones and hydroxyenones.3 0 The resulting organomercurials (32) can either be reduced or converted into hydroxy-substituted products. The hetero-Diels-Alder reaction of aldehydes as the 217 component has been extensively studied of late, and this year the use of high pressure both on its own and in combination with Lewis-acid catalysis has been extended. A combination of [ E ~ ( f o d ) ~ ] and high pressure (10 kbar) has been used to prepare amino functionalized dihydropyrans from the diene (33) and orthoaminoaldehydes,3 1 whereas high pressure alone is nnough to drive the
558
General and Synthetic Methods
OMe
+
0 Me Scheme 10
8: Saturated Heterocyclic Ring Synthesis
559
mcpba
J
i , NaOH
(43)
ii, H O A C
OH
OH
(44)
OR
mcpba
(45)
J
i, K O H
ii, H+, a c e t o n e
H
(461
General and Synthetic Methods
560
reaction of Danishefsky dienes with n-butyl glyoxalate giving better stereoselectivity than the [Eu(f~d)~l-catalysed reaction (Scheme 32 10). There have been relatively few examples of the hetero-DielsAlder reaction where the carbonyl group is part of the 4rr component. This is mainly due to the instability of both starting materials and products to heat and acid, and consequently Lewis-acid catalysis has been of minor applicability. Yamamoto et al. have now shown, however, that the molybdenum complex [ M 0 0 ~ ( a c a c ) ~ I catalyses the reaction of benzyl enol ether (34) with methacrolein under mild conditions to give the dihydropyran (35).”
Although the majority
of examples of this variant of the hetero-Diels-Alder reaction have used an enol ether as the 2n component, Denmark and Sternberg have shown that vinyl sulphides are equally good as the 2 n component in an intramolecular reaction.34
Thus, intramolecular hetero-Diels-
Alder reaction of the vinyl sulphide enal (36) under boron trifluoride catalysis affords predominantly the *-fused product (37). The application of the hetero-Diels-Alder reaction to natural product synthesis has been reviewed. 35 Pyrans.
The hetero-Diels-Alder reaction also features in one of
two approaches to pyrans described this year, whereby the
B-silyloxy-acrylonitrile (38) adds to the alp-unsaturated ketone (39) to give the pyran (40) in moderate yield (55%).36 alternative approach,
In the
the pyran series (41) is synthesized using a
method which bears much similarity to the classic Hantzsch synthesis.
Thus, addition of 8-keto-esters or B-diketones to the
acrylonitriles in the presence of triethylamine affords good yields
(60-85%) of the pyrans (41).37 Polyether Ionophores. - The complex and unusual structures of the ionophores has generated much interest amongst organic chemists, and in recent years especially, their stereo- and enantio-specific total synthesis has become a realizable goal through some inventive and intriguing chemistry.
In the monensin type ionophore, much interest
has focused on Cane’s proposed biosynthetic polyepoxide cyclization route, and two approaches which use macrocycles for stereocontrol have been simultaneously published.
Still‘s group converted the
macrocyclic trienelactone (42) into the single triepoxide (43) using m-choroperbenzoic acid, and subsequent saponification and
cyclization gave the tris-tetrahydrofuran
(44).38
Schreiber et al. ,
on the other hand, selectively epoxidized the dienelactones (451,
561
8: Saturated Heterocyclic Ring Synthesis
N C S ,A g N 0 3
Me Scheme 11
(49) x = 0 (50) X = S
General and Synthetic Methods
562
cqe
J
(511
“0
(52)
‘0H H
(531
Me02C
“‘0
/
x-
0
(55)
0 ’
(54)
Meo 0
R1
R’
SnC14
*
to
R3
(57)
(58)
8: Saturated Heterocyclic Ring Synthesis
563
and then saponified and cyclized the intermediate bisepoxides to the bis-tetrahydrofuran derivatives ( 4 6 ) .39 Hoye and Suhadolnik have investigated the epoxide cascade reaction in a completely systematic manner by preparing all the possible isomers of the triepoxide (47) and then converting them into the bis tetrahydrofuran (48).40 A s expected, reactions invariably proceed via inversion, and the authors are currently addressing the correlation of n.m.r. data of the isomers of (48) with the n.m.r. of invaricin. In the brevetoxin area of polyether ionophores, Nicolaou's group has developed two methods for the synthesis of brevetoxin part-structures based on sulphur chemistry. In the first method, the problem of forming medium-size rings is tackled by generating a sulphonium ion which is readily captured by an adjacent hydroxygroup (Scheme 11) .41 The second method relies on the rigid conformations of macrocycles for successful and efficient transannular reactions. Thus, the dithionolides (50) generated from the dilactones (49) undergo an intramolecular reductive coupling to give predominantly cis ring fusion using sodium naphthalide as reducing agent, or trans ring fusion using triethylsilane and silver tetraf luoroborate. 42 Bartlett's research group has continued its work on the stereocontrolled synthesis of tetrahydrofurans and tetrahydropyrans, and has extended this work to the synthesis of polycyclic ethers as models for brevetoxin synthesis. Iodoetherification of the cyclohexanol (51) and subsequent rearrangement affords the tetrahydropyran (52), which in a subsequent iterative iodoetherification and solvolysis generates the trans-syn-trans-fused polyether (53). 4 3 Medium Rings. - The diazo-carbonyl compounds (54) undergo rhodiumcatalysed carbene formation and subsequent intramolecular insertion to give the seven-membered cyclic ethers (55) in high yield (71-78%) and the eight-membered ring ether (56) in moderate yield (24%). 4 4 Overman et al. have developed a highly efficient and general method for eight- and nine-membered cyclic ethers which involves the direct cyclization of simple unsaturated acetals.45 Thus, Lewis-acid mediated cyclization of the 5-alken-1-01s and 6-alken-1-01s (57) affords the oxocenes (58; "=1) and hexahydrooxonins (58; n = 2 ) in good (40-70%) and moderate ( 1 0 - 2 0 % ) yields respectively.
General and Synthetic Methods
564
Si Me3
fi
S i Ph ,Bu
OSi P h2Bu
\
___)
Me0,C
4-9
Me0,C H
(62)
+
(63) OSiPh2Bu'
Me0,C H
(65)
(66)
8: Sarurated Heterocyclic Ring Synthesis
565
2 Sulphur-containing Heterocycles
Most methods for the synthesis of thiirans use epoxides as the starting materials but yields are generally low. Takido et al. have described a new approach to this conversion using dimethylthioformamide as the sulphur transfer reagent.46 Yields are good (66-95%), and the reaction is applicable to a wide range of substrates. Thiocarbonyl ylide addition to olefins features as the most popular approach to tetrahydrothiophenes published this year. The parent thiocarbonyl ylide (59) can be generated from chloromethyl trimethylsilylmethyl sulphide with caesium fluoride, and the ylide adds to olefins and acetylenes with complete retention of olefin stereochemistry in good yield(56-86%); 4 7 (59) can also be generated from bis(trimethylsily1) sulphoxide at 100°C in HMPA, and in the presence of dipolarophiles affords tetrahydrothiophenes, again with retention of the olefin stereochemistry and in good yield.48 When the ylide is substituted with a trimethylsilyl group, mixtures of tetrahydrothiophenes (60) and (61) are generated where the regiospecificity depends on the substitution pattern of both the ylide and the olefin.49 Intramolecular Diels-Alder reaction of the vinyl sulphide diene (62) furnishes the corresponding fused ring tetrahydrothiophene as a mixture of the four possible diastereoisomers, where the major isomers (63) and (64) arise from the stereocontrol exerted by the silyloxy substituent.50 Vedejs and his group have continued their studies into the hetero-Diels-Alder reaction of thioaldehyde derivatives with dienes. Their most recent work has demonstrated that thermolysis of phenacyl sulphides generates substituted thioaldehydes which form dihydrothiophene derivatives on reaction with dienes. 51
Electron-
withdrawing substituents give the 'typical' Diels-Alder regiochemistry (65) where the substituent prefers the ortho and
para
positions relative to the diene donor substituents, whereas electron-donating substituents give the opposite regiochemistry (66). The unmasking of 1,3-dithianes by electrolytic oxidation, to generate ketones, has been developed into a synthesis of 1,2-dithiolene 1-oxides. The method requires controlled electrolysis of the 1,3-dithianes in aqueous acetonitrile, and gives variable yields (20-74%) of the required products (67).52
566
General and Synthetic Methods
0 R’
x3:4
*;y4 5
R2
R3
“ R’ ; R 4
NH20H. HCI P y r i di n e
-
R1
“-0
A
(71)
A +H
(72)C 0 2 E t
8: Saturated Heterocyclic Ring Synthesis
0
+
CIS02N=C=0
567
+
R2
+
0 *YNH
0k0 0
568
General and Synthetic Methods
a,w-Dithiols are readily converted into cyclic disulphides (68) by initial transformation to the bis-tri-n-butyltin thiolates, followed by oxidation with either bromine or iodine.53
Yields are
best for the smaller ring systems, but even for the difficult ring sizes, such as the eight-membered example (68; ~ = 6 ) ,the yield is 36%. The synthesis of heterocycles containing more than one sulphur atom has been reviewed.64 3 Heterocycles Containing More than One Heteroatom Nitrogen- and Oxygen-containing Rings
-
a-Hydroxy-hydroxamic acids
react with carbonyl di-imidazole to give, after carbon dioxide extrusion either spontaneously or on heating, the substituted oxazetidin-3-ones ( 6 9 ),55 and 1 ,3-di-imines react with hydroxylamine in pyridine at room temperature to give the dihydroisoxazoles (70). 5 6 Cycloaddition reactions as an approach to nitrogen- and oxygencontaining heterocycles have dominated the literature this year and are the topic of the remainder of this section.
The intramolecular
cycloaddition of aryl oxaziridines to give fused isoxazolidines (71)
via a nitrone i n t e n r ~ e d i a t e . ~On ~ the other hand the oxime (72) undergoes an intramolecular
proceeds in good yield, presumably
cycloaddition to give the isoxazolidine (73) and can either be formulated as a 1,3-dipolar cycloaddition or as an intramolecular Michael type reaction. 58 Chlorosulphonyl isocyanate adds to epoxides to generate the carbon dioxide inserted oxazolidines (74) or dioxalones (75) depending on the substitution pattern of the epoxide.59 Denmark's research group has made extensive investigations into the cycloaddition reactions of heterodienes with olefins, and this year they have shown that nitroalkenes can participate in such reactions in both an intra- and an inter-molecular fashion. Thus, the tin tetrachloride catalysed cyclization of the nitroalkenes (76) affords the tricyclic nitronates (77) in good yield (59-80%) where the olefin geometry is retained in the product but where the exo/endo selectivity depends on the substitution pattern of the starting material.6 o The intermolecular studies were conducted using nitrocyclohexene (78) as the substrate where reaction with cyclic olefins, again in the presence of tin tetrachloride, gave predominently the =-products.
61
8: Saturated Heterocyclic Ring Synthesis
569
R’
R2
C02Et
S c h e m e 12
General and Synthetic Methods
570
buffer
37
O C
S c h e m e 13
NC
R2
p$
0
Scheme 14
57 1
8: Saturated Heterocyclic Ring Synthesis
Weinreb et al. have systematically explored the intramolecular Diels-Alder reaction of Ij-acyl-imines generated from the bisamides (79) to extend the usefulness of this little studied reaction. Thus, boron trifluoride catalysed intramolecular cycloaddition of (79) gives stereospecifically the dihydroxazines (80) in good yield (58-89%).62 Nitrogen- and Sulphur-containing Rings.- The preparation of lI3-thiazines as intermediates in the synthesis of cephalosporins has been published utilising a [4+2] cycloaddition of the l-thia-3azadienes (81) with
a,
4-unsaturated aldehydes and ketones.63
The
reaction proceeds thermally, except where R = C02 Et when a Lewisacid catalyst is required, and yields are generally high. Two research groups have published methods for the synthesis of the benzothiazepine class of molecule this year. Ishibashi et al. have prepared a 1,2,3,5-tetrahydro-4,l-benzothiazepine
via
intramolecular Friedel-Crafts reaction of the ortho-chloro intermediate (82) or acid-catalysed cyclization of the sulphoxide (83).
Similar routes are successful for the synthesis of the
benzoxathiepines (84).64 The second research group has described several routes to the previously undisclosed
4,5-dihydro-1,4-benzothiazepinones (851, and these routes are summarized in Scheme 12.65 Oxygen and Sulphur-, and Oxygen-, Nitrogen-, and Sulphur-containing Rings.- Further studies on the formation and spontaneous fragmentation of lI2-oxathietanes have been published. The 1,2oxathietanes were formed by cyclization of chloroethyl sulphoxide intermediates (Scheme 13) and their formation was deduced by formation of aldehyde- and thioaldehyde-derived products. 6 6 Thiopivaldehyde adds to a range of heteroatom-containing dipolarophiles to give oxathiazolidines, dihydro-oxathiazoles, and thiadiazolidines as outlined in Scheme 14. 67 4 Nitrogen- containing Heterocycles Three-membered Rings. - The aziridines (88) can be prepared in excellent yields, and under essentially neutral conditions, by cyclodehydration of the corresponding 6-amino-alcohols ( 8 6 ) , using
diethoxytriphenylphosphorane
.
(DTPP) 68
Substitution at C-1 or C-2
is tolerated and the reaction proceeds with retention of configuration at C-2, presumably __ via the intermediacy of the 1,3,2-
572
General and Synthetic Methods
R'
OH
DTPP
Toluene, 60 "C
(86)
L
Ph
(87)
Ar'
+
A?*N
(89)
be
(92)
t
Pb ( O A c ) & K2C03
NBU~
II
MeC-NHN=CMe2
(93)
Bu'Li
Ar2-S0,CH2CI
____.)
-78 "C
A r 2S0,
(911
(90) n = 1 or 2
Me
(94)
(95) X = C H C N (96) X = SO2
8: Saturated Heterocyclic Ring Synthesis
573
Me02C
/ (101)
(1001
qR
CH2Si Me3
R3
(102)
/Ah
CH,S i M e 3
CH;
R3
(105) R2
R' i , CF3S020CH2SiMe3 ii,CsF
+
Ph
j & i & k
Me M e
(1061
XCHSCHY
Me Me Scheme 15
Ph
General and Synthetic Methods
574
oxazaphospholane (87). The corresponding N-ethylaziridines are also available directly, if DTPP is used in excess. The sulphur-substituted azabicyclo[l.l.Olbutane sulphones and sulphoxides (91) are readily available
via reaction of the lithium
salts of the a-chloro-sulphones or -sulphoxides (90) with the arylazirines (89).69 Yields are generally good and a wide range of functionality on the parent heterocycle is potentially available. The novel dihydro-lI2,4-triazole (92), prepared by oxidation of the -
amidrazone (93), reacts with acrylonitrile and with sulphene (CH
SO2 ) to give the spiroaziridines (95) and (96) respectively.70 probable intermediates (94) were not detected.
chi
Five-membered R i . . - Four reviews in this area have appeared.
The
synthesis of five- and six-membered nitrogen heterocycles by multicomponent one-pot annulations,71 by vinylsilane- and alkynylsilane-terminated cyclization reactions, 72 and by the use of n i t r ~ a l k e n e shas ~ ~ been described, and Vedejs and West have reviewed the preparation of azomethine ylides by the desilylation of a-silyl-onium salts and their use in the synthesis of nitrogen heterocycles.74 The same research group has also reported an alternative strategy for the preparation of azomethine ylides based upon formation of the oxazolines (98) from the corresponding salts (97) by a novel reduction procedure, and subsequent ring opening and trapping with dipolarophiles to afford the pyrrolines (100) or pyrrolidines ( 1 0 1 ) .75
The method is limited to examples where R3=H, since substitution at this position increases the stability of the oxazolines (98) relative to the ring-opened dipoles (99), but yields are generally good and the compatibility of the reducing agent with the dipolarophiles makes the process a simple one-pot operation. Padwa and co-workers have continued their long standing studies in the area of azomethine ylide generation and trapping, and now report that the N-[ (trimethylsily1)methyllindoles ( 1 0 2 ) react with the electron-deficient alkenes ( 1 0 3 ) , in the presence of silver fluoride, to afford the cycloadducts (104) regio- and stereo~pecifically.~ The ~ azomethine ylide(l05) is a probable intermediate. In a similar reaction sequence, the pyrrolizines (107) can be prepared in generally good yields from the z - p y r r o l e s
(106)
via the one-pot procedure shown in Scheme 1 5 . ~ ~
Cycloaddition of heteroaromatic N-ylides with substituted alkenes is a well known method for generating five-membered nitrogen heterocycles but a disadvantage of the route is the instability of
8: Saturated Heterocyclic Ring Synthesis
515
BU Mc,SiO NEt 3
XCHZCHY
\ R1
Br(108)
M e,S i CH2N H-C-R’
II
Y Y = S or N R 3
(109)
R20Tf*
+
M e3SiCHN , H=C,
,%-C H2-i
/R’ VR
-0Tf
Scheme 16
H-C’
R’ ‘YR2
576
General ond Synthetic Methods
R4)3p’
A
R3
0
+
-HCI
0
I
A
N-R’
R2 I
‘R’ (11 3 ) n =1-3
(1141
511
6: Organornetallics in Synthesis
the primary adducts, which often rearrange or decompose in order to re-aromatize the heterocycle.
This problem has been solved in a
neat way by using the 4-(sily1oxy)pyridinium ylides (108).78 Cycloaddition with electron-deficient alkenes now gives the stable cycloadducts (109) stereospecifically, but in only moderate yields. Full details have appeared from Tsuge and co-workers of their studies of general routes to N-protonated azomethine ylides carrying a leaving group at the ylide carbon, for use in subsequent trapping reactions as synthetic equivalents of non-stabilized nitrile ylides (Scheme 16) . 7 9
Three other useful cycloaddition methods for the
synthesis of fused bicyclic nitrogen rings have been described this year.
Pearson et al. have reported the first examples of the
intramolecular cycloadddition of 2-aza-ally1 anions to qive the cis~
fused pyrrolidines (110).80 Yields are only moderate but stereoselectivity is generally high and unactivated alkenes react well as the anionophiles.
The tetrahydroindoles (112) are formed in
essentially quantitative yields by thermally induced intramolecular Diels-Alde? reaction of the allenic dienamides (111).81
The
corresponding cis-indolidines and indoles are readily prepared from the products ( 1 1 2 ) by standard reductive and oxidative methods, respectively.
The fused five-, six-, and seven-membered nitrogen
heterocycles (114) can be prepared in excellent yields from the 2-pyrone-6-carboxamides (113) by intramolecular Diels-Alder reaction, followed by loss of carbon dioxide.82
The products (114)
serve as potential precursors for a wide range of polycyclic systems by subsequent cycloaddition to the diene unit. Preliminary results published last year from the groups of H ~ d l i c k yand ~ ~ P e a r ~ o nsuggested ~~ that the formation of the fused pyrrolines (117) by pyrolysis of the azido-dienes (115) would be a useful synthetic procedure if conditions allowing the specific decomposition of the vinylaziridines (116) via cleavage of bond 'a' could be identified.
This problem has now been solved simply by
incorporating a heteroatom at R1 of the diene unit:
the acetal-like
nature of the intermediate (116) now weakens bond 'a' sufficiently to allow formation of (117) as the major reaction product in a one-pot operation.85
In the case of R1=C02Et, "=1,
the intermediate
vinylaziridine can be isolated and selectively rearranged to the product (117) via nucleophilic opening with lithium iodide.86 The synthesis of five-membered nitrogen rings via transition metal-, in particular, palladium-meditated cyclization procedures has been a major interest this year.
Trost et al. have reported a
general synthesis of the substituted pyrrolidines (119) and (120)
General and Synthetic Methods
578
ArSnBun30r ArHgCI, [ P d C I*( P h C NI2
I
CUCI2
PdCl , C u C 1 2
2 C O . MeOH R' (126) R' = CH2Ph or S02-p-Tol
R2
8: Saturated Heterocyclic Ring Synthesis
519
Pd complex, Ph3P
NaHC03 I p - xylene
+
s
130 'C
I
,,- R
(130)
(129)
' 6 R4 R 3
PhSeBr MeCN
Scheme 17
"i +c.s'? H
CUCl,CUC1*
(131)
(132)
1 H
(133) Bun3SnH
.1 H
580
Genera[ and Synthetic Methods
by palladium-catalysed cyclization of the 1 ,6-enynes (118). 87
The
ratio of products (119):(120) can be controlled by the choice of the palladium ligand, or by incorporation of allylic oxygen substituents, which direct cyclization exlusively to give (120), and the procedure is sufficiently mild to allow good yields of relatively unstablz products, including a O-lactam, to be obtained. Fused pyrrolidines are also available via this methodology and there is obvious application, therefore, to the alkaloid area.
Earlier
work by the T r o s t group on t h e use of palladium complexes of trimethylenemethane in the synthesis of nitrogen heterocycles has now been usefully extended by Jones and Kemmit, who report that the substituted 4-methylcnepyrrolidines (123) are available in one step, and with improved yields, from the mesylate (121) and the imines (122) using a d10 nickel complex as catalyst.88 The first examples of the Pd"-catalysed 1,l-arylamination of unsaturated amides to give 2-aryl-pyrrolidines and -piperidines have been reported by Tamaru et a1.89
The products (125) are produced in good yields from
the alkenyl toluene-p-sulphonamides (124) and under mild conditions. In a related procedure, Pdl*-catalysed cyclization of the allenic amine derivatives (126) in the presence of carbon monoxide and methanol affords the pyrrolidineand piperidine acrylates (127) in moderate to good yields.90
The presence of added base (Na2C03 or
Et 3N ) is sometimes necessary to ensure efficient cyclization. The x - m e t h y l e n e - ? ( - b u t y r o l a c t a m s
(129) are readily prepared from
the homoallylic chloroformamides (128) by a simple Pd"
or Pd"
-catalysed c y c l i ~ a t i o n . ~ The ~ major products (129) are accompanied by varying amounts of the isomer (130), the ratio depending upon both the nature of the catalyst and the substituents R 1 and R2. Toshimitsu et al. have extended current procedures for the formation of nitrogen heterocycles by intramolecular amidoselenation by showing
that N-alkenylamides undergo cyclization efficiently, thus allowing easy access to a wide range of fused, as well as monocyciic, pyrrolidine derivatives (Scheme 17) .92 The high level of interest shown, in previous years, in the formation of nitrogen heterocycles by radical cyclizations has waned somewhat this year but two interesting applications of known procedures have appeared.
Broka and Eng have shown that homolytic
cyclization of the N-chloramine (131) efficiently yields the chloroindolizidines (132) and (133), with some stereoselectivity. Dechlorination of (132) and (133) proceeds very easily to yield gephyrotoxin 223AB (134) and t h e epimer (135).93
The 3-alkyl-2-
oxindoles (137) can be prepared in high yields by radical
8: Saturated Heterocyclic Ring Synthesis
58 1
(136) X = Me or S E M
(137)
H C H O , CF3C02H H 2 0 , THF
CH2Ph
(1 4 0 1
0 (141)
(142)
PPSE = trimethylsilyl polyphosphate
C02Et
4hLC02Et
0
NSP 0
(143 1
(144)
582
General and Synthetic Methods
cyclization of the corresponding acryloylanilides (136).94
Ring
closure in the alternative mode, to give dihydroquinolones, is sometimes observed but selectivity for 5-=-trig always high.
cyclization is
Cyclization of N-unsubstituted acryloylanilides
(136;x=H) was unsuccessful. Grieco et al. have continued their studies of immonium ions generated in situ under aqueous conditions and now report that the amino-allylsilane (138) can be cyclized efficiently and under mild conditions to afford the 3-vinylpyrrolidine (139).95
Six-, seven-,
and eight-membered nitrogen rings are also available from the appropriate aminoallylsilanes & y
the same procedure and preliminary
results indicate that the reaction works well with primary aminoallylsilanes and with aldehydes other than formaldehyde, making this an extremely versatile and efficient method for the formation of a wide range of substituted nitrogen heterocycles.
Cationic
cyclization of a nitrilium ion, generated by Beckmann rearrangement of the corresponding oxime, onto an alkene is an efficient method for the formation of nitrogen rings but suffers from the disadvantages, firstly that the stereospecificity of the Beckmann rearrangement means that only one oxime isomer can be used to give a particular product and secondly that rearrangement conditions are not always compatible with other functionality. These drawbacks have been neatly overcome by generating the intermediate nitrilium ion not from the oxime but from the correspondinq secondary amide. Thus, the amide ester(l40) cyclizes smoothly under acid catalysis to give the pyrroline ester (141) which, in turn, gives the
benzylidenepyrrolizidinone (142) after imine reduction and cyclization. 96 Asymmetric reduction of the imine potentially gives access to optically active monocyclic and fused bicyclic nitrogen rings. An efficient synthesis of the pyrrolizidine system has been achieved by Kametani et al., which utilizes the group's intramolecular carbenoid displacement strategy to effect the key cyclization of (143) to (144).97
Swenton et al. have described a
general procedure for the preparation of the quinone imine ketals (146).9 8 Electrochemical oxidation of the readily available phenols (1451, followed by base hydrolysis, gives the products (146) in excellent overall yields. The N-substituted pyrrolidines (147) can be prepared in generally good yields by reductive amination of succinaldehyde, generated in situ by acid hydrolysis of 2,5-dimethoxytetrahydrofuran, using tetracarbonylhydroferrate as the reducing agent. 99
8: Saturated Heterocyclic Ring Synthesis
583
(146)
(145) n = 1 or 2
Me0
J A M e
I
R (147)
CH,CH,CCH
C H2C H2C 0 2 H steps
=
I I1 ZNH-CH 0 ICONH,
2R
(148)
b2,
PdlC
584
General and Synthetic Methods
0 R2
R
\c’
II
+
I
Ph3&-c=C=NPh
H
0 (150)
(151)
0
I1
R
c’‘
‘
R2
0
I II N-c-C-&-c-N I II +I
0 II
H
0
H Ph
PPh,
I-
=O
Ph-N=C
R2
H
R’
II
0
I 0II + IPPh,
H
0 (153)
(152)
Ci;$
NOC-CON
0
0
0 (155)
8: Saturated Heterocyclic Ring Synthesis
585
+ LiCH2(CH2),CH20THP
+
(C H 2 I n n 0 T H P
(156) n = 1-3
(1 5 7 )
1
10 "10 P d I C , cyclohexene
OMe
(159)
(158)
RI P hCH=N-C-C02Me
i ,A , THF, No1 & ii. H 2 0 , H C I
I
&'Z:'Me
(C H21nC I (160)
n = 3- 5
(161)
CH,Ar
C O2H
I
/I&+ ArCH=NMe
R1
130 "C
10 m i n
R1
R2
R2
(163)
(1621
T S N H-(
C H2In -N H TS
(165) n = 4 or 5
(164)
586
General and Synthetic Methods
The method works well for both aliphatic and aromatic primary amines.
An asymmetric synthesis of the cis-5-alkylproline
derivatives (149) has been described by Ho et al., which involves, as the key step, reductive cyclization of the protected keto-amides The cis products are formed generally with high (148). ' O 0 selectivity (4-9:l) and the route is sufficiently flexible to allow incorporation of a wide range of 5-alkyl substituents. The pyrrolizidinediones (153) can be prepared easily, but in variable yields, from the cyclic diacylamino-acids (150) by reaction with Ij-phenylketeniminylidenetriphenylphosphorane (151) and subsequent intramolecular Wittig reaction of the acyl ylide (152). I o 1 Optical activity present in the starting amino acid derivatives is maintained through the reaction sequence.
A mild, efficient, method
for the conversion of the monoamides (154) into the succinimides and glutarimides (155) has been reported by Kametani et al. Yields are good and the use of N,N'-disuccinimidyl
oxalate as the
condensing agent allows the conversion to be run as one-pot since only gaseous by-products (CO,CO,) are formed at the initial condensation stage. A novel route to the ring-fused lactam (159) has been described by Thomas, the key step of which involves regiospecific attack of the bifunctional nucleophiles (156) at the 6-position of 2-methoxypyridine to give the lactims (157).
Subsequent
deprotection and cyclization of (158) can be accomplished in one step to afford the products (159) in moderate to good yields.
In
another N-alkylative procedure, the halogenoalkylimines (160), readily available by alkylation of the corresponding a-amino-ester imines, are converted into the saturated nitrogen heterocycles (161) simply by refluxing in THF with sodium iodide.lo4 The method fails for n=l and 2 in (160) but for the larger rings it provides easy access to a range of cyclic a-amino-acid derivatives. The 3-alkyl-3-hydroxyisoindolones
(164) are readily available by
thermal decarboxylation of the phthalide carboxylic acids ( 1 6 2 ) in the presence of the imines (163).
The reaction does not involve
formation of the phthalidyl anions from (1621, and subsequent addition to the imines ( 1 6 3 ) , but may proceed y &
initial formation
of a [4 + 21 cycloadduct, followed by decarboxylation and rearrangement. Shono et al. have reported the synthesis of the N-tosyl-pyrrolidines and -piperidines (166) from the corresponding bistosylamides (165) via a novel anodic oxidative rearrangement. Attempted formation of the corresponding four- and seven membered rings was unsuccessful, but for five- and six-membered rings yields
587
8: Saturated Heterocyclic Ring Synthesis
MesON i. basic alumina
ii, 10"/0 P d / C , H 2 *
H (171)
(1 70)
R2j$oEt OSiR',
Lewis
+
R3
R2&
R3 (175)
(1 76)
(177)
General and Synthetic Methods
588
are generally good and the reaction is probably general since cyclization of the bistosylamides of ornithine and lysine methyl esters also proceeds efficiently. Five-membered Rings Containing More than One Nitrogen. - The A2-pyrazolines (169) are produced in excellent yields by SnC12 -catalysed ring expansion of the azocyclopropanes (1681, which are readily available
V
J
oxidative cyclization of the A useful aspect of this procedure is
@-stannylhydrazones (167).Io7
that the two-step conversion of the hydrazones (167) into the pyrazolines (169) is stereospecific:
the cyclopropanation proceeds
with inversion and the ring expansion with retention of configuration at the @-carbon.
The first synthesis of
4-imidazolidinone (171) has been reported by Nitta et al., by a route which utilizes a novel Beckmann rearrangement-ring expansion of the azetidinone oxime mesylate (170).lo8 Six-membered Rings. - The intramolecular aza Diels-Alder reaction, in all its various guises, has long been exploited as a useful synthetic method for the synthesis of six-membered nitrogen heterocyles, and this year has seen interest in this area continue at a high level, with new variants of the basic reaction and some useful extensions to known procedures being reported.
Grieco and
his group have extended their earlier finding that simple unactivated iminium salts undergo aza Diels-Alder reaction with dienes in water by showing that the reaction can be extended to include C-acyl-iminium ions.
Thus, the cycloadducts (173) are
formed in good yields and under mild conditions by reaction of the iminium salts (1721, formed in situ from the corresponding imines and aldehydes, with cyclopentadiene.l o g The reaction works well for the imines formed from glyoxylic acid and should find much application, not only in nitrogen heterocyclic synthesis but also in substituted cyclopentene synthesis since reductive cleavage of the cycloadducts (173) proceeds easily to give the cyclopentene derivatives (174).
Danishefsky and his group have continued their
studies in this area by showing that the unstable A'-pyrroline (176) participates in Lewis acid-catalysed Diels-Alder reactions with the activated dienes (175) to afford the fused cycloadducts (177), in moderate yields,'" al. have reported that the
and in a similar procedure Veyrat
cis- and
trans-N-phenyl-2-
( 1 8 0 ) can be obtained by acid-catalysed aza Diels-Alder reaction of the silyl enol ether
phenyldecahydroquinolin-4-ones
et
8: Saturated Heterocyclic Ring Synthesis
+ OSiMe3 (178)
589
WPh
Lewis
zz-
PhCHZNPh
(179)
( 1 80)
r
1
0="-:iMe3 R1
I
CsF
CH2NMe3
50-60 " C , MeCN
X(181)
(182)
(184) X = electron-withdrawing group V = H o r X
80-110 " C , benzene or
tohene 1 - 12h
R'
H&
.OEt
c i s : trans 3.5-8 : 1
(185)
(186)
General and Synthetic Methods
590
1
FVT
I OC0,Me (167)
R = H
~
$. - R q 2 1"
N
I
C0,Me
C0,Me
o r Me
(1 90)
J y02Me
(y?"-x 0 (192)
J
(191)
59 1
8: Saturated Heterocyclic Ring Synthesis
(178) with benzylideneaniline (179).
The formation of
cis- or
trans-products can be controlled to some extent by the choice of Lewis acid and reaction conditions. The intramolecular cycloaddition of o-quinone methide N-alkylimines with alkenes to form six-membered nitrogen rings is
well documented but the intermolecular reaction is less well characterised. Ito et al. have now shown that the 2-quinone methide N-alkylimines (182), generated in situ by treatment of the corresponding N-trimethylsilyltrimethylammonium salts (181) with fluoride ion, react with the electron-deficient alkenes (183) to give the tetrahydroquinolines (184) in moderate yields and The generally as a mixture of stereo- and regio-isomers.'l2 reaction strangely fails when R'=methyl.
The
hexahydroisoquinolines (186) are readily available V J a novel intramolecular aza Diels-Alder reaction of the N-(hexa-3,5-dienoyl)-acrylimidates (185), where the link between the diene and dienophile is an imidate group.'l3 Yields are good and the imidate unit can be selectively reduced in the presence of the amide function to give the corresponding ethoxyamides which are themselves useful intermediates for further modification. A thermally induced 1-aza-Cope rearrangement has been utilized by Fowler and co-workers in a novel synthesis of the c&-pyridine derivatives (189), from the hydroxamic acid derivatives (187).ll* Isomerization of the intermediate N-acylimine (188; R=H) to the corresponding enamide is not a problem in this bicyclic example but is the major reaction pathway in the analogous cyclohexene system. Incorporation of a methoxy-group at the 3-position of the cyclohexene, however, suppresses this side reaction. Winkler et al. have reported a stereoselective synthesis of the azaspiroundecane system (192) by a route which involves as the key step the quantitive conversion of the vinylogous amide (190) to the fused piperidine derivative (191) by a photochemical [2+21 cycloaddition. The exclusive formation of the adduct (191) can be rationalized in terms of the preferential formation of the transition state where the methoxycarbonyl group of (191) occupies a pseudo-equatorial position but, in view of the distance of the chiral centre from the alkene units which participate in the cycloaddtion, the observed degree of asymmetric induction is remarkable. Enamides of type (193; R=alkyl), do not undergo photocyclization but the corresponding analogues where R=aryl have now been shown to cyclize readily, to afford the
592
General and Synthetic Methods
-I-;J R'
TFA
HCHO
R2 Si Me,
.1
R1
I R2 SiMe,
PhCH2NH2.TFA HCHO
*
(195)
CH2Ph (1 9 6 ) Scheme 18
(197)
8: Saturated Heterocyclic Ring Synthesis
593
R
/--
(CO),Cr=C
\OEt
f
+ 3
PhNC
P hL C = C (CO1,Cr
L
4 'OEt
(204)
(2031
Ph
d?qR
Ph
(C0 C r (206)
- 0 Et
(205)
(208)
(207)
pc7
R2
H2N
(209)
0
(210)
General and Synthetic Methods
594
3-aryl-1-oxotetrahydroisoquinolines (194), in variable yields Two useful routes to substitut.ed piperidines, based upon intramolecular trapping of an iminium ion by an alkene have been reported.
Grieco and co-workers kave used the aminomethano
desilylation-cyclization procedure shown in Scheme 18 to prepare a
wide range of 4-hydroxypiperidi~,2derivatives.
The procedure is
mild, one-pot, and generally works well with terminal aminosilanes and primary amines, but the scope is potentially very wide since secondary amines and trisubstituted alkenes, particularly those with hydroxyalkyl substituents, also cyclize efficiently.
Of particular
interest is the observation that crotyltrimethylsilane ( 1 9 5 ) undergoes reaction with formaldehyde and benzylamine to generate the iminium ion (196) which cyclizes with stereospecific capture of water to give, as the sole product, the 3,4-trans-disubstituted piperidine (197).
In a similar type of reaction, Hartman et al.
have shown that the fused piperidine (199) can be prepared by intramolecular trapping of the iminium ion generated from the dihydropyridine (198) by treatment with titanium tetrachloride. A thiophene unit can also be used as the iminium ion trap. Transition metal-mediated routes to six-membered nitrogen rings have figured prominently this year.
Vollhardt and his group have
reported a novel route to the fused dihydroindoles (202) which utilizes a cobalt-mediated [2+2+2] cycloaddition of the pyrrole derivative (200) with the monoalkynes (201). ' I 9
Yields are generally
only moderate but may improve when conditions have been optimized. Aumann et al. have described a novel preparation of the 6-carbolines (206) by reaction of the alkenyl- or dienyl-carbene complexes (203) with phenyl isocyanide.12' are likely intermediates.
The ketenimine complexes (204) and (205) The Trost group has reported the
synthesis of the optically active isoquinuclidines (208) by a route which involves the Pdo-catalysed cyclization of the vinyl epoxide The cyclization proceeds in excellent yield and is (207).I2' regiospecific, since terminal cyclization would lead to a bridgehead olefin.
Grimaldi et al. have extended the scope of the
silver-catalysed heteroatorn-allene cyclization route to oxygen and nitrogen heterocycles by showing that the procedure works well f o r the synthesis of the 3,6-dihydro-2(1H)-pyridones (210), from the 13allenic arnides ( 2 0 9 ) . 122 Two related procedures for the synthesis of the quinolizidine ring system have been reported by Comins et al. which utilize, as the key step, regiospecific attack of a functionalized carbanion at the 2-position of a 4-substituted 1-acylpyridiniurn salt (Scheme
595
8: Saturated Heterocyclic Ring Synthesis
SnMe,
SnMe3
I
. ..
01.11
OMe
L
Reagents
i, Et02C-
CI ,
L D A , Z n C I 2 , ii, M e 0 2 C C I , iii, ( C 0 2 H ) 2 , H 2 0 , T H F .
; v , H Z , P t 0 2 , A C O H , v . H B r , A c O H , v i , C I M g ~ O E E , v i i PhCH2O2CCI.H30: , viii. T M S C I , N E t 3 . i x , R M g X . C U I
( C 0 2 H $ , H20, T H F ,
X ,
TsCI,py,
H 2 , IO "1e P d l C , L;CO3
XI.
S c h e m e 19
R
b
FVT +
4 0 0 "C
(212) n = 1 o r 2
General and Synthetic Method.
596
M e3 S i0 S 02C F3
,
"
'
O
m
R'0
+
'N\5iMe3
-0 SO 2 C F 3 (216)
.;';.I
(217)
1
0
(219)
(221)
(220)
0
8: Saturated Heterocyclic Ring Synthesis
597
19) ‘123‘124Although the general procedure is rather lengthy the starting materials are readily available and overall yields are good, making this a potentially very attractive method for the synthesis of a wide range of fused piperidine systems. A shorter but lower yielding route to the same ring system has been described by Brandi et al., who have extended their earlier finding that 4,5-dihydroisoxazole-5-spirocyclopropanes yield dihydropyridones on pyrolysis by showing that if the 3-substituent contains a potential N-alkylating function then fused piperidines of general type (212) can be formed, in one operation, from the precursors (211) A similar procedure has been employed to prepare the mono- or bi-cyclic piperidin-4-ones (214) from the isoxazolidines (213), although in this case the desired products are accompanied by varying amounts of the enaminones (251).126 Reaction of a suitably functionalized carbanion with an imine, and subsequent intramolecular trapping of the resultant secondary amide anion by an electrophile, is a useful procedure for the preparation of nitrogen heterocycles but in some cases the reaction fails because the imine is not sufficiently electrophilic. Jahangir et al. have solved this problem by using trimethylsilyl trif luoromethanesulphonate as a quaternizing agent. 127 This reagent not only increases the reactivity of the imine towards nucleophilic attack but is sufficiently labile to allow subsequent cyclization of the imine nitrogen.
The isoquino[2,l-bl [2,71naphthyridines (128),
for example, are formed in excellent yields by reaction of the dihydroisoquinolines (216) with the lithio derivatives (217), in the presence of trimethylsilyl trifluoromethanesulphonate. No reaction occurred in the absence of the latter reagent. A new route to the fused tetrahydropyridines (222) has been described by Minami et al. which involves initial nucleophilic addition of the imide anions (220) to the vinylphosphonate (219), to give the phosphonate anion (221). Subsequent addition of a further molecule of (219), followed by an intramolecular Wittig-Horner olefination gives the products (222), generally in high yields.128 A useful addition to the range of Pictet-Spengler type procedures
for the synthesis of fused nitrogen heterocycles has been reported by Orazi et al., who have shown that the tetrahydroisoquinolines (224), and the five-and seven-membered ring homologues, are readily available by intramolecular sulphonamidomethylation of the precursors (223) followed by cleavage of the sulphonamide group with Vitride or by acid treatment.12’ The cyclization works well for activated and unactivated aromatic rings.
598
General and Synthetic Methods
p-r
HCHO H+
R’
N b p 2
1
V it r id e
or
ti30+
(224)
0 1 5 ‘10
C F j S 0 3H / T H F H20 I
OMe 0
0
(226)
(225)
R
f” phy,N
NY /N\
4 ph+F R
II
0
+
____)
Ph
Ph
/N\
599
8: Saturated Heterocyclic Ring Synthesis
(231 1
(230)
(23 2)
Meo-e 0
Ac 0
(236 1
MeomH \
M eO
'Ph
(238)
General and Synthetic Methods
600
The fused piperidine-3-ones (226) are readily available from the tetrahydrofurans (225) v i a the aza analogue of the Achmatowicz rearrangernent.l3'
The products are formed stereospecifically from
the mixture of tetrahydrofuran stereoisomers, which need not be separated.
The ready availability of the starting materials,
together with the efficiency of the rearrangement and the potential for further manipulation of the functionality present in (226), makes this route very attrzctive as a synthetic entry to a range of fused nitrogen ring systems. Six-membered Rings Containing More than One Nitrogen. - The tetrahydropyrimidones (229) are formed in excellent yields via a [4+21 cycloaddition of the lI3-diazabutadienes (227) with diphenylketene (228), 1 3 1 and mild base-catalysed isomerization of the 1,2-dialkylindazolones (230) gives the dihydroquinazolinones (231) and/or (2321, the actual ratio of products depending upon the relative acidities of the 1- and 2 - s u b ~ t i t u e n t s . ~ ~ ~ Barluenga et al. have reported the first example of a Diels-Alder reaction between an electronically neutral 2-aza-1 ,3-diene (233) and an electron-poor dienophile, (234). 133 The product tetrahydrotriazines (235) are formed in excellent yields and under mild conditions. Seven-membered Rings. - Both enantiomers of the fused
1,2,4,5-tetrahydro-3-benzazepine (238) have been prepared from the corresponding optically active g-acetylmandeloyl chlorides (236) by a route which utilizes an interesting hydrogenolytic ring expansion of the aziridines (237).134
The ready availability of the resolved
a-hydroxy-acid precursors makes this a potentially general route to optically pure 2-substituted tetrahydro-3-benzazepines. In a further extension of their recent studies concerning the generation of nitrogen heterocycles by flash vacuum pyrolysis of 4,5-dihydroisoxazole-5-spirocyclopropanes and related compounds, Brandi and co-workers have found that thermolysis of the analogous spirocyclobutanes (239) and (240) affords the tetrahydro- and
hexahydro-azepine-4-ones (241) and (242) respectively, albeit in only moderate yields, although the route has in its favour simplicity of operation and ready availability of starting materials. 135 Finally, a review has appeared of recent advances in the synthesis of annelated 1,4-benzodiazepines, which includes reference to the preparation of the analogous saturated ring systems.136
601
8: Saturated Heterocyclic Ring Synthesis
R\ R
h H
( 2 39 )
FVT
600-700 " C
% (240)
.:b; (242)
i , L i A l ti4
1
;i, M e 3 S i C l
R -C=N
R2XoLiD 0
(243)
OEt
R3
(244)
R'
BUn3P ii, R 3 C H = N S T r *
o r Me3Sil
Fo??
i. LDA ii, R * , + N ~
SO,
R2jdR 0
(245)
N P r ',
r
OMe (250)
1. /
(249)
.10:1 c i s : t r o n s (251)
56-92'1. e.e. f o r p u r e cisisomer (252)
OMe
General and Synthetic Methods
602
. .. P
(253)
Me
...
--=+
R e a g e n t s : i, P h C H 2 N H L i , T H F , - 7 8 " C . i i , M e O H , - 7 8 " C ; iii, B r 2 , C H 2 C L 2 , - 7 8 " C . ;v, M e I , - 7 8 " C
Scheme 2 0
RCH=NMe
(258)
(260)
B FL-
(259)
603
8: Saturated Heterocyclic Ring Synthesis
B-Lactams. - The utility of hydroxamate-mediated N-C(4) cyclization procedures in the synthesis of a-lactam antibiotics has been reviewed by Miller. 13’
The condensation of N-trimethylsilylimines
with ester enolates is a useful procedure for the formation of N-unsubstituted B-lactams and Andreoli et al. have now extended this initial finding by showing that the 3-trimethylsilylimine can be generated and trapped in situ.138 Thus, reduction of the nitriles (243) followed by silylation ~i the resultant imine and subsequent trapping with an ester enolate gives, in a one-pot procedure, the 3,4-disubstituted azetidinones (244).
The method works for
aliphatic and aromatic nitriles but yields and stereoselectivity are generally low. Hart and his co-workers have extended the utility of the ester-imine procedure in a different way, by showing that the sulphenimines (246) react. with the enolates of the esters (245) to afford the 6-lactams (248).13’ The presence of the bulky sulphur substituent is essential in order to avoid competing attack of the enolate on sulphur but, given this restriction, the reaction is compatible with a range of substituents on ester and imine, including enolizable imines, and products are generally formed in cis-6-lactam. The high yields and with good stereoselectivity for __ tritylsulphenyl group can be removed efficiently by several procedures to give the corresponding N-unsubstituted B-lactams. The same research group has also described an asymmetric synthesis
of the azetidinones (251) by condensation of the N-arylimines (250) with the lithium salt of the optically active esters (249) Oxidative removal of the Ij-aryl substituent readily affords the N-unsubstituted @-lactams (252). Following the initial report by Liebeskind et al. last year,141 using racemic starting materials, Davies and his group have now reported their extensive studies of the asymmetric synthesis of B-lactams by Michael addition of lithium benzylamide to the optically pure a,6-unsaturated iron acyl complexes (253) and (254) (Scheme 20) The products (255) and (256) are formed with excellent optical purity (>100:1) and, given the range of substituents that could potentially be incorporated by this method, the scope of this reaction for the synthesis of optically pure B-lactams could be very wide indeed. Barrett et a1.144 have reported an alternative iron-mediated route to the 8-lactams (260) based upon addition of the cationic iron(I1) vinylidene (257) with the imines (258), followed by oxidative cleavage.
Yields are only
moderate at best and the products (259) are formed as inseparable
General and Synthetic Methods
604
Ph-CEC-C
u
+
0
hP: $hp
0
II
P h C C H-N-A
lp
PY
r
r.t,
0 (261)
(262)
C02R‘ X-CHz-C
N-CH
II I
I
(263)
7 t-I RBr ( 2 6 5 ) . 2e-
€ t 4 N+ C lo4-
I
0 R3 R 2 ( 2 6 4 ) X = Br or CI
C0,R’ I B r C H Z i j Y-i-BrI
(267)
I
2e-
E t N+ C I04-
0 R3 R 2
(268)
R’OCH,COC[
(269)
+
(270)
M e s e Y - HR I O . E F e L NEt3)
N
\
H C02R
( 271 1
0
(2721 BU”
-b1 / 3
R 10
\C02R2 (273)
H
\
0
‘C02R2 (274)
Sn
8: Saturated Heterocyclic Ring Synthesis
(276)
10mM soln.of ( 2 7 5 ) . Bun3SnH, AIBN
H
H
-
(277) H
Triton B
0 (279)
(278)
K [ Pd I o(rP P Bu hjn),I4 N I
0
0>>I 1
CO2CHZP h
C02CH2Ph
( 2 8 0 ) X = 0 or CH,
(281 1
C0 2 CH2 Ph
(282)
R3
R3
hV MeCN (284) (283)
606
General and Synthetic Methods
mixtures of diastereomers but the potential for a useful, perhaps asymmetric, route to substituted 3-lactams is clearly present. Treatment of the nitrones (262) with copper acetylide (261) affords the trans-N-arylazetidinones (263) in excellent yields145 and the 3-lactams (267) are formed, also in excellent yields by two related electrochemical methods involving formation of the C(3)-C(4) bond, from the halogenoacetamides ( 2 5 4 ) and (266)
In the former
route, the function of the bromide (265) is to provide a source of the base R- which can then abstract a proton from the precursor (264) and effect ring closure. S-acetyl cepham analogues (270) are formed in moderate The yields by low temperature photolysis of the N-acyl-2-thiotetrahydro-lf3-thiazines (268), followed by in situ
trapping of the intermediate thiols (269). 147
A useful extension to
the well known ketene-imine cycloaddition route to B-lactams has been reported by Nagao et al., which is based on the use of the methylseleno group as an activating and controlling element. 148 Thus, the reaction of the cyclic methylseleno imino compounds (272) with the alkoxyacetyl chlorides (2~71),in the presence of base, gives the 5-methylselenopenams (273) with high stereoselectivity and in generally good yields. Reductive demethylselenation is readily accomplished, to give the products (274). Knight et al. have reported a novel route to the carba-penam and -cepham analogues (276) and (277) respectively, which utilizes as the key step a radical cyclization of the vinyl bromide (275).14' The carbapenam (276) is formed with high diastereoselectivity and the regioselectivity of the cyclization can be controlled either by varying the initial concentration of the bromide (27s) or by varying the cyclization conditions (thermal or photochemical).
An
alternative approach to the carbapenam derivative (279) has been described by Dumas et al. which utilizes an efficient base-catalysed Interestingly, intramolecular N-alkylation of the iodide (278). attempted cyclization of the epimeric (at C - 3 )
iodide was
unsuccessful. Mori et al. have extended their palladium-catalysed ene-halogenocyclization methodology to provide a useful synthesis of the oxa- and carba-homocepham analogues (281) which can be closed readily with base to afford the corresponding cyclopropa-oxa- or -carba-cephams (282) The novel bis(B-lactams) (284) are formed in excellent yields by photochemical isomerization of the pyrimidinium-4-olates (283). The products (284) can be converted into monocylcic 6-lactams but
8: Saturated Heterocyclic Ring Synthesis
only in very poor yields. References 1.
2. 3. 4. 5. 6. 7. 8. 9. 10.
11 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34
-
35.
S.Rozen and M.Brand, Anqew. Chem. Int., Ed. Engl., 1986, 25, 554. D. Prat and R. Lett, Tetrahedron Lett., 1986, 27, 707. D Prat, B.Delpech, and R.Lett, Tetrahedron Lett., 1986, 27, 711. S.Kanemoto, T.Nonaka, K.Oshima, K.Utimoto, and H.Nozaki, Tetrahedron Lett., 1986, 27, 3387. E.Glotter and M.Zviely, J. Chem. SOC., Perkin Trans.1, 1986, 327. C.Clark, P.Hermans, O.Meth-Cohn, C.Moore, H.C.Taljaard, and G.van Vuuren, J. Chem. Soc., Chem. Commun., 1986, 1378. A.Pfenninqer, Synthesis, 1986, 89. J.W.ApSimon and T.L.Collier, Tetrahedron, 1986, 42, 5157. K.M. Sadhu and D.S.Matteson, Tetrahedron Lett., 1986, 27, 795. I.Noda, K.Horita, Y.Oikawa, and O.Yonemitsu, Tetrahedron Lett., 1986, 27, 1917. T.Delair and A.Doutheau, Tetrahedron Lett., 1986, 27, 2859. H.M.C.Ferraz, T.J.Brocksom, A.C.Pinto, M.A.Abla, and D.H.T. Zocher, Tetrahedron Lett., 1986, 27, 811. M.Pezechk, A.P.Brunetiere, and J.Y.Lallemard, Tetrahedron Lett., 1986, . 27, . 3715. O.MoriE, Y.Urata, Y.Ikeda, Y.Ueno, and T.Endo, J. Org. Chem., 1986, 51, 4708. H. Bhandal, G-Pattenden, and J.J.Russel1, Tetrahedron Lett., 1986, 27, 2299. G.Stork, P.M.Sher, and H.-L-Chen, J. Am. Chem. SOC., 1986, 108, 6384. M.C.Pirrung and J.A.Werner, J. Am. Chem. SOC., 1986, 108, 6060. E.J.Roskamp and C.R.Johnson, J. Am. Chem. SOC., 1986, 108, 6062. B.M.Trost and S.A.King, Tetrahedron Lett., 1986, 27, 5971. T.Mukaiyama, M.Hayashi, and J-Ichikawa, Chem. Lett., 1986, 1157. S.S.Nikam, K.-H.Chu, and K.K.Wany, J. Org. Chem., 1986, 51, 745. K.Hayakawa, S-Ohsuki, and K.Kanematsu, Tetrahedron Lett., 1986, 27, 947. J. Yoshida, K-Sakaquchi, and S.Isoe, Tetrahedron Lett., 1986, 27, 6075. V.F.Pate1, G.Pattenden, and J.J.Russel1, Tetrahedron Lett., 1986, 27, 2303. R.A.SpGevello, M.Gonzalez-Sierra, and E.A.R;veda, Synth. Commun., 1986, 16, 749. A.J.Bloodworth, K.H.Chan, and C.J.Cooksey, J. Org. Chem., 1986, 51, 2110. R.C.Winstead, T.H.Simpson, G.A.Lock, M.D.Schiavelli, and D.W. Thompson, J. Org. Chem., 1986, 51, 275. H.H.Wasserman, S.Wolff, and T.Oku, Tetrahedron Lett., 1986, 27, 4909. H.H.Wasserman and T.Oku, Tetrahedron Lett., 1986, 27, 4913. W-Kitching, J.A.Lewis, M.T.Fletcher, J.J.De Voss, R.A.I.Drew, and C.J.Moore, J. Chem. SOC., Chem. Commun., 1986, 855. A.Golebiowski, J.Izdebski, U.Jacobsson, and J.Jurczak, Heterocycles, 1986, 24, 1205. J.Jurcaz, A.Golebiowski, and A.Rahm, Tetrahedron Lett., 1986, 2 7 , 853. Y.Yamamoto, H.Suzuki, and Y.Moro-Oka, Chem. Lett., 1986, 73. S.E.Denmark and J.A.Sternberq, J. Am. Chem. Soc., 1986, 108, 8277. R.R.Schmidt, Acc.Chem.Res., 1986, 19, 250.
608
General and Synthetic Methods
36. A. A1 berola, A.M. Gonzglez , B. Gonzglez , M .A.Laguna , and F.J.Pulido, Tetrahedron Lett., 1986, 27, 2027. 37. N.S.Ibrahim, Heterocycles., 1986, 24, 935. 38. W.C.Stil1 and A.G.Romero, J. Am. C G m . SOC., 1986, 108, 2105. 39. S.L.Schreiber, T.Sammakia, B.Hulin, and G.Schulte, J. Am. Chem. SOC., 1986, 108, 2106. 40. T.R.Hoye and J.C.Suhadolnik, Tetrahedron., 1986, 42, 2855. 41. K.C.Nicolaou, M.E.Duggan, and C.-K-Hwang, J. Am. Chem. SOC., 1986, 108, 2468. 42. K.C.Nicolaou, C.-K.Hwanq, M.E.Duggan, K.B.Reddy, B.E.Marron, and D.G.McGarry, J. Am. Chem. S O T . , 1986, 108, 6800. 43. P.A.Bartlett and P.C.Ting, J. Org. Chem., 1986, 51, 2230. 44. J.C.Heslin, C.J.Moody, A.M.Z.Slawin, and D.J.WilEams, Tetrahedron Lett., 1 9 8 6 , z , 1403. 45. L.E.Overman, T.A.Blumenkopf, A.Castaneda, and A.S.Thompson, J. Am. Chem. SOC., 1986, 108, 3516. 46. T.Takido, Y.Kobayashi, and K.Itabashi, Synthesis, 1986, 779. 47. A.Hosomi, Y-Matsuyama, and H.Sakurai, J. Chem. SOC., Chem. Commun., 1986, 1073. 48. M.Aono, C.Hyodo, Y.Terao, and K.Achiwa, Tetrahedron Lett., 1986, 27, 4039. 49. Y.Terao, M.Aono, and K.Achiwa, Heterocycles, 1986, 24, 1571. 50. D.R.Williams and R.D.Gaston, Tetrahedron Lett., 1986, 27, 1485. 51. E.Vedejs, T.H.Eberlein, D.J.Mazur, C.K.McClure, D.A.Perry, R.Rugerri, E.Schwartz, J.S.Stults, D.L.Varie, R.G.Wilde, and S.Wittenberaer. J. Ora. Chem.. 1986.. 51. . 1556. 52. R.S.Glass, A-Petsom, and G.S.Wilson, J. Org. Chem., 1986, 4337. 53. D.N.Harpp, S.J.Bodzay, T.Aida, and T.H.Chan, Tetrahedron Lett., 1986, 27, 441. 54. R.K.Dieter, Tetrahedron, 1986, 42, 3029. 55. T.Lauterbach and D.Geffken, Liebigs Ann. Chem., 1986, 1478. 56. J.Barluenga, J-Jardon, and V.Gotor, .J. Chem. Res. ( S ) , 1986, 464. 57. A.Padwa and K.F.Koehler, Heterocycles, 1986, 24, 611. 58. E.Malamidou-Xenikaki and D.N.Nicolaides, Tetrahedron, 1986, 42, 5081. 59. T.Lorincz, I.Erden, R.Nader, and A.de Meijere, Synth. Commun., 1986, 16, 123. 60. S.E.Dezark, M.S.Dapen, and C.J.Cramer, J. Am. Chem. SOC., 1986, 108, 1306. ___ 61. S.E.Denmark, C.J.Cramer, and J.A.Sternberg, Helv. Chim. Acta., 1986, 69, 1971. 62. P.M.Scza and S.M.Weinreb, J. Org. Chem., 1986, 51, 3248. J.P.Pradere, J.C.Roze, H.Quiniou, R.Danion-Bougot, D.Danion, and 63. L.Toupet, Can. J. Chem., 1986, 64, 597. 64. H.Ishibashi, M.Okada, A.Akiyama, K.Nomura, and M.Ikeda, J. Heterocycl. Chem., 1986, 23, 1163. 65. J.Szab6, L.Fodor, A.KatbcZ G.BernSth, and P.Sohgr, Chem. Ber., 1986, 119, 2904. 66. J.W.Lown, R.R.Koganty, and A.Naghipur, J. Org. Chem., 1986, 51, 2116. 117. 67. E.Vedejs and R.G.Wilde, J.Org.Chem., 1986, 68. J.W.Kelly, N.L.Eskew, and S.A.Evans, Jr., J. Orq. Chem., 1986, 51, 95. 69. S.Calet and H.Alper, Tetrahedron Lett., 1986, 27, 2739. 70. A.L.Schwan and J.Warkentin, J. Chem. SOC., Chem. Commun., 1986, 1721. 71. G.H.Posner, Chem. Rev., 1986, 86, 831. 72. T.A.Blumenkopf and L.E.Overman, Chem. Rev., 1986, 857. 73. R.S.Varma and G.W.Kabalka, Heterocycles., 1986, 24, 2645. 74. E.Vedejs and F.G.West, Chem. Rev., 1986, 86, 9 4 1 7 ~
2
I
I
b
.
z,
8: Saturated Heterocyclic Ring Synthesis
609
75. E.Vedejs and J.W.Grissom, J. Am. Chem. SOC., 1986, 108, 6433. 76. A.Padwa and J.R.Gasdaska, J. Am. Chem. SOC., 1986, 108, 1104. 77. P.F.Belloir, A-Laurent, P.Mison, S.Lesniak, and R . B Z n i k , Synthesis, 1986, 683. 78. O.Tsuge, S.Kanemasa, and S-Takenaka, J. Org. Chem., 1986, 51, 1853. 79. O.Tsuge, S.Kanemasa, and K.Matsuda, J. Org. Chem., 1986, 51, 1997. 80. W.H.Pearson, M.A.Walters, and K.D.Oswel1, J. Am. Chem. SOC., 1986, 108, 2769. 81. K.Hayakawa, T.Yasukouchi and, K.Kanematsu, Tetrahedron Lett., 1986, 27, 1837. 82. M.Noguchi, S.Kakimoto, H.Kawakami, and S.Kajigaeshi, Bull. Chem. SOC. Jpn., 1986, 2,1355. 83. T.Hudlicky, J.O.Frazier, and L.D.Kwart, Tetrahedron Lett., 1985, 26, 3523. 84. W.H.Pearson, Tetrahedron Lett., 1985, 26, 3527. 85. W.H.Pearson, J.E.Celebuski, Y.-F.Poon, B.R.Dixon, and J.F.Glans, Tetrahedron Lett., 1986, 27, 6301. 86. T.Hudlicky, J.O.Frazier, G.Seoane, M.Tiedje, A.Seoane, L.D.Kwart and, C.Beal, J. Am. Chem. SOC., 1986, 108, 3755. 87. B.M.Trost and S.-F.Chen, J. Am. Chem. SOC., 1986, 108, 6053. 88. M.D.Jones and R.D.W.Kemmit, J. Chem. SOC., Chem. Commun., 1986, 1201. 89. Y.Tamaru, M.Hojo, S.Kawamura, and Z.Yoshida, J. Org. Chem., 1986, 51, 4089. 90 - D.Lathbury, P.Vernon, and T.Gallagher, Tetrahedron Lett., 1986, 27, 6009. 91. F.Henin, J.Muzart, and J.-P.Pete, Tetrahedron Lett., 1986, 27, 6339. 92. A.Toshimitsu, K.Terao, and S.Uemura, J. Org. Chem., 1986, 51, 1724. 93. C.A.Broka and K.K.Eng, J. Org. Chem., 1986, 2,5043. 94. K.Jones, M.Thompson, and C.Wright, J. Chem. SOC., Chem. Commun., 1986, 115. 95. P.A.Grieco and W.F.Fobare, Tetrahedron Lett., 1986, 27, 5067. 96. R.E.Gawley and S.Chemburkar, Tetrahedron Lett.,1986, 27, 2071. 97 * T.Kometani, H.Yukawa, and T.Honda, J. Chem. Soc., Chem. Commun., 1986, 651. 98. C.-P.Chen, C.Shih, and J.S.Swenton, Tetrahedron Lett., 1986, 27, 1891. 99. S.C.Shim, K.T.Huh, and W.H.Park, Tetrahedron, 1986, 42, 259. lOO.T.L.Ho, B.Gopalan, and J.J.Nestor, Jr., J. Org. C h e m z 1986, E l 2405. lOl.H.J.Bestmann, T.Moenius, and F.Soliman, Chem. Lett., 1986, 1527. 1O2.T.KametaniI T-Fitz, and D.S.Watt, Tetrahedron Lett., 1986, 2, 919. lO3.E.W.Thomasl J. Org. Chem., 1986, 51, 2184. 104.M.Joucla and M. El Goumzili, Tetrzedron Lett., 1986, 27, 1681. 105.J.ChiefariI W.Janowski, and R.Prager, Tetrahedron Lett., 1986, 27, 6119. 106.T.Shon0, Y.Matsumura, S.Katoh, K.Inoue, and Y.Matsumoto, Terahedron Lett., 1986, 27, 6083. 107.H.NishiyamaI H.Arai, Y.Kanai, H.Kawashima, and K.Itoh, Tetrahedron Lett., 1986, 27, 361. 108.Y.NittaI T.Yamaguchi, and T.Tanaka, Heterocycles, 1986, 24, 25. 109.P.A.GriecoI S.D.Larsen, and W.F.Fobare, Tetrahedron Lett., 1986, 27. 1975 11O.Ti.Danishefsky and C.Voge1, J. Org. Chem., 1986, 51, 3915. lll.C.Veyrat, L.Wartski, and J.Seyden-Penne, Tetrahedron Lett., 1986, 27, 2981. 112.Y.It0, E.Nakajo, and T.Saegusa, Synth. Commun., 1986, 16, 1073. ~
General and Synthetic Methods
610
113.K.J.Shea and J.J.Svoboda, Tetrahedron Lett., 1986, 27, 4837. 114.M.ChuI P.-L-Wu, S.Givre, and F.W.Fowler, Tetrahedron Lett., 1986, 27, 461. 115.J.D.WinklerI P.M.Hershberger, and J.P.Springer, Tetrahedron Lett., 1986, 27, 5177. 1 1 6 . m u t u r e andP.Grandclaudon, Synthesis, 1986, 576. 117.S.D.LarsenI P.A.Grieco, and W.F.Fobare, J. Am. Chem. Soc, 1986, 108, 3512. 118.rn.Hartmanl W.Halczenko, B.T.Phillips, S.M.Pitzenberger, J.P.Springer, and J-Hirshfield, J. Org. Chem., 1986, 51, 2202. ., 1986751, 5496. 119.G.S.Sheppard and K.P.C.Vollhardt, 120.R.AumannI H.Heinen, C.Kruger, and Y.-H.Tsay, Chem. Ber., 1986, 119, 3141. 121.G.Trost and A.G.Romero, J. Org. Chem., 1986, 51, 2332. 122.J.Grimaldi and A.Cormons, Tetrahedron Lett., 1986, 27, 5089. 123.D.L.Comins and J.D.Brown, Tetrahedron Lett., 1986, 27, 2219. 124.D.L.Comins and J.D.Brown, Tetrahedron Lett., 1986, 27, 4549. 125.A.BrandiI A.Guarna, A.Goti, and F.De Sarlo, Commun., 1986, 813. 126.A.BrandiI A.Guarna, A.Goti, and F.De Sarlo, Tetrahedron Lett., 27, 1727. 127.=hangir, D.B.MacLean, M.A.Brook, and H.L.Holland, J. Chem. SOC., Chem. Commun., 1986, 1608. 128.=inami, K-Watanabe, and K.Hirakawa, Chem. Lett., 1986, 2027. 129.0.0.0raziI R.A.Corra1, and H.Giaccio, J. Chem. SOC. Perkin Trans. 1, 1986, 1977. 130.M.A.Ciufolini and C.Y.Wood, Tetrahedron Lett., 1986, 27, 5085. 131.S.N.MazumdarI I.Ibnusaud, and M.P.Mahajan, Tetrahedron Lett., 1986, 27, 5875. 132.L.Baiocchi and G.Picconi, Tetrahedron Lett., 1986, 2,5255. 133.J.Barluenga, F.J.Gonzalez, S.Fustero, and V.Gotor, J. Chem. Soc., Chem. Commun., 1986, 1179. l34.J.R.Pfisterl Heterocycles, 1986, 24, 2099. 135.A.GotiI A.Brandi, F.De Sarlo,and A.Guarna, Tetrahedron Lett., 1986, 27, 5271. 136.G.Mohiuddir-1,P.S.Reddy, K.Ahmed, and C.V.Ratnam, Heterocycles, 1986, 2,3489. 137.M.J.MillerI Acc. Chem. Res., 1986, 2,49. 138.P.AndreoliI G.Cainelli, M-Contento, D.Giacomini, G-Martelli, and M-Panunzio, Tetrahedron Lett., 1986, 27, 1695. 139.D.A.BurnettI D.J.Hart, and J.Liu, J. Org. Chem., 1986, 22_, 1929. 140.D.J.Hart, C.-S.Lee, W.H.Pirkle, M.H.Hyon, and A.Tsipouras, J. Am. Chem. SOC., 1986, 108, 6054. 141.L.S.Liebeskind and M.E.Welker, Tetrahedron Lett., 1985, 26, 3079. 142.S.G.DaviesI 1.M.Dordor-Hedgecock, K.H.Sutton, and J.C.Walker, Tetrahedron Lett., 1986, 27, 3787. 143.S.G.Davies, 1.M.Dordor-Hedgecock, K.H.Sutton, J.C.Walker, R.H.Jones, and K.Prout, Tetrahedron, 1986, 42, 5123. 144.A.G.M.Barrett and M.A.Sturgess, TetrahedronLett., 1986, 27, 3811. 145.D.K.DuttaI R.C.Boruah, and J.S.Sandhu, Heterocycles, 1986, 24, 655. 146.I.CarelliI A.Inesi, V.Carelli, M.A.Casadei, F.Liberatore, and F.M.Moracci, Synthesis, 1986, 591. 147.M.Sakamot0, H.Aoyama, and Y.Omote, Tetrahedron Lett., 1986, 27, 1335. 148.Y.Naga0, T.Kumagai, S.Takao, T.Abe, M.Ochiai, Y.Inoue, T.Taga, and E.Fuiita. J. Ors. Chem.. 1986., 51, , 4737. 149.J.KnightI P.J.Parsons, and R.SouthgZe, J. Chem, SOC., Chem. Commun., 1986, 78. 3725. 15O.F.Dumas and J.D'Angelo, Tetrahedron Lett., 1986, 3, <
.
8: Saturated Heterocydic Ring Synthesis
151.M.Mori, N.Kanda, and Y.Ban, 1375. 152.H.Gotthasd and K.-H.Schenk, 687.
611
J. Chem. SOC., Chem. Commun., J. Chem. SOC.,
1986,
Chem.Commun., 1986,
Highlights in Total Synthesis of Natural Products BY K. CARR, D.J. COVENEY, AND G. PATTENDEN 1
Terpenes
A neat four-step synthesis of the triquinane sesquiterpene hirsutene (4) has been described, which feztures the novel iodotrimethylsilane induced rearrangement of the dione ( 1 ) , to (2), as a key step. Reductive methylation of the enone (2) to (3),followed by Wittig methylenation then completed the synthesis.' In a rather lengthy synthesis of the marine metabolite capnellene(l2), Stille and Grubbs have highlighted the interesting use of titanethylene (7) in reactions with alkenes, leading to metallacyclobutanes, and their subsequent rearrangement Thus, aikylation of the tosylate (5) with cyclopentadienyl Grignard reagent followed by intramolecular cycloaddition first led to (6).
Treatment
of (6) with (7) then gave rise to the metallacyclobutane (8). Heating (8) to 9 0 ° C initiated ring opening to (9), which then suffered intramolecular trapping leading to the cyclobutene enol ether (10). After conversion of (10) to the corresponding dioxolan ( 1 1 1 , ring expansion together with functional group manipulation then completed the synthesis of capnellene (12).
Although a synthesis of the
8-epimer of natural capnellenediol (13) was described as early as 1982, it is only just now that a total Synthesis of the natural isomer has been described.
Contemporaneous work by Shibasaki
et
al. , 4 has also realised syntheses of capnellenetriols and
capnellenetetrols which co-occur with (13) i.n the soft coral Capnella imbricata. Although a number of syntheses of the angular triquinane sesquiterpene isocomene (18) have now been published, the synthesis by Dreiding et a1.5 is interesting since it features the sequential alkynone cyclisations
(14)-(15)
5-ring annulation reactions.
and ( 1 6 ) - ( 1 7 )
as the two key
In a new synthesis of the related
sesquiterpene silphinene (23) intramolecular[2+2] photocycloaddition from (19) is first used to elaborate the tricycle (201, which on brief exposure to iodotrimethylsilane produces (21). Reduction of (21) to ( 2 2 ) , and functional group elaboration then completed the 612
9: Highlights in Total Synthesis of Natural Products
613
+
hV
4 H H O
C02But
OBU' (111
I
(10)
(9)
General and Synthetic Methods
614
dcozH
(17)
1
steps
9 (18)
(20)
1
Me3SiI
steps
B u 3SnH
c
0
9: Highrights in Total Synthesis of Natural Products
' (2 8)
615
steps
HCOZH BF3 O E t Z
___.)
(27)
t
90°c /2h
(29)
HO
H
(30)
Y
.'
616
General and Synthetic Methods
H I (36)
J *co2Me
J
617
9: Highlights in Total Synthesis of Natural Products
Meoz
MeOzC
\
H %
“H \
0
0
(46)
(47)
General and Synthetic Methods
618
Jsteps
P
"
619
9: Highlights in Total Synthesis of Natural Products
synthesis. The intramolecular cyclopropanation from (24) to (25), followed by regioselective reductive cleavage of (25) to (26) in the presence of sodium-liquid ammonia has featured in a new synthesis of
( 5 )-pentalenene (27).
In alternative approaches to pentalenene,
Mehta and Rao
have described the transannulation reaction ( 2 8 ) -
(291, and Hua
has further highlighted the use of his asymmetric
induction reaction of chiral sulphinylallyl anions and enones, __ viz (30) (311, to provide a neat asymmetric synthesis. ---f
Punctatin A (341, also known as antibiotic M 95464, is an unusual metabolite which has been isolated from the dung fungus Poronia punctata. An enantiospecific synthesis of (34) has now been described which features, amongst other things, use of the Norrish type I 1 photoreaction in the natural product."
(32)--(33) to elaborate the cyclobutane ring The not unrelated, linear 5,6,4-ring fused
sesquiterpene 6-protoilludane (39) has also been synthesised during the period under review.
This particular synthesis featured the
-
use of the type-I magnesium ene reaction (35)+(36), and the intramolecular vinylketene-alkene cycloaddition (37)
(381, to
elaborate the tricycle. A total synthesis of allamcin (451, which also constitutes
formal syntheses of plumericin (46) and allamandin (47) found in Allamanda nerifolia has been described.12 The synthesis uses a strategy based on spiro-annulation of the B-oxy-8'-butyrolactone ring system onto the bicyclo [3.3.0] octenone (40) ?+
the key
acetoxy-aldehyde intermediate (41), followed by specific oxidation of the more nucleophilic C=C bond in (42)(to 43) ,and in situ oxidative-cleavage and cyclisation from the 1,2-diol acetate (44). Several spectacular syntheses of the sesquiterpene sativene ( 5 1 ) have been published in the past, but few are more interesting than the one now described by Dreiding et a d 3 This synthesis uses the novel conversion of (48) to (50),
involving addition of buta-1,2-
dienyltitanium, then acid treatment, and _ in _ situ _ _intramolecular [4+21 cycloaddition of the resulting cyclopentadiene allene derivative (49), as the key step. Although a number of synthetic approaches have now been developed for elaboration of the 14-membered ring systems found in the cembranoid family of diterpenes e.g.(54), not many look more aesthetically pleasing than the[2,31- Wittig rearrangement
strategy
from 17-membered propargyl ethers (52)+(53), described by Marshall and his co-workers.14 Other methods which have been
General and Synthetic Methods
620
P
O
L
0s i Me, B ut
%
4\
(58) (5 9)
ke
i:”R-
SeOz
@OH
(60)
(611
(62)
(63) steps
OAc
9: Highlights in Total Synthesis of Natural Products
62 1
S
H0,C
(65)
(64)
n
' H
J
-
0 (67)
(68)
General and Synthetic Methods
622
(70 1
(69)
T FA
-78 "C
SnBu3
(74)
(73)
0
(75)
623
9: Highlights in Total Synthesis of Natural Products
(77)
(76)
OMe
(78)
OMe OMe
OMc OMe
OMe
OMc
(79)
OMe OMe
J
Me
I
OTBDMS
OBn
Hoq
OMe
OMe
(83)
(82)
Me0
DDQ
Me0
OMe (84)
OMe (85)
General and Synthetic Methods
624
highlighted this year for the synthesis of the 14-rings in cembranoids include T - a 1 lyl palladium macrocyclisation, I5 intramolecular Wadsworth - Emmons olefination
l7 and sulphone
alkylation. l8
A concise synthesis of the dolastane metabolite, isoamijiol (61), found in the brown seaweed Dictyota linearis, starts from the enamine (55) and uses only seven C-C bond forming reactions, four of
e.,
which (56)-+(57) : (57)-(58) and (59)---(60) , involve free radical intermediates;” this must be a record? An alternative route to the dolastane ring system has featured use of the photochemical 20 rearrangement of a,@-epoxyketones __ i.e (62)-(63) . Bertyadionol (68), which is a member of the lathyrane diterpenes, has been synthesised from (-)-c-chrysanthemic acid (64), following elaboration to (65), then to (66) and finally a Wadsworth - Emmons cyclisation to (67) and functional group manipulation. 21 2 Steroids
Ring B aromatic steroids (72) have been constructed by sequential cobalt-catalysed cyclisation of enetriynes (69), and intramolecular Diels-Alder reaction of the resulting 2-quinodimethanes (71) derived from the benzocyclobutene intermediates (70). The stereochemistry at the CD ring junction was found to be exclusively trans.22 The highly facile, stereoselective acid-catalysed cyclisation of the epoxystannane (73) has been used to prepare the intermediate(74) towards estra-1,3,5(10)-triene-6,11,17-trione (75).23
In a new
synthetic approach to oestrone ( 7 8 ) , use was made of the novel sodium hydride - mediated cyclisation of the cyclopropyl alcohol (76) to elaborate the D-ring,
+
(76)*(77)
.24
3 Alkaloids Bringman et
have described a synthesis of the unusual
isoquinoline alkaloid ancistrocladine (82) starting from the chiral tetrahydroisoquinoline (79). Conversion of (79) to the ester ( 8 0 ), followed by a palladium catalysed coupling reaction led to the helicene-type lactone (81) which was then easily converted to ( 8 2 ) . In a new route to the morphine ring system, Ludwig and Schafer have developed the intramolecular Lewis acid catalysed coupling of the tetrahydroisoquinoline ( 8 3 ) to (84) as a key step.26
The tetracycle
625
9: Highlights in Total Synthesis of Natural Products
OMe
OMe
I
OMe
I
I
OMe
(88) \
(911
0
NWSPh
I
COzMe
C0,Me
(93) (92)
(94)
0
J
626
General and Synthetic Methods
COLEt
+
C HO
(97)
(98)
P N - l
A C0,Et OMe
C0,Me L
(100)
steps
q - & C 0 2 M e
H
OMe
COZMe
(101)
H
I
OMe
(102)
627
9: Highlights in Total Synthesis of Natural Products
Me0
+
0
Meo%
0
Me0
(103)
J
J Me0 OMe
-
OMe H
OMe (104)
OMe (105)
628
General and Synthetic Methods
(109)
OH
(110)
(108)
OGlc
MeOLC (111)
P-gluco s
i d 7
NH 4 0
A c / NaC N8 H
WNH
'5
(112)
Scheme 1
629
9: Highlights in Total Synthesis of Natural Products
OH
&
steps
0
(113)
(116)
(115)
p TSA
steps
Me0,C--
630
General and Synthetic Methods
(84) was then dehydrogenated to (-)-salutaridine (85) which has already been converted into morphine yi? codeine. Using their asymmetric alkylation of formamidine method, Meyers et al. have developed a very neat synthesis of (+)-ocoteine (88). 2 7 Thus, deprotonation of the formamidine (86), followed by alkylation with 2,3-dimethoxybenzyl bromide and cleavage of the formamidine group first yielded the 7-benzyltetrahydroisoquinoline (87). N-methylation of (87) and thallium (111)-induced coupling then
produced (+)-ocoteine in high yield. The key feature of a synthesis of (-)-cytochalasan H (91) described by Thomas et al. was the intramolecular Diels-Alder reaction (89)-(90) . 28 Utilising their indole-2,3-quinodimethane strategy, Magnus et al. have now described a synthesis of (+)-8-oxotabersonine (96). Thus, heating the imine (92) in the presence of the mixed anhydride (93) first yielded the tetracyclic adduct (94).
Oxidation of (94) to the sulphoxide, followed by a
Pummerer reaction then yielded the sulphide (95) which was smoothly transformed into 8-oxotabersonine. 29 In a new synthesis of the cyclindrocarine group of alkaloids, it has been shown that when the spirocyclic ammonium ion (99) generated in _ situ _ _ from the amine (97) and the chloroaldehydoester (98) is heatedfit generates the intermediate (100) which then undergoes intramolecular Diels-Alder reaction to (101); further elaboration of (101) then produces cyclindrocarine (102). 3 0 The unusual benzyne cycloaddition (103)-(104)
has been used as
a basis for an interesting synthesis of corydaline (105) 8-oxoprotoberberine (104), 31 and cycloaddition
via the acylnitroso
intermediate (106) has featured in a synthesis of the ant trail pheromone ( 5 )- monomorine (107). j L A n intramolecular carbenoid insertion reaction (108)-(109)
has
been used in a short synthesis of the indolizidine alkaloid ipalbidine (110), 3 3 and Brown and Curless have outlined a stereospecific synthesis of erythro ____Cinchona alkaloids e.g. starting from secologanin (111) (Scheme 1 ) .34
(112)
In an enantiocontrolled synthesis of (+)-vincamine (118), the optically active enedione (113) was first converted to the hydroxy lactone ( 1 1 4 ) , which was then condensed with tryptamine, affording the amide (115). Oxidative cleavage of the glycol in (115) next produced the cyclic hemi-acetal (116) which was converted into the 35 lactam precursor(ll7) to vincamine. Fuji et al. have reported a chiral synthesis of (-)-ankorine ( 1 2 3 )
9: Highlights in Total Synthesis of Natural Products
toy.
631
BnO
Et
+
COZEt
“M. eO OfiB.
(119)
(120)
J Me0
i
OH
Me0
steps
Me0
0
General and Synthetic Methods
632
Me0
Me0
Me0
Me0
(124)
T:H H"
(125)
Me0
Me0
Me0
'H CH,Li (127)
(126)
Me0
Me0
steps
OMe
OMe
633
9: Highlights in Total Synthesis of Natural Products
CHO
5 -
C0,Et
qK$
Boc
N Me
Boc
BzN (130)
(132)
(131)
&
J
HN
Meom
(1 3 4 )
(133)
B nO
’y \ S i M e g
En0
(1361
(135)
Me0
J
M eO
-
B nO
( 1 39)
+
NH
(138)
634
General and Synthetic Methods
MeS03H
J
1
steps
635
9: Highlights in Total Synthesis of Natural Products
C0,Me
COLMe
I
@ (143)
HCI
(144)
(145)
(146)
(147)
&f
0
(148)
OBn
COzMe
i steps
->&: 0
(151)
' N
(150)
636
General and Synthetic Methods
1
st eps
(152) Scheme 2
631
9: Highlights in Total Synthesis of Natural Products
starting from the lactim-ether (119). Thus, alkylation of (119) with (120) first led to the adduct (121).
Reduction of (121) next gave
the lactam phenol (122) which was converted into (-)-ankorine by several steps.36 In a synthesis of ernetine (129), reductive photocyclisation of the enamide (124) first yielded the
dihydrofuranoquinolizidine (125) which could be easily converted into the lactam (126). A Michael reaction between ( 1 2 6 ) and the 1-(lithiomethyl)isoquinoline (127) then yielded the adduct (128), a known precursor of emetine.37 An aldol type condensation between the B-aminoester (131) and the aldehyde (130), leading to the ally1 alcohol (132), constitutes the basis of a new synthesis of (+)-lysergic acid (134). Mesylation of (132), followed by deprotection and base-induced cyclisation to (133), completed this formal synthesis of (134).38 In a synthesis of alangimaridine (139) and related alkaloids, the imine starting material (135) was firstly activated towards nucleophilic attack by reaction with trimethylsilyl triflate. The resulting salt (136) was next treated with the lithio derivative (1371, and subsequent cyclisation then produced the amidine intermediate (138) towards (139).39 The interesting tetracyclic ring system present in matrine (142) has been nicely constructed by cyclisation of the N-acylimminium ion (141) produced when the hydroxylactam (140) is treated with methane sulphonic acid.40 A similar strategy has also been used in a 41 synthesis of (+)-anatoxin (146), (143)+(145) &y (144). Heathcock et al. have reported the first synthesis of a i.e (151).42 The keto lactam (147) was first
Daphniphyllum alkaloid
cyclised to the tricyclic lactam ketal (148) using p-toluenesulphonic acid. After annulation of the fourth ring and modification, the alcohol (149) was then cyclised to the pentacyclic diketone (150) following treatment with sulphuric acid. Further manipulation of (150) then gave the natural product (151). Finally in this section, a novel ring expansion reaction of B-lactams has been described by Crombie et al. for the synthesis of members of the Homalium family of alkaloids such as hopromalinol (152) (Scheme 2).
43
4 Prostaalandins Tandem C-C bond-forming reactions have been the vogue this year in assembling the prostaglandins. For example, Stork et al. 44 have
General and Synthetic Methods
638
bc"'
OEt
*Sn B u 3
'
SiMe3
(155)
C5H11
I
I
OSiR,
0
OSiR3
(153)
(1 56) 140
p<Et
Qq( 0
OSiR,
J
steps
?H
C5Hll
(158)
I
OSiR,
COZH
I
O S i R,
OH
PGE,
639
9: Highlights in Total Synthesis of Natural Products
,OMe
N
I
O S i R,
(163)
(162)
v
OBZ
OBZ
(165)
OTHP
OBZ
(166)
(167)
BzO
steps
Bzo+
OH (169) a ; R = H
M i l b e m y c i n a7, R = H M i l b e m y c i n a8, R = Me
b;R=
& H
General and Synthetic Methods
640
OMe (172)
. I
OH (173)
(174)
OMOM %O OTBDPS
“OBz
(1 78)
CHO
641
9: Highlights in Total Synthesis of Natural Products
used radical intermediates to add, in a single step, two differentiated carbon functionalised appendages (precursors for the a- and B-side chains in PG's) to a pre-existing cyclopentenediol nucleus. Radical cyclisation from the mixed iodo-acetal (153) first leads to the product radical (154) which is then trapped with the enone (155) producing (156). Thermal rearrangement of (156) next leads to (157) which was oxidised directly to the enone (158). Manipulation of (153) finally gave ( + ) - P G F Z
.
Johnson and Penning 45 have described the use of (159), containing an acetonide grouping to mask an aldol, in the three-component coupling reaction sequence (159)+ (160)+ (161) (highlighted previously by Noyori et al.) leading to PGE2, and Corey et al.46 have summarised the use of the oxime (162) together with the intermediates (163) and (164) in yet another 'tandem' C-C
bond
forming reaction approach to prostanoids 5 Spiroacetals The chiral lactone (165) used earlier in a synthesis of the spiroacetal subunit of milbemycin 03, has now been applied in the enantiospecific synthesis of the dioxyqenated spiroacetal (169) of milbemycin a7 and a8.47 Combination of (165) with (166) first led to the adduct (167), which by partial reduction and acid-catalysed cyclisation then provided the unsaturated spiroacetal (168). Epoxidation of (168) and subsequent hydrolysis next led to the diaxial diol (1692).
Bis-silylation of (1692) followed by selective
de-silylation at C-23, acylation and removal of the remaining silyl residue then provided the spiro-acetal (169b) for use in milbemycin a7 and
a8
synthesis.
In other studies of the synthesis of milbemycins, published during the year under review, Barrett et a1.48 have described a total synthesis of milbemycin B 3 (173) which uses the three building blocks (170), (171) and (172), and Baker and c o - w ~ r k e r shave ~ ~ outlined an alternative synthesis of the spiro-acetal moiety (174) involved in an earlier total synthesis of (173). An enormous amount of effort in recent years has been expended towards a total synthesis of the marine toxin okadic acid (175). Isobe et al.
have now secured practical syntheses of the three
major segments (1761, (177) and (1781, starting from glucose derivatives, and a unique combination of sulphonyl carbanion chemistry, i.e. (177)+(178), followed by addition of (176), was then ~
642
General and Synthetic Methods
. OH
(179)
\
OR Et OBz
OBz (181)
(182)
OTB S
I
(183)
(184)
643
9: Highlights in Total Synthesis of Natural Products
OTBS
0 Bz (185)
(187)
644
General and Synthetic Methods
OTBS OH
v.0 (190)
TIPSO'
'-OTBS
OTBS
(191)
645
9: Highlights in Total Synthesis of Natural Products
used to stitch the pieces together leading to this demanding synthetic target. 6 Ionophores and Macrolides In a retrosynthetic analysis of the structurally complex ionophore antibiotic X206 (179), Evans and Bender51 have identified the keto-aldehyde (180) as a key sub-unit.
A
possible asymmetric
synthetic approach to structures of the type (180) was then investigated, using the tetrahydrofuran (181) as a model compound. The required absolute stereochemistries at centres C-18, C-22 and C-23 (antibiotic X206 numbering) in (181) were established 2 two separate asymmetric aldol condensations involving the norephedrine derived chiral auxilliary (182). Thus, subunits (183) and (184) were obtained and coupled by conversion of the latter into the corresponding vinyllithium reagent. Hydrogenation of the adduct (185) using Wilkinson's catalyst then gave predominantly the desired 20g-isornerl from which the target molecule (181) was ultimately derived. Evans et al. 52 have also used an asymmetric aldol condensation in the construction of the particular 1,3-dimethyl stereochemical relationships present in two of the key sub-units of the ionophore antibiotic ionomycin (186), namely (187) and (188). The synthesis of (187) features both boron and sodium enolates (189), giving excellent diastereochemical control (-J 98:2), and a hydrogenation step is used to establish the third chiral centre.
An analogous series of
reactions was used to access (188). The naturally occurring cryptand aplasmomycin (190) is one of a unique family of ionophore antibiotics, and several syntheses of the total structure, half structure and various abbreviated segments have been published. White et al.53 have now described a new approach to (190) which features a novel ring contraction based on the rearrangement of a-(acyloxy) acetates originally described by Chan et al. Thus, the key intermediate (191) was treated successively with lithium diisopropylamide and trimethylsilyl triflate leading to (192) which was ultimately converted to aplasmomycin.
In Corey's recent
synthesis of aplasmomycin (190), segment (193) was a key intermediate. Nakata et al. 54 have now devised an alternative route to (193) which features coupling between the tetrahydrofuranaldehyde (194) and the sulphone (195). Protomycinolide IV (196), a macrolide antibiotic of microbial
General and Synthetic Methods
646
B.'Ho
TIPSO'
(194)
I
(195)
( 1 96)
OH
(197)
(198)
OEE
647
9: Highlights in Total Synthesis of Natural Products
HO
NHZ
OMe
OR
(203) R = T B S
HO
o
q
O
OH NHZ
H
General and Synthetic Methods
648
CHO
21
(207)
649
9: Highrights in Total Synthesis of Natural Products
origin, has been cleverly disconnected into the two major sub-units (197) and (198) by Suzuki et al. 5 5 Both (197) and (198) were synthesised from ethyl (?)-lactate, by methods which featured a reductive 1,2-rearrangement of (199) to (200) using DIBAL-Et3N as a key stage. After conversion of (198) into the terminal enyne (201) and thence into the corresponding lithio derivative, condensation with (197), followed by macrocyclisation and subsequent minor modifications provided the naturai product. As a result of the amorphous nature of many polyene macrolides, their absolute stereochemistries remain largely unknown. Hence much work has been carried out on the degradation and subsequent re-assembly of these compounds.
Fraser-Reid et al.,56 for example,
working on pimaricin (natamycin) (202) in a poly-protected form, have now been able to 'excise' the polyhydric array (203) in (2021, in a sequence which briefly involved ozonolysis, sodium borohydride reduction, acid catalysed removal of the mycosamine moiety and persilylation.
Amphotericin B(204) is the only polyene macrolide
whose structure has been wholly determined by Z-ray crystallography. Nicolaou et al. 57 have now selectively protected the compound and subjected it to ozonolytic degradation. The largest fragment (shown here in functional group modified form) was shown to be compound (2051, and represented the C-1 to C-20 fragment of amphotericin B. A smaller product, the trio1 (206), was elaborated to the polyene (207) which constituted the C-21 to C-38 portion of (204). An esterification reaction between fragments (205) and (207) then furnished a precusor which underwent ring closure by an intramolecular Wadsworth-Emmons reaction to produce the poly-protected aglycone of amphotericin B.
7
Other Natural Products A novel and neat synthesis of the gibberellin phytohormone
(+)-GA5 (212) has been reported in preliminary form by De Clercq a1 .58 The 16-step synthesis starts from m-methoxybenzoic acid and features the intramolecular Diels-Alder reaction of the furan (208) in water in the presence of a-cyclodextrin (to 209) as a key stage. Refunctionalisation of the cycloadduct (209) to the ketone (2101, followed by Wittig reaction and selective quaternisation to (211) then leads to the correctly functionalised A-ring for transformation to (212).
General and Synthetic Methods
650
mm .
‘OMEM
‘0 R
EtOzC
0 (210)
“OH
OMe
(211)
COZH
(212) OMe
9: Highlights in Total Synthesis of Natural Products
65 1
OMe
HO
aof (216)
Me
‘9
OH
OMe
(218)
(2191
General and Synthetic Methods
652
(221)
(222)
(223)
aNH2 aNH2 +* OH
I
COzMe
(227)
(228)
C02Me
**
OH
(229)
14
COLMe
0
COzMe
0
(230)
(231)
C0,H
CO,MeL
(232)
(233)
653
9: Highlights in Total Synthesis of Natural Products
F
C0,Mc
C0,Me
1
I
COLMe
0 (234)
(235)
COZMe
C0,Me
I
I
Mefi OMe
Me@oH
(236)
(237)
OH
OH
Bo c - L- C y s ( A c m 1- L- a T h r - D - ( l e u ) T h z- O M e (239)
L
(240)
654
General and Synthetic Methods
The lignan styraxin (215) shows interesting antitumoural activity, and an expeditious synthesis of this molecule has now been achieved by way of the intramolecular Mukaiyama aldolisation reaction (213)*(214) as a key stage. 59 Another interesting secondary metabolite is kadsurenone (220) which has been isolated from the Chinese herbal plant Piper futokudsura. Kadsurenone is a potent and specific antagonist of platelet activating factor (PAF), which is a lipid mediator of inflammation and anaphylaxis. Ponpipom et al. 6o have described a three-step synthesis of (220) involving: (i) condensation between the allyloxyphenol (216) and the cinnamyl alcohol (217) leading to (218), (ii) heating (218) in diethylamine at 225°C which effects two Claisen rearrangements followed by a 1,5-homosigmatropic shift, producing (219), and (iii) oxidation of (219) with lead tetracetate. The Ireland ester enolate variant of the Claisen rearrangement has featured in a synthesis of the antifungal metabolite isoavenaciolide (226) described by Burke et al. 61 Thus, conversion of the butenolide glycolate (221) to the corresponding silyl ketene acetal (222) at -1OO"C, followed by warming to room temperature first led to the carboxylic acid (223). After masking the a-methylene moiety in (223) as the thiophenol adduct, conversion to (224) and double transesterification in the presence of camphorsulphonic acid gave rise to (225), the immediate precursor to isoavenaciolide (226). Virantmycin (233) is a highly unusual metabolite produced by Streptomyces which has been found to possess pronounced antiviral activity. In a total synthesis of (233), described by Hill and RaphaelI6' the iodoaromatic (227) is first coupled with the acetylenic alcohol (228) in the presence of Pd" leading to the central intermediate (229). Meyer-Schuster rearrangement of (229) in the presence of methane sulphonic acid then gave rise to (231) presumably y& the initially formed ketone (230). Reduction of (231) followed by dehydration next led to (232), which was elaborated to virantmycin, y& epoxidation, reduction, deprotection, treatment with thionyl chloride, and finally ester hydrolysis. The naturally occurring phenalenone atrovenetin (2381, produced by the fungus Penicilliurn atroveneturn, has been synthesised by a route which employs the novel, regioselective Claisen rearrangement-cyclisation (234)-(235), together with the regioselective acid-catalysed cyclisation (236)--(237) as critical steps.63 Ulithiacyclamide (243) is a new member of the growing family of
655
9: Highlights in Total Synthesis of Natural Products
?H
OH
0
0
A
0
0
A 0
0
Boc- L-Cys-L-aThr-D-(leu)
I
T h z-OMe
B oc -L-C y s- L- aT h r - 0-(1 e u 1 T h z - 0 M e (244)
656
General and Synthetic Methods
cytotoxic cyclic peptides found in marine tunicates, which contains A total synthesis of (243) has now
an interesting disulphide bridge.
been disclosed which features the use of diphenyl phosphorazidate [DPPA; (PhO)2PON3 1 as the peptide coupling agent.64 Thus, cyclodirnerisation of the deblocked tripeptide (240), derived from (239), in the presence of DPPA and triethylamine first leads to (241) in 33% yield. Treatment of (241) with iodine in methanol next effected disulphide bridge formacion to (242) which by treatment with thionyl chloride gave the natural product.
In an alternative
sequence to (243), the tripeptide (239) was first converted to the hexapeptide disulphide (244), using iodine in methanol, which after deprotection to (245) and double cyclisation of the latter with DPPA also gave rise to (242). References 1.
M. Iyoda, T.Kushida, S. Kitami and M. Oda, J.Chem.Soc., Chem.Commun., 1986,1049.
2.
J.R. Stille and R.H. Grubbs, J.Am.Chem.Soc.,
3.
M. Ladlow, G. Pattenden and S.J. Teague, Tetrahedron Lett., 1986,2,3279. M. Shibasaki, T. Mase and S. Ikegami, J.Am.Chem.Soc., 1986,~,2090; T. Mase and M. Shibasaki, Tetrahedron Lett., 1986,=,5245. G.G.G. Manzardo, M. Karpf and A.S. Dreiding, Helv.Chim.Acta., 1986,69,659.
4.
5.
~
1986,108,855.
6. 7.
M.T. Crimmins and S . W .
8.
G. Mehta and K.S. Rao, J.Am.Chem.Soc., 1986,108,8015.
Mascarella, J.Am.Chem.Soc., 1986,108,3435. T. Imanishi, F. Ninbari, M. Yamashita and C. Iwata, Chem.Pharm.Bull., 1986,%,2268.
9. D.H. Hua, J.Am.Chem.Soc., 1986,108,3835. 10. L.A. Paquette and T . Sugimura, J.Am.Chern.Soc., 1 9 8 6 , ~ , 3 8 4 1 . 11. W. Oppolzer and A. Nakao, Tetrahedron Lett., 1986,22,5471. 12. K.E.B. Parkes and G. Pattenden, Tetrahedron Lett., 1 9 8 6 , ~ , 1 3 0 5 . 13. R. Sigrist, M. Rey and A.S. Dreiding, ________ J.Chem.Soc., Chem.Commun; 1986,944. 14. J.A. Marshall, T.M. Jenson and B . S .
DeHoff, J.Org.Chem.,
1986,51,4316. 15. J.A. Marshall and R.C. Andrews, Tetrahedron Lett., 1986,27,5197. 16. M.A. Tius and A. Fauq, J.Am.Chem.Soc., 1986,108,6389.
17. J.A. Marshall and B.S. DeHoff, Tetrahedron Lett., 1986,=,4873.
651
9: Highlights in Total Synthesis of Natural Products 1 8 . J.A. Marshall and D.G. Cleary, J.Org.Chem., 1 9 8 6 , 5 1 , 8 5 8 . 19.
G. Pattenden and G.M. Robertson, Tetrahedron Lett., 1 9 8 6 , 2 7 , 3 9 9 .
20.
L.A. Paquette, H-S. Lin, D.T. Belmont and J.P. Springer,
21
A.B. Smith, B.D. Dorsey, M. Visnick, T. Maeda and M.S.Malamus, J.Am.Chem.Soc., 1 9 8 6 , ~ , 3 1 1 0 .
J.Org.Chem. I
22.
S.H.
,
1986,~,4807.
Lecker, N.H. Nguyen and K.P.C. Vollhardt, J.Am.Chem.Soc.,
1986,108,856. 23. 24.
D.N. Jones and M.R. Peel, J.Chem.Soc., Chem.Comun., 1 9 8 6 , 2 1 6 . N.S. Narasimhan and P.A. Patil, Tetrahedron Lett., 1 9 8 6 , 2 7 , 5 1 3 3 .
25.
G. Bringmann, J.R. Jansen and H.P.Rink, Angew.Chim.Int.Eng.Edn.,
26.
W. Ludwig and H.J. Schafer, Angew.Chim.Int.Eng.Edn.,
27.
D.A. Dickman and A.I. Meyers, Tetrahedron Lett., 1 9 8 6 , E l 1 4 6 5 .
28.
E.J. Thomas and J.W.F. Whitehead, J.Chem.Soc., Chem.Commun.,
29.
M. Ladlow, P.M. Cairns and P.. Magnus, J.Chem.Soc., Chem.Commun.,
30.
J.P. Brennan and J.E. Saxton, Tetrahedron, 1 9 8 6 , 2 4 , 6 7 1 9 .
31.
C. Saa, E. Guitian, L. Castedo, R. Suau and J.M. Saa, J.Org.Chem.,
32.
H. Iida, Y. Watanabe and C. Kibayashi, Tetrahedron Lett.,
33.
C.W. Jefford, T. Kubota and A. Zaslona, Helv.Chim.Acta.,
34.
R.T. Brown and D. Curless, Tetrahedron Lett., 1 9 8 6 , ~ , 6 0 0 5 .
35.
S . Takano, S . Sato, E. Goto and K. Ogasawara, J.Chem.Soc., Chem.Commun., 1 9 8 6 , 1 5 6 .
36.
T. Fujii, M. Ohba, K. Yoneyama, H . Kizu and S. Yoshifuji, Chem.Pharm.Bull., 1 9 8 6 , 2 , 6 6 9 .
37.
T. Naito, N. Kojima, 0. Miyata and I. Ninomiya, Chem.Pharm.Bull.,
38.
T. Kurihara, T. Terada and R. Yoneda, Chem.Pharm.Bull.,
39.
Jahangir, D.B. MacLean, M.A. Brook and H . L . Chem.Commun., 1 9 8 6 , 1 6 0 8 .
40.
J. Chen, L.J. Browne and N.C. Gonnela, J.Chem.Soc., Chem.Commun.,
41.
K.H. Melching, H. Hiemstra, W.J. Klaver and W.N. Speckamp,
42.
Tetrahedron Lett., 1 9 8 6 , 2 7 , 4 7 9 9 . C.H. Heathcock, S.K. Davidsen, S. Mills and M.A. Sanner, J.Am.Chem.Soc., 1 9 8 6 , ~ , 5 6 5 0 .
1986,25,913. 1986,25,1025.
1986,727.
1986,1756.
1986,51,2781. 1986,27,5513.
1986,69,2048.
1986,34,3530. 1986,=,442.
Holland, J.Chem.Soc.,
1986,905.
658
43.
General and Synthetic Methods
L . Crombie, R . C . F .
Jones,
a n d D.
Haigh,
Tetrahedron Lett.,
1986,27,5147. 44.
G.
45.
C.R.
Johnson
E.J.
C o r e y , K. N i i m u r a ,
46.
Stork,
P.M.
S h e r a n d H-L.
a n d T.D.
Baker, C.J.
R.
Y.
1986,108,6384.
J.Am.Chem.Soc.,
1986,108,5655.
J.Am.Chem.Soc.,
Konishi,
S . H a s h i m o t o a n d Y . Homada,
1986,27,2199.
Tetrahedron Lett., 47.
Chen,
Penning,
Swain a n d J.C.
Head,
J.Chem.Soc.,
Chem.Commun.,
1986,874. 48.
S.V.
Attwood,
J.Chem.Soc., 49.
Baker,
R.
Barrett,
A.G.M.
M.J.
R.A.E.
C a r r and G.
Richardson,
1986,479.
Chem.Commun.,
O'Mahony a n d C . J .
Swain, Tetrahedron L e t t . ,
1986,27,3059. 50.
Isobe,
M.
51. D . A . 52.
D.A.
53. J.D.
Y.
Ichikawa and T.
T.
Tetrahedron Lett.,
Bender, Tetrahedron L e t t . ,
E v a n s a n d R.L.
Dow,
White,
T.R.
Nakata,
Tetrahedron Lett.,
V e d a n a n d a , M.
1986,~,963.
1986,=,799.
1986,~,1007.
Kanq a n d S . C .
Choudhry,
1986,108,8105-
J.Am.Chem.Soc., 54.
Goto,
Evans and S.L.
K. S a i t o a n d T . O i s h i , T e t r a h e d r o n L e t t . ,
1986,27,6341,6345. 55.
K. S u z u k i , K. T o m o o k a , E . K a t a y a m a ,
56.
57.
I . Opponq, H.W.
Pauls,
D.
Chem. Commun.,
1986,1241.
K.C.
T.K.
Nicolaou,
J.Chem.Soc.,
L i a n g and B.
Chakraborty,
Chem. Commun.,
58.
W.M.
Grootaert and P.J.DeClercq,
D.R.
S t e v e n s and D.A.
60.
M.M.
Ponpipom,
61.
S.D.
B.Z.
R.A.
G.J.
Fraser-Reid,
Tsuchihashi
Yue,
J.Chem.Soc.,
Daines and N.S.
Tetrahedron Lett.,
Whiting, Tetrahedron L e t t . , R.L.
Bugianesi,
Shen, T e t r a h e d r o n L e t t . ,
Burke,
Matsumoto a n d G.
Simpkins,
1986,413.
59.
a n d T.Y.
T.
1986,108,5221.
J.Am.Chem.Soc.,
P a c o f s k y a n d A.D.
1986,27,1731.
1986,=,4629.
Brooker,
D.R.
M.N.
Chanq
1986,zI3O9. Piscopio,
Tetrahedron Lett.,
1986,27,3345. 62.
M.L.
63.
G.
Buchi and J.C.
64.
S.
Kato,
H i l l and R.A.
Y.
Raphael, Leunq,
Hamada a n d T .
Tetrahedron Lett.,
J.Org.Chem.,
1986,27,1293.
1986,~,4813.
Shioiri, Tetrahedron Lett.,
1986,=,2653.
Reviews on General and Synthetic Methods COMPILED BY K. CARR, D.J. COVENEY, AND G. PATTENDEN
1 Esters and Lactones
J.C.Sarma and R.P.Sharma, 'Synthesis of a-Methylene-butyrolactones', Heterocycles, 1986,
y
23, 441.
N.Petragnani, H.M.C.Ferraz and G.V.J.Silva, 'Advances in the Synthesis of a-Methylenelactones', Synthesis, 1986, 157. L.A.Pavlova, Y.A.Davidovich and S.V.Rogozhin, 'Alkyl Orthoesters and their Applications in Organic Synthesis', Russ.Chem.Rev., 1986,
55,
1026.
2 Fluoroorganic Compounds S.T.Purrington, B.S.Kagen and T.B.Patrick, 'The Application of Elemental Fluorine in Organic Synthesis', Chem.Rev., 1986, 86, 997. N.P.Gambaryan and E.M.Rokhlin, 'Characteristic Features of the Chemical Properties of Fluorine-containing Unsaturated Compounds', Russ.Chem.Rev., 1986,
55,
480.
R.Bolton and G.H.Williams, 'Homolytic Arylation of Aromatic and Polyfluoroaromatic Compounds', Chem.Soc.Rev., 1986,
Is,
261.
3 Ketenes ~~
H.W.Moore and O.H.W.Decker, 'Conjuqated Ketenes: New Aspects of Their Synthesis and Selected Utility for the Synthesis of Phenols, Hydroquinones and Quinones', Chem.Rev., 1986,
86,
821.
H.R.Seikaly and T.T.Tidwel1, 'Addition Reactions of Ketenes', Tetrahedron, ______
1986,
42,
2587.
R.J.Clemens, 'Diketene', Chem.Rev., 1986,
€5241. ,
4 Nitrogen-containing Functional Groups A.G.M.Barrett and G.G.Graboski, 'Conjugated Nitroalkanes:
659
General and Synthetic Methods
660
Versatile Intermediates in Organic Synthesis', Chem.Rev., 1986, 86, 751. L.B.Volodarsky and A.Y.Tikhonov,
'Synthesis and Reactions of
Q-
Hydroxylamino-oximes', Synthesis, 1986, 704. M.F.Marshalkin and L.N.Yakhontov, 'Reactions of Orqanic Compounds with Dissociation of N-N Bonds', g s . C h e m . R e v . , 1986,
55,
1016.
'Diazo Compounds: Properties and Synthesis', M.Reqitz and G.Maas, Academic Press: Orlando, FL.
1986.
J.Collard-Mette and Z.Janousek, 'Ynamines', Top.Curr.Chem., 1986, 130, 89. R.J.Berqeron, 'Methods for the Selective Modification of
~
Spermidine and its Homologues', Acc.Chem.Res., 1986, V.A.Usov, L.V.Timokhina and M.G.Voronkov,
2,105.
'Nucleophilic
Substitution in @-Heterofunctional Q,@-Unsaturated Iminium Salts', Russ.Chem.Rev., 1986,
2,1003.
5 Orqanometallics General 'Advances in Organometallic Chemistry', Vo1.25, Ed. F.G.A.Stone and R.West, Academic Press: New York. 1986. M.P.Doyle, 'Catalytic Methods for Metal Carbene Transformations', Chem.Rev., 1986, 86, 919. 'Organometallic Intramolecular-coordination Compounds', I.Omae, Elsevier Science Publishers: Amsterdam and New York.
1986.
Main Group Elements G.W.Klumpp, 'Oxygen- and Nitrogen-assisted Lithiation and Carbolithiation of Non-aromatic Compounds; Properties of Non-aromatic Orqanolithium compounds Capable of Intramolecular Co-ordination to Oxygen and Nitrogen', Recl.Trav.Chim.Pays-Bas, 1986, 105, 1 . L.M.Dyagileva and Y.A.Aleksandrova, 'The Reactivity of Organozinc and Orqanocadmium Compounds in Decomposition Reactions', Russ.Chem.Rev., 1986,
55,
1054.
D.S.Matteson, 'The Use of Chiral Organoboranes in Organic Synthesis', Synthesis, 1986, 973. B.Ganem and J.O.Osby, 'Synthetically Useful Reactions with Metal Boride and Aluminium Catalysts', Chem.Rev., 1986,
86,
763.
'Organosilicon Chemistry', S.Pawlenko, Walter de Gruyter: Berlin and New York. 1986.
Reviews on General and Synthetic Methods
66 1
T.A.Blumenkopf and L.E.Overman,
'Vinylsilane- and Alkynylsilane-
terminated Cyclization Reactions', Chem.Rev., 1986,
E,
857.
'Organophosphorus Chemistry', Vo1.16, Ed. D.W.Hutchinson and B.J. Walker, The Royal Society of Chemistry: London. 1986. V.M.Neplyuev, 1.M.Bazarova and M.O.Lozinskii,
'Geminal Sulphones',
Russ.Chem.Rev., 1986, 55, 883. M. Madesclaire, 'Synthesis of Sulfoxides by Oxidation of Thioethers', Tetrahedron, 1986,
42, 5459.
'Selenium Reagents and Intermediates in Organic Synthesis', C. Paulmier, Pergamon Press: Oxford.
1986.
'The Chemistry of Organic Selenium and Tellurium Compounds Vol.l', Ed. S.Patai and Z.Rappaport,
John Wiley and Sons: Chichester. 1986.
N.Petragnani and J.V.Comasseto, 'Synthetic Applications of Tellurium Reagents', Synthesis, 1986, 1. Transition Elements J.K.Stille,
'The Palladium-catalysed Cross-coupling Reactions of
Organotin Reagents with Electrophiles', Angew.Chim.Int.Eng.Edn., 1986, 2,5 0 8 . J.Tsuji, 'New General Synthetic Methods Involving n-Allylpalladium Complexes as Intermediates and Neutral Reaction Conditions', Tetrahedron, 1986,
42,
4361.
G.R.Newkome, W.E.Puckett, V.K.Gupta and G.E.Kiefer, 'Cyclometallation of the Platinum Metals with Nitrogen and Alkyl, Alkenyl and Benzyl Carbon Donors', Chem.Rev., 1986, 'Organotransition Metal Chemistry.
86,
451.
Fundamental Concepts and
Applications', Ed. A.Yamamoto, Wiley Interscience: New York.
1986.
'Chemistry of Organo-zirconium and -hafnium Compounds', D.J. Cardin, M.F.Lappert and C.L.Raston, Ellis Horwood: Chichester. 1986. U.M.Dzhemilev, 0.S.Vostrikova and A.G.Ibragimov,
'Zirconium
Complexes in Synthesis and Catalysis', Russ.Chem.Rev., 1986,
E,
66. 'Organotitanium Reagents in Organic Synthesis', M.T.Reetz, Springer: Berlin.
1986.
6 Carbocylic Ring Synthesis B.M.Trost, ' [3 + 2 1 Cycloaddition Approaches to Five-membered Rings via Trimethylenemethane and its Equivalents', %ew.Chim. Int.Eng.Edn., 1986, 2,1.
General and Synthetic Methods
662
R.D.Little, 'The Intramolecular Diyl Trapping Reaction. Tool f o r Organic Synthesis', Chem.Rev., 1986,
A Useful
3,875.
L.A.Paquette, 'Silyl-substituted Cyclopropanes as Versatile Synthetic Reagents', Chem.Rev., 1986, 86, 733. P.L.Fuchs and T.F.Braish, 'Multiply Convergent Syntheses Conjugate-addition Reactions to Cycloalkenyl Sulphones', Chem.Rev., 1986, 86, 903. G.H.Posner, 'Multicomponent One-pot Annulations Forming Three to Six Bonds', Chem.Rev., 1986,
86,
831.
7 Heterocycles B.H.Lipshutz, 'Five-membered Heteroaromatic Rings as Intermediates in Organic Synthesis', Chem.Rev., 1986,
86,
795.
W.Verboorn and D.N.Reinhoudt, 'Recent Approaches to the Pyrrolo [1,2-a1 indoles', Recl.Trav.Chim.Pays-Bas, 1986, 105, 199.
- a General Method of Synthesis of Five-membered Nitrogen-containing
0.V.Drygina and A.D.Garnovskii, '1,3-Dipolar Cycloaddition
Heterocycles with Organoelemental Substituents', Russ.Chem.Rev.,
55, 851. 'Oxazoles', E d . I.J.Turchi, John Wiley and Sons: New York.
1986,
1986.
A.F.Kluge, 'Synthesis of lI7-Dioxaspiro [5.5] Undecanes', Heterocycles, 1986, 23, 1699. G.Mohiuddin, P.S.Reddy, K.Ahmed and C.V.Ratnam, 'Recent Advances in the Synthesis of Annelated 1,4-Benzodiazepines', Heterocycles, 1986, 23, 3489. R.S.Varma and G.W.Kabalka, 'Nitroalkanes in the Synthesis of Heterocyclic Compounds', Heterocycles, 1986, F.M.Abde1-galil, S.M.Sherif and M.H.Elnagdi,
23, 2645 'Utility of
Cyanoacetamide and Cyanothioacetamide in Heterocyclic Synthesis', Heterocycles, 1986,
23, 2023.
A.L.Weis and H.C.Van der Plas, 'Dihydropyrirnidines: Synthesis, Structure and Tautomerism', Heterocycles, 1986, 23, 1433. W. Sliwa, 'The Reactivity of g-Substituted Pyridinium Salts', Heterocycles, 1986,
23, 181.
8 Natural Products
S.J.Danishefsky, 'Reflections on Organic Synthesis:
The Evolution
of a General Strategy f o r the Stereoselective Construction of
Reviews on General and Synthetic Methods
663
Polyoxygenated Natural Products', Aldrichimica Acta, 1 9 8 6 , 2,5 9 . R.R.Schmidt, 'Hetero-Diels-Alder Reaction in Highly Functionalised Natural Product Synthesis', Acc.Chem.Res., 1 9 8 6 , 19, 2 5 0 . R.P.Evstigneeva and G.I.Myagkova, 'Leukotrienes - Natural Biologically Active Metabolites of Polyunsaturated Acids', Russ. Chem.Rev., 1 9 8 6 , 55, 4 5 5 . V.A.Dombrovskii, E.V.Gracheva and P.M.Kochergin, 'The Synthesis of Prostacyclin and its Analogues', Russ.Chem.Rev., 1 9 8 6 , 55, 9 7 8 . E.D.Matveeva, A.L.Kurts and Y.G.Bunde1, 'The Synthesis of Lepidoptera Pheremones', Russ.Chem.Rev., 1 9 8 6 , 55, 6 7 2 . V.K.Kansa1 and P.Potier, 'The Biogenetic, Synthetic and Biochemical Aspects of Ellipticine, an Antitumour Alkaloid', Tetrahedron, 1 9 8 6 , 42, 2 3 8 9 . T.Kametani and T.Honda, 'Application of Aziridines to the Synthesis of Natural Products', Adv.Heterocycl.Chem., 1 9 8 6 , 2, 182.
J.E.Saxton, 'Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites', Nat.Prod.Rep., 1 9 8 6 , 2, 3 5 3 . K. Krohn, 'Total Synthesis of Anthracyclinone', Angew.Chim.Int. Eng-Edn., 1 9 8 6 , 25, 7 9 0 . J.Elks, 'Steroids: Reactions and Partial Synthesis', Nat.Prod.Rep., 1 9 8 6 , 2, 515. M.B.Groen and F.J.Zeelen, 'Steroid Total Synthesis', Recl.Trav. Chim.Pays-Bas, 1 9 8 6 , 105, 4 6 5 . 9 Asymmetric and Selective Synthesis
A.Pfenninger, 'Asymmetric Epoxidation of Allylic Alcohols: The Sharpless Reaction', Synthesis, 1 9 8 6 , 8 9 . J.ApSimon and T.Lee Collier, 'Recent Advances in Asymmetric Synthesis-11', Tetrahedron, 1 9 8 6 , 42, 5 1 5 7 . 'Asymmetric Catalysis', Ed. B.Bosnich, Martinus Nijhoff Publishers: The Netherlands. 1 9 8 6 . H.Wynberg, 'Asymmetric Catalysis by Alkaloids', Top.Stereochem., 1986,
16, 8 7 .
P.Beak and A.I.Meyers, 'Stereo and Regiocontrol by Complex Induced Proximity Effects: Reactions of Organolithium Compounds', Acc.Chem.Res., 1 9 8 6 , 2, 3 5 6 . J.Jurczak, S.Pikul and T.Bauer, ' ( E l - and (S_)-2,3-_0Isopropylideneglyceraldehyde in Stereoselective Organic
General and Synthetic Methods
664
Synthesis', Tetrahedron, 1986,
42,
441.
B.M.Trost, 'Strain and Reactivity: PGrtners for Selective Synthesis', Top.Curr.Chem., 1986,
332, 3 .
Y.Yamamoto, 'Selective Synthesis by Use of Lewis Acids in the Preserice of Orqanocopper and Related Reagents', Angew.Chim.Int. Eng.Edn., 1986,
2,947.
10 Enzvmic Reactions J.B.Jones, 'Enzymes in Organic Synthesis', Tetrahedron, 1986,
42,
3351.
S.Butt and S.M.Roberts,
'Recent Advances in the use of
Enzyme-catalyzed Reactions in Organic Research:
The Synthesis of
Biologically Active Natural Products and Analogues', Nat.Prod.Rep 1986, 3, 489. 1 1 Reduction
J.M.Hook and L.N.Mander, 'Recent Developments in the Birch Reduction of Aromatic Compounds: Applications to the Synthesis of Natural Products', Nat.Prod.Rep., 1986,
2,
35.
N.Ono and A.Kaji, 'Reductive Cleavage of Aliphatic Nitro Groups in Organic Synthesis', Synthesis, 1986, 693. J.G.Keay, 'The Reduction of Nitrogen Heterocycles with Complex Metal Hydrides', Adv.Heterocycl.Chem.,
2,2.
1986,
N.M.Alpatova, S.E.Zabusova and A.P.Tomilov,
'The Reduction of
Organic Compounds by Solvated Electrons Generated Electrochemically', Russ.Chem.Rev., 1986,
55,
99.
S.K.Pradhan, 'Mechanism and Stereochemistry of Alkali Metal Reductions of Cyclic Saturated and Unsaturated Ketones in Protic Solvents', Tetrahedron, 1986,
42, 6351.
12 Photochemistry, Electrochemistry and Sonochemistry 'Organic Photochemistry', Ed. J.M.Coxon and B.Halton, Cambridge University Press: Cambridge.
1986.
'Photochemistry in Organic Synthesis', Ed. J.D.Coyle, Royal Society of Chemistry: London.
1986.
V.Ramamurthy, 'Organic Photochemistry in Organised Media', Tetrahedron, 1986,
42, 5753.
Reviews on General and Synthetic Methods
665
'Advances in Photochemistry', Vo1.13, Ed. D.H.Volman, K.Gollnick and G.S.Hammond, John Wiley and Sons: New York. 1 9 8 6 . F.D.Lewis, 'Bimolecular Photochemical Reactions of Stilbenes', Adv.Photochem., 1 9 8 6 , 13, 1 6 5 . 'Modern Synthetic Methods. Volume 4. 1 0 8 6 : Sound and Light in Synthesis; Synthesis of Enantiomerically Pure Compounds with C,C Bond Formation'. Ed. R.Scheffold, Springer-Verlag: New York. 1986.
K.Suslick, 'Organometallic Sonochemistry', Adv.Organomet.Chem., 1986,
25, 7 3 .
'Electrochemistry and Reactivity of Systems Containing T-Electrons', Ed. W.H.Watson, VCH Publishers: New York. 1 9 8 6 . 'Topics in Organic Electrochemistry', Ed. A.J.Fry and W.E.Britton, Plenum Press: New York. 1 9 8 6 . S.Torri, 'The New Role of Electroreductive Mediators in Electroorganic Synthesis', Synthesis, 1 9 8 6 , 0 7 3 . E.Steckhan, 'Indirect Electroorganic Synthesis. A Modern Chapter of Organic Electrochemistry', Angew.Chim.Int.Eng.Edn., 1 9 8 6 , 2, 683. 1 3 Radical Chemistry
'Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds', B.Giese, Perqamon Press: Oxford. 1 9 8 6 . J.I.G.Cadogan, C.L.Hickson and H.McNab, 'Short Contact Time Reactions of Large OrganicFree Radicals', Tetrahedron, 1 9 8 6 , 42, 2 1 3 5 . 1 4 General
'Some Modern Methods of Organic Synthesis', A.W.Carruthers, Cambridge University Press: 1 9 8 6 . H.B.Kaqan and J.L.Namy, 'Lanthanides in Organic Synthesis', Tetrahedron, 1 9 8 6 , 42, 6 5 7 3 . F.E.Ziegler, 'New Synthetic Methods-11', Tetrahedron (Symposium in Print), 1 9 8 6 , 42, 2 7 7 7 . P.Eaton, 'Synthesis of Non-natural Products; Challenge and Reward', Tetrahedron (Symposium in Print), 1 9 8 6 , 42, 1 5 4 9 . 'Reagents €or Organic Synthesis', Vo1.12, M.Fieser, John Wiley and Sons: New York.
1986.
General and Synthetic Methods
666
M.S.Salakhov and S.A.Ismailov, 'Intramolecular [4 + 21 Cycloaddition', ______ Russ.Chem.Rev., 1986,
55,
3.145.
R.M.Moriarty and O.Prakash, 'Hypervalent Iodine in Organic Synthesis', Acc.Chem.R=.,
1986,
19, 244.
M.G.Vinogradov, 1.P.Kovalev and G.I.Nikishin, 'Oxallyl Complexes in Organic Synthesis', Russ.Chem.Rev., 1986,
5 5 , 1130.
P.Laszlo, 'Catalysis of Organic Reactions by Inorganic Solids', Acc.Chem.Res., 1986, 19, 121. T.Nakai and K.Mikami, ' [2,3]-Wittig Sigmatropic Rearrangements in Organic Synthesis', Chem.Rev., 1986,
86,
885.
H.H.Wasserman, K.E.McCarthy and K.S.Prowse, 'Oxazoles in Carboxylate Protection and Activation', Chem.Rev., 1986,
86,
845.
M.J.Miller, 'Hydroxamate Approaches to the Synthesis of 6-Lactam Antibiotics', Acc.Chem.Res., 1986, 19, 49. M.Karpf, 'Organic Synthesis at High Temperatures - Gas-phase Flow Thermolysis', Angew.Chim.Int.Eng.Edn., 1986, 25, 414. N.M.M.Nibbering,
'Gas-phase Organic Reactions at Low Pressures', 105, 245.
Recl.Trav.Chim.Pays-Bas, 1986,
D.L.Boger, 'Diels-Alder Reactions of Heterocyclic Azadienes: Scope and Applications', Chem-Rev., 1986, 86, 781. 15 Miscellaneous E.Vedejs and F.G.West, 'Ylides by the Desilylation of a-Silyl Onium Salts', Chem.Rev., 1986,
86, 941.
Z.K.Witczak, 'Monosaccharide Isothiocyanates and Thiocyanates: Synthesis, Chemistry and Preparative Applications', Adv.Carbohyd. Chem.and Biochem., 1986,
44,
91.
G.A.Olah, P.S.Iyer and G.K.S.Prakash, 'Perfluorinated Resinsulphonic Acid (Nafion-H (R)) Catalysis in Synthesis ' Synthesis, 1986, 513.
,
R.G.Harvey, 'Synthesis of Oxidized Metabolites of Polycyclic Aromatic Hydrocarbons', Synthesis, 1986, 6 0 5 . A.N.Pudovik, 1.V.Konovalova and L.A.Burnaeva, 'Reactions of Isocyanato- and Substituted Methyleneamino-phosphine Derivatives with Compounds Containing Multiple Bonds', Synthesis, 1986, 793. F.M.Hauser and S.R.Ellenberger, 'Synthesis of 2,3,6-Trideoxy-3amino- and 2,3,6-Trideoxy-3-nitrohexoses', Chem.Rev., 1986, 35.
86,
667
Reviews on General and Synthetic Methoak
B.M.Dilworth and M.A.McKervey,
'Organic Synthesis with
a-Chlorosulfides', Tetrahedron, 1986,
42, 3731.
J.Mann, 'The Synthetic Utility of Oxyallyl Cations', Tetrahedron, 1986, 42, 4611. A.Krief, 'Syntheses of Tetraheterofulvalenes and of Vinylene Triheterocarb0nates:- Strategy and Practice', Tetrahedron, 1986, 42 , 1209. M.P.Doyle, 'Electrophilic Metal Carbenes as Reaction Intermediates in Catalytic Reactions', Acc.Chem.Res., 1986,
19,
348. R.K.Dieter,
'a-0x0 Ketene Dithioacetals and Related Compounds:
Versatile Three-carbon Synthons', Tetrahedron, 1986,
42,
3029.
H.N.C.Wong, K-L.Lan and K-F.Tam, 'The Application of Cyclobutane Derivatives in Organic Chemistry', Top.Curr.Chem., 1986, 133, 83. A.J.Fatiadi,
'New Applications of Tetr2cyanoethylene in Organic
Chemistry', Synthesis, 1986, 249.
Author Index
I n t h i s i n d e x t h e number g i v e n i n p a r e n t h e s i s i s t h e C h a p t e r number o f t h e c i t a t i o n and t h i s is f o l l o w e d b y t h e r e f e r e n c e number of numbers o f t h e r e l e v a n t c i t a t i o n s w i t h i n t h a t Chapter
Abdel-Baky, S. ( 3 ) 85 Abdel-Magid, A . ( 3 ) 120 Abd-El Rahman, A.H. ( 5 ) 242 Abdul-Majid, Q. ( 5 ) 469 Abe, A. ( 5 ) 83 Abe, T. ( 9 ) 148 Abed, O.H. ( 6 i i ) 229 A b e l l , C. ( 3 ) 194 Abelman, M.M. ( 7 ) 29 Abeywickrema, A.N. ( 4 ) 198 A b i d i , S.L. ( 1 ) 1 0 3 ; ( 5 ) 389 Abiko, A . ( 3 ) 1 Abiko, S. ( 1 ) 104; ( 6 i i ) 101 Abla, M.A. ( 9 ) 1 2 Aboujaude, E.E. ( 6 i i ) 240 Abramovitch, R.A. ( 5 ) 1 2 Abul-Hajj, Y.J. ( 2 ) 119 Acher, F. ( 5 ) 254 Achiwa, K . ( 3 ) 3 4 4 ; ( 5 ) 6 1 ; ( 6 i i ) 252; ( 9 ) 4 8 , 49 A c k r e l l , J. ( 2 ) 161; ( 5 ) 1 8 7 ; ( 6 i i ) 38 Acuna. A.C. ( 6 i i ) 204 Adam, 'M.A. (1) 6 0 ; ( 4 ) 51; ( 6 i i 128 Adam, W. ( 4 ) 9 A d l i n g t o n , R.M ( 2 ) 4 7 , 48; ( 3 ) 1 9 7 , 237, 354; ( 5 ) 495-497; ( 6 i i ) 1 0 , 1 1 , 211, 212 Aeschimann, R. ( 3 ) 464; ( 5 ) 154 A f s h a r i , G.M. ( 2 ) 3 ; ( 3 ) 6 ; ( 4 ) 147 Agawa, T . (1) 112; ( 2 ) 29, 42; ( 3 ) 247, 309; ( 6 i ) 4 2 , 43
Ager, D . J . ( 2 ) 190; ( 6 i i ) 5 6 , 204 Aguero, A. ( 1 ) 1 5 A g u i l a r , M . A . ( 6 i i ) 233 Ahmad, S. ( 3 ) 280; ( 4 ) 238 Ahmed, K . ( 9 ) 1 3 6 Ahn, S.M. ( 7 ) 9 6 A i d a , T. ( 9 ) 53 A i t k e n , R.A. ( 2 ) 83 A i z p u r a , J . M . ( 4 ) 188 Ajimura, N . ( 3 ) 8 6 ; ( 5 ) 234 Akai, S. ( 3 ) 86; (5) 234 Akashi, T. ( 5 ) 520 Akiba, K . ( 1 ) 59; ( 4 ) 46; ( 6 i i ) 245 A k i t a , H. ( 3 ) 1 6 3 A k i t a , Y . ( 4 ) 199 Akitomo, Y. ( 3 ) 361 Akiyama, A. ( 9 ) 6 4 Akkerman, O.S. ( 6 i i ) 77 A k s s i r a , M. ( 3 ) 57 A k t e r i e s , B. (5) 507 Akutagawa, K . ( 3 ) 71; ( 6 i i ) 21-23 A 1 Ashmawy, M . I . (3) 314 A l b e r i c i o , F. ( 3 ) 527 A l b e r o l a , A. ( 5 ) 305; ( 9 ) 36 A l b i n a t i , A . ( 3 ) 338 A l b i n i , A. ( 5 ) 506 Alemagna, A. ( 5 ) 404 A l e x a k i s , A . (1) 100; (2) 95; (3) 107; ( 4 ) 93; ( 6 i i ) 195 Alfheim, T. ( 5 ) 8 9 A l - K h a l i l , S . I . ( 5 ) 363 Almond, H . R . , j u n . ( 6 i i ) 230 Alo, B.I. ( 3 ) 441 A l p e r , H. ( 3 ) 104, 300, 668
308; ( 4 ) 1 9 7 ; ( 5 ) 209; ( 6 i ) 10, 1 2 ; ( 9 ) 6 9 A l t e n b a c h , H.-J. ( 3 ) 367 Altman, J. ( 5 ) 241 Amano, T . (3) 80, 8 1 ; ( 5 ) 329 Amedio, J . C . ( 2 ) 73; ( 3 ) 192 Amri, H. ( 4 ) 6 6 Amrollah-Madjdabadi, A . ( 4 ) 1 9 4 ; ( 5 ) 388 A n d e l l , O.S. (5) 302 Anderson, M.W. ( 3 ) 2 3 Ando, K . ( 3 ) 186 Ando, M. ( 4 ) 101 Ando, S. ( 5 ) 489 Ando, T. ( 1 ) 1 1 1 ; ( 3 ) 112; ( 4 ) 6 7 , 252 Ando, W. ( 6 i i ) 249 Andrade, J. ( 3 ) 506 A n d r e i n i , B.P. (1) 117; ( 6 i i ) 168 A n d r e o l i , P. ( 9 ) 138 Andrew, S.S. ( 6 i i ) 223 Andrews, R.C. ( 3 ) 359; (8) 15 Andrews, S.W. ( 5 ) 392; ( 7 ) 45; ( 6 i i ) 153 A n g e l e s , E. ( 2 ) 1 5 5 Angermann, A . (3) 475 ( 5 ) 160 Angle, S.R. ( 1 ) 8 9 ; ( 6 i ) 71 Annoura, H. ( 3 ) 414; (4) 69 Annunziata, R. ( 3 ) 8 2 ( 4 ) 7 7 ; ( 6 i i ) 51, 5 Anorbe, B. (1) 1 2 3 A n t e b i , S. ( 5 ) 209 A n t o n a k i s , K. ( 4 ) 129 Anwar, S. ( 4 ) 2 0 ; ( 6 i i ) 191
Author Index
Anzai, K. ( 5 ) 337 Aono, M. ( 6 i i ) 252; ( 9 ) 48, 49 Aoyagi, H. ( 3 ) 509 Aoyama, H. ( 9 ) 147 Aoyama, I . ( 5 ) 232; ( 6 i ) 80 Aoyama, T. ( 5 ) 13, 18; ( 6 i i ) 188 Apki, S. ( 5 ) 6 3 ApSimon, J . W . ( 3 ) 504; (9) 8 A r a i , H. ( 4 ) 4 ; ( 6 i i ) 192, 215; (9) 107 A r a i , I . ( 1 ) 106, 109; ( 4 ) 5 3 , 72; ( 6 i i ) 133 A r a k a i , T. ( 4 ) 159 Arakawa, E. ( 4 ) 338 A r a k i , S. ( 4 ) 162 Araki, T. ( 1 ) 1; ( 6 i i ) 200 Arase, A. ( 6 i i ) 164 Aravind, S. ( 5 ) 485 Arcadi, A . ( 1 ) 29; ( 4 ) 205 Arey, J. ( 5 ) 381 A r i g a , M. ( 3 ) 183 Armati, A. ( 3 ) 185 Armesto, D. ( 5 ) 431, 436 Armstrong, R . J . ( 7 ) 111, 112 Arumugam, N . ( 5 ) 485 Asada, S. ( 5 ) 318 Asahina, M. ( 5 ) 359 A s c h e r l , B. ( 5 ) 412 Asensio, G. ( 1 ) 27 Asirvatham, E. ( 2 ) 196; ( 3 ) 137, 333; ( 6 i i ) 265; ( 7 ) 89-91 A s l a m . A. ( 6 i i ) 272 Y. ( 2 ) 62; ( 3 ) 299; ( 4 ) 237 Assercq, J.-M. ( 2 ) 74; ( 7 ) 64; ( 6 i i ) 221 A s t r a b , D.P. ( 3 ) 90; ( 7 ) 34 A s t r u c , D. ( 6 i ) 26 A t k i n s , R.L. ( 5 ) 136, 373, 374 Atkinson, R. ( 5 ) 381 Atoh, A. ( 5 ) 418 A t t a n a s i , 0. ( 5 ) 265 Attwood, S.V. ( 6 i i ) 27; ( 8 ) 48 Aubry, A. ( 5 ) 403 Auburn, P.R. ( 4 ) 241; ( 6 i ) 33 Aumann, R. ( 9 ) 120 Aumueller, A. ( 5 ) 438 Aurich, H.G. ( 5 ) 515 Auvray, P. ( 1 ) 8 5 ; ( 6 i i ) 273
669 AUZOU, G. ( 5 ) 119 Avanaghi, M. ( 4 ) 195 AvendaEo, C. (5) 180 Awata, T. ( 3 ) 101 Azadani, M.N. (2) 1 5 Azerad, R. ( 3 ) 164; ( 4 ) 38 Aznar, F. ( 5 ) 120, 121, 124
Baar, M.R. ( 7 ) 12 Baba, K . ( 5 ) 16 Babot, 0. ( 5 ) 189 Babston, R.E. ( 3 ) 256 Babu, J . R . ( 4 ) 239 Bachi, M.D. ( 3 ) 362 Baciocchi, E. ( 3 ) 131 Badger, D. ( 2 ) 17 Badrudin, Y. ( 5 ) 398 Baeckvall, J.-E. ( 5 ) 302 Bagby, B. ( 6 i ) 31; ( 7 ) 42 B a i l e y , F.C. ( 5 ) 8 6 B a i l e y , T.R. ( 6 i i ) 216 B a i l l a r g e o n , V.P. ( 2 ) 51; ( 3 ) 384; ( 4 ) 207 B a i o c c h i , L. ( 9 ) 132 B a i r d , M.S. ( 2 ) 80 B a i z e r , M.M. ( 3 ) 101 Baker, R. ( 8 ) 47, 49 Bakhmutov, V . I . ( 3 ) 454 Balavoine, G. ( 3 ) 513; ( 5 ) 39 B a l d o l i , C. ( 5 ) 404 Baldwin, J . E . ( 2 ) 47, 48; ( 3 ) 197, 237, 354; (4) 133; ( 5 ) 495-497; ( 6 i i ) 10, 11, 211, 212 Baldwin, R.M. ( 5 ) 57 B a l e s t r a , M. ( 3 ) 258 B a l i n a , G. ( 5 ) 366 Balkovec, J . M . ( 1 ) 89; ( 6 i ) 41, 71; ( 7 ) 13, 124, 125 B a l l , W.A. ( 3 ) 27 B a l l e s t e r o s , P. ( 3 ) 132; ( 7 ) 12 B a l l i n i , R . ( 2 ) 193; ( 3 ) 56, 121, 229; ( 5 ) 360, 362 B a l l i s t r e r i , F.P. ( 2 ) 137 Balme, G. ( 4 ) 171 B a l t h a z o r , T.M. ( 5 ) 27 Bamilton, B . J . ( 3 ) 486 Ban, Y. ( 3 ) 425; ( 6 i ) 8 4 ; ( 9 ) 151 Bando, T. ( 5 ) 452 Banerjee, A.K. ( 1 ) 126; ( 6 i i ) 86 B a n f i , L. ( 2 ) 115; ( 3 ) 28; ( 4 ) 34 Bansal, H.S. ( 3 ) 401;
( 6 i ) 27 Banta, W.E. ( 6 i i ) 33 Baran, J . S . ( 5 ) 221 Barancyk, S.V. ( 3 ) 244 Barbot, F. ( 6 i i ) 136 Barcelo, G . ( 3 ) 515, 517 B a r i n e l l i , L.S. ( 6 i ) 25 B a r l o s , K . ( 3 ) 525 Barluenga, J. ( 1 ) 1 6 , 27; ( 2 ) 120; ( 3 ) 364; ( 4 ) 172, 174; (5) 91, 112, 120, 121, 124, 427, 432; ( 6 i i ) 3, 34, 95, 96; ( 9 ) 56, 133 Barnes, C.L. ( 2 ) 136; ( 3 ) 57 B a r r a n s , R.E. ( 4 ) 135 B a r r e t t , A.G.M. ( 3 ) 284; (5) 349; ( 6 i i ) 27; ( 8 ) 48; ( 9 ) 144 Bartkowiak, F. ( 5 ) 252 B a r t l e t t , P.A. ( 3 ) 311; ( 4 ) 222; ( 5 ) 254; ( 9 ) 43 Bartmann, W. ( 3 ) 412 B a r t n i k , R. ( 9 ) 77 Barton, D.H.R. ( 2 ) 30; ( 3 ) 116, 225, 521; ( 5 ) 64, 421; ( 6 i i ) 246, 247 Barton, J . C . ( 2 ) 183 B a r t r o l i , J. ( 3 ) 152; ( 4 ) 81 B a r t s c h , R . A . ( 3 ) 100 Barua, N.C. ( 3 ) 234, 349, 386, 387; ( 4 ) 134; ( 6 i i ) 46 Basavaiah, D. (1) 7, 104; ( 2 ) 28, 179; ( 6 i i ) 101, 118 Basha, A. (5) 59; ( 6 i i ) 4 Bashir-Hashemi, A. ( 3 ) 392 B a t e s , G.S. ( 1 ) 70 Batsanov. A.S. ( 3 ) 454 Battiste, M.A. (3) 336 Bauer, W. ( 6 i i ) 40 Bauld, N.L. ( 7 ) 3 Baumann, M.E. ( 3 ) 87 Baumberger, F. ( 5 ) 226 Bauta, W.E. ( 1 ) 36 Bazbouz, A . ( 2 ) 151; ( 6 i i ) 222 Beak, P. ( 3 ) 440; ( 5 ) 59, 210; ( 6 i i ) 4 ; ( 7 ) 23 Beal, C. ( 5 ) 478; ( 9 ) 8 6 Beck, G. ( 3 ) 412 Becker, A.M. ( 3 ) 382 Beckhaus, H.D. ( 5 ) 494 Beckwith, A.L. ( 3 ) 321; ( 4 ) 198; ( 7 ) 16, 17 Beddoes, R.L. ( 5 ) 460
670 Bedford, C.D. ( 4 ) 216 Beekes, M.L. ( 5 ) 465, 516 Beer, P.D. ( 5 ) 368, 454 Beeson, C. ( 5 ) 45 Behforouz, M. ( 3 ) 108 Behnke, M . ( 3 ) 264 B e i n e r t , G. ( 5 ) 109 Belanger, P.C. (1) 2 ; ( 4 ) 164 B e l c h e r , T. ( 2 ) 17 Belikov, V.M. ( 3 ) 454 B e l l , A . (5) 66 B e l l , K.H. ( 3 ) 430 Bell, T.W. ( 5 ) 191; ( 6 i i ) 104 B e l l a s s o u e d , M . ( 3 ) 49; ( 4 ) 90 B e l l e s i a , F. ( 4 ) 183 B e l l o , K . A . ( 5 ) 505 B e l l o i r , P.F. ( 9 ) 77 Belmont, D.T. ( 8 ) 20 Belokon', Y.N. ( 3 ) 454 Bencini, E. ( 4 ) 208 Bender, S.L. ( 8 ) 51 Benn, M.N. ( 5 ) 512 Bennamara, A . ( 5 ) 127 Benneche, T. ( 6 i i ) 185 Bensoam, J. ( 3 ) 517 B e n t l e y , T.W. ( 5 ) 49 B e r b r e i t e r , D.E. ( 3 ) 37 Berchadsky, Y . ( 5 ) 398 B e r e t t a , M.G. ( 2 ) 172; ( 3 ) 287 Bergh, C.L. ( 3 ) 4 Bergman, J. ( 5 ) 7 Berkard, U. ( 3 ) 473 B e r l a n , J . ( 3 ) 107; ( 6 i i ) 195 Berlin, A. ( 6 i i ) 63 B e r n a r d i , A . ( 3 ) 195, 287; ( 4 ) 8 5 B e r n a r d i n e l l i , G. ( 3 ) 17 Bernatchez, M. ( 7 ) 26 Berngth, G. ( 9 ) 65 Bernet, B. ( 5 ) 135 Berney, D. ( 5 ) 73 Bernloehr, W. ( 5 ) 494 B e r r i o s , R.R. ( 3 ) 14 Berry, N.M. ( 2 ) 166 Berry, W.M. ( 6 i i ) 25 Berstermann, H.-M. ( 5 ) 289 B e r t h a , F. ( 5 ) 462 B e r t h e l o t , J . ( 4 ) 173 Berthiaume, G. ( 2 ) 194, 195; ( 7 ) 97, 98 B e r t o l i n i , G. ( 3 ) 466; ( 5 ) 171 Bertounesque, E. ( 3 ) 49; ( 4 ) 90 B e r t z , S.H. ( 2 ) 181;
General and Synthetic Methods ( 4 ) 95; ( 7 ) 52 Besace, Y. ( 3 ) 107; ( 6 i i ) 195 B e s l i n , P. ( 3 ) 292 Bessodes, M. ( 4 ) 129 B e s t , W.M. ( 3 ) 282 Bestmann, H . J . ( 7 ) 25; ( 9 ) 101 Betancor, C. (5) 30 Betancourt de P e r e z , R.M. ( 2 ) 136 Beugelmans, R. ( 4 ) 194; ( 5 ) 388 B e u t t l e r , T. ( 5 ) 252 Bey, P. ( 3 ) 496; ( 5 ) 202 Bhandal, H . ( 3 ) 323; ( 6 i ) 8 9 ; ( 9 ) 15 Bhat, K.S. (1) 61; ( 4 ) 52; ( 6 i i ) 116, 127, 129 Bhat, N.G. (1) 104; ( 3 ) 242; ( 4 ) 179; ( 6 i i ) 101, 118, 119, 122 B h a t t , M.V. ( 4 ) 239 B h a t t a c h a r y a , A . ( 3 ) 34; ( 7 ) 100 Bhide, R.S. ( 3 ) 89 Bickelhaupt, F. ( 6 i ) 24, 77 B i e r i , J.H. ( 5 ) 368 B i l g e r , C. ( 5 ) 367 B i l i n s k i , V. ( 3 ) 374 B i l l e d e a u , R . ( 3 ) 501; ( 5 ) 159 Binder, J . ( 3 ) 146 B i n e t , J . L . ( 5 ) 224 B i r c h , D . J . ( 3 ) 237; ( 6 i i ) 211 B i r t w h i s t l e , D.H. ( 4 ) 3 Blade, R . J . (1) 79 Blagbrough, I.S. ( 3 ) 433; ( 5 ) 207 Blagg, J. ( 4 ) 230; ( 6 i ) 38, 51 Blair, I.A. ( 5 ) 280 Blair, L.K. ( 2 ) 17 Blanchard, L.A. ( 3 ) 494; (5) 81 Bloch, R . ( 3 ) 268; ( 5 ) 217 Block, E. ( 6 i i ) 272 Bloodworth, A.J. ( 6 i i ) 9 4 ; ( 9 ) 26 Bloom, A . J . (1) 69; ( 5 ) 345, 346 Bloom, S.H. ( 7 ) 70 Blumenkopf, T.A. ( 1 ) 38; ( 4 ) 228; ( 6 i i ) 173, 174; ( 7 ) 6 7 ; ( 9 ) 45, 72 B l u n t , J . W . (5) 55
Bluthe, N . ( 2 ) 57 Bo, L. ( 3 ) 213; ( 6 i i ) 49 Boche, G . ( 5 ) 340 Bock, M.G. ( 3 ) 482 Bodnar, T.W. ( 6 i ) 78 Bodzay, S.J. ( 9 ) 53 Bohnke, H. ( 3 ) 481 Boehshar, M. ( 6 i i ) 35 Boesten, W . H . J . ( 3 ) 486 B o i l e a u , J . ( 5 ) 369 Bolan, .J.L. ( 3 ) 108 B o l d r i n i , G.P. (1) 58; ( 3 ) 262; ( 4 ) 75; ( 6 i i ) 89 Bolger, D.L. ( 7 ) 35 B o l t e , J. ( 4 ) 33 Bolton, G.L. ( 1 ) 90 Bongini, A . ( 5 ) 140, 141 Borbaruah, M. ( 4 ) 134 Borgain-Commercon, M. (3) 63 Bormann, C. ( 3 ) 478 B o r s , D.A. ( 6 i i ) 64 B o r t o l i , D. ( 6 i i ) 288 B o r t o l i n i , 0. ( 2 ) 12; ( 4 ) 140 Boruah, R.C. ( 9 ) 145 Bosch, E. (1) 96; ( 3 ) 362 Bosnich, B. ( 4 ) 241; ( 6 i ) 33 Bosshard, H. ( 3 ) 87 Bossio, R. ( 5 ) 334 B o t t a r o , J . C . ( 2 ) 47; ( 3 ) 197; ( 4 ) 216; ( 5 ) 495, 496; ( 6 i i ) 10, 11 Boucherle, A. ( 3 ) 73 Boudjouk, P. ( 6 i i ) 1 Boudreaux, G . J . ( 6 i i ) 70 Boukouvalas, J. ( 3 ) 55, 389 Bourdon, F. ( 3 ) 283; ( 4 ) 166 B o u t i n , R.H. ( 5 ) 192 Bowman, R.P. ( 6 i i ) 81 Bowman, W.R. ( 5 ) 363 Boyd, D.R. ( 5 ) 419 Bradamante, S. ( 6 i i ) 6 3 B r a e n d l i , U. ( 5 ) 387 Braga, A . L . ( 1 ) 125 B r a i s h , T.F. ( 4 ) 122 Bram, G. ( 5 ) 283 Brambilla, A. ( 3 ) 8 2 Brand, C. ( 5 ) 33 Brand, M. ( 3 ) 1 1 7 , 241; (9) 1 B r a n d i , A. ( 9 ) 125, 126, 135 Brandsma, L. ( 1 ) 1 0 ; ( 6 i i ) 30 Brandsma, R . ( 5 ) 380 Brannon, M.J. ( 2 ) 81;
67 1
Author Index ( 5 ) 129 BI-:?,~~. Braun, M . ( 3 ) 50 Braun, S. ( 3 ) 27 Bravo, P. ( 3 ) 338 Brecht, A. (3) 272 B r e i t e n s t e i n , W. ( 3 ) 87 Brelow, R. ( 5 ) 425 Brena, F.K. ( 3 ) 190 Brennan, J.P. (8) 30 Breslow, R . ( 4 ) 186; ( 5 ) 424, 426 B r i l l , W.F. ( 6 i i ) 295 B r i l l o n , D. ( 3 ) 92; ( 7 ) 120 Bringmann, G. ( 8 ) 25 Brinkhaus, D.-H.G. ( 3 ) 273 B r i t t o n , T.C. ( 3 ) 467; ( 5 ) 172 B r i x , B. ( 6 i i ) 40 Brocksorn, T.J. ( 4 ) 221; ( 6 i i ) 141; ( 9 ) 1 2 Broka, C.A. ( 9 ) 93 Brook, M.A. ( 5 ) 451; ( 8 ) 39; ( 9 ) 127 Brooker, D.R. (8) 6 0 B r o s s i , A. ( 5 ) 68, 461, 510 B r o t h e r s , D. ( 2 ) 93 B r o t h e r t o n , C.E. ( 7 ) 35 Brouwer, A.C. (5) 344 Brown, C.A. (1) 104; ( 6 i i ) 106 Brown, H.C. (1) 5-7, 61, 104; ( 2 ) 26-28; ( 3 ) 142, 242; ( 4 ) 2 , 24-26, 52, 179; ( 5 ) 32; ( 6 i i ) 101, 107, 109-119, 122, 125-127, 129 Brown, J . D . ( 3 ) 71; ( 6 i i ) 16; ( 9 ) 123, 124 Brown, J.M. ( 4 ) 3 Brown, K.C. ( 5 ) 396 Brown, M. ( 7 ) 128 Brown, P.A. ( 4 ) 65; (7) 81 Brown, R.T. (8) 34 Brown, S.L. ( 6 i ) 5 4 , 77 Brownbridge, P. ( 3 ) 235, 25 1 Browne, L.J. ( 7 ) 40 Brozova, I. ( 4 ) 30 Bruckner, C. ( 4 ) 218 Bruhn, P.R. ( 6 i ) 36 B r u n e l e t , T. ( 2 ) 1; ( 4 ) 148 Brunetiere, A.P. (9) 13 Brunner, H. ( 3 ) 507; ( 6 i i ) 247 Bruzik, K.S. ( 5 ) 143
( 2 ) 134; ( 6 i i ) 237 Campbell, J.R., j u n . ( 3 ) 242; ( 6 i i ) 122 Campos, P.J. (1) 27; ( 4 ) 174 Camps, F. ( 2 ) 31 Canonne, P. ( 3 ) 57; ( 7 ) 26 Caporusso, A.M. ( 1 ) 101 Capozzi, G. ( 6 i i ) 260 Capuano, L. (5) 444 Caputo, R . ( 3 ) 96 C a r a i l , M. ( 5 ) 369 Cardani, S. ( 3 ) 195; ( 5 ) 156 C a r d i l l o , G. ( 5 ) 140, 141 C a r e l l i , I . ( 9 ) 146 C a r e l l i , V. ( 9 ) 146 Carey, J.T. ( 2 ) 84 C a r i n i , D . J . (1) 105; ( 4 ) 78 C a r i o u , M. ( 5 ) 117 Carlier, R. ( 5 ) 117 C a r l i n g , R.W. ( 3 ) 424 Carman, L. ( 2 ) 56 C a r p e n t e r , A . J . ( 6 i i ) 14 C a r p e n t e r , J.F. ( 6 i i ) 269 Carpino, P.A. (1) 44; ( 3 ) 516; ( 5 ) 31, 67; ( 6 i i ) 287 C a r p i t a , A. (1) 8 6 , 117, 118; ( 6 i i ) 168 Carr, C.S. ( 2 ) 107, 108 C a r r , R.A.E. ( 6 i i ) 27; ( 8 ) 48 Carranza R., S. ( 2 ) 14 C a r r a u , R. ( 5 ) 30, 439 C a r r e l l , H.L. (5) 230 C a r r e t e r o , J . C . ( 3 ) 91; ( 6 i i ) 66 C a r r i e , R. ( 3 ) 497; ( 5 ) 420 Carroy, A . ( 5 ) 97 Cabal, M.-P. ( 5 ) 124 Cabiddu, S. ( 4 ) 254; Casadei, M.A. ( 9 ) 146 ( 6 i i ) 44 C a s a r e s , A. ( 3 ) 264 Cacchi, S. (1) 29, 122; C a s a t i , P. ( 3 ) 158, 496, 524 ( 3 ) 275; ( 4 ) 165, 205; C a s t a l d i , G . (2) 118 ( 6 i ) 65 Cadamuro, S. ( 3 ) 25 Castangda, A . (1) 38; Cahiez, G. ( 4 ) 59, 60 ( 4 ) 228; ( 6 i i ) 173; C a i l l e , J . C . (5) 402, ( 9 ) 45 Castedo, L. (1) 122; 403 C a i n e l l i , G . ( 9 ) 138 (8) 31 C a i r n s , P.M. (8) 29 C a s t e l h a n o , A.L. ( 3 ) 501; C a l d i r o l a , P. ( 3 ) 166 ( 5 ) 159 C a l e t , S. ( 9 ) 69; ( 6 i ) 10 C a s t e l l i n o , S. ( 4 ) 8 3 C a l l e n , G . R . ( 4 ) 42 C a s t i l l o n , S. ( 5 ) 484 Calmes, M. ( 3 ) 448; C a s t l e , P.L. ( 4 ) 203 ( 5 ) 170 C a t a n i , V. ( 1 ) 125 C a l b , V. ( 3 ) 249; ( 6 i ) 47 C a t i v i e l a , C. ( 3 ) 498, Calogeropoulou, T. 499; ( 5 ) 220
B r y c e , M.R. ( 6 i i ) 217 Brynolf, A. ( 5 ) 7 Bubenheim, 0. ( 5 ) 515 Buchan, C. ( 3 ) 104 Buchanan, C.M. ( 3 ) 3 4 , 35 Buchman, 0. ( 4 ) 200 Buck, T. ( 5 ) 75 Buechi, G. (5) 390; (8) 63 B u g i a n e s i , R.L. (8) 60 Buhlmayer, P. ( 6 i i ) 41; ( 7 ) 13, 124 Buisson, D. ( 3 ) 164; ( 4 ) 38 Bulychev, A.G. ( 3 ) 454 Bumgardner, C.L. ( 2 ) 117 Bunce, R.A. ( 3 ) 208; ( 4 ) 136 Bugfen, S. ( 5 ) 8 9 , 99 Burckhardt, H. ( 3 ) 510 Burford, S.C. ( 6 i i ) 29 Burg, D . A . ( 7 ) 23 Burger, K . ( 5 ) 289 Burger, U. ( 5 ) 492 Burkard, U. ( 3 ) 147; ( 5 ) 165, 166 Burke, S.D. ( 3 ) 361; ( 6 i ) 76; ( 8 ) 61 Burnaeva, L.A. ( 5 ) 509 B u r n e t t , D.A. ( 9 ) 139 Burrows, C . J . ( 5 ) 42 Burton, J.T. ( 7 ) 123 Bush, B.D. ( 3 ) 194 Bushnell, G.W. ( 5 ) 377 Busse, U . ( 3 ) 459, 460; ( 5 ) 149, 150 Butsugan, Y. ( 4 ) 162 Buurman, D . J . ( 5 ) 441 Byrne, B. ( 2 ) 79 Byun, H.-S. ( 2 ) 13; ( 4 ) 213
672 C a t o n , M.P.L. ( 3 ) 403 Cava, M.P. ( 3 ) 523; ( 6 i i ) 291 C a v a l e i r o , J.A.S. ( 5 ) 382 Cavero, I. ( 5 ) 224 C a v i c c h i o l i , S. ( 2 ) 118 Cederbaum, F.E. (1) 6 3 C e f e l i n , P. ( 4 ) 211 C e g l a , M. ( 4 ) 29 Cekovic, Z . ( 7 ) 1 5 , 21 Celebuski, J.E. (9) 85 C e r v i n k a , 0. ( 4 ) 30 Cha, J . S . ( 6 i i ) 107 Chabaud, B. ( 1 ) 21; ( 6 i i ) 279 Chadha, V.K. ( 5 ) 56 Chadwick, D . J . ( 6 i i ) 14 C h a k r a b o r t y , T.K. ( 1 ) 134; ( 8 ) 57 Chamberlain, A.R. ( 6 i i ) 47; ( 7 ) 70 Chambers, R.D. ( 6 i i ) 217 Chan, K.-S. ( 1 ) 3 6 ; ( 6 i i ) 33 Chan, T.H. ( 3 ) 194; (4) 175; (9) 26, 53; ( 6 i i ) 169 Chandrasekaran, S. ( 2 ) 2 4 , 154; ( 3 ) 307 Chandrasekharan, J . ( 4 ) 2 4 ; ( 6 i i ) 109 Chang, M.N. ( 8 ) 6 0 Changyou, Z. ( 3 ) 455; ( 5 ) 157 C h a p l e o , C.B. ( 3 ) 224 Chapman, D. ( 3 ) 264 Chapman, K.T. ( 4 ) 1 9 Chapman, S.L. ( 6 i i ) 278 C h a p u i s , C. ( 4 ) 222 C h a t a n i , N . (1) 1 9 ; ( 5 ) 284, 296, 332 C h a u s s a r d , J. ( 2 ) 44 Chawla, H.M. ( 5 ) 379 Chehna, M. ( 5 ) 433 Chemburkar, S. ( 9 ) 96 Chen, B.C. ( 5 ) 447 Chen, C. ( 3 ) 211; ( 5 ) 437; ( 6 i i ) 243; (9) 98 Chen, C.-S. ( 3 ) 79 Chen, H.-H. ( 3 ) 3 3 , 34 Chen, H.-L. ( 8 ) 44; ( 9 ) 16 Chen, H.-M. ( 6 i i ) 166 Chen, J. ( 8 ) 4 0 Chen, M.-H. ( I ) 28; ( 7 ) 20 Chen, Q.-Y. ( 6 i ) 15 Chen, S.-F. (1) 83; (9) 87 Chen, S.-T. ( 3 ) 486 Chenard, B.L. (1) 31;
General and Synthetic Methods ( 2 ) 4 9 , 6 7 ; ( 3 ) 75; ( 6 i i ) 1 7 6 , 209; ( 7 ) 5 8 C h s n e v e r t , R . ( 4 ) 33 Cheng, C.-W. ( 5 ) 126; ( 6 I i ) 32 Cheng, F.C.W. ( 3 ) 3 7 0 , 371 Cheng, M.-C. ( 3 ) 1 4 3 , 397 Cheon, S.H. ( 4 ) 177 Chhabra, B.R. ( 4 ) 151 C h i a n e l l i , D. ( 6 i i ) 288 C h i b a , M. ( 3 ) 344 C h i c h e , L. ( 5 ) 127 C h i e f a r i , J. ( 9 ) 105 C h i e s i - V i l l a , A. ( 6 i ) 5 5 C h i h a r a , T. ( 4 ) 127 C h i k a s h i t a , H. ( 2 ) 3 3 , 34 Chikugo, T. ( 1 ) 3 7 ; ( 3 ) 363; ( 6 i i ) 232 C h i n o , K. ( 3 ) 322 C h i r i a c , C . I . ( 3 ) 70 C h i t r a c o r n , S. ( 2 ) 2 3 Cho, B.P. ( 5 ) 5 6 Cho, B.T. ( 3 ) 142; ( 4 ) 25, 26; ( 6 i i ) 110-112 Cho, Y . ( 5 ) 347 C h o i , K . N . ( 5 ) 11 Choi, Y.M. (5) 204 Chong. J . M . ( 1 ) 102 ( 6 i i ) 68 Chou, S.-S.P. Choudry. S.C. ( 8 ) 53 Chow, H. ( 2 ) 169 Chow, K . ( 5 ) 325 C h r i s t , W.J. ( 4 ) 4 4 , 177 C h r i s t a e n s , L.E. ( 6 i i ) 283 C h r i s t a u , H . J . (1) 21 C h r i s t i a n s e n , M.L. ( 6 i i ) 185 C h r i s t o l , H. (1) 2 1 ; ( 2 ) 4 ; ( 4 ) 149; ( 5 ) 1 2 7 ; ( 6 i i ) 279 Chu, K.-H. (1) 3 5 ; ( 6 i i ) 202; ( 9 ) 21 Chu, M. (5) 1 1 3 ; ( 9 ) 114 Chua, V. ( 4 ) 135 Chucholowski, A. ( 3 ) 327 C h u i t , C. ( 3 ) 445 Chun, M.W. ( 7 ) 9 6 Chung, W.-K. (7) 96 C i a c c i o , J . A . ( 6 i i ) 104 C i a n c a g l i o n e , M. ( 3 ) 166 C i a t t i n i , P.G. ( 3 ) 275, 372; ( 4 ) 165 C i n q u i n i , M. ( 4 ) 77; ( 6 i i ) 51, 52 C i t t e r i o , A. ( 3 ) 435; ( 5 ) 235, 467 C i u f o l i n i , M.A. ( 9 ) 130 C l a r d y , J. (1) 1 2 7 ;
( 3 ) 1 3 7 ; ( 5 ) 435; ( 6 i i ) 265 Clarembeau, M. ( 6 i i ) 71 Claremon, D . A . ( 5 ) 148 C l a r k , C. ( 3 ) 118; ( 9 ) 6 C l a r k , M.T. ( 5 ) 260 C l a r k , R. ( 2 ) 130 C l a r k e , E.T. ( 5 ) 105 C l a u s , R.E. ( 3 ) 204 C l e a r y , D.G. ( 3 ) 207; ( 8 ) 18 Clemens, R . J . ( 3 ) 303 Clemo, N.G. ( 3 ) 376 Cle/ophax, J . ( 3 ) 30 C l e r i c i , A. ( 3 ) 171 C l i v e , D.L.J. ( 7 ) 49 C o a t e s , R.M. ( 5 ) 1 4 6 , 519 Cobb, J . E . ( 6 i ) 76 Coburn, R.A. ( 5 ) 260 Coffman, K.J. (5) 395 Cohen, T. ( 6 i i ) 42, 43 C o l c l o u g h , M.E. ( 2 ) 100 C o l e , T.E. (1) 104; ( 4 ) 2 ; (5) 32; ( 6 i i ) 101, 113, 1 2 5 , 126 C o l l , J . ( 2 ) 31 C o l l i e r , T.L. ( 3 ) 504; (9) 8 C o l l i g n o n , N. ( 6 i i ) 240 C o l l i n , J. (4) 143 Collum, D.B. ( 4 ) 119; ( 5 ) 435; ( 6 i i ) 9 8 Colombo, L. ( 3 ) 1 4 9 , 466; (4) 86; (5) 171 Comasseto, J . V . (1) 125; ( 6 i i ) 290, 294 Comins, D.L. ( 3 ) 7 1 ; ( 6 i i ) 1 6 ; ( 9 ) 1 2 3 , 124 Comte, M.-T. ( 3 ) 231 Concell6n, J.M. (1) 16; (6ii) 3 Condon, B.D. ( 4 ) 124 Conlon, H.D. ( 3 ) 496 Conrow, R. ( 2 ) 139 C o n t e , V. ( 2 ) 12; ( 4 ) 140 C o n t e n t o , M. (9) 138 Cook, A.P.F. ( 3 ) 282 Cook, C. ( 5 ) 347 Cook, J.C. ( 5 ) 55 Cook, J . M . ( 7 ) 5 2 Cooke, G.E. ( 6 i i ) 204 Cooke, M.P. ( 2 ) 41; ( 3 ) 109 Cooksey, C.J. ( 9 ) 26 Cooper, K . ( 4 ) 112 Cooper, M.M. ( 5 ) 1 2 Cooper, M.S. (5) 77 Cooper, P.N. ( 6 i i ) 9 4 C o r b e r a , J . ( 3 ) 328 C o r e y , E.J. ( 1 ) 6 4 , 132; ( 2 ) 182; (5) 8 8 ;
673
Author Index ( 6 i ) L4, 102; ( 7 ) 2 4 , 102, 1 0 3 ; ( 8 ) 4 6 Corey, P.F. ( 3 ) 26 Cork, D.G. ( 4 ) 252 Cormons, A . ( 9 ) 122 C o r n e l i s s e , J . ( 5 ) 380 C o r r a d o , E. ( 3 ) 9 6 C o r r a l , R.A. ( 9 ) 129 C o r r i u , R . J . P . ( 3 ) 445 Cossar, J. (5) 58 C o s s i o , F. ( 4 ) 188 C o s t a , A . ( 3 ) 492 C o s t e l l o , A . T . ( 4 ) 192 C o s t e l l o , G. ( 5 ) 316 C o s t e r o , A.M. ( 1 ) 1 7 ; ( 4 ) 189 Coury, J. ( 5 ) 76 C o u s s e , H. ( 3 ) 7 3 C o u t r o t , P. ( 3 ) 61; ( 6 i i ) 7 6 , 239 C o u t u r e , A. ( 9 ) 116 C o z z i , F. ( 4 ) 7 7 ; ( 6 i i ) 5 1 , 52 Cram, D . J . ( 5 ) 9 5 , 96 Cramer, C . J . ( 3 ) 330; (9) 60, 61 C r a n d a l l , J.K. ( 7 ) 1 9 Crawford, E . J . ( 6 i ) 7 8 C r a w f o r d , J.A. ( 3 ) 237; ( 6 i i ) 211 C r e a r y , X . ( 3 ) 115 C r i c h , D. ( 3 ) 116 Crimmins, M.T. (8) 6 C r i s t a u , H.-J. ( 2 ) 4 , 151; ( 4 ) 1 4 9 ; ( 6 i i ) 279 Crombie, L. ( 5 ) 356; (8) 43 C r o n i n , J . P . ( 6 i i ) 248 Crowe, K . E . ( 6 i ) 3 2 ; ( 7 ) 117 Crowley, P . J . ( 6 i i ) 1 9 C r u s t a u , H . J . ( 6 i i ) 222 C r u z , A. ( 3 ) 190 Csuk, R. ( 3 ) 1 4 8 ; ( 4 ) 118; ( 6 i i ) 8 0 , 84, 85 C u e r v o , H. ( 5 ) 91 Cummins, C.H. ( 5 ) 1 4 6 Cun-Heng, H. ( 3 ) 137; ( 6 i i ) 265 Cunico, R.F. ( 2 ) 1 3 2 ; ( 6 i i ) 184 Cunningham, A.F. ( 6 i i ) 74; ( 7 ) 3 2 Cunningham, I. ( 5 ) 341 C u r c i , R . ( 2 ) 137 C u r l e s s , D. ( 8 ) 34 C u r l e y , R.W., j u n . ( 3 ) 210 C u r r a n , D.P. (1) 28; ( 2 ) 105; (3) 52; ( 7 ) 20, 47
C u r r a n , T.T. ( 3 ) 108 C u t l e r , A . R . ( 6 i ) 78 Cuvigny, T. ( 6 i i ) 274 C y r , P. ( 3 ) 313 Dabbagh, G. ( 2 ) 181; (4) 95 Dabdoub, M . J . ( 6 i i ) 294 Dabdoub, V.B. ( 6 i i ) 294 D a h l h o f f , W.V. ( 4 ) 1 2 3 ; ( 6 i i ) 103 D a i , L. ( 4 ) 107 D a i n e s , R.A. ( 1 ) 134; ( 8 ) 57 D a l c a n a l e , E . (3) 3 D a l e , J. ( 5 ) 8 9 , 99 Damour, D. ( 6 i i ) 158 Danan, A . ( 3 ) 125 Dancey, K.F. ( 5 ) 106 d ' A n g e l o , J . ( 3 ) 487; ( 5 ) 195; ( 9 ) 150 D a n g l e s , 0. ( 3 ) 513; (5) 39 D a n h e i s e r , R.L. (1) 1 0 5 ; (4) 78 Danion, D. ( 9 ) 6 3 Danion-Bougot, R . ( 9 ) 63 D a n i s h e f s k y , S . J . ( 9 ) 110 Dankwardt, J . W . ( 6 i i ) 1 7 Danmark, S.E. ( 3 ) 395 Dappen, M.S. ( 3 ) 3 3 0 ; ( 9 ) 60 Darey, M.C.P. ( 2 ) 166 Da S e t t i m o , F. ( 1 ) 101 Datema, R . ( 5 ) 222 Daub, C.W. ( 3 ) 255 Dauben, W.G. ( 2 ) 145 D a u n i s , J. ( 3 ) 448; ( 5 ) 170 Dave, P. ( 2 ) 1 3 ; ( 4 ) 213 Davidsen, S.K. ( 2 ) 176; ( 3 ) 4 8 ; ( 4 ) 8 8 ; ( 7 ) 51; ( 8 ) 42 D a v i e s , S.G. ( 4 ) 229, 230; ( 6 i ) 38, 51-54, 56-58, 7 2 , 7 7 ; ( 9 ) 1 4 2 , 143 D a v i s , A.P. ( 4 ) 2 0 ; ( 6 i i ) 191 D a v i s , F.A. ( 2 ) 1 1 0 ; ( 3 ) 140; ( 5 ) 26 Dawson, B.A. ( 5 ) 58 Dawson, I . M . ( 6 i i ) 271 De A m i c i , M. ( 3 ) 166 Deana, A.A. ( 3 ) 409 d e Boer, Th.J. ( 5 ) 465, 516 D e Buyck, L. ( 5 ) 448 Decker, O.H.W. ( 3 ) 260 D e c l e r c q , J.-P. ( 5 ) 211; ( 8 ) S8
D e g a n i , I . (3) 25 Degner, D. ( 3 ) 273 D e g u e i l - C a s t a i n g , M. DeitLrfoW. ( 3 ) 478 DeHoff, B.S. ( 3 ) 207, 359; ( 4 ) 232; ( 8 ) 1 4 , 17 D e i s e n r o t h , T.W. ( 5 ) 139 De Kimpe, N . ( 5 ) 2 9 , 211, 3 3 1 , 428, 448 Delair, T. ( 9 ) 11 d e L a s a l l e , P. ( 3 ) 5 1 Delgado, M. ( 5 ) 364 Dell'Aira, D. ( 3 ) 131 D e l l ' E r b a , C. ( 4 ) 245 D e l l a r i a , J.F. ( 3 ) 467; ( 5 ) 172 De Lombaert, S. ( 3 ) 9 1 de Lopez-Cepero, I . M . ( 2 ) 135 Delpech, B. ( 9 ) 3 D e m a i l l y , G . ( 3 ) 373; (4) 7 deMaldonado, V.C. ( 3 ) 14 de M e i j e r e , A . ( 9 ) 59 Demers, J . P . ( 3 ) 519; ( 6 i i ) 196 Demerseman, P. ( 5 ) 367 De M i c h e l i , C. ( 3 ) 166 Demir, A.S. ( 3 ) 392 Demko, D.M. ( 3 ) 519; ( 5 ) 6 9 ; ( 6 i i ) 196 Demuth, M. ( 7 ) 9 D e n i s , J.-N. ( 3 ) 493 Denmark, S.E. ( 2 ) 6 5 ; ( 3 ) 330; ( 6 i i ) 1 7 5 ; (7) 57, 73; ( 9 ) 34, 60, 61 de P e r e z , R.M.B. ( 3 ) 57 Depezay, J . C . ( 3 ) 476; ( 5 ) 155 Depreux, P. ( 5 ) 8 5 DePue, R.T. ( 5 ) 435 De R u g g i e r i , P. ( 3 ) 1 8 5 Desai, M.C. ( 1 ) 104 De S a r l o , F . ( 9 ) 1 2 5 , 126, 135 Deshmukh, J . G . ( 3 ) 13 DeShong, P. ( 1 ) 4 6 ; (5) 65 Deslongchamps, P. ( 2 ) 194, 1 9 5 ; ( 7 ) 9 7 , 98, 119, 1 2 0 Desmond, R . W . , j u n . ( 6 i i ) 154; ( 7 ) 54 Devant, R . ( 3 ) 50 De Voss, J.J. ( 9 ) 30 Dey, A.K. ( 7 ) 9 Deya, P.M. ( 3 ) 5 3 Deyo, D. ( 3 ) 3 4 Dhanak, D. ( 5 ) 409
674
Dhar, D.N. ( 5 ) 264, 508 Diaz de V i l l e g a s , M.D. ( 3 ) 4 9 8 , 499; ( 5 ) 220 Dickman, D.A. ( 8 ) 27 D i e t e r , R . K . ( 2 ) 187; ( 3 ) 294; ( 9 ) 54 D i e t r i c h , H. ( 5 ) 434 D i F u r i a , F. ( 2 ) 1 2 ; ( 4 ) 140 D i l w o r t h , B.M. ( 4 ) 246; ( 6 i i ) 248 DiMare, M. ( 3 ) 152 d ' I n c a n , E. ( 2 ) 4 4 ; ( 4 ) 61 D i n g w a l l , J . G . ( 3 ) 302 DiPardo, R.M. ( 3 ) 482 D i p p e l , J. ( 3 ) 461; ( 5 ) 151 D i t t m e r , D.C. (1) 4 2 ; ( 4 ) 104; ( 6 i i ) 293 D i T u l l i o , D. ( 3 ) 174 D i x n e u f , P.H. ( 3 ) 276 Dixon, B.R. ( 9 ) 85 D l u b a l a , A. ( 3 ) 292 Doedens, R . ( 5 ) 325 Doherty, A.M. ( 6 i i ) 13 D o l l i n g , V.-H. ( 7 ) 100 Dordor-Hedgecock, I . M . ( 6 i ) 57, 5 8 ; ( 9 ) 1 4 2 , 143 Dorey, M.C.P. ( 6 i i ) 25 Dorow, R.L. ( 3 ) 467; ( 5 ) 172 Dorsey, B.D. (8) 21 Dost, H. ( 5 ) 504 D o s t , J. ( 5 ) 243 Doubleday, C. ( 2 ) 6 3 Dougherty, T.K. ( 7 ) 8 2 Doutheau, A . ( 9 ) 11 Dow, R.L. ( 3 ) 10, 152; ( 4 ) 8 1 ; ( 8 ) 52 Dowd, P. (3) 502; (5) 201 Doyama, K . ( 7 ) 4 1 D r e i d i n g , A.S. ( 3 ) 3 1 7 , 374; ( 5 ) 216, 458; ( 7 ) 75-77; ( 8 ) 5 , 13 Drew, R . A . I . ( 9 ) 30 Drewes, S.E. ( 3 ) 241 Du, C.J.F. ( 6 i i ) 7 8 Dubois, J.-E. ( 3 ) 49; ( 4 ) 90 Duboudin, F. ( 5 ) 189 D u e s l e r , E.N. ( 2 ) 108 D u f r e s n e , C. ( 1 ) 2; ( 4 ) 164 Duggan, M.E. ( 9 ) 41, 42 Duguay, G. (5) 4 3 3 Duhamel, L. ( 3 ) 451 Duhamel, P. ( 2 ) 144 Dumas, A.P. (5) 224 Dumas, F. ( 9 ) 150 Dunlap, N.K. ( 3 ) 392
General and Synthetic Methods Dunogues, J. ( 5 ) 189 Dupuy, C. ( 2 ) 186 D u r g a u l t , A. ( 3 ) 476; (5) 155 Durman, J. (3) 233, 251 D u t t a , A.S. ( 5 ) 176 D u t t a , D.K. ( 9 ) 1 4 5 Dvorak, D. ( 3 ) 187 Dyrbusch, M. (3) 459 Dzhemilev, U.M. ( 6 i ) 7 E a s t , M.B. ( 2 ) 1 9 0 ; ( 6 i i ) 5 6 , 204 E a s t o n , R.J.C. ( 6 i ) 52 E b e r l e , M. ( 3 ) 159 E b e r l e i n , T.H. ( 6 i i ) 251; (9) 51 Ebner, C.B. ( 3 ) 239; ( 5 ) 115 Echegoyen, L. ( 5 ) 364 E c k e r t , H. ( 3 ) 520; ( 5 ) 247; ( 6 i ) 91 E c k e r t , T.P. ( 5 ) 395 E c k h a r d t , G. ( 5 ) 445 Eda, Y. ( 5 ) 63 Edstrom, E. ( 6 i i ) 259, 286 Edwards, M.P. ( 6 i i ) 13 E f f e n b e r g e r , F. ( 3 ) 147, 473; ( 5 ) 1 6 5 , 166 E g e r t , E. ( 3 ) 459, 461; ( 5 ) 151 E g g e r s , W. ( 5 ) 471 E g g l e s t o n , D.S. ( 3 ) 120 E g l i , M. ( 3 ) 317; ( 5 ) 216 E h r e n k a u f e r , R.E. ( 3 ) 484; ( 5 ) 186 E h r l e r , R . ( 5 ) 361 E i l b r a c h t , P. ( 6 i ) 81 E i n h o r n , C. ( 4 ) 9 6 , 103 E i n h o r n , J. (3) 4 3 4 ; ( 6 i i ) 18 E i s c h , J.J. ( 5 ) 416 E i s e n h a r t , E.K. ( 6 i i ) 190 E l - E b r a s h i , N.M.A. ( 5 ) 242 E l e v e l d , M.B. ( 5 ) 52; (6ii) 7 E l Goumzili, M. ( 3 ) 456, 457; ( 9 ) 104 E l i e l , E.L. (3) 3 8 8 , 413 E l l e n b e r g e r , S.R. ( 5 ) 230 E l l i o t t , J. ( 1 ) 11 E l Satnu, Z.K.M.A. ( 3 ) 314 Emerson, K. ( 6 i ) 1 4 Emziane, M. ( 4 ) 121; (5) 473 E n d e r s , D. ( 5 ) 2 4 , 406, 407 Endo, H. ( 3 ) 1 1 3 ; ( 4 ) 206 Endo, T. ( 1 ) 1 ; ( 4 ) 159,
187, 224; ( 6 i i ) 200; ( 9 ) 14 Endo, Y. (5) 223 Eng, K . K . ( 9 ) 93 E n g e l , R. ( 2 ) 1 3 ; ( 4 ) 213 E n g e l , W. ( 6 i i ) 182 E n g l e r , T.A. ( 3 ) 214, 270 Enk, M. ( 3 ) 263 Xnoki, T. (5) 310 Enomoto, M. (1) 92 Entezari-Moghaddam, M. (2) 6, 7 E r a , M . ( 5 ) 269 Erden, I. ( 9 ) 5 9 E s a k i , N . ( 5 ) 161 Eschenmoser, A. ( 5 ) 316 E s c r i b a n o , F.C. ( 5 ) 484 Eskew, N.L. ( 6 i i ) 225; (9) 68 Eswarakrishnan, V. ( 6 i i ) 272 E t t e r , J.B. ( 7 ) 71 Euerby, M.R. ( 4 ) 253 Evans, D.A. ( 3 ) 10, 1 5 2 , 467; ( 4 ) 1 9 , 81, 8 2 ; ( 5 ) 1 3 7 , 172, 339; ( 8 ) 5 1 , 52 Evans, R.D. ( 2 ) 1 2 1 ; (3) 402 Evans, R.T. ( 5 ) 260 Evans, S.A. ( 4 ) 1 7 0 ; ( 6 i i ) 225; ( 9 ) 6 8 Evans, T.L. ( 4 ) 249 E v e r s , M . J . ( 6 i i ) 283 E y e r , M. ( 5 ) 387 F a b e r , K . ( 3 ) 485; ( 5 ) 183 Fabryova, A. ( 4 ) 30 F a g h i h , R . ( 5 ) 484 F a i l l a , S. ( 2 ) 137 F a l c k , J . R . ( 4 ) 108 F a l l i s , A . G . ( 3 ) 213; ( 4 ) 1 1 0 ; ( 6 i i ) 49 F a l o r n i , M. ( 4 ) 2 8 ; ( 6 i i ) 73 F a l t e r , W. ( 3 ) 214, 270 Fan, W.-Q. ( 3 ) 71; ( 6 i i ) 22 Fang, J.-M. ( 3 ) 348 F a n k h a u s e r , J . E . ( 1 ) 44; ( 5 ) 3 1 ; ( 6 i i ) 287 F a r k h a n i , D. ( 6 i ) 5 0 Farmar, J . G . ( 3 ) 257 F a r n e t t i , E. ( 4 ) 1 4 ; ( 6 i ) 11 F a r n i e r , M. ( 5 ) 402, 4 0 3 F a r o n , K.L. ( 1 ) 3 6 ; ( 6 i i ) 33 F a s a n i , E. (5) 506 F a t a f t a h , Z.A. ( 2 ) 77
675
Author Index
F a t i a d i , A.J. ( 5 ) 308 F a u l , D. ( 5 ) 131 Fauq, A . ( 3 ) 90; ( 7 ) 34; ( 8 ) 16 Fauvarque, J.-F. ( 3 ) 68 F a v i n i , G. ( 2 ) 172 Feese, R.C. ( 2 ) 17 Feger, H. (5) 357, 358 Fehr, C. ( 2 ) 96 F e i t , B.-A. ( 3 ) 365 F e i t h , B. ( 3 ) 134; ( 5 ) 442 F e l b e r , H. ( 5 ) 412 F e l d e r , L. ( 3 ) 339; ( 4 ) 32 ( 3 ) 348 Feng, J.-M. Fenk, C . J . ( 3 ) 52 Fenton, D.E. ( 5 ) 106 F e r i n g a , B.L. (5) 443 Fernandez, J . R . ( 3 ) 364; ( 6 i ) 14; ( 6 i i ) 34 Fernandez-Simon, J . L . (1) 16; ( 6 i i ) 3 F e r r , C. ( 6 i i ) 79 F e r r a b o s c h i , P. ( 2 ) 1 5 F e r r a c c i d i , R. ( 6 i i ) 6 3 F e r r a z , H.M.C. (3) 352; ( 4 ) 221; ( 6 i i ) 141; ( 9 ) 12 F e r r e i r a , J.T.B. (1) 125 F e r r e r , P. (1) 17 F e r r e r G , F. (3) 220 F e r r e r i , C. ( 3 ) 96 F e r r i e r , P. ( 4 ) 189 Ferroud, D. (1) 57; (3) 452, 453; ( 5 ) 181, 182 F e t t e r , J. ( 5 ) 462 Fiandanese, J. ( 6 i i ) 261 F i e l d , L. ( 5 ) 280 F i f e , W.K. ( 3 ) 83, 84 F i g a d e r e , B. ( 4 ) 59 F i l a r d o , G. ( 3 ) 39; (4) 48 F i l i p p i n i , L. ( 3 ) 435; ( 5 ) 235, 467 F i l i p p o n e , P. (5) 265 Finch, M.A.W. ( 6 i i ) 27 F i n e t , J. (2) 30; ( 3 ) 225, 521; (5) 64; ( 6 i i ) 247 F i n e t , K.-F. ( 6 i i ) 246 Finn, J. ( 3 ) 406 F i r e s t o n e , A . (5) 191 F i r o u z a b a d i , H. ( 2 ) 3, 5-7; ( 3 ) 6 ; ( 4 ) 147, 153, 154 F i r s a n , S.J. ( 5 ) 519 F i s c h e r , A. ( 5 ) 376, 377 F i s c h e r , K. ( 3 ) 253; ( 5 ) 299, 300; ( 7 ) 113 F i s c h e r , S. ( 5 ) 289
Fishwick, B.R. ( 5 ) 384 F i t t s c h e n , C. ( 3 ) 342 F i t z , T. ( 9 ) 102 F i t z i , R . ( 3 ) 463 F i t z n e r , J . N . (1) 44; (5) 31; ( 6 i i ) 287 F i t z w a t e r , S. ( 5 ) 76 Fivush, A. ( 2 ) 9 3 F i z e t , C. ( 3 ) 343 Flamm-ter Meer, M.A. (5) 494 F l a v e r , W . J . ( 8 ) 41 Fleischmann, M. ( 5 ) 346 Fleming, I . (1) 32, 52; ( 3 ) 153; ( 4 ) 8 9 ; ( 6 i i ) 146, 147, 181, 182, 208 Fleming, S.A. ( 7 ) 8 F l e t c h e r , M.T. ( 9 ) 30 F l e u r y , J.-P. ( 5 ) 110, 111 Flippen-Anderson, J . L . ( 5 ) 68 F l i p p i n , L.A. ( 2 ) 176; ( 3 ) 48; ( 4 ) 88 F l i r i , A. ( 5 ) 316 Flood, T.C. ( 3 ) 181 F l o r e n t , J.-C. ( 6 i i ) 27 F l o r e s , H . J . ( 3 ) 190 F l o r i a n i , C. ( 6 i ) 55 F l o r i s , C. ( 4 ) 254; ( 6 i i ) 44 F l u d z i n s k i , P. ( 3 ) 226 Foa, M. ( 4 ) 208 Fobare, W.F. ( 5 ) 78; ( 6 i i ) 152; ( 9 ) 95, 109 117 Fochi, R. ( 3 ) 25 Fodor, L. ( 9 ) 65 F o n t , J. ( 3 ) 328, 347 F o r n a s i e r , R. ( 4 ) 1 6 F o r t o u l , R.C. ( 6 i i ) 204 F o s t e r , D.F. ( 6 i ) 54 Foucaud, A. ( 4 ) 146; (5) 353 Fouchet, B. ( 3 ) 456 Foulon, J . P . (3) 6 3 Fouquay, S. ( 3 ) 451 Fourcaud, A. ( 5 ) 514 F o u r n e t , G. ( 4 ) 171 F o u r n i e r , M. ( 4 ) 173 Fowler, F.W. ( 5 ) 113; ( 9 ) 114 Foxman, B.M. ( 6 i ) 30 Foxton, M.W. ( 4 ) 3 Frahm, A.W. (5) 22 F r a n c a l a c i , F. ( 4 ) 208 F r a n c i s c o , C.G. ( 5 ) 30; ( 6 i i ) 285 Franck-Neumann, M. ( 6 i ) 5 0 , 61, 62 Frank, J. ( 3 ) 483
Frank, W.C. ( 5 ) 139 Fraser-Reid, B. ( 4 ) 68, 169; ( 7 ) 108; ( 8 ) 56 F r A t e r , G. ( 3 ) 351; ( 7 ) 10 F r a u e n r a t h , H. ( 3 ) 350 F r a z i e r , J. ( 5 ) 136, 478; ( 7 ) 60; ( 9 ) 8 3 , 8 6 Frechou, C. ( 3 ) 373; (4) 7 F r e i , B. ( 5 ) 476; ( 6 i i ) 187 F r e i d i n g e r , R.M. ( 3 ) 482 F r e i r e , R. ( 3 ) 420; ( 5 ) 439 F r e i s s l e r , A . ( 3 ) 51 F r e y e r , A . J . ( 3 ) 331 Friedmann, A . ( 5 ) 398 F r i e s e , C. ( 6 i i ) 57 Frydrych-Houge, C.S.V. (1) 126; ( 6 i i ) 8 6 Frye, S.V. ( 3 ) 413 Fryzuk, M.D. (1) 70 Fu, G.C. ( 3 ) 487 Fuchigami, T. ( 3 ) 101, 127, 221; ( 5 ) 80 F u c h i t a , Y . ( 5 ) 98 Fuchs, P.L. ( 2 ) 78; ( 3 ) 503; ( 4 ) 122 Fueno, T. ( 6 i i ) 280 Fuentes, L.M. ( 2 ) 136; ( 3 ) 57 F u r s t n e r , A. ( 3 ) 148; ( 4 ) 118; ( 6 i i ) 8 0 , 8 4 , 85 Fugami, K . (1) 34 F u g a n t i , C. ( 3 ) 158, 496, 524; ( 5 ) 197 F u j i , K . ( 2 ) 59; ( 3 ) 176, 390; ( 4 ) 99; ( 5 ) 348; ( 6 i i ) 62; ( 7 ) 61 F u j i , M. (3) 414 F u j i h a r a , H. ( 6 i i ) 75 F u j i h a r a , Y. ( 3 ) 247 F u j i i , K. (3) 344 F u j i i , M. ( 2 ) 39 F u j i i , S. (1) 19 F u j i i , T. ( 7 ) 11; ( 8 ) 36 F u j i k a , S. (5) 297; ( 6 i i ) 150 Fujimoto, A. ( 3 ) 97 Fujimoto, E. ( 2 ) 35, 36 Fujimoto, I. ( 6 i i ) 275 Fujimoto, K . ( 3 ) 45; ( 4 ) 115 Fujinami, T. ( 3 ) 324, 337; ( 4 ) 15, 55 F u j i o k a , H. ( 3 ) 414; ( 4 ) 69 F u j i s a k i , S. ( 3 ) 306; ( 4 ) 137 Fujisawa, T. ( 3 ) 162,
676 170, 269, 358; ( 6 i i ) 48 F u j i s e , Y. ( 4 ) 231 F u j i t a , E. ( 3 ) 151; ( 7 ) 61; ( 9 ) 148 F u j i t a , H . ( 5 ) 152 F u j i t a , M. ( 5 ) 408 F u j i t a , S. ( 3 ) 318 F u j i t a , Y. ( 2 ) 16; ( 3 ) 41, 8 0 , 81; ( 4 ) 214; ( 5 ) 329 F u j i w a r a , J . ( 4 ) 234 F u j i w a r a , S. ( 2 ) 97 F u j i w a r a , T. ( 2 ) 164; ( 6 i i ) 257; ( 7 ) 11 F u j i w a r a , W. ( 6 i i ) 280 F u j i w a r a , Y. ( 5 ) 257 Fukazawa, Y. ( 3 ) 399 Fukuhara, K . ( 5 ) 250 Fukumoto, K . ( 7 ) 83 Fukuyama, K . ( 3 ) 505 Fukuzawa, S. ( 3 ) 74, 324, 337; ( 4 ) 15, 55 Funahashi, H. (1) 87 Funk, R.L. (1) 90; ( 7 ) 29 Furber, M. ( 6 i i ) 29 Furukawa, N . ( 6 i i ) 75 F u s t e r o , S. ( 5 ) 91, 112, 432; ( 9 ) 133 F y l e s , D.L. ( 5 ) 376 Gai, Y.-Z. ( 5 ) 57 Gainor, J . A . ( 5 ) 205 G a i s , H.-J. ( 3 ) 27 Gajda, T. ( 5 ) 128 G a j u r e l , C.L. ( 5 ) 328 Galan, A . A . ( 3 ) 224 G a l a n t e , J . M . ( 5 ) 395 G a l e a z z i , E. ( 2 ) 161; ( 5 ) 187; ( 6 i i ) 38 Galindo, J . ( 2 ) 96; ( 6 i i ) 79 G a l l a g h e r , T. ( 9 ) 90 G a l l o , R. ( 5 ) 369 Gambino, S. ( 3 ) 3 9 ; ( 4 ) 48 Gambori, R. ( 3 ) 139 Ganazzoli, F. ( 3 ) 338 Ganboa, I . ( 3 ) 98 Ganguly, A . K . (5) 164 Garbarino, G. ( 4 ) 245 G a r c i a , J. (5) 484 G a r c i a F r a i l e , A . ( 4 ) 185 Garcia-Raso, A . ( 3 ) 53 Gardano, A . ( 4 ) 208 Garg, C.P. ( 2 ) 27 Garratt, P.J. ( 1 ) 74; ( 6 i i ) 135 G a r r i n g u e s , B. ( 5 ) 194 Gasdaska, J . R . ( 9 ) 76 Gassman, P.G. ( 5 ) 342 Gaston, R.D. ( 9 ) 50
General and Synthetic Methods
Gateau-Oleskar, A . ( 3 ) 30 G a t t o , V . J . ( 5 ) 364 Gaude, D. ( 5 ) 371 Gaudemar, M. ( 3 ) 310 Gaudemar-Bardone, F. ( 3 ) 310 G a u t h i e r , J . Y . ( 3 ) 283; ( 4 ) 166 Gavai, A . V . ( 7 ) 39 Gavina, F. ( 1 ) 17; ( 4 ) 189 Gawish, A . ( 7 ) 52 Gawley, R . E . ( 6 i i ) 1 2 ; ( 9 ) 96 Gebreyes, K . ( 6 i i ) 272 Gedge, D.R. ( 3 ) 378 Geffken, D. (5) 410; ( 9 ) 55 Gelbard, G . ( 2 ) 1; ( 4 ) 148 Genco, R . J . ( 5 ) 260 Genet, J . P . (1) 5 7 ; ( 3 ) 452, 453; ( 5 ) 181, 182 Gennari, C . ( 2 ) 172; ( 3 ) 149, 287, 466; ( 4 ) 8 5 , 86; ( 5 ) 171 George, C. ( 5 ) 68 Georgopoulos, A . ( 5 ) 73 Gerdes, J . M . ( 2 ) 145 G e r h a r t , F. ( 3 ) 496; (5) 202 Gero, S.D. ( 3 ) 30 G e r t h , D.B. ( 3 ) 394 Gessner, W.P. ( 5 ) 461 Gesson, J.-P. ( 7 ) 101 G h a d i r i , M.R. (1) 116; ( 6 i i ) 137 G h e l f i , F. ( 4 ) 183 Ghosez, L. ( 3 ) 91; ( 6 i i ) 66 Ghosh, S. ( 3 ) 89 Ghribi, A . (3) 61; ( 6 i i ) 239 G i a c c i o , H. ( 9 ) 129 G i a c o m e l l i , G. ( 4 ) 28; ( 6 i i ) 73 Giacomini, D. ( 9 ) 138 Giangiordano, M . A . ( 5 ) 26 G i e r e n , A . (5) 486 G i e s e , B. ( 3 ) 130, 394 Giese, R.W. (3) 8 5 G i e s e l , K . ( 5 ) 307 G i l , G. ( 5 ) 313, 314 G i l b e r t s o n , S.R. ( 1 ) 3 6 ; ( 3 ) 377; ( 6 i ) 3 3 , 87 G i l d a y , J.P. ( 6 i ) 48, 49 Giles. M.B. ( 5 ) 176 G i l l , M. ( 2 ) 112 G i l l e t , J . P . ( 1 ) 24, 25; ( 3 ) 222; ( 6 i i ) 3 1 , 91 Gillmann, T. ( 3 ) 291
Gilman, .J.W. ( 7 ) 82 Giordano, C. ( 2 ) 118; ( 3 ) 82 G i r a l t , E. ( 3 ) 527 Girijavallabhan, V.M. ( 5 ) 164 G i u l i a n o , R . M . ( 5 ) 139 G i v r e , S. ( 5 ) 113; ( 9 ) 114 Gladysz, \ J . A . ( 6 i ) 1 4 , 59 G l a n z e r , B . I . ( 3 ) 485; ( 5 ) 183; ( 6 i i ) 8 5 Glans, J.F. (9) 85 G l a n z e r , B . I . ( 6 i i ) 85 G l a s e r , J . ( 4 ) 184 G l a s s , R.S. ( 9 ) 52 Gleiter, R . (1) 127 Gless, R.D., j u n . ( 3 ) 429; ( 5 ) 270 G l o t t e r , E. ( 9 ) 5 Glue, S.E.J. ( 2 ) 50 G l u s k e r , J . P . ( 5 ) 230 Goasdone, N . ( 3 ) 310 G o e r d e l e r , J . ( 5 ) 471 G o f f , D . A . ( 4 ) 216 Gogte, V . N . ( 5 ) 179 Gokel, G.W. ( 5 ) 364 Gokoechea-Pappas, M. ( 6 i i ) 12 Gokou, C.T. ( 5 ) 433 Goldman, B.E. ( 2 ) 8 2 Goldsmith, D . J . ( 5 ) 429; ( 7 ) 27 Golebiowski, A . ( 9 ) 31, 32 Gollman, H. ( 3 ) 205 Ggmez, E. ( 5 ) 180 Gonnela, N.C. ( 8 ) 40 Gonzales, A . ( 6 i ) 52 Gonzalez, A . M . ( 5 ) 305; ( 9 ) 36 Gonzalez, B. ( 5 ) 305; ( 9 ) 36 Gonzalez, F.B. ( 3 ) 311 Gonzalez, F.J. ( 5 ) 432; ( 9 ) 133 Gonzalez, J . M . (1) 27; ( 4 ) 174 Gonzalez-Sierra, M. ( 9 ) 25 Goo, Y . M . ( 5 ) 267 Goodfellow, C.L. ( 6 i ) 38 Gopalan, B. ( 9 ) 100 Gora, J . ( 2 ) 146 G o r d i l l o , B. ( 6 i i ) 233 Gore, J . ( 2 ) 57; ( 4 ) 171 Gore, M.P. ( 2 ) 109; ( 3 ) 38 G o t i , A . ( 9 ) 125, 126, 135 Goto, E. ( 8 ) 35 Goto, G. ( 5 ) 415
677
Author Zndex Goto, T. ( 5 ) 5 ; ( 8 ) 50 Gotor, V. ( 5 ) 91, 112, 427, 432; ( 9 ) 56, 133 G o t t h a r d , H. ( 9 ) 152 Gould, T . J . ( 3 ) 259 ( h ) 33 Gourcy, J.-G. Gouzoules, F.H. ( 3 ) 169; ( 6 i i ) 93 Govai, A.V. ( 7 ) 62 Gowriswari, V.V.L. ( 2 ) 179 Graboski, G.G. ( 3 ) 284; ( 5 ) 349 Grabowski, E . J . J . ( 7 ) 100 Grade, M.M. ( 4 ) 249 Gradwood, R.C. ( 7 ) 115 G r a f , W. ( 3 ) 515 G r a f f , M. ( 3 ) 2109 Gramatica, P. ( 2 ) 157 Grandclaudon, P. ( 9 ) 116 Grandi, R. ( 4 ) 183 Granger-Veyron, H. (4) 60 G r a n i t z e r , W. (5) 73 Granzer, E. ( 3 ) 412 G r a s s e l l i , P. ( 3 ) 158, 496, 524; ( 5 ) 197 Gray, M . J . ( 5 ) 355 Grayson, J . I . ( 3 ) 233 G r a z i a B e r e t t a , M. ( 4 ) 8 5 G r a z i a n i , M. ( 4 ) 1 4 ; ( 6 i ) 11 Greck; C. ( 3 ) 373, 476; ( 5 ) 155 Green, J.R. ( 3 ) 440, 441 Greene, A.E. ( 3 ) 493 Greenspoon, J. (1) 3 Greenspoon, N . ( 2 ) 32; ( 3 ) 123 Greeves, N . (1) 11; ( 6 i i ) 231 Gregory, J.A. ( 6 i i ) 271 Grehn, L. ( 5 ) 222, 238 G r e i n , F. ( 2 ) 195 Grieco, P.A. ( 3 ) 406; ( 5 ) 78; ( 6 i i ) 152; ( 9 ) 95, 109, 117 G r i e n g l e , H. ( 3 ) 485; ( 5 ) 183 Griesbeck, A. (4) 9 G r i e s s e r , H. ( 5 ) 252 G r i f f i t h s , J . (5) 505 Grimaldi, J. ( 9 ) 122 Grimm, E.L. ( 2 ) 90; ( 6 i i ) 69; ( 7 ) 84 G r i s o n , C. ( 6 i i ) 76 Grissom, J . W . (9) 75 G r o o t a e r t , W.M. ( 8 ) 58 Gross, R.S. ( 3 ) 392 Grubbs, R.H. ( 8 ) 2 Grunwald, J. ( 2 ) 22 Gstach, H. ( 5 ) 499 G u , Q.-M. ( 3 ) 24, 79
G u a n t i , G. ( 2 ) 115; (3) 28; ( 4 ) 34 Guaragna, A. ( 2 ) 115; ( 4 ) 34 Guarna, A. ( 9 ) 125, 126, 135 G u a s t i n i , C. ( 6 i ) 55 G h t h e r , W. ( 3 ) 351; ( 7 ) ,lo G u e t t e , J.P. ( 5 ) 378 Guibe, F. ( 3 ) 513; ( 5 ) 39 G u i l a r d , R. ( 5 ) 402, 403 Guillerm, D. (1) 121 Guinamant, J.L. ( 3 ) 114 G u i t a r t , J. ( 2 ) 31 G u l l , R. ( 3 ) 462; ( 5 ) 413 Gunnarsson, K . ( 5 ) 238 Gunther, C. ( 3 ) 346 Guo, B.S. ( 6 i i ) 42 Guo, G. ( 4 ) 107 Guo, H. ( 6 i i ) 241 Guo, S. (5) 392 Gupton, J.T. ( 5 ) 75, 76 Gustavson, L.M. ( 2 ) 140 Gustowski, D.A. ( 5 ) 364 G u t h r i e , J.P. ( 5 ) 58 G u t i a n , E. ( 8 ) 31 Guy, A. ( 5 ) 378 Guzman, A. ( 2 ) 161; ( 5 ) 187; ( 6 i i ) 38 Haag, B. ( 3 ) 365 Haberman, L.M. ( 5 ) 342 Habermas, K.L. ( 2 ) 65; ( 6 i i ) 175; ( 7 ) 57 H a c k e t t , S. ( 3 ) 198; ( 4 ) 255; ( 6 i i ) 5 8 , 59 H a e r l e , H. (5) 324 H a f e l i , E.K. ( 4 ) 40 H a f f n e r , C.D. ( 7 ) 8 2 Haga, K . (5) 74 Hagenmaier, H . ( 3 ) 478 Hagihara, T. ( 1 ) 55; ( 3 ) 126 Hagiwara, H. ( 3 ) 193; ( 4 ) 87 Hagiwara, Y. ( 3 ) 151 Hahn, C.S ( 2 ) 8 ; ( 4 ) 155 Hahn, G. 2 ) 37; ( 3 ) 246; ( 4 ) 106 Hahn, H . 3 ) 478 Haigh, D. ( 8 ) 43 Hal, G.S. ( 6 i i ) 36 Halczenko, W. ( 9 ) 118 Haley, B.E. ( 5 ) 481 Haley, G . J . ( 1 ) 127 H a l l , S.S. ( 5 ) 6 H a l l b e r g , A. (1) 30; ( 6 i i ) 160 Hallnemo, G. ( 3 ) 109 Halterman, R.L. ( 4 ) 49
Hamada, F. ( 5 ) 501 Hamada, M. ( 3 ) 444 Hamada, T. ( 4 ) 212; (5) 70 Hamada, Y. (3) 309; ( 8 ) 64 Hamamoto, I. ( 1 ) 48; ( 2 ) 162; ( 3 ) 138 Hamana, M. ( 3 ) 76 Hamano, S. ( 4 ) 17 Hamatani, T. (1) 107; ( 3 ) 68, 145; ( 4 ) 45; ( 6 i i ) 219 Hamel, N. ( 3 ) 104 Hamelin, J. ( 3 ) 458 Hamer, N . K . ( 2 ) 141 H a m i l l , T.G. ( 3 ) 137; ( 6 i i ) 265 Hamilton, R . J . ( 3 ) 252 Hammond, G.B. ( 2 ) 133, 134; ( 6 i i ) 237, 238 Han, B.-H. (6ii) 1 Han, C.-Q. ( 3 ) 174 Hanaby, M. ( 6 i i ) 255 Hanafusa, T. ( 3 ) 112; ( 5 ) 284, 296, 327, 332 Hanaki, M. ( 3 ) 8 8 ; ( 5 ) 375 Hanamoto, T. ( 1 ) 37; ( 3 ) 9 , 45; ( 4 ) 114; ( 6 i i ) 232 Hanazaki, Y. ( 5 ) 2 Hane, J.T. ( 1 ) 134; ( 3 ) 427 Hanessian, S. (1) 81; ( 3 ) 366; ( 6 i i ) 72, 284 Hannack, M. ( 4 ) 185 Hannon, F.J. ( 2 ) 182; ( 5 ) 8 8 ; ( 6 i ) 44 Hanre, R. ( 3 ) 12 Hanson, G . J . ( 5 ) 221 Hanson, R.M. ( 6 i ) 16 Haque, M.S. ( 1 ) 115; ( 2 ) 52, 110; ( 3 ) 140; ( 4 ) 102; ( 6 i i ) 36, 37 Haquin, C. ( 5 ) 514 Hara, S. (1) 6 7 ; ( 6 i ) 67, 124 Harada, S. ( 2 ) 8 8 ; ( 5 ) 310; ( 7 ) 36 Harada, T. ( 1 ) 20; ( 4 ) 111, 242; ( 6 i i ) 248 Harano, Y. ( 3 ) 309 Harbermas, K.L. ( 6 i i ) 175 Harder, C.L. ( 6 i i ) 81 Haregawa, M. ( 7 ) 126 Zarkema, S. ( 5 ) 464 Harms, K . ( 5 ) 340 Harpp, D.N. ( 4 ) 236; ( 9 ) 53 H a r r i s , A.R. ( 4 ) 180 H a r r i s , D.J. (1) 60;
678 ( 4 ) 51; ( 6 i i ) 128 H a r r i s , F.L. ( 7 ) 112 H a r r i s , R . N . ( 4 ) 216 H a r r i s o n , J.J. ( 5 ) 105 H a r t , D . J . ( 9 ) 139, 140 H a r t , G. ( 6 i i ) 12 H a r t , H. ( 6 i i ) 78 Hartke, K . ( 3 ) 291 Hartman, G.D. ( 9 ) 118 Hartshorn, M.P. ( 5 ) 355 Harusawa, S. (5) 288. 311, 317, 323 Harwood, L. ( 2 ) 166; ( 6 i i ) 25 Hasabe, K . ( 3 ) 136; ( 7 ) 22 Hase, T. ( 4 ) 132; ( 6 i ) 66 Hasegawa, H. ( 3 ) 36 Hasegawa, M. ( 2 ) 58; ( 4 ) 109; ( 5 ) 90, 94 H a s e l t i n e , J . N . ( 6 i i ) 28 Hashimoto, K. ( 3 ) 151 Hashimoto, M. ( 5 ) 6 3 Hashimoto, S. ( 3 ) 428; ( 7 ) 53; ( 8 ) 46 Hashimoto, Y. ( 3 ) 110, 202, 509; ( 5 ) 215 Hasomi, A. ( 6 i i ) 253 Hass, W. ( 3 ) 478 Hassan-Gonzalez, D. ( 3 ) 268; ( 5 ) 217 Hassner, A. ( 5 ) 480, 487 Hata, N . ( 3 ) 425 Hatada, A . ( 6 i i ) 180 Hatanaka, Y. ( 2 ) 89, 103; ( 6 i i ) 193; ( 7 ) 104 Hatano, M. ( 4 ) 162 H a t a s h i , M. ( 5 ) 62 Haterman, R.L. ( 6 i i ) 128 H a t t o r i , K. ( 3 ) 74 H a t t o r i , M. ( 3 ) 344 H a u p t r e i f , M. ( 3 ) 461; ( 5 ) 151 Hauser, F.M. ( 5 ) 230 Hawkins, J.M. ( 3 ) 487 Hawkins, L.D. ( 4 ) 177 Hayakawa, K. (1) 97; ( 3 ) 329; ( 6 i i ) 275; ( 9 ) 22, 81 Hayama, N . ( 5 ) 84 Hayama, T. ( 3 ) 447; ( 5 ) 169 Hayashi, G. (5) 233 Hayashi, H. (5) 318, 319 Hayashi, K. ( 1 ) 47; ( 5 ) 351 Hayashi, M. ( 3 ) 491; ( 9 ) 20 Hayashi, S. ( 5 ) 269 Hayashi, T. (1) 5 5 , 56; ( 2 ) 40; ( 3 ) 124, 126, 479; ( 5 ) 138; ( 6 i ) 63,
General and Synthetic Methods
88, 139, 145 Hayashi, Y . ( 3 ) 110 Hayasi, Y. (1) 113; ( 3 ) 66 Hayden, H. ( 5 ) 175 Hayes, T.K. ( 3 ) 331 He, G.-X. ( 5 ) 8 3 He, Y.-B. ( 6 i ) 15 Head, <J.C. ( 8 ) 47 Heah, P.C. ( 6 i ) 59 Heaney, H. ( 5 ) 77 Heathcock, C.H. ( 2 ) 176, 197, 198; ( 3 ) 48, 58, 215, 258, 405, 408; ( 4 ) 88; ( 7 ) 51, 6 7 ; ( 8 ) 42 Heckendorn, R. (5) 493 Hecker, S.J. ( 3 ) 408 Heeg, M . J . ( 2 ) 136; ( 3 ) 57 Hegarty, A.F. ( 5 ) 341 Hehre, W.J. ( 6 i i ) 266 Heide, B. ( 5 ) 453 Heil, B. ( 4 ) 31 H e i l i g , G. ( 5 ) 457 Heilmann, S.M. ( 5 ) 147, 304 Heimgartner, H. ( 5 ) 248, 271, 274 Heinen, H. ( 9 ) 120 Heitmann, P. ( 2 ) 170; ( 3 ) 150; ( 6 i i ) 105 H e i t z , M.-P. ( 6 i i ) 50 Helberg, L.H. ( 5 ) 45 Helfmeier, G. ( 5 ) 453 Hell, W. ( 5 ) 444 Helle, M.A. ( 1 ) 13; ( 3 ) 206 H e l q u i s t , P. ( 2 ) 8 4 Henderson, G.N. ( 5 ) 376, 377 Hendrickson, J . B . ( 6 i i ) 70 Henin, F. ( 3 ) 245; ( 9 ) 91 Henke, H. ( 3 ) 483 Hennequin, L. ( 2 ) 144 Hennessy, M . J . ( 3 ) 192; ( 5 ) 483 Hensel, M . J . ( 3 ) 503 Heraldsson, G.G. ( 4 ) 133 H e r b e r t , R.B. ( 6 i i ) 271 H e r b e r t , S.A. ( 2 ) 142 H e r d e i s , C. ( 5 ) 203 Hermann, K . ( 5 ) 458 Hermans, P. ( 3 ) 118; (9) 6 Hermkens, P.H.H. (5) 517 Hernandez, E. (5) 231 Hernandez, R. (5) 439 Herndon, J.W. ( 6 i ) 73 H e r r e n d o r f , W. ( 3 ) 483 Herrmann, R. (5) 36, 37
Herscheid, J.D.M. ( 3 ) 522 Hershberger, P.M. ( 9 ) 115 H e r t e n s t e i n , U . ( 5 ) 298 H e r t z l e r , D.V. ( 4 ) 136 Herve du Penhoat, C. ( 6 i i ) 274 Herzig, T. ( 5 ) 135 Heschel, M. ( 5 ) 243 H e s l i n , J . C . ( 4 ) 225; ( 6 i ) 39; ( 9 ) 44 Hesse, M. ( 3 ) 421-423; ( 5 ) 354, 386 Hewlins, M.J.E. ( 5 ) 382 Heyer, D. ( 5 ) 71 Hiemstra, H. ( 3 ) 40; ( 8 ) 41 Higashiyama, T. (5) 84 Higuchi, M. ( 3 ) 181 Higuchi, N. ( 4 ) 4 ; ( 6 i i ) 192 Hikima, H. ( 4 ) 219 H i l l , E.A. ( 6 i i ) 81 H i l l , J . S . ( 3 ) 240 H i l l , M.L. ( 8 ) 62 H i l l , R.K. ( 5 ) 161 H i l l h o u s e , J . H . (5) 280 H i l p e r t , H. ( 5 ) 458 Himbert, G. (5) 131 Himeno, Y. (3) 418 H i n e r , R.N. ( 3 ) 286 Hino, T. ( 2 ) 180; ( 4 ) 176, 178; ( 5 ) 142 H i n r i c h s , R. ( 3 ) 460; ( 5 ) 149 Hirakawa, K . (7) 9 2 ; ( 9 ) 128 H i r a k i , K. ( 5 ) 9 8 Hirama, M. (3) 160, 161; ( 5 ) 133 H i r a o , I. ( 2 ) 97 H i r a o , T. ( 1 ) 112; ( 2 ) 29, 42; ( 3 ) 247; ( 6 i ) 42, 4 3 Hirayama, M. ( 3 ) 279 H i r i , H. ( 5 ) 228 Hirobe, M. ( 5 ) 414 H i r o i , K. ( 2 ) 76, 131, 168; ( 6 i ) 22, 35, 151, 263; ( 7 ) 65, 66 H i r o t a , S. (3) 505 H i r s h f i e l d , J. (3) 410; ( 9 ) 118 Hisaeda, Y. (5) 3 5 Hishrnat, O.H. (5) 242 Hita, G.A. ( 6 i i ) 175 Hite, G.A. (2) 65; ( 7 ) 57 Hiyama, T. (3) 77, 78; ( 4 ) 131; (5) 60, 408 Ho, S . P . ( 5 ) 95, 96 Ho, T.L. ( 9 ) 100 Hobbs, F.W. ( 2 ) 72 Hoberg, H. ( 5 ) 231
Author Index Hodges, P . J . (1) 8 1 ; ( 3 ) 366; ( 6 i i ) 7 2 , 284 Hoffman, R . V . ( 2 ) 1 0 7 , 108 Hoffmann, H.M.R. ( 5 ) 307 Hoffmann, R.W. ( 4 ) 50; ( 6 i i ) 130 Hogeveen, H. ( 5 ) 5 2 ; (6ii) 7 Hojo, M . ( 1 ) 8 0 ; ( 2 ) 1 4 9 ; ( 3 ) 5 4 , 62; ( 9 ) 8 9 Holcombe, J.L. ( 4 ) 1 2 8 H o l l a n d , H.L. ( 5 ) 451; (8) 3 9 ; ( 9 ) 127 H o l l i n s , R.A. ( 5 ) 374 Holman, N.J. ( 4 ) 230 Holmes, A.B. ( 3 ) 424 H o l t o n , R.A. ( 3 ) 200, 334; ( 6 i i ) 267; ( 7 ) 9 9 Homada, Y . ( 8 ) 46 Homoto, Y. ( 4 ) 111 Honda, T. ( 3 ) 341; ( 9 ) 97 Honda, Y. ( 3 ) 250 Hong, B.-C. ( 3 ) 348 Honig, E.D. ( 6 i ) 28 Hooper, D.L. ( 5 ) 500 Hopkins, P.B. ( 1 ) 4 4 ; ( 5 ) 3 1 , 6 7 ; ( 6 i i ) 287 Hoppe, D . ( 3 ) 342 H o r i , K . ( 3 ) 3 1 5 , 355; ( 5 ) 359; ( 7 ) 121 H o r i , Y . ( 3 ) 188; ( 5 ) 257 H o r i g u c h i , Y. ( 1 ) 1 8 ; ( 6 i i ) 195 H o r i k e , F. ( 3 ) 509 H o r i t a , K. (4) 130; ( 9 ) 10 H o r l e r , H . ( 3 ) 130 Hormi, O.E.O. ( 3 ) 133 Horne, S. ( 3 ) 501; ( 5 ) 159 H o r s p o o l , W.H. ( 5 ) 436 H o s h i , M. ( 6 i i ) 164 Hosokawa, T. (3) 128 Hosomi, A . (1) 7 5 ; ( 4 ) 1 0 1 ; ( 8 ) 8 6 ; ( 9 ) 47 Hosoya, K . ( 3 ) 1 6 8 H o s s e i n i , M.W. ( 5 ) 107 Houk, K.N. ( 4 ) 2 7 ; ( 6 i i ) 108 H o u p i s , I . H . ( 7 ) 24 Howard, D.K. ( 3 ) 216, 244 Hoye, T.R. ( 9 ) 4 0 Hoyer, S . ( 4 ) 125 Hronowski, L.J.J. ( 5 ) 273 Hsu, S.-Y. ( 6 i ) 36 Hu, N.X. ( 2 ) 6 2 ; ( 4 ) 237 Hu, W.J.S.S. ( 6 i i ) 9 7 Hua, D.H. ( 7 ) 6 9 ; ( 8 ) 9 Huang, X. ( 3 ) 135 Huang, Y . ( 3 ) 211; ( 5 ) 114; ( 6 i i ) 243
679 Huber, S. ( 5 ) 511 Hubschwerlen, C. ( 2 ) 111 H u c k s t e p , M.R. ( 3 ) 403 H u d l i c k y , T. ( 2 ) 56; ( 5 ) 478; ( 7 ) 6 0 ; ( 9 ) 8 3 , 86 Huebener, G . ( 5 ) 36 Huebner, T. ( 5 ) 486 Huellmann, M. ( 6 i ) 40 Huenig, S. ( 3 ) 253; ( 5 ) 298-301, 438 H u f f , B. ( 3 ) 470; ( 5 ) 153 Huffman, J . C . ( 6 i i ) 54 H u f f o r d , C.D. ( 5 ) 461 Hug, K.T. ( 2 ) 1 7 6 ; ( 3 ) 48; ( 4 ) 88 H u i , R.A.H.F. ( 3 ) 6 7 , 404 H u i , R.C. ( 2 ) 192 H u l i n , B. ( 3 ) 419; ( 9 ) 39 Hullmann, M . ( 4 ) 6 2 , 6 3 Hung, M.-H. (1) 84 Hunt, P.G. ( 3 ) 233, 235, 251 H u n t e r , R. ( 2 ) 1 6 5 ; ( 6 i i ) 258 H u p f e l d , B. ( 3 ) 462 H u r s t , G.D. ( 6 i i ) 1 2 5 H u s s a i n , H.H. ( 2 ) 80 H u t c h i n g s , M.G. (5) 49 H u t c h i n s o n , C.R. ( 3 ) 205 H u t c h i n s o n , J. ( 6 i i ) 272 H v i d t , T. ( 3 ) 469; ( 5 ) 174 Hwang, C.-K. ( 9 ) 4 1 , 42 Hwang, K.J. ( 6 i i ) 277 Hwu, J . R . ( 4 ) 135 Hyon, M.H. ( 9 ) 1 4 0 Hyondo, C. ( 9 ) 4 8 Hyuga, S. ( 1 ) 6 7 ; ( 6 i i ) 124 I b n u s a u d , I . ( 9 ) 131 I b r a h i m , J. ( 5 ) 459 I b r a h i m , N.S. ( 9 ) 37 I b u k a , T. ( 3 ) 248 I c h i h a r a , J. ( 3 ) 112 I c h i h a r a , Y. ( 5 ) 401 I c h i k a w a , J. ( 9 ) 20 I c h i k a w a , Y. ( 8 ) 5 0 I c h i m u r a , Y. ( 4 ) 127 I d e , H. ( 2 ) 3 4 I g a r i s h i , T. ( 2 ) 159; ( 6 i i ) 210 I h a r a , M . ( 7 ) 83 I h l e , N.C. (1) 9 1 ; ( 7 ) 118 I i d a , H. ( 2 ) 4 5 , 99, 1 1 3 , 1 9 1 ; ( 3 ) 196; ( 5 ) 250; ( 6 i i ) 6 0 , 6 1 , 276, 280; ( 8 ) 32 I i h a m a , T. ( 2 ) 9 9 ;
( 6 i i ) 276 I i m o r i , T. ( 3 ) 490 I i o , H. ( 1 ) 1 4 I k a r i y a , T. ( 3 ) 304, 305, 381; ( 4 ) 1 4 1 , 142 Ikeda, I. (5) 82 Ikeda, K. (5) 61 Tkeda, M. ( 2 ) 8 8 ; ( 7 ) 4 , 36; ( 9 ) 64 I k e d a , N . ( 1 ) 106; ( 3 ) 411; ( 4 ) 5 3 ; ( 6 i i ) 133 I k e d a , S. ( 3 ) 526 I k e d a , T. ( 5 ) 83 I k e d a , Y. ( 4 ) 224; ( 9 ) 1 4 Ikegami, S. ( 3 ) 447; ( 5 ) 1 6 9 ; ( 7 ) 53, 6 8 ; (8) 4 Ikekawa, N. (5) 10 Ikemoto, Y . ( 3 ) 145; ( 4 ) 4 5 ; ( 6 i i ) 219 I k e n o , K . ( 3 ) 88; ( 5 ) 375 I k e y a , T. (3) 20 T k o t a , N . ( 5 ) 422 I l k k a , S.J. ( 1 ) 4 1 [ l l i g , C.R. ( 5 ) 339 Imada, Y. ( 1 ) 4 5 ; ( 5 ) 479; ( 6 i ) 3 4 Imai, T. ( 4 ) 27; ( 6 i i ) 108, 118 Imai, Y. ( 3 ) 431 Imamoto, T. ( 4 ) 5 8 , 250; (7) 2 I m a n i s h i , T. (8) 7 I m w i n k e l r i e d , R . ( 4 ) 70 I n a b e , M. ( 3 ) 119 I n a d a , A . ( 2 ) 1 9 ; ( 4 ) 144 I n a g a k i , T. ( 3 ) 88; ( 5 ) 375 Inamoto, N . ( 6 i i ) 281 I n a n a g a , <J. ( 1 ) 9 , 6 8 , 95; ( 3 ) 325, 3 2 6 , 426; ( 4 ) 5 6 , 57 I n e s i , A . ( 9 ) 146 I n n e r s , R . R . ( 6 i i ) 230 I n o k u c h i , H. ( 5 ) 310 I n o k u c h i , T. ( 2 ) 9 ; ( 3 ) 5 ; ( 4 ) 1 3 9 ; ( 5 ) 352 Inomada, K. ( 6 i i ) 270 Inomata, K . ( 3 ) 491; (5) 62 I n o u e , A. ( 4 ) 199 I n o u e , K. ( 2 ) 125; ( 3 ) 281; ( 5 ) 518; ( 9 ) 106 I n o u e , M. ( 3 ) 77, 78; ( 6 i ) 75 I n o u e , S. ( 1 ) 128; ( 5 ) 318, 319 I n o u e , T. ( 3 ) 151 I n o u e , Y. (9) 1 4 8 I n o u g e , M. ( 3 ) 212
General and Synthetic Methods
680 Inouye, K . ( 3 ) 157; ( 4 ) 37 I p a k t s c h i , J . ( 7 ) 56 I q b a l , J. ( 3 ) 280; ( 4 ) 238 I q b a l , T. ( 7 ) 8 5 Iranpoor, N . (2) 5 I r e l a n d , R.E. ( 3 ) 379 I r i e , M. ( 5 ) 327 I r i t a n i , K . ( 3 ) 320 I r v i n e , R.W. ( 3 ) 382 I s a a c s , N.S. ( 3 ) 240; ( 6 i i ) 229 I s e k i , K . (1) 113; ( 3 ) 66 I s h i b a s h i , H. ( 2 ) 8 8 ; ( 5 ) 401; ( 7 ) 4 , 3 6 ; ( 9 ) 64 I s h i d a , K. ( 4 ) 199 I s h i d a , T. ( 2 ) 54 I s h i d a , Y . ( 3 ) 490 I s h i g a m i , Y. ( 4 ) 144 I s h i g e , 0. ( 3 ) 417 I s h i g u r o , M. ( 5 ) 329 I s h i h a r a , H. ( 3 ) 298; ( 4 ) 67; ( 5 ) 520 I s h i h a r a , K . ( 1 ) 109; ( 4 ) 72, 73 I s h i h a r a , T. (1) 26, 111 I s h i i , A . ( 6 i i ) 281 I s h i i , Y . ( 2 ) 10, 11, 1 9 , 20; ( 3 ) 304, 305, 381; ( 4 ) 141, 142, 144, 145, 156, 157; ( 6 i ) 20, 21 Ishikawa, M . (1) 8; ( 4 ) 204; ( 5 ) 130, 452; ( 6 i i ) 121 Ishiyama, K. ( 2 ) 8 8 ; ( 7 ) 36 Ishiyama, T. (1) 8 ; ( 4 ) 204; ( 6 i i ) 121 I s h i z a k i , M. ( 3 ) 36; ( 4 ) 219 I s h i z u , M. ( 3 ) 97 Ismail, M.M.F. ( 5 ) 242 Ismail, Z.M. ( 5 ) 307 I s o b e , K . ( 4 ) 18 I s o b e , M. ( 8 ) 50 I s o b e , Y. ( 3 ) 353; ( 6 i i ) 212 I s o d a , T. ( 3 ) 36 I s o e , S . ( 1 ) 54; ( 6 i i ) 157; ( 9 ) 23 I t a b a s h i , K . ( 9 ) 46 I t o , K. ( 5 ) 28 I t a , S. ( 3 ) 160, 161; ( 5 ) 133 I t o , W. ( 3 ) 144, 468; ( 5 ) 51; ( 6 i i ) 131 I t o , Y . (1) 55, 56; ( 3 ) 126, 479; ( 4 ) 4 ; ( 5 ) 130, 138, 452; ( 6 i ) 88, 192; ( 9 ) 112
I t o h , K . ( 2 ) 33, 34; ( 6 i i ) 215; ( 9 ) 107 I t o h , M. (1) 104; ( 6 i i ) 101 I t o h , T. ( 3 ) 162 I t s u n o , S. ( 5 ) 28 Iwachido, T. ( 5 ) 84 I w a i , T. ( 5 ) 6 3 Iwamura, H. ( 3 ) 236; ( 5 ) 48, 295 I w a s a k i , G. ( 3 ) 76 Iwasaki, H. (1) 87 Iwasawa, N . ( 2 ) 130, 177; ( 3 ) 489 I w a t a , C. ( 8 ) 7 I w a t a , M. ( 5 ) 100, 212, 262 Iwaya, K . ( 5 ) 74 I y e r , P.S. ( 4 ) 217 I y e r , R. ( 6 i i ) 272 Iyobe, A . ( 6 i i ) 268 Iyoda, M. (8) 1 I z d e b s k i , J . ( 9 ) 31 Izumi, Y. ( 1 ) 53; ( 2 ) 173, 174; ( 4 ) 126; ( 5 ) 475; ( 6 i ) 23, 142 Izumiya, N . ( 3 ) 509 J a b r i , N . ( 2 ) 95 J a c h i e t , D. ( 4 ) 9 3 Jackson, A.H. ( 5 ) 382 Jackson, Y . A . ( 3 ) 523; ( 6 i i ) 291 Jacobsen, E.J. ( 7 ) 31; ( 6 i i ) 74 J a c o b s o n , U . ( 9 ) 31 Jacquesy, J.-C. ( 7 ) 101 J a c q u i e r , R . (3) 448; ( 5 ) 170 Jacyno, J. ( 5 ) 245 Jadhav, P.K. ( 1 ) 104; ( 4 ) 52; ( 6 i i ) 129 J a e g e r , V. ( 5 ) 361 J a g d a l e , M.H. ( 3 ) 13 J a g g i , D. ( 3 ) 389 Jagodzinska, E. ( 5 ) 272 J a g o d z i n s k i , T. ( 5 ) 272 J a g u e l i n , S. ( 3 ) 114 J a h a n g i r , ( 5 ) 451; ( 8 ) 39; ( 9 ) 127 J a i n , A . U . ( 2 ) 47, 48; ( 3 ) 197; ( 5 ) 495; ( 6 i i ) 10 Jakubke, H.-D. ( 3 ) 510 J a l a l i - N a i n i , M. ( 4 ) 220 James, B.R. ( 4 ) 31 James, D. ( 3 ) 34; ( 6 i i ) 269 Jankowski, B.C. ( 2 ) 108 J a n o u t , V. ( 4 ) 211 Janowski, W. ( 9 ) 105
J a n s e n , J.F.G.A. (5) 443 J a n s e n , J.R. ( 8 ) 25 J a o u h a r i , R. ( 3 ) 276 J a r d o n , J. ( 5 ) 427; ( 9 ) 56 J a s p e r s e , C.P. ( 3 ) 238 J a u e r , E.-A. ( 5 ) 504 Jawalkar, D.G. ( 3 ) 310 Jawanda, G.S. ( 4 ) 151 J e f f o r d , C.W. ( 3 ) 55, 389; (8) 33 Jeganathan, A . ( 5 ) 481 J e l i t t e , R. ( 6 i ) 81 J e n d r a l l a , H. ( 3 ) 412 J e n k i n s , K.F. ( 2 ) 17 J e n k i n s , P.R. ( 4 ) 65; (7) 81 J e n k i n s , T.E. ( 3 ) 313 Jenny, C. (5) 271, 274 Jenny, T. ( 5 ) 511 J e n s e n , C.M. ( 5 ) 229 J e n s e n , K.M. ( 5 ) 147, 304 J e n s e n , O . E . ( 5 ) 275 Jenson, T.M. ( 4 ) 232; ( 8 ) 14 J e r o p o u l o s , S. ( 4 ) 196 Jew, S. ( 5 ) 347 Jeyaraman, R. ( 5 ) 12, 383 J i n , H. ( 4 ) 177 Jochims, J . C . ( 5 ) 324, 507 J o g l a r , J. ( 5 ) 112 J o h , T. ( 7 ) 41 Johnson, C.R. ( 2 ) 66; ( 5 ) 491; ( 6 i i ) 213; ( 7 ) 59; ( 8 ) 45; ( 9 ) 1 8 Johnson, R.P. ( 1 ) 98; ( 5 ) 213 Johnson, W.S. ( 7 ) 110 Johny, C . J . ( 5 ) 379 J h c z y k , A . ( 5 ) 118 J o n e s , D.N. ( 7 ) 105; ( 8 ) 23 J o n e s , J . B . ( 3 ) 67, 404 J o n e s , J.H. ( 3 ) 512; ( 4 ) 120 J o n e s , K . (9) 94 J o n e s , M.D. ( 6 i ) 69; (9) 88 Jones, P.G. ( 3 ) 342 J o n e s , R.C.F. ( 3 ) 23; ( 8 ) 43 J o n e s , R.H. ( 6 i ) 58; ( 9 ) 143 J o n e s , R . J . ( 3 ) 523; ( 6 i i ) 291 J o n e s , T.K. ( 2 ) 65; ( 6 i i ) 175; ( 7 ) 57 Joseph, S.P. ( 5 ) 264 J o u c l a , M. ( 3 ) 456, 457; ( 9 ) 104 J o u i t t e a u , C. ( 2 ) 1;
68 1
Author Index ( 4 ) 148 Joyce, R . P . ( 5 ) 205 J u a r i s t i , E. ( 6 i i ) 233 J u g e , S. (1) 5 7 ; ( 3 ) 453; ( 5 ) 182 J u i i a , M. ( 6 i i ) 274 J u l i n a , R. ( 5 ) 135 J u n , H. ( 4 ) 44 Jung, M. ( 3 ) 4 9 6 ; ( 5 ) 202 Jung, S.H. ( 2 ) 1 0 2 ; ( 6 i i ) 227; ( 7 ) 114 Jung, Y.W. ( 6 i i ) 132 J u n k e r , A. ( 5 ) 108 J u r c z a k , J. ( 9 ) 3 1 , 32 J u r g a n s , A.R. ( 5 ) 461 J u s t , G. ( 3 ) 416 J u t l a n d , A. ( 3 ) 68
Kabalka, G.W. ( 5 ) 5 7 , 466; ( 6 i i ) 9 9 ; ( 9 ) 7 3 Kabeta, K. ( 6 i ) 6 3 , 145 Kachensky, D.F. ( 3 ) 407 Kachinsky, J.L.C. ( 2 ) 106 Kaden, T.A. ( 5 ) 7 2 , 102-104 K a e r l e i n , C.-P. ( 5 ) 486 K a e s l e r , R.W. ( 1 ) 36; ( 6 i i ) 33 Kagan, H.B. ( 3 ) 508; ( 4 ) 143; ( 6 i ) 5 Kagiya, T. ( 5 ) 41 Kai, Y . ( 1 ) 4 7 ; ( 5 ) 351 Kaimal, T.N.B. ( 3 ) 95 K a i s a l o , L. ( 4 ) 132 K a i s e r , J . H . ( 5 ) 494 K a j i , A. (1) 2 2 , 4 8 ; ( 2 ) 162; ( 3 ) 138, 168, 353, 375; ( 4 ) 244; ( 5 ) 365, 385; ( 6 i i ) 212, 250, 262 K a j i g a e s h i , S. ( 3 ) 306; ( 4 ) 1 3 7 ; ( 9 ) 82 K a j i k i , T. ( 2 ) 9 9 ; ( 6 i i ) 276 Kajiwara, K . ( 6 i i ) 62 Kakihana, M. ( 1 ) 4 7 ; ( 5 ) 351 Kakimoto, M. ( 3 ) 431 Kakimoto. S . ( 9 ) 82 Kallmerten, J . ( 3 ) 258, 259 K a l s i , P.S. ( 4 ) 151 Kamada, M. ( 6 i i ) 145 Kambe, N. ( 5 ) 258; ( 6 i i ) 292 Kamei, M. ( 6 i i ) 197 Kametani, T. ( 3 ) 341; ( 7 ) 8 3 ; ( 9 ) 102 Kamimura, A. (1) 2 2 , 4 8 ; ( 3 ) 1 3 8 ; ( 5 ) 365; ( 6 i i ) 262
Kamitori, Y. ( 2 ) 149 Kanai, Y. ( 6 i i ) 215; ( 9 ) 107 Kanakawa, M. (5) 288 Kanatomo, S . ( 6 i ) 66 Kanda, N. ( 9 ) 151 Kanda, Y. ( 4 ) 231 Kanefusa, T. ( 3 ) 297 Kaneko, T. ( 1 ) 128 Kaneko, Y. (1) 4 0 ; ( 2 ) 1 2 6 , 164; ( 4 ) 9 7 ; ( 5 ) 188; ( 6 i i ) 257 Kanemasa, S. ( 2 ) 6 4 ; ( 5 ) 450; ( 6 i i ) 1 8 0 , 235; ( 7 ) 8 7 ; ( 9 ) 7 8 , 79 Kanematsu, K . ( 1 ) 9 7 ; ( 3 ) 329; ( 6 i i ) 275; ( 9 ) 2 2 , 81 Kanemoto, S. ( 3 ) 304; ( 4 ) 158; ( 9 ) 4 Kang, J. ( 4 ) 13 Kang, M. ( 8 ) 53 Kaninski, Z.J. ( 3 ) 511 Karabelas, K . (1) 3 0 ; ( 6 i i ) 160 Karadawa, A. ( 6 i i ) 248 Karady, S. ( 7 ) 100 Karasawa, A. (1) 2 0 ; ( 4 ) 242 K a r l s s o n , J.O. ( 5 ) 325 Karpf, M. ( 3 ) 374; ( 7 ) 75-77; ( 8 ) 5 Kasai, N. ( 5 ) 310 Kaschube, W. ( 3 ) 263 Kashimura, S . ( 3 ) 417, 446 Kashimura, T. ( 3 ) 6 9 , 277; ( 4 ) 209 Kaspar, J. ( 6 i ) 11 Kaspar, S. ( 4 ) 14 Kassou, M. ( 3 ) 57 K a s t , J. ( 3 ) 365; ( 6 i i ) 53 Kasuga, T. ( 3 ) 4 5 ; ( 4 ) 115 K a t a g i r i , N. ( 3 ) 182 Katayama, E. ( 8 ) 55 Kathawala, F.G. ( 3 ) 172 Kato, A. ( 5 ) 215 Kato, H. ( 3 ) 379 Kato, J. ( 3 ) 2 Kato, M. ( 6 i i ) 197 Kato, N. ( 7 ) 116 Kato, S. ( 3 ) 298; ( 8 ) 64 Kato, T. ( 1 ) 5 3 ; ( 3 ) 509; ( 5 ) 338, 338; ( 6 i ) 23, 142 Rat&, A . ( 9 ) 65 Katoh, M. ( 4 ) 235 Katoh, S . ( 2 ) 125; ( 5 ) 1 4 4 ; ( 9 ) 106 Katoh, T. ( 3 ) 341
K a t r i t z k y , A.R. ( 3 ) 7 1 ; ( 5 ) 1 5 , 116, 4 4 7 ; ( 6 i i ) 21-23 K a t s u k i , T. (1) 9 2 ; ( 3 ) 9 , 4 5 , 4 6 , 447; ( 4 ) 113, 114; ( 5 ) 169 Katz, J.J. ( 1 ) 7 ; ( 2 ) 28; ( 6 i i ) 118 Katzenellenbogen, J.A. ( 4 ) 191 Kauffmann, T. ( 3 ) 263 Kaumoglo, K . ( 6 i i ) 169 Kawabata, A. ( 3 ) 103 Kawabata, N . ( 1 ) 87 Kawada, K . ( 3 ) 111 Kawada, M. ( 1 ) 7 8 ; ( 3 ) 267; ( 5 ) 227 Kawada, N . ( 4 ) 101 Kawada, Y. ( 5 ) 48 Kawahata, Y. ( 5 ) 10 Kawai, K . ( 4 ) 7 6 ; ( 6 i i ) 92 Kawai, M. ( 2 ) 1 7 3 ; ( 4 ) 126 Kawakami, H. ( 9 ) 82 Kawakita, K. ( 5 ) 415 Kawamoto, K. ( 3 ) 4 4 ; ( 6 i i ) 161 Kawamoto, T. ( 2 ) 4 0 ; ( 3 ) 124; ( 6 i i ) 139, 144 Kawamura, K . ( 3 ) 426; ( 5 ) 520 Kawamura, S . ( 9 ) 89 Kawasaki, H. ( 3 ) 390 Kawasaki, S . ( 3 ) 444 Kawashima, H. ( 6 i i ) 215; ( 9 ) 107 Kawashima, K . ( 3 ) 355; ( 7 ) 121 Kawashima, T. ( 3 ) 183 Kawazoe, Y. ( 5 ) 16 Kay, I.T. ( 2 ) 50 Kaye, A.D. ( 1 ) 120; ( 6 i i ) 178 Kazama, S. ( 3 ) 69 Keck, G.E. ( 3 ) 407; ( 4 ) 83 Keckeisen, A. ( 3 ) 478 Keinan, E. (1) 3 , 96; ( 2 ) 32; ( 3 ) 123; ( 4 ) 40 Keller, J . W . ( 3 ) 486 Keller, 0. ( 3 ) 515 Keller, W. ( 3 ) 515 Kellogg, R.M. ( 3 ) 116, 486 K e l l y , J.W. ( 4 ) 170; ( 6 i i ) 225; ( 9 ) 68 K e l l y , M . J . ( 6 i i ) 190 Kemmit, R.D.W. (6i) 89; ( 9 ) 88 Kemya, J. ( 5 ) 179 Kende, A.S. ( 3 ) 226
General and Synthetic Methods
682 Keneko, C. ( 3 ) 182 Keneko, R . ( 5 ) 74 Kennedy, M. ( 3 ) 332 Kennedy, R.M. (3) 200, 334; ( 4 ) 27; ( 6 i i ) 108; ( 7 ) 99 Keogh, J. ( 5 ) 480 K e s l e r , P. ( 5 ) 366 K e s s l e r , H. ( 5 ) 251 Keumi, T. ( 5 ) 375 Kharnliche, L. ( 5 ) 321 Khamsi, J. ( 3 ) 225, 521; ( 5 ) 64; ( 6 i i ) 247 Khan, S.D. ( 6 i i ) 266 Khanna, R . K . ( 6 i i ) 97 Khoudary, K.P. ( 4 ) 135 Khoukhl, M. ( 3 ) 497 Kiaeezadeh, F. ( 2 ) 5 Kiagawa, I. ( 7 ) 121 Kibayashi, C. ( 8 ) 32 Kidburn, J.D. ( 6 i i ) 181 K i e f e l , M.J. ( 2 ) 112 Kikuchi, ,J. ( 5 ) 35 Kikuchi, T. ( 5 ) 250 K i k u i , T. ( 5 ) 82 Kikukawa, K. ( 5 ) 8 3 ; ( 6 i i ) 218 K i l b u r n , J.D. ( 3 ) 153; ( 4 ) 89 K i m , B. ( 2 ) 105; ( 3 ) 289; ( 4 ) 79 K i m , D. (1) 28; ( 7 ) 20, 96 Kim, H. ( 5 ) 347; ( 6 i i ) 267 Kim, H.-J. ( 4 ) 226; ( 5 ) 282 K i m , K. ( 4 ) 2, 13; ( 5 ) 32, 472; ( 6 i i ) 126 K i m , K.S. ( 2 ) 8 ; ( 4 ) 155 Kim, K.W. ( 6 i i ) 113 K i m , S. ( 2 ) 2; ( 3 ) 94, 432; ( 4 ) 150; ( 5 ) 266, 292 K i m , Y.H. ( 3 ) 437; ( 5 ) 236, 282, 472 Kimmel, T. ( 3 ) 91; ( 6 i i ) 66 Kimura, J . ( 5 ) 370 Kiinura, K. ( 3 ) 193; ( 4 ) 87 Kimura, M. ( 3 ) 177, 236; ( 5 ) 295; ( 6 i ) 84 Kimura, T. ( 2 ) 92, 149; ( 3 ) 218; ( 4 ) 252 Kinchi, S. ( 6 i i ) 276 King, S . A . ( 1 ) 39; ( 6 i ) 70; ( 9 ) 19 K i n o s h i t a , H. ( 3 ) 49 ( 5 ) 62; ( 6 i i ) 270 Kinzel, E. ( 3 ) 506 K i o l l e , R. (3) 452; t
( 5 ) 181 K i r k i a c h a r i a n , B.S. ( 3 ) 125 Kirmse, W. (5) 502, 503 Kise, N . ( 4 ) 47 K i s f a l u d y , L. ( 3 ) 518 K i s h i , N . ( 3 ) 41 K i s h i , Y . ( 2 ) 180; ( 4 ) 4 4 , 176-178 Kishigami, Y . ( 2 ) 19 K i t a , Y. ( 3 ) 8 6 ; ( 5 ) 234 Kitagawa, I . ( 3 ) 355 Kitagawa, 0. ( 3 ) 113; ( 4 ) 206 Kitagawa, Y. ( 5 ) 401 K i t a h a r a , H . ( 4 ) 235 K i t a j i m a , H. ( 3 ) 8 8 ; ( 5 ) 375 K i t a j i m a , Y . ( 3 ) 363 Kitami, S. ( 8 ) 1 Kitamura, Y. ( 4 ) 76; ( 6 i i ) 92 Kitarnura, N . ( 3 ) 69 K i t a n o , Y . ( 4 ) 91 K i t a o k a , M. ( 3 ) 227; ( 4 ) 116 Kitazurne, T. ( 3 ) 20, 29 K i t c h i n g , W. ( 9 ) 30 Kiuchi, S. ( 2 ) 99 Kiyooka, S . ( 2 ) 143; ( 4 ) 21 Kizu, H. ( 8 ) 36 Kjonaas, R . A . ( 2 ) 104, 184, 185; ( 6 i i ) 140 K l a r , S. ( 1 ) 130 Klaveness, J . ( 6 i i ) 280 K l e i j n , H. ( 6 i i ) 67 Klibanov, A.M. ( 2 ) 22 K l i e r , K. ( 5 ) 129 Klumpp, G.W. ( 2 ) 91; ( 7 ) 127 K n e i s l e y , A . ( 3 ) 340 Knight, J. ( 9 ) 149 Knobler, C.B. ( 5 ) 9 5 Knochel, P. (1) 8 5 , 8 8 ; ( 3 ) 266; ( 6 i i ) 8 7 , 88, 273 Knorr, R. ( 5 ) 434 Knors, C. ( 2 ) 84 Knutson, P.L. ( 3 ) 205 K O , K.-Y. ( 3 ) 388 KO, T. ( 3 ) 414 Kobayashi, H. ( 5 ) 370 Kobayashi, I. ( 5 ) 401 Kobayashi, K. ( 5 ) 50, 328 Kobayashi, M. ( 2 ) 6 8 , 69; ( 4 ) 236 Kobayashi, S. ( 2 ) 180, 199-202; ( 3 ) 203, 393; ( 4 ) 176; ( 7 ) 94 Kobayashi, T. ( 3 ) 29, 129; (5) 352; ( 6 i i ) 270
Kobayashi, Y . ( 3 ) 113; ( 4 ) 91, 206; (5) 318, 319; ( 9 ) 46 Kober, R . ( 5 ) 449 Kocienski, P. ( 4 ) 112 Kocovsky, P. ( 3 ) 187 Koehler, K.F. ( 5 ) 411; ( 9 ) 57 Koekeus, B. ( 6 i i ) 66 Konig, W . A . ( 3 ) 478 Koft, E.R. ( 3 ) 443; ( 6 i i ) 26 Koga, G . ( 5 ) 48 Koga, K. ( 3 ) 19, 186, 201, 390; ( 5 ) 422; ( 6 i ) 45, 6 Koga, T. ( 5 ) 92, 101 Koganty, R.R. ( 5 ) 391; ( 9 ) 66 Koharna, H. ( 3 ) 269 Kohda, K . ( 5 ) 16 Kohle, J.N. ( 2 ) 47; ( 5 ) 495, 496 Kohno, T. ( 5 ) 261 Koizumi, T. ( 5 ) 359; ( 6 i i ) 268 Kojima, M. ( 6 i i ) 120 Kojirna, N . ( 8 ) 37 Kokko, B. ( 5 ) 59; ( 6 i i ) 4 Kolhe, J. ( 2 ) 48; ( 3 ) 197; ( 6 i i ) 1 0 , 11 K o l l e r , M. ( 7 ) 75, 76 Komatsu, T. ( 3 ) 144, 468; ( 5 ) 51; ( 6 i i ) 131 Kometani, T. ( 9 ) 97 Komiotis, D. ( 4 ) 129 Komiyama, M. (5) 228 Kondo, H. ( 3 ) 414; ( 4 ) 69 Kondo, K . ( 5 ) 327, 352 Kondoh, T. ( 3 ) 491; ( 5 ) 62 K o n i s h i , M. ( 6 i ) 63; ( 6 i i ) 145 K o n i s h i , S . ( 4 ) 39 Konishi, Y. ( 8 ) 46 Kono, T. ( 3 ) 128 Konoike, T. ( 3 ) 396 Konovalova, I.V. ( 5 ) 509 K o n s t a n t i n o v i c , S. ( 4 ) 152 Kopola, N . ( 6 i i ) 15 Koreeda, M. ( 3 ) 44 Koser, G.F. ( 3 ) 312, 313; (5) 25 Koshiba, M. ( 5 ) 418 Koshikawa, 0. ( 2 ) 99; ( 6 i i ) 276 Kosugi, H. ( 3 ) 227; ( 4 ) 116 Kosugi, M. ( 5 ) 417, 618 Kotake, H. (3) 491: ( 5 ) 62; ( 6 i i ) 270
683
Author Index Koto, H. ( 4 ) 58, 250; (7) 2 K o t s u j i , K . ( 2 ) 76; ( 6 i i ) 151; ( 7 ) 65 Kotsuki, H . ( 2 ) 183; ( 3 ) 178, 361; ( 4 ) 11 Kowalski, C . J . ( 1 ) 115; ( 2 ) 52; ( 4 ) 102; ( 6 i i ) 36, 37 Koyama, S. ( 1 ) 128 Kozikowski, A.P. ( 2 ) 102; ( 3 ) 339, 396; ( 4 ) 32; ( 6 i i ) 227; ( 7 ) 114 Kpegba, K . ( 3 ) 295 K r a f f t , G.A. ( 6 i i ) 281 K r a f f t , M.E. ( 2 ) 18; ( 3 ) 334, 360; ( 7 ) 99 Krantz, A. ( 1 ) 124; ( 3 ) 319, 501; ( 5 ) 159 Krautwurst, K.D. ( 5 ) 8 9 K r e i s z , S. ( 3 ) 272 K r e p s k i , L.R. (5) 147, 304 Krespan, C.G. ( 5 ) 285 Kress, J. (1) 15 Kresze, G. ( 5 ) 129, 412, 463 Kretzschmar, G. ( 3 ) 116 K r i e f , A. ( 2 ) 8 7 , 153; ( 6 i i ) 71 Krishnamurthy, S. ( 6 i i ) 106 Krishnamurti, R . ( 3 ) 153 Kruger, C. ( 7 ) 9 ; ( 9 ) 120 Kubo, M. (5) 94 Kubota, H. (5) 219 Kubota, N. ( 5 ) 90 Kubota, T. ( 8 ) 33 Kudo, J. ( 3 ) 345 Kudo, K . ( 3 ) 69, 277; ( 4 ) 209 Kudo, T. (5) 1, 54 Kuehn, M. ( 5 ) 251 Kukenhohner, T. ( 4 ) 64; ( 6 i ) 41 Kuemi, T. ( 3 ) 88 Kuh, K.T. ( 9 ) 99 Kuhl, P . ( 3 ) 510 Kuhn, C. ( 2 ) 17 K u i v i l a , H.G. ( 3 ) 153 Kula, J. ( 2 ) 146 Kulharni, S.U. ( 6 i i ) 118 Kulinkovich, O.G. ( 3 ) 229 Kulkarni, S.U. ( 1 ) 7 ; ( 2 ) 26, 28 Kumada, M. ( 6 i ) 6 3 Kumagai, T. ( 3 ) 151; ( 9 ) 148 Kumagawa, T. ( 2 ) 128 Kumarasingh, L.T. ( 5 ) 485 Kunieda, N . (5) 320 Kunisch, F. ( 2 ) 170;
( 3 ) 150; ( 6 i i ) 105 Kunishima, M. ( 7 ) 61 Kunitake, T. (5) 268, 269 Kunz, H. ( 5 ) 253 Kunz, M. ( 3 ) 507 Kuo, F. ( 2 ) 78 Kuo, S.C. ( 7 ) 47 KUO, Y.-H. ( 3 ) 368; ( 5 ) 333 Kuomaglo, K. ( 4 ) 175 Kupfer, R . (5) 455, 456 Kurihara, T. (5) 288, 311, 317, 323; ( 8 ) 38 K u r i k i , H. (3) 59 Kuroboshi, M. (1) 26 Kuroda, H. ( 4 ) 21 Kuroda, T. ( 4 ) 43 Kurokawa, H. ( 2 ) 123; (5) 192 Kurokawa, K . ( 3 ) 247 Kurokawa, N. ( 3 ) 480, 514; (5) 244 Kurth, M . J . (3) 260 Kurth, R. ( 3 ) 478 Kusano, Y. ( 4 ) 131 Kushida, T. ( 8 ) 1 Kusumoto, S. ( 5 ) 482 Kusumoto, T. ( 5 ) 60 Kuwajima, I . (1) 18, 62; ( 2 ) 89, 103; ( 3 ) 173, 261; ( 6 i i ) 193, 195; ( 7 ) 104, 107 Kuzaj, M. ( 5 ) 289 Kuzuhara, H. ( 5 ) 100, 212, 262 K v i n t o v i c s , P. ( 4 ) 31 Kwart, L.D. ( 2 ) 56; ( 5 ) 478; ( 7 ) 60; ( 9 ) 83, 86 Kwasigroch, C.A. ( 1 ) 105; ( 4 ) 78 Kwiatowska, C. ( 3 ) 300 Kyung, S.H. ( 4 ) 62; ( 6 i ) 40 L a b a u d i n i e r e , R. (1) 21; ( 6 i i ) 279 L a B e l l e , B.E. (3) 246 L a b i a , R. ( 3 ) 481; ( 5 ) 163 Laboureur, J.L. ( 2 ) 87 L a c r o i x , A . ( 5 ) 111 Ladlow, M. ( 8 ) 3 , 29 Ladner, D.W. ( 3 ) 72 L a f i t t e , J.A. ( 6 i i ) 272 Laguna, M . A . (5) 305; ( 9 ) 36 Lakshmikantham, M . V . ( 3 ) 523; ( 6 i i ) 291 L a l , G.S. ( 1 ) 115 Lal, K. ( 7 ) 6
Lallemand, J.-Y. ( 4 ) 220; ( 9 ) 13 L a l l y , D.A. ( 2 ) 112 Lam, L.K.P. (3) 404 LaMattina, J.L. ( 3 ) 438; ( 5 ) 277 Lambert, C. ( 3 ) 320 Lambert, P.H. ( 5 ) 420 Lamed, R. ( 4 ) 40 L a m e r , 0. ( 3 ) 167; ( 4 ) 94 Lampropoulon, M. ( 3 ) 525 Lander, S.W., j u n . ( 1 ) 46; (5) 65 Landmann, B. ( 4 ) 50; ( 6 i i ) 130 Lang, M. ( 5 ) 110, 111 Langick, C.R. (5) 97 L a n g l o i s , R. ( 5 ) 17 Lansbury, P.T. ( 6 i i ) 69 Lantos, I. (3) 120 LarchGveque, M. ( 2 ) 114 L a r d i c c i , L. (1) 101; ( 4 ) 28; ( 6 i i ) 73 Larock, R.C. ( 1 ) 4 1 L a r r a z a , M . I . ( 3 ) 190 Larsen, G.L. ( 3 ) 14 Larsen, R.H. ( 6 i ) 1 4 Larsen, S.D. ( 6 i i ) 152; ( 9 ) 109, 117 Larson, G.L. ( 2 ) 135, 136; ( 3 ) 57; ( 6 i i ) 170 Lasowski, H.4. (5) 253 L a s z l o , P . ( 2 ) 153; ( 4 ) 125 Lathbury, D. ( 9 ) 9 0 L a t v a l a , A . ( 4 ) 132 Lau, C.K. (1) 2 Lau, C.M. (5) 498 Laughton, C.A. ( 4 ) 230 L a u r e n t , A . ( 9 ) 77 Laurenzo, K.S. ( 5 ) 1 5 Lauterbach, G. ( 7 ) 56 Lauterbach, T. ( 9 ) 55 L a v e l l e e , J.-F. ( 2 ) 194, 195; ( 7 ) 97, 98 (5) 8 6 Law, K.-Y. Lawrence, R.M. ( 3 ) 33 L a z a r i d i s , N . V . ( 2 ) 117 Lazbin, I . M . (5) 25 Lazraq, M. ( 5 ) 194 Leach, M.R. ( 6 i i ) 19 Leau, C.K. ( 4 ) 164 L e a v i t t , R . K . ( 3 ) 450 Lebioda, L. ( 3 ) 217 Le Breton, G.C. (5) 56 L e c h e v a l l i e r , A. ( 4 ) 194; ( 5 ) 388 Lecker, S.H. ( 7 ) 8 0 ; ( 8 ) 22 L e c o l i e r , S. ( 3 ) 276 Lecomte, C. ( 5 ) 403
General and Synthetic Methods
684
Lee, C . 4 . ( 9 ) 140 Lee, G.C.M. ( 5 ) 390 Lee, H.D. (1) 7 ; ( 2 ) 28; ( 6 i i ) 118 L e e , L.G. ( 4 ) 4 1 Lee, N.H. ( 2 ) 8 ; ( 4 ) 155 Lee, O.F.D. ( 2 ) 17 L e e , S.-J. ( 6 i i ) 68 L e e , S.H. (1) 23; ( 4 ) 181 Lee, T.V. ( 3 ) 224; ( 7 ) 5 5 , 129; ( 6 i i ) 155 Lee, Y.B. ( 5 ) 267 L e f h r e - B o r g , F. ( 5 ) 224 L e f k e r , B.A. ( 2 ) 83 L e g i n u s , J . M . ( 1 ) 46; (5) 6 5 Le G o a l l e r , R . ( 5 ) 371 (5) 71, 97, Lehn, J.-M. 107 L e i , X. ( 2 ) 6 3 L e i d h o l d t , R. ( 5 ) 309 L e i s i n g , M. ( 3 ) 130 Lemaire, M. ( 5 ) 378 Lempert, K. ( 5 ) 462 L e n h e r t , P.G. ( 6 i ) 74 Leon, E . I . ( 6 i i ) 285 Leone-Bay, A. ( 2 ) 38; ( 4 ) 163; ( 6 i i ) 224 Leplawy, M.T. ( 3 ) 511 L e p o r t , L. ( 4 ) 6 1 L e q u i t t e , M. ( 6 i i ) 234 L e r c h e , H. ( 3 ) 6 0 ; ( 5 ) 400 L e s n i a k , S. ( 9 ) 77 L e s p a g n o l , C. ( 5 ) 291 L e s s e n , T.A. ( 3 ) 519; ( 5 ) 6 9 ; ( 6 i i ) 196 L e t o u r n e a u , M . ( 3 ) 486 L e t t , R. ( 7 ) 1 1 5 ; ( 9 ) 2 , 3 Leung, J.C. ( 8 ) 6 3 Levenberg, P.A. ( 2 ) 9 4 L e v i n , D. ( 6 i i ) 231 L e v i s o n , B.S. ( 3 ) 8 9 Lewis, C.N. ( 3 ) 278 Lewis, F.D. ( 3 ) 216, 244 Lewis, J . A . ( 9 ) 30 Ley, S.V. ( 6 i i ) 13, 6 5 , 283 Leyendecker, F. ( 3 ) 231 L e z n o f f , C.C. ( 3 ) 338 Lhim, D.C. ( 2 ) 2 ; ( 4 ) 150 L i , C.S. ( 3 ) 339; ( 4 ) 32 L i , L. ( 2 ) 98 L i , P. ( 4 ) 197 L i , 2. ( 6 i i ) 241 L i a n g , D. ( 8 ) 5 6 L i a o , L.-F. ( 3 ) 348 L i b e r a t o r e , F. ( 9 ) 146 L i c a n d r o , E. ( 5 ) 404 L i d b e t t e r , P.S. ( 3 ) 254 L i e b e r k n e c h t , A. ( 5 ) 252
L i e b e s k i n d , L.S. ( 9 ) 141 L i e d , T. ( 3 ) 27 L i e s , R. ( 5 ) 307 L i e t j e , S. ( 6 i i ) 240 L i e w , W.-F. ( 3 ) 419 L i n , H.-S. ( 8 ) 20 L i n , J. ( 3 ) 29; ( 6 i i ) 3 5 L i n , R.-J. (5) 94 L i n , Y.-T. ( 6 i i ) 134 L i n d b e r g , T. ( 5 ) 221 L i n d e l l , S.D. ( 7 ) 110 L i n d n e r , H.J. ( 3 ) 27 L i n s t r u m e l l e , G. (1) 121 L i o t t a , D. ( 2 ) 93 L i p p a r d , S.J. ( 5 ) 6 6 L i p s h u t z , R.H. ( 2 ) 183; ( 3 ) 470; ( 5 ) 1 5 3 L i s , R. ( 3 ) 406 L i s t e r , M . A . ( 2 ) 171; ( 4 ) 80 L i t t l e , R.D. ( 7 ) 50 L i u , C. (1) 7 3 ; ( 3 ) 3 4 ; ( 6 i i ) 68 L i u , H . ( 2 ) 1 4 8 ; ( 3 ) 285; ( 5 ) 286, 287 L i u , J . ( 9 ) 139 L i v i n g h o u s e , T. ( 3 ) 1 9 8 ; ( 4 ) 1 2 8 , 255; ( 5 ) 3 4 3 ; ( 6 i i ) 58, 5 9 , 259, 286 L i z , R. (5) 1 2 0 , 121, 124 Lloyd, D.H. ( 5 ) 4 Lock, G.A. ( 4 ) 227; ( 9 ) 27 L o e s c h n e r , T. ( 5 ) 251 L o f f e t t , A. ( 3 ) 517 Logusch, E.W. ( 5 ) 177 Loh, J.-P. ( 2 ) 7 4 ; ( 6 i i ) 221; ( 7 ) 6 4 Lombaert, S.D. ( 6 i i ) 6 6 Lombardo, D.A. ( 3 ) 243 Lonsky, R. ( 3 ) 460; ( 5 ) 149 Loo, D. (5) 5 9 ; ( 6 i i ) 4 Look, G.C. ( 2 ) 1 4 5 Lopez, L. ( 3 ) 249; ( 6 i ) 47 Lorencak, P. ( 5 ) 315 Lorenz, K.T. ( 7 ) 3 L o r e y , H. ( 3 ) 1 9 9 , 357; ( 4 ) 218; ( 5 ) 79 L o r i m e r , J . P . ( 4 ) 180 L o r i n c z , T. ( 9 ) 5 9 Lou, €3. ( 4 ) 107 Loupy, A. ( 3 ) 9 9 ; ( 5 ) 283 Lovey, R.G. (5) 1 6 4 Low, C.M.R. ( 6 i i ) 283 Lowe, J.A., I11 (5) 240 Lown, J . W . ( 5 ) 391; ( 9 ) 66 Lu, S.-B. ( 2 ) 196; (3) 333; ( 7 ) 89, 91 Lu, X. ( 6 i i ) 242
Lub, J. ( 5 ) 465, 516 L u b i n e a u , A. ( 2 ) 175 L u c c h i n i , V. ( 4 ) 16 Luche, J . L . ( 2 ) 1 8 6 ; ( 3 ) 434; ( 4 ) 9 6 , 1 0 3 ; ( 6 i i ) 18 Luche, M.-J. ( 3 ) 493 Ludwig, J.W. ( 3 ) 37 Ludwig, W. (8) 26 L u e e r s e n , H. ( 5 ) 289 L u e t t k e , W. (5) 457 L u g t e n b u r g , J. ( 5 ) 380 L u i s , S.V. (1) 1 7 ; ( 4 ) 189 Lukacs, G. ( 5 ) 484 Lukas, K.L. ( 3 ) 27 Luke, R.W.A. ( 5 ) 213 L u k e h a r t , C.M. ( 6 i ) 74 Lumma, P.K. (5) 148 Lussmann, J. ( 3 ) 342 Lux, R . ( 5 ) 463 Lygo, B. ( 6 i i ) 6 5 Lynch, J. ( 7 ) 38 Lynch, L.E. (5) 304 Maas, G . ( 3 ) 134; ( 5 ) 442 McArthur, C.R. ( 3 ) 338 McCarthy, J . R . ( 5 ) 336 McCarthy, K.E. ( 2 ) 1 8 3 ; (3) 90 McClure, C.K. ( 2 ) 1 7 1 ; (4) 8, 80; (9) 51; ( 6 i i ) 251 McCombe, K.M. ( 5 ) 419 McComsey, D.F. ( 4 ) 161 McCormick, A.S. ( 3 ) 382 Macdonald, T.L. ( 2 ) 86 McDougal, P.G. ( 4 ) 1 2 4 ; ( 6 i i ) 45 McGarry, D.G. ( 9 ) 42 McGarvey, G . J . ( 3 ) 177, 286; ( 6 i i ) 1 7 0 Macher, I . ( 5 ) 368 Machiba, M. ( 5 ) 250 M a c i e l a g , M. (3) 442 McIntosh, J.C. ( 5 ) 4 2 3 McIntosh, J . M . (3) 449, 450 Mackenzie, N.E. ( 3 ) 433; (5) 207 McKervey, M.A. (3) 332; ( 6 i i ) 248 M c K i l l i p , A . ( 5 ) 180 MacLean, D.B. ( 5 ) 451; ( 8 ) 39; ( 9 ) 127 McMurry, J . E . (1) 127 McPhail, A.T. ( 5 ) 1 6 4 Maddaluno, J. ( 3 ) 487; ( 5 ) 195 M a d e s c l a i r e , M. ( 4 ) 247; ( 6 i i ) 249
Author Index
Maeda, K. (2) 116 Maeda, T. (1) 119; (3) 42; (6ii) 177; (8) 21 Maekawa, E. (3) 297, 318 Maekawa, T. (1) 111; (4) 67 Maetzke, T. (3) 12, 464; (5) 154 Magnin, D.R. (2) 85; (4) 210; (7) 122 Magnus, P. (8) 29 Maguire, A.R. (3) 332 Mahajan, M.P. (9) 131 Mahajer, D. (2) 7 Mahasay, S.R. (5) 376, 377 Mahdi, W. (5) 434 Mai, K. (5) 206, 290, 293 Maier, F.K. (1) 130 Maiorana, S. (5) 404 Maiti, S.N. (5) 9 Majetich, G. (3) 264; (6ii) 154; (7) 54 Majewski, M. (3) 440, 441 Makino, K. (6i) 22 I*Zakita,(6ii) 120 Mal, D. (3) 93 Malacria, M. (2) 57 Malamidou-Xenikaki, E. (9) 58 Malamus, M.S. (8) 21 Malassa, I. (5) 185 Mallardi, P.A. (5) 395 Maloney, M.G. (3) 189 Malpezzi, L. (5) 197 Manabe, 0. (5) 268 Mandai, T. (1) 78; (3) 267; (5) 227, 320 Mandal, A.K. (3) 310; (5) 53 Mander, L.N. (3) 252 Mandon, D. (6i) 26 Mane, R.B. (3) 13 Mangeney, P. (1) 100 Mani, R.S. (5) 481 Manitto, P. (2) 157 Mann, A . (1) 76; (6ii) 206 Manna, S. (1) 43 Manoury, P.M. (5) 224 Xanzardo, G.G.G. (7) 77; (8) 5 Mao, M.K.-T. (6ii) 41; (7) 13, 124, 125 Marcaccini, S. (5) 334 Marcano, M.M. (1) 72 Marchand, E. (5) 514 Marcinal-Lefebvre, A. (5) 85 Marco, J.A. (1) 17; (4) 189
685
Marco-Contelles, J. (3) 154 Marecek, J.F. (5) 42 Marek, I. (1) 100 Marinelli, F. (1) 29; (4) 205 Marji, D. (5) 459 Marmaras, V. (3) 525 Marotta, E. (2) 193; (3) 229; (5) 360 Marples, B.A. (3) 254 Marrero, J.J. (3) 420 Marron, B.E. (9) 42 Marsch, M. (5) 340 Marshall, J.A. (3) 207, 359; (4) 232; (8) 14, 15, 17, 18 Martell, A.E. (5) 105 Martelli, G. (9) 138 Martin, J.-A.F. (5) 436 Martin, O.R. (3) 469; (5) 174 Nartin, S. (6ii) 172 Martin, V.S. (1) 123 Martina, D. (6ii) 50 Martinez, A.G. (4) 185 Martinez Alvarez, R. (4) 185 Martinez-Gallo, J.M. (2) 120; (4) 172; (6ii) 95, 96 Naruoka, K. (2) 58, 61; (3) 8; (4) 1, 109, 117, 234; (6ii) 135 Maruyama, K. (1) 51, 108; (3) 144, 468; (5) 51; (6ii) 131, 207 Maryanoff, B.E. (4) 161; (6ii) 230 Maryanoff, C.A. (4) 161; (5) 440 Marzorati, L. (2) 46 Masamune, S. (3) 1, 289; (4) 27, 79; (6ii) 108 Mascarella, S.W. (8) 6 Mase, T. (7) 68; (8) 4 Mason, T.J. (4) 180 Masuda, R. (1) 80; (2) 149; (3) 54, 62 Masuda, T. (3) 399; (5) 5 Masunda, Y. (6ii) 164 Matheny, C. (5) 175 Matsubara, S. (3) 236; (5) 295 Matsubara, Y. (3) 286 Matsuda, H. (5) 263; (6ii) 244 Matsuda, I. (1) 53; (2) 174; (6i) 23, 142, 185 Matsuda, K. (2) 64; (6ii) 180; (9) 79
Matsuda, T. (5) 83; (6ii) 218 Matsuda, Y. ( 5 ) 35 Matsuhashi, Y. (1) 128 Matsui, M. (5) 312 Matsukura, H. (3) 163 Matsumoto, K. (3) 428; (5) 219 Matsumoto, T. (8) 55 Matsumoto, Y. (2) 125; (3) 486; (5) 144, 474, 477; (9) 106 Matsumura, K. (6ii) 75 Matsumura, Y. (2) 125; (5) 144, 518; (9) 106 Matsuo, T. (3) 112 Matsuoka, A . (5) 401 Matsuoka, H. (2) 159 Matsuura, T. (3) 274, 368; (5) 130, 333, 452, 488 Matsuyama, H. (2) 68, 69 Matsuyama, N . (2) 131; (6ii) 263 Matsuyama, Y. (6ii) 253; (9) 47 Matsuzawa, S. (1) 18; (6ii) 195 Matteson, D.S. (3) 346; (6ii) 2, 100, 125; (9) 9 Matthes, K.E. (5) 97 Matthews, D.P. (5) 336 Matthies, D. (5) 185 Matusubora, S. (6ii) 205 Matusuoka, H. (6ii) 210 MQtyus, P. (5) 445 Matz, J . R . (1) 127 Mauger, J. (5) 330 Mauna, S. (4) 108 Maverick, E. (5) 95 Mayer, R . (5) 504 Mayr, H. (6ii) 148 Mazumdar, S.N. (9) 131 Mazur, D.J. (9) 51; (6ii) 251 Meguri, H. (6ii) 282 Meh, D. (6ii) 81 Mehrotra, M.M. (1) 132 Mehta, G. (7) 78, 79; (8) 8 Mehta, M. (4) 186; (5) 424-426 Mei, A. (5) 265 Meinke, P.T. (6ii) 281 Mekata, H. ( 2 ) 39 Melching, K.H. (8) 41 Melendez, E. (3) 498, 499; (5) 220 Melis, S. (4) 254; (6ii) 44 Mellor, J . M . (1) 69;
686
( 3 ) 314; ( 5 ) 345, 346 Melot, J.-M. ( 4 ) 146; ( 5 ) 353 Menge, W.M.P.E. ( 6 i i ) 7 Mengoli, M. ( 3 ) 262; ( 6 i i ) 89 Meou, A . (5) 313, 314 Merce, R. ( 3 ) 347 Mereyala, H.B. ( 5 ) 476 Merritt, A . ( 2 ) 8 1 ; (7) 95 Meth-Cohn, 0. ( 3 ) 102, 118; ( 5 ) 394; ( 6 i i ) 19; (9) 6 Metz, P. (1) 134; ( 3 ) 427 Metzner, P. ( 3 ) 295, 296 Meyer, E.M. ( 3 ) 486 Meyer, G. ( 4 ) 182 Meyer, W.L. ( 2 ) 8 1 ; ( 7 ) 95 Meyers, A . I . (2) 8 3 ; ( 3 ) 142; ( 7 ) 8; ( 8 ) 27 Meyers, H.V. ( 3 ) 395; ( 7 ) 72 M i c c o l i , G. ( 6 i i ) 261 M i c e t i c h , R.G. ( 5 ) 9 Micha-Screttas, M. ( 6 i i ) 39 Michalik, M. ( 5 ) 303 Midland, M.M. ( 1 ) 104; ( 6 i i ) 101 Miginiac, L. ( 3 ) 232; ( 6 i i ) 158 Miginiac, P. ( 6 i i ) 136 M i g i t a , T. ( 4 ) 160; ( 5 ) 417, 418; ( 6 i i ) 194 Mignani, S. ( 6 i ) 68, 149; ( 6 i i ) 162; ( 7 ) 37 M i h a i l o v i c , M.L. ( 4 ) 152 Mikami, K . (1) 119; ( 3 ) 41-45, 47; ( 4 ) 115; ( 6 i i ) 177 Miki, D. ( 4 ) 17 Miki, M. ( 5 ) 311, 323 Miki, T. ( 5 ) 415 Milenkov, B. ( 3 ) 421 Miller, J . G . ( 3 ) 22 Miller, M . J . ( 9 ) 137 M i l l s , F.D. ( 2 ) 55 M i l l s , J.E. (5) 276 M i l l s , O.S. ( 5 ) 460 M i l l s , R . J . ( 3 ) 15, 154; ( 6 i i ) 183 M i l l s , S. ( 8 ) 42 M i l n e r , D . J . ( 4 ) 192 Minami, I . (1) 9 , 93, 94; ( 2 ) 21, 92; ( 3 ) 218, 271; ( 4 ) 138; ( 5 ) 294; ( 6 i ) 13, 8 5 Minami, K. ( 5 ) 430 Minami, T. (1) 37; ( 3 ) 136, 363, 444, 505;
General and Synthetic Methods ( 6 i i ) 232; ( 7 ) 22, 9 2 ; ( 9 ) 128 Minato, M. ( 3 ) 127 Minoguchi, M. ( 2 ) 191; ( 3 ) 196; ( 6 i i ) 6 0 Minowa, N . (1) 58; ( 4 ) 74 Minton, M.A. ( 3 ) 34 Mintz, E. ( 3 ) 217 Miranda, E . I . ( 2 ) 150 Miranda, R . ( 2 ) 155 Misawa, H. ( 1 ) 77; ( 2 ) 16; ( 4 ) 214 Mishra, P. (3) 449; (5) 38, 423 M i s i n t s e v , V.V. ( 5 ) 322 Mison, P. ( 9 ) 77 Misu, D. ( 2 ) 29, 42; ( 6 i ) 42, 43 Misu, K. (1) 112 M i s u m i , S. ( 5 ) 327 M i t c h e l l , T.N. ( 6 i ) 6 , 201, 218 Mitsudo, T. ( 3 ) 188 Mitsuhashi, T. ( 5 ) 399 Mitsunobu, 0. (5) 370 M i t t a l , R.S. ( 5 ) 379 Miyachi, N . ( 3 ) 425 Miyahara, M. ( 5 ) 393 Miyahara, 0 . ( 5 ) 370 Miyai, T. ( 3 ) 162; ( 4 ) 36 M i y a j i , K. ( 5 ) 319 Miyake, H. (1) 49; ( 5 ) 306 Miyami, H. ( 6 i i ) 186 Miyamoto, 0. ( 1 ) 128 Miyasaka, T. ( 2 ) 43; ( 3 ) 97, 279 Miyata, 0. ( 8 ) 37 Miyaura, N. (1) 8 , 66, 104; ( 4 ) 201, 204; ( 6 i ) 67, 101, 121-124 Miyazaki, M. ( 3 ) 119 Miyazawa, M. ( 3 ) 361, 391; ( 4 ) 23 Miyazawa, T. ( 4 ) 187 Miyazawa, Y. ( 2 ) 69 Miyoshi, N. ( 3 ) 2; ( 6 i i ) 292 M i z a t a k i , S. ( 3 ) 74 Mkhairi, A . ( 3 ) 458 Mladenova, M. ( 3 ) 310; ( 5 ) 46 Mobbs, B.E. ( 4 ) 230 Moberg, C. ( 5 ) 302 Mochida, K . ( 6 i i ) 8 3 Mochizuki, A. ( 3 ) 431 Modena, G. ( 2 ) 12; ( 4 ) 140 Modro, T . A . ( 5 ) 208 Modrow, H. ( 5 ) 504 Moebus, M. (5) 76, 75 Moenius, T. ( 7 ) 25;
( 9 ) 101 Moens, L. ( 5 ) 211 Moghaddam, M.E. ( 4 ) 153, 154 Mohajer, D. ( 2 ) 6 Mohamadi, F. ( 4 ) 119; ( 7 ) 5 ; ( 6 i i ) 98 Mohammed, A.Y. ( 7 ) 49 Mohan, L. ( 5 ) 383 Mohayer, D. ( 4 ) 153, 154 Mohiuddin, G. ( 9 ) 136 Mohri, K . ( 4 ) 18 Moingeon, M.-0. ( 2 ) 44 Mokhi, M. ( 6 i ) 61, 62 Molander, G . (1) 5 ; ( 2 ) 37; ( 3 ) 246; ( 4 ) 106, 202; ( 6 i i ) 101, 124, 143, 153; ( 7 ) 45, 71 Mole, S.J. ( 6 i i ) 204 Molik, M. ( 4 ) 30 Molino, B. ( 4 ) 169 M l l e r , J. (5) 462 Molokanov, V.V. ( 5 ) 322 Moloney, M.G. ( 6 i i ) 220 Monahan, R. ( 2 ) 9 3 Monkiewicz, J. (1) 12; ( 3 ) 191; ( 6 i i ) 228 Monobe, H. ( 2 ) 4 3 Montanari, F. ( 3 ) 3 Montes, J.R. (1) 57; ( 3 ) 453; ( 5 ) 182 Monti, D. ( 2 ) 157 Moody, C . J . ( 2 ) 70; ( 4 ) 225; ( 6 i ) 39; ( 7 ) 28; ( 9 ) 44 Mook, R . , j u n . ( 7 ) 1 8 Moore, C. ( 3 ) 118; ( 9 ) 6 , 30 Moore, H.W. ( 5 ) 325 Moore, L.L. ( 5 ) 136 Moore, R . N . ( 5 ) 246 Moosavipour, H. ( 2 ) 3 ; ( 3 ) 6 ; ( 4 ) 147 Mootoo, D. ( 4 ) 169 Moracci, F.M. ( 9 ) 146 Morales, C.B. ( 6 i i ) 170 Morand, P. ( 2 ) 4, 151; ( 4 ) 149; ( 6 i i ) 222 Morcano, M.M. ( 6 i i ) 163 Morel, G. ( 5 ) 514 Morera, E. (1) 122; ( 3 ) 275; ( 4 ) 165; ( 6 i ) 65 M o r e t t i , R. ( 3 ) 1 7 , 465, 474; ( 5 ) 158, 168 Morgan, T.M. ( 3 ) 239; ( 5 ) 115 Mori, A . ( 1 ) 109; ( 4 ) 72, 73 Mori, K . ( 3 ) 165; ( 6 i i ) 289
687
Author Index
Mori, M. ( 6 i ) 84; ( 9 ) 151 Mori, S. (3) 69, 277; ( 4 ) 209; ( 5 ) 13, 18 Mori, Y. (3) 183 Moriarty, R . A . ( 2 ) 156 Morikawa, M. ( 3 ) 183 Morikawa, T. (3) 113; ( 4 ) 206 Morimoto, T. ( 3 ) 344; (4) 47 Morimoto, Y. ( 5 ) 257 Morin, C. ( 3 ) 481; ( 5 ) 163 Morisaki, K. ( 3 ) 68 Morita, K. (7) 11 Morita, T. (3) 88; ( 5 ) 261, 375 Morita, Y. (5) 430 Moriwake, T. ( 3 ) 119; ( 4 ) 17 Moriwaki, F. ( 5 ) 501 Moriya, 0. (3) 322; ( 4 ) 224; ( 9 ) 14 Moriya, T. ( 5 ) 219 Moriyama, T. ( 1 ) 78; ( 3 ) 267; ( 5 ) 227 Moriyasu, M. ( 5 ) 215 Morizawa, Y. ( 3 ) 139 Moro, G. (3) 287; ( 4 ) 85 Moro-oka, M. ( 3 ) 400 Moro-oka, Y. ( 9 ) 33 Moroni, M. (5) 506 Morris, D. ( 2 ) 17 Mortezaei, R. (3) 245 Mosandl, A. ( 3 ) 346 Moser, H. ( 5 ) 316 MOSS, S. ( 5 ) 106 Mosset, P. (1) 43; ( 4 ) 108 Motekaitis, R . J . (5) 105 Motherwell, W.B. (1) 126; ( 2 ) 30; ( 5 ) 421; ( 6 i i ) 86, 246 Motohashi, S. (2) 127, 129 Motoo, Y. ( 5 ) 318 Mourino, A . ( 1 ) 122 Mouzin, G. (3) 73 Mtsuda, A . (3) 279 Mualla, M. (7) 19 Mucharczyk, N. ( 5 ) 204 Muchmore, S. ( 2 ) 75; ( 6 i ) 31; ( 7 ) 43 Muchowski, J . M . ( 2 ) 161; ( 5 ) 187; ( 6 i i ) 38 Muller, U. ( 3 ) 351; ( 7 ) 10 Mugrage, B.B. ( 3 ) 339; ( 4 ) 32 Mukaiyama, T. ( 1 ) 58; ( 2 ) 130, 152, 163, 177, 199-202; ( 3 ) 2, 110,
184, 202, 203, 288, 393, 471, 488, 489; (4) 74, 92; ( 5 ) 196; (7) 94; ( 9 ) 20 Mukerjee, A . K . ( 5 ) 218 Mukerji, I. ( 4 ) 95 Mularski, C . J . ( 3 ) 438; ( 5 ) 277 Mullins, S.T. ( 6 i i ) 217 Mulzer, J. (3) 51, 167, 327, 475; ( 4 ) 94; ( 5 ) 33, 160 Munger, J . D . , jun. ( 7 ) 29 Munro, M.H.G. ( 5 ) 55 Murahashi, S. (1) 45; (3) 128; (5) 256, 479; ( 6 i ) 34 Murai, K. ( 5 ) 501 Murai, S. (1) 19; ( 2 ) 101; (5) 258; ( 6 i i ) 161, 292 Murakami, M. (2) 152, 163; ( 3 ) 288, 488; (5) 196 Murakami, N. ( 3 ) 355; ( 7 ) 121 Murakami, Y. (3) 486; ( 5 ) 35 Murata, I. ( 5 ) 310 Murata, K. ( 3 ) 20 Murata, M. (5) 405 Murata, N. ( 5 ) 10 Murata, S. (5) 48 Murata, T. (1) 54; ( 6 i i ) 157 Murayama, A . ( 5 ) 359 Murayama, E. ( 2 ) 159; ( 6 i i ) 210 Murray, A.W. (1) 82; ( 5 ) 335 Murray, C.K. (1) 36; ( 6 i i ) 33 Murray, N.D. (1) 82; (5) 335 Murray, P . J . (3) 366; ( 6 i i ) 72 Murray, R.W. ( 5 ) 383 Murtahashi, S. ( 3 ) 436 Murthy, A . N . ( 7 ) 79 Murthy, K.S.K. (5) 508 Muruoka, K. ( 7 ) 109, 126 Musakami, M. (4) 92 MUSSO, H. ( 3 ) 483 Muto, S. ( 3 ) 298 Mutter, M.S. ( 6 i i ) 230 Muzart, J . ( 2 ) 25; ( 3 ) 245; ( 6 i ) 4; (9) 91 Nader, F.W. (3) 272 Nader, R. ( 9 ) 59 Naef, R . ( 2 ) 182; ( 5 ) 88;
( 6 i ) 44 Nasman, J . H . ( 6 i i ) 15 Nag, K . ( 5 ) 53 Nagahara, Y. (3) 505 Nagai, S. ( 6 i ) 66 Nagano, H. ( 3 ) 398 Nagano, T. ( 5 ) 414 Nagano, Y. (5) 257 Nagao, Y. ( 3 ) 119, 151; (7) 61; (9) 148 Nagaoka, H. ( 2 ) 163 Nagasaki, N. ( 3 ) 306; ( 4 ) 137; (7) 87 Nagasawa, €I. ( 3 ) 390; ( 5 ) 348 Nagata, S. ( 3 ) 309 Nagel, U. ( 3 ) 506 Naghipur, A . ( 9 ) 66 Naito, T. ( 8 ) 37 Najera, C. ( 2 ) 120; ( 4 ) 172; ( 6 i i ) 95, 96 Nakagawa, A . ( 3 ) SO9 Nakagawa, M. ( 2 ) 180; ( 4 ) 176; ( 5 ) 142 Nakagawa, T. ( 3 ) 306; ( 4 ) 137 Nakagawa, Y. (5) 19 Nakahara, Y. (4) 215 Nakai, S. (2) 61; (3) 8; (4) 1 Nakai, T. (1) 119; ( 3 ) 41-45, 47; ( 4 ) 115; ( 6 i i ) 177 Nakajima, T. ( 4 ) 4 ; ( 6 i i ) 186, 192 Nakajo, E. ( 9 ) 112 Nakakyama, K. ( 5 ) 142 Nakame, M. ( 3 ) 205 Nakamine, T. ( 3 ) 160, 161 Nakamura, E. (1) 18; ( 3 ) 173, 261; ( 6 i i ) 195 Nakamura, K. ( 2 ) 39; ( 3 ) 162; (4) 36, 37 Nakamura, N. ( 3 ) 157 Nakamura, S. ( 5 ) 268 Nakamura, T. ( 1 ) 47; (3) 265; ( 5 ) 351; ( 6 i ) 64, 90 Nakanishi, A. ( 3 ) 324; ( 4 ) 55 Nakanishi, K. ( 7 ) 116 Nakanishi, S. ( 3 ) 181 Nakano, M. ( 5 ) 232; ( 6 i ) 80 Nakano, T. ( 2 ) 19, 20; (4) 144, 145; ( 6 i ) 21 Nakao, A . ( 7 ) 33; ( 6 i i ) 74; ( 8 ) 11 Nakao, K . ( 3 ) 74 Nakao, T. ( 3 ) 248 Nakashima, N. ( 5 ) 268, 269
General and Synthetic Methods
688 Nakasuji, K. ( 5 ) 310 Nakasuji, Y . ( 5 ) 8 2 Nakata, T. ( 8 ) 54 Nakatani, H. ( 7 ) 4 Nakatani, M. ( 2 ) 32 Nakatsuka, M. ( 5 ) 310 Nakatsuka, S. ( 5 ) 5 Nakatsukasa, S. ( 6 i i ) 254 Nakayama, T. ( 5 ) 161 Namikawa, K. ( 2 ) 223 Namy, J . L . ( 6 i ) 5 Nanaka, 'r. ( 6 i i ) 205 Nanbu, H. ( 4 ) 54 Nancy, .J.-L. ( 4 ) 143 Naniwa, Y. ( 3 ) 390; (5) 348 Nanninga, T.N. ( 6 i ) 68; ( 6 i i ) 149; ( 7 ) 37 Naota, T. ( 3 ) 436; ( 5 ) 256 Narasaka, K. (1) 58; ( 3 ) 141, 155, 175; ( 4 ) 6 , 74; ( 5 ) 134; ( 6 i ) 18, 75, 24 Narasimhamur t h y , N . ( 3 ) 301 Narasimhan, N.S. ( 8 ) 24 Narisano, E. ( 2 ) 115; ( 3 ) 28; ( 4 ) 34 Naruse, Y. ( 6 i i ) 138 Naruta, Y. ( 1 ) 51; ( 6 i i ) 207 Nashima, T. ( 5 ) 401 Naso, F. ( 6 i i ) 261 Natalie, K . J . (2) 86 Natu, A . A . ( 5 ) 179 Nazer, B. ( 6 i i ) 107 Neal, J . R . ( 5 ) 278 Negareche, M. ( 5 ) 398 N e g i s h i , E. (1) 7 , 63; ( 2 ) 28, 71; ( 3 ) 385; ( 7 ) 46; ( 6 i i ) 118, 171 Negoro, K . ( 6 i i ) 256 N e i d l e i n , R. (5) 309 Neier, R . ( 5 ) 511 Nelson, P.S. ( 5 ) 249, 255 Nemery, I . ( 3 ) 91; ( 6 i i ) 66 Nemeto, H. ( 4 ) 231 Nestor, J . J . , jun. ( 9 ) 100 Neumann, R. ( 3 ) 72 Neves, M.G.P.M.S. (5) 382 Newcomb, M. ( 3 ) 37 Newington, T.M. ( 3 ) 197; ( 5 ) 496, 497; ( 6 i i ) 11 Newton, C. ( 7 ) 110 Ng, K.-K.D. ( 6 i i ) 78 Ngoviwatchai, P. ( 6 i i ) 97 Nguyen, H. ( 6 i i ) 47 Nguyen, N.H. ( 7 ) 8 0 ; ( 8 ) 22
Nguyen, N.V. ( 5 ) 325 Nguyen, S.L. ( 2 ) 183 Nicholas, K.M. ( 7 ) 42, 43; ( 6 i ) 25, 31 Nicholas, K.U.K.G. ( 5 ) 237 Nichols, D . E . (5) 4 Nickson, T . E . ( 3 ) 335; (5) 3 N i c o l a i d e s , D.N. ( 9 ) 58 Nicolaou, K.C. ( 1 ) 131, 132, 134; ( 8 ) 57; ( 9 ) 4 1 , 42 N i c o l a s , K.M. ( 2 ) 75 Nieduzak, T.R. ( 3 ) 396 Nieger, M. ( 3 ) 461; ( 5 ) 151 Niibo, Y . ( 4 ) 233 Niimura, K . ( 8 ) 46 N i i t s u , M. (5) 4 3 Nikam, S.S. (1) 72; ( 6 i i ) 163; ( 9 ) 21 N i k i s h i n , G . I . (5) 322 N i n b a r i , F. (8) 7 Ninomiya, I. ( 8 ) 37 Nisar, M. ( 3 ) 228; ( 4 ) 105 N i s h i , S. ( 2 ) 53 N i s h i d a , A . ( 5 ) 70 N i s h i g a i c h i , Y. ( 1 ) 51; ( 6 i i ) 207 N i s h i h a r a , H. ( 2 ) 11 N i s h i i , S. (1) 108; ( 3 ) 248, 468; (5) 51; ( 6 i i ) 131 Nishimoto, S. ( 5 ) 41, 219 Nishimura, A . ( 5 ) 320 Nishimura, K . ( 5 ) 92 Nishimura, S. (5) 130 Nishinaga, A . ( 3 ) 274; ( 5 ) 488 Nishino, J. (5) 401 Nishiwaki, T. ( 3 ) 113; ( 4 ) 206 Nishiyama, E. ( 4 ) 35 Nishiyama, H. ( 6 i i ) 215; ( 9 ) 107 N i s h i z a k i , I . (5) 133 N i t t a , K. ( 4 ) 190 Nitta, Y. ( 9 ) 108 N i w a , S. ( 4 ) 219 Nkusi, G. ( 3 ) 448; ( 5 ) 170 Noda, I. ( 9 ) 10 Node, M. ( 2 ) 59; ( 3 ) 176, 390; ( 4 ) 99; ( 5 ) 348 Nogami, Y. ( 5 ) 92, 101 Noguchi, M. ( 9 ) 8 2 Noguchi, S. ( 2 ) 43; ( 3 ) 97 Nogusa, H. ( 3 ) 446 Nohira, H . ( 6 i i ) 197
Nokai, S. ( 6 i i ) 135 Nokami, J . ( 3 ) 355; (5) 320 Nomura, K . ( 9 ) 64 Nomura, R . ( 3 ) 505; ( 5 ) 263; ( 6 i i ) 244 Nomura, Y. ( 5 ) 474, 477 Nonaka, T. ( 1 ) 33; ( 3 ) 101, 127; ( 5 ) 8 0 ; ( 6 i i ) 167; ( 9 ) 4 Nordmann, R . ( 5 ) 413 Normant, J . F . (1) 2 4 , 25, 85, 88, 100; ( 2 ) 95; ( 3 ) 63, 222, 266; ( 4 ) 93; ( 6 i i ) 31, 87, 88, 91, 172, 273 Nose, A . ( 5 ) 1, 54 Novi, M. ( 4 ) 245 Noyori, R. ( 4 ) 76; ( 6 i i ) 92 Nozai, K . ( 6 i i ) 167 Nozaki, H. (1) 3 4 ; ( 2 ) 147; ( 3 ) 103, 304, 418; ( 4 ) 43, 158; ( 6 i i ) 144, 205; ( 9 ) 4 Nozaki, I. ( 3 ) 320 Nozaki, K. ( 1 ) 33; ( 3 ) 162; ( 4 ) 36 Nuebling, C. ( 5 ) 24 Nugent, W . A . ( 2 ) 72 N u z i l l a r d , J . M . ( 3 ) 508 N y i t r a i , J. ( 5 ) 462 Oae, S. ( 6 i i ) 75 Oare, D . A . ( 2 ) 197 Obermann, U. ( 6 i i ) 247 Ochai, M. ( 3 ) 151 Ochi, M. ( 3 ) 178, 361; ( 4 ) 11 O c h i a i , H. ( 3 ) 265; ( 6 i ) 6 4 ; ( 6 i i ) 90 O c h i a i , M. ( 7 ) 61; ( 9 ) 148 O'Connor, B. ( 3 ) 416 Oda, D. ( 1 ) 47; ( 2 ) 123; ( 5 ) 192, 350, 351 Oda, M. ( 8 ) 1 Oda, Y. (5) 152 Oehlschlager, A . C . ( 6 i i ) 199 O e h r l e i n , R. (5) 361 Ogasawara, K . ( 3 ) 345; (8) 35 Ogata, K . ( 5 ) 60 Ogata, M. ( 4 ) 160; ( 6 i i ) 194 Ogata, S. ( 3 ) 431 Ogata, T. ( 5 ) 417 Ogawa, H. ( 3 ) 355; ( 4 ) 127 Ogawa, M. ( 2 ) 1 1 , 1 9 , 20;
689
Author Index ( 4 ) 144, 145, 156, 157; ( 6 i ) 20, 21 Ogawa, S. ( 5 ) 338 Ogibnin, Y.N. ( 5 ) 322 Ogura, F. ( 2 ) 62; (3) 299; ( 4 ) 237 Ogura, K. ( 2 ) 45, 99, 113, 191; (3) 196; ( 6 i i ) 60, 61, 276, 280 Ogura, S. ( 6 i i ) 83 Oguri, T. (1) 113; ( 3 ) 66 Oh, T. ( 3 ) 286 Oh, Y.-I. ( 4 ) 124; ( 6 i i ) 45 Ohannesian, I . ( 4 ) 195 Ohashi, K. ( 3 ) 355; ( 7 ) 121 Ohashi, M. (5) 19 Ohfune, Y. ( 3 ) 315, 480, 514; ( 5 ) 244 Ohki, H. (1) 59; ( 4 ) 46; ( 6 i i ) 245 O h n i s h i , H . ( 3 ) 361 Ohno, A. ( 2 ) 39; ( 3 ) 157, 162; ( 4 ) 36, 37 Ohno, K. ( 6 i i ) 186 Ohno, T. ( 5 ) 35 Ohnuma, T. (3) 425 Ohshima, M. ( 2 ) 152, 163; (3) 2 Ohshima, T. ( 3 ) 230 Ohshiro, Y. ( 3 ) 247 Ohsuki, S. ( 3 ) 329; ( 9 ) 22 Ohta, A . ( 4 ) 199 Ohtani, B. ( 5 ) 41 Ohtsuka, T. ( 3 ) 178; ( 4 ) 11 O h t s u k i , K. ( 2 ) 45, 191; ( 3 ) 196; ( 6 i i ) 60, 280 Ohuchi, Y. ( 3 ) 8 0 , 81; (5) 329 O i , R . ( 5 ) 352 Oida, T. (5) 50 Oikawa, Y. ( 4 ) 130; ( 9 ) 10 O i s h i , H. ( 5 ) 408 O i s h i , T. ( 3 ) 163; ( 8 ) 54 Oka, S. ( 2 ) 39; ( 3 ) 157, 162; ( 4 ) 36, 37 Okabe, M. (3) 281 Okada, E. (1) 80 Okada, M. ( 2 ) 53, 88; ( 7 ) 4 , 36; ( 9 ) 64 Okada, Y . ( 1 ) 26; ( 3 ) 505 Okahara, M. ( 5 ) 82 Okamoto, T. ( 5 ) 50 Okamoto, Y. ( 6 i ) 63, 145 Okawara, M . ( 3 ) 322; ( 6 i i ) 200 Okazaki, M.E. ( 5 ) 38 Okazaki, R . ( 6 i i ) 281
Oku, A. ( 1 ) 20; ( 4 ) 111, 242; ( 6 i i ) 248 Oku, T. ( 9 ) 28, 29 Okuda, K . (4) 233 Okuda, Y. ( 6 i i ) 167, 205 Okutani, T. ( 5 ) 415 Okuyama, T. ( 6 i i ) 280 Olah, G.A. ( 4 ) 195, 217 Olano, B. ( 5 ) 91 O l e s k e r , A. ( 5 ) 484 O l i v e r , J.P. ( 6 i i ) 166 Olofson, R.A. ( 6 i i ) 230 Olsen, R.S. ( 2 ) 77 Olson, L.A. ( 5 ) 395 Olson, R.E. ( 6 i i ) 190 O'Mahoney, M . J . ( 8 ) 49 O'Malley, G . J . ( 3 ) 523; ( 6 i i ) 291 Omori, K. (3) 411; ( 6 i i ) 133 Omote, Y. ( 9 ) 147 Omura, K . (3) 486 Omura, S. (5) 10 Onaka, M. ( 2 ) 173; (4) 126; ( 5 ) 475 O ' N e i l , I . A . ( 6 i i ) 283 O n i s h i , T. ( 2 ) 16; ( 4 ) 214 Ono, A . ( 2 ) 35, 36 Ono, N. ( 1 ) 22, 48; ( 2 ) 162; ( 3 ) 138; ( 4 ) 244; ( 5 ) 365, 385; ( 6 i i ) 250, 262 Ookawa, A. (3) 18; ( 4 ) 12 Oppenlaender, T. ( 3 ) 142 Oppolzer, W. (3) 15-17, 64, 154, 465, 474; ( 5 ) 158, 168; ( 6 i ) 46, 74, 183; (7) 30-33; ( 8 ) 11 Oppong, I . (8) 56 O r a z i , 0.0. ( 9 ) 129 Orena, M. ( 5 ) 140, 141 Organ, H.M. ( 6 i i ) 13 O r i , A. ( 3 ) 250 Oriyama, T. (1) 58; ( 4 ) 74 O r l e k , B.S. (5) 87 O r l o v i c , M. ( 4 ) 125 O r t a r , G. ( 1 ) 122; (3) 275, 372; ( 4 ) 165; ( 6 i ) 65 O r t i z , C. ( 3 ) 433; ( 5 ) 207 Ortiz, M..J. ( 5 ) 431 Ortuno, R.M. ( 3 ) 328, 347 Osa, T. ( 5 ) 501 Osakada, K. ( 3 ) 304; ( 4 ) 141 Osaki, H. (5) 41 Osanai, Y. (5) 6 3 Osano, 0. ( 5 ) 5
Osborn, J . A . ( I ) 1 5 O'Shea, D.M. ( 7 ) 17 Oshima, K . ( 1 ) 33, 34; (3) 304; ( 4 ) 43, 158; ( 6 i i ) 167, 205, 226; (9) 4 Oshima, M. (3) 228; ( 4 ) 105 Oshino, H. (3) 173 Ostercamp, D.L. (5) 116 O s w e l l , K.D. ( 6 i i ) 9 ; ( 9 ) 80 Ota, T. ( 3 ) 81 Otaka, K. (1) 75; ( 7 ) 8 6 O t a n i , S. (3) 428 Otera, J. (1) 77, 78; ( 2 ) 16, 147; (3) 103, 267, 418; ( 4 ) 214, 233, 256 Otsubo, K. (3) 325 Otsubo, T. ( 2 ) 62; (3) 299; ( 4 ) 237 O t s u j i , Y. ( 7 ) 44 Otsuka, S. ( 5 ) 184 Otsuka, T. ( 5 ) 405 O t t a n a , R. ( 6 i i ) 260 Ottenheijm, H . C . J . ( 3 ) 522; ( 5 ) 517 ( 3 ) 90; Ousset, J.-B. ( 7 ) 34 Overman, L.E. (1) 38; ( 4 ) 228; ( 5 ) 3 8 ; ( 6 i i ) 173, 174; ( 9 ) 4 5 , 72 Owczarczyk, Z. ( 5 ) 118 Oxman, J . D . (3) 216, 244 Oyamada, H. ( 3 ) 526 Oyhba, M. ( 8 ) 36 Ozawa, F. ( 3 ) 439; ( 5 ) 232, 239; ( 6 i ) 79, 80 Ozinskas, A . J . (5) 162 Pachinger, W. ( 3 ) 154; ( 6 i i ) 183 Pacofsky, G . J . ( 3 ) 361; ( 8 ) 61 Padwa, A. ( 5 ) 411; ( 9 ) 57, 76 Pagani, G.A. ( 6 i i ) 63 Page, P.C.B. ( 3 ) 180; ( 6 i i ) 189 Pagnoni, U.M. ( 4 ) 183 P a i k , Y i H . ( 3 ) 502; ( 5 ) 201 Pak, C.S. 1 ) 4 ; ( 3 ) 122; ( 6 i i ) 82 Palazon, J M. (1) 123 P a l a z z i , C ( 3 ) 149; ( 4 ) 86 Palck, J . R
690
Palomer, M. ( 7 ) 9 Palominos, M.A. ( 3 ) 290 Palomo, C . ( 3 ) 98; ( 4 ) 188 Palumbo, G. ( 3 ) 96 Palumbo, P.S. ( 6 i i ) 70 Panuncio, M. ( 9 ) 138 Papadopoulos, K . ( 5 ) 406 Papagni, A. ( 5 ) 404 Papaioannou, D. ( 3 ) 525 Paquer, D. ( 4 ) 248 P a q u e t t e , L.A. ( 6 i i ) 179; ( 7 ) 1 , * 6 3 ; ( 8 ) 10, 20 P a r i k h , I . ( 5 ) 458 P a r i s h , E.J. ( 2 ) 23 P a r k , J. ( 6 i ) 86 Park, N . ( 3 ) 509 Park, W.H. ( 9 ) 99 Park, W.S. ( 3 ) 142; ( 4 ) 25, 26; ( 6 i i ) 110-112 P a r k e r , D. ( 2 ) 183; ( 5 ) 97 P a r k e r , K.A. ( 3 ) 257; (7) 85 P a r k e s , K.E.B. (8) 12 P a r k i n , A . ( 6 i i ) 217 P a r k i n s , A.W. ( 6 i ) 2 P a r r i s , K.D. ( 2 ) 17 P a r s o n s , P . J . ( 9 ) 149 Parvez, M. (3) 331 P a s c a l , R.A., jun. ( 5 ) 225 P a t e l , S.S. ( 3 ) 496 P a t e l , V.F. ( 6 i ) 9 0 ; (9) 24 P a t e r s o n , G.A. ( 6 i i ) 33 P a t e r s o n , I . ( 2 ) 171; (4) 80 P a t i l , G. ( 5 ) 206, 290, 293 P a t i l , P.A. ( 8 ) 24 P a t i l , V . D . ( 2 ) 26 P a t t e n d e n , G. (1) 120; ( 3 ) 323, 376, 378; ( 6 i ) 8 9 , 90, 178; ( 7 ) 106; ( 8 ) 3, 12, 1 9 ; ( 9 ) 15, 24 P a t t o n , A.T. ( 6 i ) 59 P a d s , H.W. ( 8 ) 56 P a u l y , M. ( 5 ) 291 Peake, C . J . ( 5 ) 470 Pearson, A . J . ( 3 ) 401; ( 6 i ) 27, 29 Pearson, A.K. ( 6 i ) 36 Pearson, W.H. (3) 143; ( 6 i i ) 9 ; ( 9 ) 80, 8 4 , 8 5 Pgdoussaut, M. (3) 99; ( 5 ) 283 Pedrosa, R. (3) 474; ( 5 ) 158 Pedroso, E. (3) 527
General and Synthetic Methods
P e e l , M.R. ( 2 ) 66; ( 6 i i ) 213; ( 7 ) 59, 105; ( 8 ) 23 Peevey, R.M. (1) 44; ( 5 ) 31; ( 6 i i ) 287 Pegg, N . ( 3 ) 378 P e l l i s s i e r , H. ( 5 ) 313, 314 P e l t e r , A. ( 2 ) 100 Pennanen, S.I. ( 3 ) 369 P e n n e t r e a u , P. ( 2 ) 153 Penning, T.D. ( 8 ) 4 5 Pensar, G. ( 6 i i ) 15 Pepino, R. ( 5 ) 334 Perez G . , C. ( 2 ) 14 Perez G . , S. ( 2 ) 1 4 Perez-Ossorio, R. ( 5 ) 431, 436 Periasamy, M. (1) 65 Perichon, J. ( 2 ) 44; ( 4 ) 61, 182 P e r r y , D.A. ( 6 i i ) 251; ( 9 ) 51 P e r r y , M.W.D. ( 2 ) 47, 48; (3) 197; (5) 495, 496; ( 6 i i ) 10, 11 Perumal, P.T. ( 4 ) 52; ( 6 i i ) 129 P e r z , R. ( 3 ) 445 Pesce, G. (3) 249; ( 6 i ) 47 Pesce, M. ( 4 ) 14; ( 6 i ) 11 Peseke, K. ( 5 ) 303 P e t e , J.-P. ( 3 ) 245; ( 9 ) 91 P e t e r s e n , J.S. ( 6 i i ) 108 P e t e r s o n , G.A. (1) 36 P e t e r s o n , J.S. ( 4 ) 27 P e t e r s o n , M.L. ( 3 ) 346; ( 6 i i ) 125 P e t i t , G.R. (5) 249, 255 P e t i t , Y. ( 2 ) 114 P e t r a g n a n i , N. ( 3 ) 352; ( 6 i i ) 290, 294 P e t r a n y i , G. ( 5 ) 73 P e t r e , J. ( 5 ) 366 P e t r i e r , C. ( 2 ) 186 P e t r i g n a n i , J.-P. ( 3 ) 300 P e t r i l l o , G. ( 4 ) 245 P e t r i n i , M. ( 2 ) 193; ( 3 ) 56, 121, 229; ( 5 ) 360, 362 Petsom, A . (9) 52 P e t t i , M.A. ( 3 ) 75 P e t t i g , D . (3) 459; ( 5 ) 150 Pezechk, M. ( 9 ) 13 P f a e n d l e r , H.R. (1) 130 Pfander, H . (5) 40 P f e n n i n g e r , A. ( 9 ) 7 P f i s t e r , J . R . (9) 134 P f l u g e r , F. (3) 68
Pgawa, M. ( 2 ) 10 Pham, D. ( 5 ) 366 Pham, T.N. ( 3 ) 296 P h i l l i o n , D.P. ( 6 i i ) 223 P h i l l i p s , B.T. ( 5 ) 148; ( 9 ) 118 P h i l l i p s , J.B. (3) 100 P h i l l i p s , J.G. ( 4 ) 223; ( 6 i i ) 54, 55 P h i l l i p s , N.H. ( 6 i i ) 198 P h i l l i p s , R.B. (2) 142 P h i l l i p s , T. ( 3 ) 350 P i , R. ( 6 i i ) 40 P i a n e t t i , P. (1) 110 P i c c o l o , 0. ( 3 ) 435; ( 5 ) 235 P i c c o n i , G. ( 9 ) 132 Pichon, C. ( 2 ) 30; ( 3 ) 225; ( 6 i i ) 246, 247 P i c o t o n , G. ( 6 i i ) 136 P i e r c e , J . D . (3) 208 P i e r r e , J.L. ( 5 ) 371 P i e r s , E. ( 3 ) 223; ( 5 ) 214; ( 6 i i ) 203; ( 7 ) 39, 62 P i e t r e , S. (1) 2 ; ( 4 ) 164; ( 5 ) 506 P i e t r u s i e w i c z , K.M. (1) 12; ( 3 ) 191; ( 6 i i ) 228 Pigou, P.E. ( 3 ) 321 P i l l e y , B.A. ( 3 ) 383; ( 5 ) 326 Pinhey, J.T. (3) 189; ( 6 i i ) 220 P i n t o , A . C . ( 9 ) 12 P i r k l e , W.H. (3) 521; (5) 178; ( 9 ) 140 P i r r u n g , M.C. (5) 490; ( 7 ) 7 ; (9) 1 7 P i s c o p i o , A . D . ( 3 ) 361; ( 8 ) 61 P i t t s , J . N . , j u n . ( 5 ) 381 P i t z e n b e r g e r , S.M. ( 9 ) 118 P i v a , 0. ( 3 ) 245 Plampin, %J.N. ( 5 ) 440 P l a q u e v e n t , J.-C. ( 3 ) 451 P l a t e , R. ( 5 ) 517 P l e n a t , F. ( 5 ) 127 Poarch, J . W . (3) 286 Pochapsky, T.C. (3) 521; ( 5 ) 178 Pock, R. ( 6 i i ) 148 P o i r i e r , J . M . ( 2 ) 144 Poli, G. (3) 16, 195 P o l l a , E. ( 4 ) 125 P o l l e r , R.C. ( 6 i ) 2 Polson, G. (1) 42; ( 4 ) 104; ( 6 i i ) 293 P o l t , R.L. ( 5 ) 126; ( 6 i i ) 32
69 1
Author Index Polywka, M.E.C. ( 4 ) 229 Ponaras, A.A. ( 2 ) 122 P o n c e t , J. ( 5 ) 119 Ponpipom, M.M. ( 8 ) 6 0 P o n t , C. ( 5 ) 110, 111 Poon, Y.-F. ( 9 ) 8 5 P o r n e t , J. (3) 232; ( 6 i i ) 158 P o r t a , 0. ( 3 ) 171 P o r t e r , N.A. ( 2 ) 8 5 ; ( 4 ) 210; ( 7 ) 122 P o r t o g h e s e , P.S. ( 2 ) 139 P o s n e r , G.H. ( 2 ) 196; ( 3 ) 137, 333; ( 6 i i ) 265; ( 7 ) 89-91, 93; ( 9 ) 71 P o s t i g o , C. ( 5 ) 121 Pougny, J . R . (1) 110 P o u l i n , J . C . ( 3 ) 508 Powers, D. ( 3 ) 313 P r a d e r e , J.-P. ( 5 ) 433; (9) 63 P r a g e r , B. ( 3 ) 172 P r a g e r , R. ( 9 ) 105 P r a k a s h , G.K.S. ( 4 ) 217 P r a k a s h , 0 . ( 2 ) 156 P r a s a d , C.V.C. ( 3 ) 194 P r a s a d , G. ( 2 ) 8 6 P r a s a d , J.V.N.V. ( 6 i i ) 115, 117 P r a s a d , K. (3) 172 P r a t , D. ( 8 ) 3 ; ( 9 ) 2 P r a t i , L. ( 5 ) 156 P r a t t , A.C. ( 5 ) 469 P r a t t , D.V. (1) 44; ( 5 ) 31; ( 6 i i ) 287 P r e s c h e r , G. ( 3 ) 506 P r e s t o n , S.C. ( 6 i ) 52 Prewo, R . ( 5 ) 368 Pri-Bar, I. ( 4 ) 200 P r i c e , J . D . (1) 9 8 P r i d g e n , L.N. ( 3 ) 120 P r o u t , K. ( 6 i ) 58; ( 9 ) 143 Prowse, K.S. ( 3 ) 9 0 Prugh, J . D . (3) 409 Puddephatt, R.J. ( 7 ) 123 Pudovik, A.N. ( 5 ) 509 P u l i d o , F . J . (1) 32; ( 5 ) 305; ( 6 i i ) 146; ( 9 ) 36 Pulwer, M . J . ( 5 ) 27 P u r r i n g t o n , S.T. ( 2 ) 117 Pyne, S.G. (3) 21; ( 6 i i ) 278 Q u i l l e n , S.L. ( 3 ) 216 Quiniou, H. ( 9 ) 6 3 Q u i n t a r d , J.-P. ( 2 ) 124; ( 5 ) 190; ( 6 i i ) 214
Raabe, G. ( 5 ) 315 Rach, N.L. ( 3 ) 312, 313 Racha, R. ( 6 i i ) 234 R a c h e r l a , U.S. ( 6 i i ) 114 Radel, P.A. (3) 258 Radziszewski, J.J. ( 5 ) 315 Ragnarsson, U. ( 5 ) 222, 238 Rahm, A. ( 4 ) 10; ( 9 ) 32 Raimondi, L. ( 4 ) 77; ( 6 i i ) 51, 52 Rajagopalan, S. ( 4 ) 179; ( 6 i i ) 119 RajanBabu, T.V. (3) 75 R a k o t o n i r i n a , R. ( 3 ) 295 R a m , S . ( 3 ) 484; ( 5 ) 186 Ramachandran, P.V. ( 6 i i ) 109 Ramaswamy, S. ( 3 ) 67 Ramband, M. ( 3 ) 209 Ramchandran, P.V. ( 4 ) 24 Ramdahl, T. ( 5 ) 381 Ramer, S.E. ( 5 ) 246 R a m j i t , H.G. (3) 409 Rampersand, A. ( 6 i i ) 204 Rampulla, R.A. ( 5 ) 23 Rangaishenvi, M.V. ( 6 i i ) 125 Ranu, B.C. ( 7 ) 6 0 Rao, A.V.R. (3) 65 Rao, C.G. ( 2 ) 26 Rao, C.S. ( 3 ) 6 5 Rao, K.S. ( 7 ) 78; (8) 8 Raphael, R.A. ( 8 ) 62 Rapoport, H. ( 5 ) 192 Rasmussen, J.K. ( 5 ) 147, 304 Rathke, M.W. ( 2 ) 77 Rathmann, R. ( 3 ) 478 R a t h o r e , R. ( 2 ) 24, 154; ( 3 ) 307 Ratnam, C.V. ( 9 ) 136 Raucher, S . ( 2 ) 140 Ravichandran, K. ( 3 ) 523; ( 6 i i ) 291 Rayadh, A . ( 3 ) 232 Reagan, J. ( 4 ) 71 Reddy, A.V. ( 7 ) 79 Reddy, D.R. ( 3 ) 24 Reddy, D.S. ( 7 ) 79 Reddy, G.N. (1) 129 Reddy, K.B. ( 9 ) 42 Reddy, P.S. ( 9 ) 136 Reese, C.B. (5) 409 R e e t z , M.T. ( 2 ) 170; ( 3 ) 150; ( 4 ) 62-64; ( 5 ) 397; ( 6 i ) 3, 40, 41, 105 Reger, D.L. ( 3 ) 217 R g g l i e r , M. (3) 15 Regondi, V. (3) 25
Reich, H . J . (3) 238; ( 6 i i ) 190, 198 R e i c h e l t , H. ( 5 ) 298, 301 R e i c h e l t , I. ( 3 ) 199 Reid, R.G. (1) 8 2 ; ( 5 ) 335 Reinhoudt, D . N . (5) 464 R e i s s e n , A . ( 5 ) 102, 103 R e i s s i g , H.-U. ( 2 ) 90; ( 3 ) 199, 357; ( 4 ) 218; ( 5 ) 79; ( 7 ) 84 R e i t z , A . B . ( 4 ) 161; ( 6 i i ) 230 Remiszewski, S.W. ( 6 i i ) 269 Renaud, P. (3) 496; (5) 198; ( 7 ) 38 Rendenbach, R.E.M. ( 5 ) 406, 407 Rene, L. ( 5 ) 119 Renga, \J.M. ( 3 ) 238 Renoux, B. ( 7 ) 101 Renson, M . J . ( 6 i i ) 283 Repic, 0. ( 3 ) 172 Resman, W. ( 6 i i ) 201 R e s n a t i , G. ( 3 ) 338 Rey, M. ( 8 ) 13 R e y e , C. (3) 445 Rheinheimer, J. ( 5 ) 397 Ricca, D . J . (3) 44 Ricci, A. ( 4 ) 98 Ricci, M. ( 3 ) 7 ; ( 6 i ) 1 9 R i c h a r d s , D.J. ( 5 ) 49 Richardson, G. ( 6 i i ) 27; ( 8 ) 48 Richardson, K . A . ( 6 i i ) 155; ( 7 ) 55, 129 Richardson, S.K. ( 5 ) 481 Rico, J . G . (4) 124 R i e b e n s p i e s , J. ( 3 ) 472 Riego, J. ( 3 ) 492 Riesen, A. ( 5 ) 72 Rieu, J.-P. ( 3 ) 7 3 Rigby, H.L. ( 7 ) 60 Rigo, B. ( 5 ) 291 R i n e h a r t , K.L., j u n . ( 5 ) 55 Rink, H.P. ( 8 ) 25 Rise, F. ( 6 i i ) 280 R i s t , G. ( 3 ) 8 7 R i t t e r , A . ( 5 ) 412 R i t t e r , R.H. ( 6 i i ) 4 3 Riva, R. (3) 28 R i v a s - E n t e r r i o s , J. ( 4 ) 60 Robbins, J.D. ( 5 ) 278 Robert, A. ( 3 ) 114; ( 5 ) 321, 330 R o b e r t s , B.W. (3) 132; ( 7 ) 12 R o b e r t s , D.H. ( 7 ) 16 R o b e r t s , J.C. (3) 1
General and Synthetic Methods
692 Roberts, K.A. (1) 114; ( 6 i i ) 35 Roberts, S.M. (1) 120; ( 6 i i ) 178 Robertson, G.M. ( 7 ) 106; ( 8 ) 19 Robichaud, A . J . ( 2 ) 142 Robinson, J . E . (1) 79 Robinson, V . J . ( 1 ) 124; ( 3 ) 319 Roche, E.G. ( 3 ) 189; ( 6 i i ) 220 Rochin, C. ( 5 ) 189 Rode, J. ( 5 ) 502, 503 Rode, K. ( 5 ) 502 Rodenburg, L. ( 5 ) 380 Rodeschini, R. ( 3 ) 287 Rodriguez, M.A. (1) 27; ( 4 ) 174 Rodriguez, M.S. ( 3 ) 420 Rodriguez, R. ( 3 ) 290 Roekens, B. ( 3 ) 91 R o l l i n , P. ( 1 ) 110; ( 4 ) 167 R o l l i n , Y. ( 4 ) 182 Romana, S. ( 5 ) 409 Romanashin, J . N . ( 3 ) 229 Romeo, G. ( 6 i i ) 260 Romero, A.G. ( 9 ) 38, 121 R o n z i n i c i , L. ( 6 i i ) 261 Rooney, C.S. ( 3 ) 409, 410 ROOS, G.H.P. ( 3 ) 241 Rose, E. ( 6 i ) 37 Rose-Munch, F. ( 6 i ) 37 Rosen, T. (3) 215, 405 Rosenblum, M. ( 6 i ) 30 Rosenstock, R. (3) 27 Rosenthal, G.A. ( 5 ) 162 Rosenthal, S. ( 3 ) 180; ( 6 i i ) 189 R o s i n i , C. ( 4 ) 28; ( 6 i i ) 73 R o s i n i , G. (2) 193; ( 3 ) 229; ( 5 ) 360 Roskamp, E.J. ( 5 ) 491; ( 9 ) 18 R o s s i , E. ( 3 ) 31, 185 R o s s i , R. ( 1 ) 8 6 , 117, 118; ( 6 i i ) 168 R o s s i e r , J.-C. ( 3 ) 55 Roughley, B.S. ( 5 ) 356 Roush, W.R. ( 1 ) 60; ( 4 ) 49, 51; ( 6 i i ) 128 Roussel, J. ( 5 ) 378 Rowles, D.K. ( 5 ) 384 Rowley, M. ( 3 ) 153; ( 6 i i ) 208 Roy, B.L. ( 7 ) 119 Roy, P.J. (1) 8 1 ; ( 6 i i ) 284 Royer, R. ( 5 ) 367 Roze, J.C. ( 9 ) 6 3
Rozen, S. (3) 117; ( 9 ) 1 Ruckle, R.E. ( 3 ) 192; ( 5 ) 483; ( 7 ) 40 Ruechardt, C. ( 5 ) 494 Ruggeri, R. ( 6 i i ) 251; ( 9 ) 51 RuizlGayo, M. ( 3 ) 527 Rusek, G. ( 5 ) 12 Rusik, C.A. ( 6 i ) 6 0 R u s s e l l , G.A. ( 6 i i ) 97 R u s s e l l , J.J. ( 3 ) 282, 323; ( 6 i ) 8 9 , 90; ( 9 ) 1 5 , 24 R u s s e l l , M.A. (3) 284; ( 5 ) 349 R u s s e l l , R.A. (3) 382, 383; ( 5 ) 326 R u s s e l l , R.K. ( 5 ) 23 RGveda, E.A. ( 9 ) 25 Ruzziconi, R. ( 3 ) 131 Ryan, K.M. ( 7 ) 100 Ryan, W.J. (5) 395 Ryu, I . ( 2 ) 101 Ryzhov, M.G. ( 3 ) 454 S a a , C. ( 8 ) 31 Sag, J.M. (3) 53, 492; (8) 31 S a b u r i , M. ( 3 ) 304, 305, 381; ( 4 ) 141, 142; ( 5 ) 129 S a c k s t e d e r , L. ( 6 i ) 74 S a d d l e r , J . C . ( 5 ) 339 Sadhu, K.M. ( 3 ) 346; ( 6 i i ) 2 , 125; ( 9 ) 9 Saegusa, M. ( 3 ) 54 Saegusa, T. ( 2 ) 40, 53, 54; ( 3 ) 124; ( 6 i i ) 139; ( 9 ) 112 S a e k i , S. (3) 76 Saengchantara, S.T. ( 6 i i ) 264 Sagawa, Y. ( 2 ) 201; ( 7 ) 94 Saha, C.R. ( 5 ) 446 Saha, M. ( 2 ) 75; ( 6 i ) 31, 31; ( 7 ) 42, 4 3 Sahoo, S.P. (1) 81; (3) 366; ( 6 i i ) 72, 284 S a i c i c , R. ( 7 ) 1 5 , 21 S a i g o , K. (5) 90, 94 Saimoto, H. ( 4 ) 131 Saindane, M. ( 2 ) 93 S t . L a u r e n t , D.R. ( 7 ) 6 3 S a i t o , E. (3) 436; ( 5 ) 256 S a i t o , G. (5) 310 S a i t o , I. ( 3 ) 368; (5) 333 S a i t o , K . ( 3 ) 77, 78; ( 8 ) 54
S a i t o , M. (3) 318 S a i t o , S. (3) 119; ( 4 ) 1 7 ; (5) 269 S a i t o , Y. (5) 312 Saka, T. ( 3 ) 4 3 Sakaguchi, K . ( 9 ) 23 Sakaguchi, S . ( 3 ) 62 S a k a i , H. ( 5 ) 422 S a k a i , K. (5) 482 S a k a i , S. ( 3 ) 324, 337; ( 4 ) 1 5 , 55 S a k a i , T. ( 3 ) 59 S a k a i t a n i , M. ( 3 ) 315, 514 Sakamoto, M. ( 9 ) 147 Sakane, S. ( 4 ) 117, 234; ( 7 ) 109 S a k a t a , K . ( 2 ) 126; ( 5 ) 188 S a k a t a , Y. ( 5 ) 327 Saksena, A.K. ( 5 ) 164 S a k u r a i , H. (1) 75; ( 4 ) 101; ( 6 i i ) 253; ( 7 ) 86; ( 9 ) 47 S a k u r a i , K . ( 2 ) 19; ( 4 ) 144 S a k u r a i , M. (2) 61; ( 3 ) 8 Salami, B. ( 4 ) 248 S a l a z a r , J . A . ( 6 i i ) 285 S a l i m i , N . (3) 51 S a l i n k h e , M.M. ( 3 ) 13 Salmdn, M. ( 2 ) 155 Salomon, R.G. ( 2 ) 106; (3) 89; ( 7 ) 6 S a l v i n o , J . M . ( 2 ) 158 Samejima, K . ( 5 ) 4 3 S a m a k i a , T. ( 7 ) 117; ( 6 i ) 32; ( 9 ) 39 Sammes, P.G. ( 5 ) 145; ( 6 i i ) 271 Sampson, P. ( 2 ) 133; ( 6 i i ) 238 Samuelson, A.G. ( 3 ) 301 Sanchez, I . H . ( 3 ) 190 Sanchez, R. ( 5 ) 416 Sanderson, D.R. ( 2 ) 67; ( 7 ) 5 8 ; ( 6 i i ) 176 Sandhu, J.S. (9) 145 S a n d r i , S. ( 5 ) 140, 141 Sanner, M.A. ( 8 ) 42 Sano, H. ( 3 ) 54; (4) 1, 18, 160; (5) 417, 418; ( 6 i i ) 135, 194 Sano, T. (3) 80, 81; ( 5 ) 329 Sano, Y. ( 3 ) 526 S a n s o u l e t , J. ( 3 ) 99 S a n t a n i e l l o , E. ( 2 ) 1 5 S a n t i a g o , A. ( 2 ) 135 S a n t o , K . ( 5 ) 311, 317 S a r a n d e s e s , L.A. ( 1 ) 122 S a r d a r i a n , A.R. (2) 3;
693
Author Index ( 3 ) 6 ; ( 4 ) 147 S a r k a r , A.K. ( 1 ) 52; ( 6 i i ) 147 Sarma, D . N . ( 4 ) 134 Sarma, J.C. ( 4 ) 134 S a r o j a , M. (3) 9 5 S a s a k i , K. (3) 299 S a s a k i , S. ( 5 ) 401 Sasaoko, S. ( 6 i i ) 270 S a s h a r a , H. (3) 379 Sassano, S. (3) 31 Sasson, Y. (3) 72; ( 4 ) 100 S a t o , F. (3) 80, 81; ( 4 ) 91 S a t o , H. (2) 76; ( 6 i i ) 151; (7) 65, 66 S a t o , K. (1) 128; (3) 78; ( 4 ) 101 S a t o , M. (1) 133; (3) 182, 380; ( 5 ) 350 S a t o , S. ( 1 ) 53; ( 2 ) 168, 174; ( 6 i ) 23, 35, 142, 185; (8) 3 5 S a t o , T. (2) 159; ( 3 ) 29, 162, 170, 269, 289, 358; ( 4 ) 27, 79; ( 5 ) 80; ( 6 i i ) 48, 108, 210 S a t o h , M. (1) 66; ( 4 ) 201; ( 6 i i ) 123, 124 S a t o h , T. ( 1 ) 40; ( 2 ) 126-129; (4) 9 7 ; (5) 188 S a t o h , Y. ( 6 i ) 67 Satomi, H. ( 2 ) 40; (3) 124; ( 6 i i ) 139 Satyanarayana, N . ( 1 ) 6 5 Saunders, J. (3) 23 S a u v g t r e , R. ( 1 ) 24, 25; ( 3 ) 222; ( 6 i i ) 31, 91, 172 S a v i g n i a c , P. ( 6 i i ) 240 S a v i t s k a y a , L.N. ( 3 ) 229 Sawada, A. ( 3 ) 97 Sawada, H . (2) 71; ( 7 ) 46 Sawada, M. ( 5 ) 327 Sawada, S. ( 5 ) 161 Sawaki, Y. (3) 236; ( 5 ) 295 Sawamura, M. ( 3 ) 479; ( 5 ) 138; ( 6 i ) 88 Sawluk, A. ( 3 ) 293 Sawyer, J.S. (2) 8 6 Saxena, N. ( 2 ) 24 Saxton, J.E. ( 8 ) 30 Scanlan, T.S. (1) 50 Scanlon, T.S. (4) 240 Schade, C. ( 1 ) 10; ( 6 i i ) 30, 40 S c h a f e r , H.J. (8) 26 S c h a f e r , W. ( 1 ) 127
Schakel, M. ( 2 ) 91; ( 7 ) 127 S c h a l l e r , R. (5) 298 Schamp, N . ( 5 ) 29, 211, 331, 428, 448 S c h a n t l , J.G. ( 5 ) 499 S c h a t , G. ( 6 i i ) 77 Schauble, J . H . ( 2 ) 121; (3) 402 Schaumann, E. ( 6 i i ) 57 S c h e i g e t z , J. (1) 2; ( 4 ) 164 S c h e l l e r , M.E. ( 6 i i ) 187 Schenk, K.-H. ( 9 ) 152 S c h i a v e l l i , M.D. ( 4 ) 227; ( 9 ) 27 S c h i n e r , C.S. ( 6 i i ) 32 S c h i n z e r , D. (1) 9 9 ; ( 6 i i ) 159 S c h l e c h t , M.F. ( 4 ) 226 S c h l e y e r , P.von R. (1) 10; ( 6 i i ) 30, 40 Schmidt, M. ( 5 ) 515 Schmidt, R.R. ( 3 ) 234, 349, 365, 386, 387; ( 6 i i ) 46, 53; ( 9 ) 35 Schmidt, U. ( 5 ) 252, 281 S c h m i t t e l , M. ( 5 ) 494 S c h n e i d e r , F. ( 2 ) 178 ( 5 ) 108 S c h n e i d e r , H.-J. Schneider, J.A. ( 3 ) 415, 494; ( 5 ) 81 S c h n e i d e r , M. ( 4 ) 248 S c h n e i d e r , P. (3) 154; ( 7 ) 30 S c h n e i d e r , R. (5) 72 S c h o l l k o p f , U. (3) 459-462; ( 5 ) 149-151 Schoemaker, H.E. (3) 486 Schoenenberger, B. (5) 68, 510 Schoenhusen, U. (5) 303 Schoeni, J.-P. ( 5 ) 110 Schon, I. ( 3 ) 518 S c h r e i b e r , J. ( 5 ) 316 S c h r e i b e r , S.L. (3) 204, 395, 419; ( 4 ) 71; ( 6 i ) 32; ( 7 ) 72, 117; (9) 39 Schroeder, J.E. (4) 135 S c h u b e r t , B. (3) 475; ( 5 ) 160 Schubert, D.C. ( 4 ) 202 S c h u b e r t , H. ( 5 ) 24 Schuda, P.F. (3) 239; (5) 115 Schudde, E.P. ( 5 ) 52 S c h u l t e , G. (9) 39 S c h u l t z , A.G. (3) 442 Schwab, W. (5) 361 Schwan, A.L. ( 9 ) 70
Schwartz, E. ( 6 i i ) 251; ( 9 ) 51 Schwartz, J. (1) 23; ( 4 ) 181 Schwoebel, A. (5) 463 S c o l a , P.M. ( 9 ) 62 S c o l a s t i c o , C. ( 2 ) 172; ( 3 ) 195, 287; ( 4 ) 8 5 S c o l l a r , M.P. ( 2 ) 22 S c o t t , A.I. ( 3 ) 433; ( 5 ) 207 S c o t t , W . J . (1) 71 S c r e b n i k , M. ( 6 i i ) 113 S c r e t t a s , C.G. ( 6 i i ) 39 S c r i m i n i , P. ( 4 ) 1 6 S e d r a t i , M. ( 6 i ) 61, 62 Seebach, D. ( 2 ) 81, 169; ( 3 ) 12, 156, 159, 463, 464, 496; ( 4 ) 70; ( 5 ) 154, 198, 387; ( 7 ) 95 S e e l y , F.L. (1) 1 3 ; (3) 206 Seeman, J.I. (€6) 53, 54 S e e t h a l e r , T. ( 3 ) 500; ( 5 ) 167 S e g i , M. ( 6 i i ) 186 S e i b e l , W.L. (1) 64; ( 6 i i ) 102 S e i d e l , C. (3) 520; ( 5 ) 247; ( 6 i ) 91 S e i l z , C. ( 3 ) 475; (5) 160 S e k i , M. ( 5 ) 219 S e k i , Y. ( 6 i i ) 161 Sekiya, M. ( 5 ) 61 S e m e l h a c k , M.F. ( 6 i ) 8 6 Semra, A. ( 6 i ) 37 S e n e c i , P.F. ( 3 ) 158, 496 S e n e t , J.-P. ( 3 ) 515, 517 Senning, A. ( 5 ) 275 Sennyey, G. (3) 515, 517 Seoane, A. ( 5 ) 478; (9) 86 Seoane, G. ( 5 ) 478; (9) 86 S e p e r , K.W. (2) 160; (6ii) 8 S e p i o l , J. ( 5 ) 8 S e r r a , A.A. (3) 493 S e r r a - Z a n e t t i , F. ( 5 ) 265 S e r v i , S. (3) 496 S e t h , K.K. ( 4 ) 40 S e t h i , S.P. (3) 252 S e v e r i n i , T. (3) 60; ( 5 ) 400 Seyden-Penne, J. ( 2 ) 188; ( 9 ) 111 S e y f e r t h , D. ( 2 ) 192 Shah, M. ( 3 ) 312, 313 S h a n k l i n , P.L. (3) 255 S h a p i r o , M . J . ( 3 ) 172
General and Synthetic Methods
694
Sharma, N.D. ( 5 ) 419 Sharma, R.P. ( 3 ) 8 9 ; ( 4 ) 134 Sharma, S. ( 6 i i ) 199 S h a r p l e s s , K.B. ( 6 i ) 16 Shea, K . J . ( 7 ) 8 2 ; ( 9 ) 113 Shea, R.G. (1) 4 4 ; ( 5 ) 31; ( 6 i i ) 287 S h e l d r i c k , G.M. (3) 342 Shen, T.Y. ( 8 ) 60 Shen, Y. ( 3 ) 211; ( 6 i i ) 243 Shengde, W. ( 3 ) 4 5 5 ; ( 5 ) 157 Sheppard, G.S. ( 9 ) 119 S h e r , P.M. ( 8 ) 4 4 ; ( 9 ) 10 S h e r r i l l , R.G. ( 2 ) 7 3 ; ( 3 ) 192 Shiba, T. ( 5 ) 152, 482 S h i b a s a k i , M. (1) 1 1 3 ; (3) 66, 4 9 0 ; ( 7 ) 6 8 ; (8) 4 S h i b a t a , H. ( 5 ) 422 S h i b a t a , K. ( 2 ) 9 7 ; ( 5 ) 312 S h i b a t a , Y. ( 3 ) 221 S h i b u t a n i , T. ( 6 i i ) 75 Shibuya, H. ( 3 ) 3 5 5 ; ( 7 ) 121 Shigemoto, T. ( 5 ) 133 S h i h , C . ( 5 ) 437; ( 9 ) 98 Shim, S . B . ( 5 ) 472 Shim, S.C. ( 5 ) 1 1 ; ( 9 ) 9 9 Shimasaki, Y. ( 4 ) 21 Shimazaki, M. ( 3 ) 361; ( 4 ) 23, 109 Shimizu, I. (1) 9 ; ( 2 ) 9 2 ; ( 3 ) 218, 228; ( 4 ) 105 Shimizu, M. ( 4 ) 215 Shimizu, Y. ( 5 ) 294 Shimomura, M. ( 5 ) 269 S h i n , J . M . ( 3 ) 437; ( 5 ) 236 S h i n e r , C.S. ( 5 ) 126 S h i n k a i , S . ( 5 ) 268 Shinmaki, M. ( 4 ) 22 Shinoda, K. ( 4 ) 1; ( 6 i i ) 135 Shinoda, M. ( 1 ) 113; ( 3 ) 66 Shinoda, T. ( 7 ) 53 S h i n o z a k i , K . ( 3 ) 526 Shioharo, T. ( 7 ) 41 S h i o i r i , T. ( 5 ) 1 3 , 1 8 ; ( 6 i i ) 188; ( 8 ) 64 Shiono, M. ( 3 ) 8 0 , 8 1 ; ( 5 ) 329 S h i o t a , M. ( 3 ) 398 Shiragami, H. ( 6 i i ) 144 S h i r a i , R. ( 6 i i ) 6
S h i r a t s u c h i , M. ( 5 ) 520 S h i r o , M. ( 7 ) 61 S h i z u r a , Y. ( 7 ) 74 Shoef, N . ( 5 ) 241 Shono, T. ( 2 ) 1 2 5 ; ( 3 ) 417, 4 4 6 ; ( 4 ) 4 7 ; ( 5 ) 1 4 4 , 5 1 8 ; ( 9 ) 106 S h o r t , R.P. ( 7 ) 60 S h r a d e r , T. ( 5 ) 449 S h u b e r t , D.C. ( 6 i i ) 143 Shudo, K. ( 2 ) 223 S i b i , M.P. ( 6 i i ) 17 S i b i l l e , S. ( 2 ) 4 4 ; ( 4 ) 61 S i b t a i n , F. ( 3 ) 300 S i d a n i , A. ( 6 i i ) 20 S i e b e l , W.L. ( 7 ) 102, 103 S i e g e l , C. ( 4 ) 8 4 S i g l m u e l l e r , F. ( 5 ) 36, 37 S i g r i s t , R. ( 8 ) 13 S i h , C . J . ( 3 ) 2 4 , 7 9 , 174 S i k o r s k i , J.A. ( 1 ) 1 0 4 ; ( 6 i i ) 101, 107 S i l k s , L.A. ( 2 ) 187 S i l v a , G . V . J . ( 3 ) 352 Silverman, E.M. ( 7 ) 91 S i l v e r s m i t h , E.F. ( 7 ) 9 1 S i l v e r s t e i n , R.M. ( 3 ) 22 S i l v e s t r i , G. ( 3 ) 3 9 ; ( 4 ) 48 Simchen, G. ( 3 ) 5 0 0 ; ( 5 ) 167, 357, 358 Simon, C.D. ( 2 ) 1 6 5 ; ( 6 i i ) 258 Simon, E . S . ( 5 ) 421 Simon, H. ( 3 ) 11 Simon, R . ( 2 ) 178 Simonet, J . ( 5 ) 117 Simpkins, N . S . ( 1 ) 1 3 4 ; ( 2 ) 167; ( 6 i i ) 5 ; (.8.) 57 Simpson, T.H. ( 4 ) 2 2 7 ; ( 9 ) 27 S i n c l a i r , J . A . (1) 1 0 4 ; ( 6 i i ) 101 S i n c l a i r , P.J. ( 3 ) 472 Singaram, B. ( 5 ) 3 2 ; ( 6 i i ) 126 S i n g e r , G.M. ( 5 ) 392 S i n g e r , R.D. ( 5 ) 500 Singh, J. ( 4 ) 151 Singh, M.P. ( 5 ) 9 Singh, S.M. ( 6 i i ) 125 S i n g h , S.P. ( 2 ) 138 Singh, V.K. ( 5 ) 512 Sinou, D. ( 4 ) 1 2 1 ; ( 5 ) 473 Sivasubramanian, S. ( 5 ) 485 S j o g r e n , E.B. ( 3 ) 1 5 2 ; ( 4 ) 81
S k e r l j , R.T. ( 3 ) 223; ( 6 i i ) 203 Sladowska, H. ( 5 ) 21 Slawin, A.M.Z. ( 4 ) 225; ( 6 i ) 3 9 ; ( 9 ) 44 S l i w a , H. ( 3 ) 27 Sluma, H.-D. (7) 9 S l u s a r s k a , E. ( 4 ) 1 6 8 ; (5) 34 Smart, C.J. (5) 230 S m i g i e l s k i , K. ( 2 ) 146 Smith, A.B. ( 2 ) 9 4 ; ( 6 i i ) 2 8 ; ( 8 ) 21 Smith, A.G. ( 3 ) 378 Smith, A.L. ( 6 i i ) 12 Smith, E.H. ( 4 ) 196 Smith, K.M. ( 7 ) 67 Smith, R. ( 5 ) 343, 395 S m i t h e r s , R.H. ( 6 i i ) 182 S m i t s , J.M.M. ( 5 ) 517 S n i d e r , B . B . ( 2 ) 82 S n i e c k u s , V. ( 3 ) 440, 4 4 1 ; ( 6 i i ) 17 Snowden, R.L. ( 5 ) 122, 1 2 3 ; (7) 88 Snyder, J . K . ( 4 ) 5; ( 6 i ) 17 S o a i , K. ( 3 ) 1 8 , 3 6 ; ( 4 ) 1 2 , 219 Soda, K . ( 5 ) 161 S o d e r q u i s t , J . A . ( 2 ) 150 S o f i a , R.D. ( 5 ) 204 Sohar, P. ( 9 ) 65 S o i c k e , H. ( 3 ) 367 Soliman, F. ( 9 ) 101 S o l l a d i e , G. ( 3 ) 373; (4) 7 S o l l a d i e - C a v a l l o , A. ( 6 i ) 50 Solyom, S. (1) 9 9 ; ( 6 i i ) 159 Somanathan, R. ( 5 ) 45 Somei, M. ( 5 ) 44 Somers, T.C. (1) 129 Sondej, S.C. ( 4 ) 191 Song, Y.H. ( 2 ) 8 ; ( 4 ) 155 Sonoda, N . (1) 1 9 ; ( 2 ) 101; ( 5 ) 258; ( 6 i i ) 161, 292 Sooriyakumaran, R . (6ii) 1 S o r i , I. ( 3 ) 526 S o r i a , J.J. ( 5 ) 4 2 9 ; ( 6 i i ) 154; ( 7 ) 2 7 , 54 S o t e l o , 0. (3) 190 S o u l a , G. (5) 17 S o u t h g a t e , R . ( 9 ) 149 Spagnuolo, C . J . ( 6 i i ) 6 9 Spaltenstein, A. ( 1 ) 44; ( 5 ) 3 1 , 6 7 ; ( 6 i i ) 287 S p a n e v e l l o , R.A. ( 9 ) 25 Spanka, C . ( 6 i i ) 57
695
Author Index
Spargo, P.L. ( 3 ) 278 Speckamp, W.N. (8) 4 1 Spencer, R.W. (1) 124; ( 3 ) 319 Speranza, G. ( 2 ) 157 S p e r g e l , J. ( 5 ) 225 S p o g l i a r i c h , R. ( 4 ) 14; ( 6 i ) 11 S p r e n g e l e r , P.A. ( 6 i i ) 28 S p r i n g e r , J.P. (3) 377, 396; ( 6 i ) 87; (8) 20; ( 9 ) 115, 118 S r e b n i k , M. ( 4 ) 2 ; ( 6 i i ) 125 S r i d a r , V. ( 7 ) 48 S t a a b , E. ( 4 ) 9 S t a b l e r , R.S. ( 3 ) 172 S t a c h , H. ( 3 ) 422, 423; ( 5 ) 354; 386 Stamm, H. ( 2 ) 60; ( 3 ) 495; (5) 199, 200 Stammer, C.H. ( 5 ) 245 Stamos, I . K . ( 6 i i ) 236 Stamouli, P. ( 5 ) 511 S t a n g , P.J. ( 1 ) 114; ( 6 i i ) 35 S t a n s f i e l d , F. ( 5 ) 460 S t a n z i o n e , R.C. ( 5 ) 440 S t a r n e r , W.E. ( 5 ) 26 S t a u n t o n , J. ( 3 ) 194, 278 Steckhan, E. (3) 273; ( 4 ) 193 S t e e l e , R.W. ( 5 ) 213 S t e f a n e l l i , S. ( 4 ) 77; ( 6 i i ) 51 S t e f f e n , J. ( 1 ) 99; ( 6 i i ) 159 S t e g l i c h , W. (3) 316; ( 5 ) 449 S t e i g e r , A. (5) 316 S t e i n , J . ( 5 ) 243 Steinman, D.H. ( 7 ) 38 S t e r n , M. ( 5 ) 487 S t e r n b e r g , <J.A. (3) 395; ( 7 ) 73; ( 9 ) 34, 61 S t e r n b e r g , S.E. ( 3 ) 330 S t e r n f i e l d , F. ( 6 i i ) 65 S t e v e n s , D.R. (8) 59 S t e v e n s , R.W. ( 3 ) 288; ( 4 ) 92 Stevenson, T. ( 3 ) 6&, 154; (6i) 46, 183 S t i l l , W.C. ( 4 ) 119; ( h i i ) 98; ( 7 ) 5; ( 9 ) 38 S t i l l e , J . K . (1) 71; ( 2 ) 51; (3) 384; ( 4 ) 207; ( 6 i i ) 218; (8) 2 S t i r c h a k , E.P. ( 3 ) 340 S t i r l i n g , C.J.M. (5) 384 S t o k k e r , G.E. ( 3 ) 410 S t o l l , A.T. ( 2 ) 71;
( 7 ) 46 S t o l l , G. ( 3 ) 483 S t o n e , C. (1) 70 S t o r k , G. ( 5 ) 126; ( 6 i i ) 32; ( 7 ) 18; (8) 44; ( 9 ) 16 Storm, C.B. (5) 175 S t o w e l l , J . C . ( 5 ) 498 S t r a d i , R. (3) 31, 185 S t r e i t w i e s e r , A . , jun. (611) 64 Strekowski, L. ( 3 ) 336 S t r i c k l a n d , J.H. (5) 470 S t r i j t v e e n , B. ( 3 ) 116 Struchkov, Yu.T. ( 3 ) 454 Stucky, G. ( 4 ) 70 S t u d e r , M. ( 5 ) 104 S t u e t z , A . (5) 73 S t u f f l e b e r n e , G. ( 7 ) 3 S t u l t s , J.S. ( 6 i i ) 251; (9) 51 S t u r g e s s , M.A. ( 9 ) 144 Su, W. (7) 24 Sugrez, E. ( 3 ) 420; ( 5 ) 30, 439; ( 6 i i ) 285 Suau, R. ( 8 ) 31 Subramanian, L.R. (4) 185 Su bramanian , P. K ( 3 ) 477; ( 5 ) 259 Suda, T. ( 2 ) 10; ( 4 ) 156, 157; ( 6 i ) 20 Sudow, I. ( 7 ) 83 Suenaga, T. (3) 19; ( 6 i ) 45 Suga, H. ( 6 i i ) 235 Suga, S. (4) 76; ( 6 i i ) 92, 186 Sugimoto, K . (1) 77 Sugimura, T. (8) 10 S u g i t a , K. (5) 475 S u g i t a , N . ( 3 ) 69, 277; (4) 209 S u g i u r a , T. ( 1 ) 93, 94; ( 2 ) 9; ( 3 ) 5, 271; ( 4 ) 139; ( 6 i ) 1 3 , 8 5 Suhadolnik, J.C. ( 9 ) 40 S u i t s , J.Z. ( 2 ) 94 Sulbaran de C a r r a s c o , M.C. (1) 126; ( 6 i i ) m 8 6 Sulmon, P. ( 5 ) 29, 211, 331, 448 Sumi, K. ( 6 i i ) 62 Sumiya, R . ( 4 ) 4 ; ( 6 i i ) 192 Sunay, U. ( 4 ) 169 S u n d a r a r a j a n , G. ( 2 ) 181 S u t t o n , K.H. ( 6 i ) 38, 52, 57, 58; ( 9 ) 142, 143 Suya, K. ( 2 ) 168; ( 6 i ) 35 Suyarez, E. ( 5 ) 30 Suzuki, A . (1) 8, 66, 67, 104; ( 4 ) 201, 204;
.
( 6 i ) 67, 101, 121; ( 6 i i ) 123, 124 Suzuki, H. (3) 212, 400, 471; ( 5 ) 2, 297; ( 6 i i ) 150; (9) 33 Suzuki, K. (3) 305, 361, 399; (4) 22, 23, 109, 142; (8) 55 Suzuki, M. (3) 279, 358; ( 5 ) 35; ( 6 i i ) 48 Suzuki, S. ( 2 ) 16; ( 4 ) 214; (5) 1 9 Suzuki, T. ( 2 ) 64 Suzuki, Y. ( 3 ) 221 Suzumara, Y. ( 5 ) 338 Suzumoto, T. ( 4 ) 47 Svoboda, J.J. ( 9 ) 113 Swain, C.J. (8) 47, 49 Sweeney, J . B . ( 3 ) 237, 354; ( 6 i i ) 211, 212 S w e i g a r t , D . A . ( 6 i ) 28 Swenton, J.S. ( 5 ) 437; ( 9 ) 98 Swierzak, A . ( 4 ) 168 S w i t z e r , C. ( 6 i i ) 265 Symes, J. ( 5 ) 208 Symons, M.C.R. (5) 363 Szabo', J. ( 9 ) 65 S z a l o n t a i , G. ( 5 ) 513 Szarek, W.A. ( 3 ) 469; ( 5 ) 174, 273 Taba, K.M. ( 4 ) 123; ( 6 i i ) 103 T a b e i , T. (3) 47 Taber, D.F. (2) 73; ( 3 ) 192; ( 5 ) 483; ( 7 ) 40 Tabuchi, T. (1) 9 , 68, 95; ( 3 ) 326, 426; ( 4 ) 56, 57 Tada, M. (3) 281 Taddei, M. ( 1 ) 76; ( 4 ) 98; ( 6 i i ) 206 Taga, J. (4) 18 Taga, T. (9) 148 Tagashura, M. ( 4 ) 4 3 T a g l i a p i e t r a , S. ( 2 ) 157 T a g l i a v i n i , E. (1) 5 8 ; ( 3 ) 262; ( 4 ) 75; ( 6 i i ) 89 Taguchi, T. (3) 113; ( 4 ) 206 Takacs, J.M. (1) 13; (3) 206 Takagawa, M. ( 3 ) 62 T a k a g i , K . ( 4 ) 243; ( 5 ) 84 Takahashi, A. ( 3 ) 227; ( 4 ) 116 Takahashi, H. ( 3 ) 88,
General and Synthetic Methods
696 344; ( 5 ) 375 T a k a h a s h i , I . ( 6 i i ) 252 Takahashi, K. ( 2 ) 45, 92, 9 9 , 113, 191; ( 3 ) 196, 218; ( 6 i i ) 6 0 , 6 1 , 276 T a k a h a s h i , 0. ( 3 ) 4 2 , 4 3 , 47 T a k a h a s h i , S . ( 7 ) 41 T a k a h a s h i , T. ( 3 ) 391; ( 4 ) 231; ( 6 i i ) 1 7 1 , 280 T a k a h a s i , M. ( 3 ) 345 T a k a h a t a , H. ( 5 ) 279 T a k a i , K. ( 4 ) 4 3 , 1 9 0 ; ( 6 i i ) 254 T a k a k i , K . ( h i i ) 256 Takano, K . ( 2 ) 1 4 3 ; ( 5 ) 47 Takano, S . ( 3 ) 345; ( 8 ) 35 T a k a o , S . ( 9 ) 148 T a k a t a , T. ( 6 i i ) 249 T a k a t s u t o , S. ( 5 ) 10 Takayama, H. ( 6 i i ) 268 T a k e b a y a s h i , S. ( 5 ) 90 T a k e d a , A. ( 3 ) 3 2 , 5 9 ; ( 4 ) 39 Takeda, K . ( 1 ) 1 3 3 ; ( 3 ) 379, 380 Takeda, T. ( 2 ) 164; ( 4 ) 3 5 ; ( 5 ) 320; ( 6 i i ) 257; ( 7 ) 11 Takeda, Y. ( 4 ) 91 T a k e i , Y. ( 2 ) 68 Takemasa, T. ( 3 ) 1 Takenaka, S . ( 9 ) 7 8 T a k e s h i t a , H. ( 7 ) 116 T a k e s h i t a , K . ( 6 i i ) 161 T a k e u c h i , H. ( 5 ) 47 T a k e u c h i , R. ( 3 ) 1 0 5 , 414; ( 4 ) 6 9 ; ( 6 i ) 83 T a k e u c h i , Y. ( 5 ) 359, 474, 477 Takewaki, M. ( 6 i i ) 275 Takeyama, T. ( 7 ) 2 Takeyasu, T. ( 5 ) 296 T a k i d o , T. ( 9 ) 46 T a k i n a m i , S . (1) 6 7 ; ( 6 i i ) 124 T a l j a a r d , H.C. ( 3 ) 1 1 8 ; (9) 6 Tam, T.F. ( 1 ) 1 2 4 ; ( 3 ) 319 Tam, W. ( 6 i ) 82 Tamaki, K . ( 3 ) 74 Tamao, K. ( 2 ) 116; ( 4 ) 4 ; ( 6 i i ) 192 Tamaoka, T. ( 3 ) 355 Tamaru, Y . ( 3 ) 265; (6i) 64; ( 9 ) 89 Tamazaki, T. ( 5 ) 279 T a m , C . ( 3 ) 139, 149 Tamura, H. ( 5 ) 417
Tamura, M. ( 2 ) 199, 200; ( 3 ) 203; ( 5 ) 245 Tamura, R . (1) 4 7 ; ( 2 ) 123; ( 5 ) 192, 350, 351 Tamura, T. ( 2 ) 8 8 ; ( 4 ) 2 7 ; ( 6 i i ) 108, 256 Tamura, Y. ( 3 ) 86, 4 1 4 ; ( 4 ) 6 9 ; ( 5 ) 234; ( 6 i i ) 9 0 ; ( 7 ) 4 , 36 Tanabe, M. ( 6 i i ) 186 Tanabe, Y. ( 3 ) 184 T a n a g u c h i , Y. (1) 45 Tanaka, H. (1) 1 0 7 ; ( 3 ) 6 8 , 145, 230, 279; ( 4 ) 4 5 ; ( 5 ) 161; ( 6 i i ) 219 Tanaka, J. (5) 310 Tanaka, K. ( 3 ) 3 5 3 ; ( 5 ) 2 8 ; ( 6 i i ) 212 Tanaka, M. ( 3 ) 1 2 9 ; (6ii) 6 T a n a k a , S. ( 3 ) 136; ( 7 ) 22 T a n a k a , T. ( 4 ) 4 , 1 3 0 ; ( 5 ) 327; ( 6 i i ) 192; ( 9 ) 108 Tanaka, Y . ( 6 i i ) 270 T a n i , K. ( 5 ) 184 Tanigawa, E. ( 5 ) 184 Tanigawa, Y. ( 1 ) 4 5 ; ( 5 ) 479; ( 6 i ) 34 T a n i g u c h i , H. ( 5 ) 257 T a n i g u c h i , M. ( 2 ) 1 8 0 ; ( 4 ) 176-178; ( 5 ) 142 T a n i g u c h i , Y. ( 5 ) 4 7 9 ; ( 6 i ) 34 T a n i k a g a , R. (3) 1 6 8 , 375 Tanimoto, S . ( 5 ) 50 Tannenbaum, S.R. ( 5 ) 390 Tao, K. ( 6 i ) 25 T a o , Y.-T. ( 6 i i ) 68 T a p i a , R. ( 5 ) 372 T a s c h n e r , M . J . ( 3 ) 215, 312, 313 T a s h i r o , J. ( 2 ) 143 T a s h t o u s h , H. ( 5 ) 459 T a t a , C. ( 3 ) 255 T a t e m i t s u , H. ( 5 ) 327 T a t s u n o , Y . ( 5 ) 184 T a v e l , G . ( 2 ) 144 T a y l o r , D . A . ( 6 i i ) 155; ( 7 ) 5 5 , 129 T a y l o r , R.J.K. ( 3 ) 403; ( 6 i i ) 29 Tazuke, S. ( 3 ) 69 Teague, S.J. ( 8 ) 3 Tekeyama, T. ( 4 ) 58 T e l l i e r , F. ( 6 i i ) 91 T e m p l e t o n , J . L . ( 6 i ) 60 Tenge, B.J. ( 1 ) 4 4 ; ( 5 ) 3 1 ; ( 6 i i ) 287
t e n Hoeve, W. ( 3 ) 486 T e r a d a , S. ( 3 ) 390; ( 5 ) 348 T e r a d a , T. ( 2 ) 2 0 ; ( 4 ) 145; ( 6 i ) 21; ( 8 ) 38 T e r a d a , Y . ( 7 ) 74 Teramae, T. ( 5 ) 5 T e r a m o t o , K . ( 3 ) 88; ( 5 ) 375 T e r a o , K . ( 5 ) 233; ( 6 i i ) 285; ( 9 ) 92 T e r a o , Y. ( 6 i i ) 252; ( 9 ) 4 8 , 49 T e r a t a n i , S. ( 4 ) 127 T e r u i , K . ( 4 ) 199 Terunuma, D. ( 6 i i ) 197 T e s t a f e r r i , L. ( 6 i i ) 288 T e u l a d e , M.P. ( 6 i i ) 240 T e x i e r - R o u l l e t , F. ( 4 ) 146; ( 5 ) 353; ( 6 i i ) 234 Tezuka, T. ( 5 ) 405, 489 Thang, T.T. ( 5 ) 484 T h a n o s , I. ( 3 ) 11 Thea, S . ( 3 ) 28 T h e t f o r d , D. (5) 145 T h i b o u l o t , S. ( 4 ) 33 T h i e l , W. ( 5 ) 504 Thomas, D.W. ( 4 ) 120 Thomas, E. (1) 1 2 4 ; ( 3 ) 319; ( 8 ) 28 Thomas, E . W . ( 9 ) 103 Thomas, S.E. ( 4 ) 229 Thompson, A.S. ( 4 ) 228; ( 6 i i ) 173; ( 9 ) 45 Thompson, D.W. ( 4 ) 227; ( 9 ) 27 Thompson, M. (9) 94 Thompson, S . A . ( 7 ) 7 T h o r n t o n , E.R. ( 4 ) 8 4 T i c o r a s , C . J . ( 3 ) 210 T i e c c o , M. ( 6 i i ) 288 T i e d j e , M. ( 5 ) 4 7 8 ; ( 7 ) 60; ( 9 ) 8 6 T i e t z e , L.F. ( 5 ) 132 T i k d a r i , A . M . ( 5 ) 218 Tikhonov, A . Y . ( 5 ) 468 T i n g , P.C. ( 9 ) 43 T i n g o l i , M . (6ii) 288 T i n t e l , C. ( 5 ) 380 T i n t i , 0 . (5) 156 T i n u c c i , L. ( 3 ) 4 3 5 ; ( 5 ) 235 T i s c h e n k o , I.G. ( 3 ) 229 T i u s , M . A . ( 3 ) 90; ( 7 ) 3 4 ; ( 8 ) 16 Toczek, J. ( 2 ) 7 0 ; ( 7 ) 28 Toda, F. ( 6 i i ) 289 T o d e s c h i n i , R. ( 2 ) 172; ( 4 ) 85 Toga, K . ( 4 ) 127
697
Author Index
Toh, N. ( 5 ) 92 Tohda, Y. (3) 183 Tokai, M. ( 2 ) 54 Tokles, M. (4) 5 ; ( 6 i ) 17 Tokoroyama, T. (1) 1 4 Tokumitsu, T. ( 5 ) 125 Tokunaga, Y. ( 3 ) 398 T o l i o p o u l o s , E. ( 3 ) 263 T o l s t i k o v , G.A. ( 6 i ) 7 T o m a s e l l i , G . A . ( 2 ) 137 Tomasini, C. ( 5 ) 140, 141 Tomioka, H. ( 3 ) 304; ( 4 ) 158 Tomioka, K . ( 3 ) 19, 186, 201, 390; ( 6 i ) 45 Tomita, K. (3) 111 Tomoda, S. ( 5 ) 474, 477 Tomooka, K. (8) 55 Tondys, H. (5) 20 T o n e l l a t o , U. ( 4 ) 16 Toni, S. (4) 45 Tonker, T.L. ( 6 i ) 6 0 Toofan, J. ( 2 ) 5 Tordo, P. ( 5 ) 398 T o r i i , S. (1) 107; ( 2 ) 9 ; ( 3 ) 5, 68, 230, 356; ( 4 ) 17, 54, 139; (5) 352; ( 6 i i ) 219 T o r r e i l l e s , E. ( 2 ) 4 , 151; ( 4 ) 149; ( 6 i i ) 222 T o r r e s , E. ( 6 i i ) 170 T o r r e s , G. ( 5 ) 372 T o m , S. (3) 145 Toru, T. (3) 297, 318 Toshimitsu, A. ( 5 ) 233; ( 6 i i ) 285; ( 9 ) 92 Toth, T. ( 4 ) 184 Toupet, L. ( 5 ) 433; ( 6 i ) 26; ( 9 ) 6 3 Tour, J . M . ( 3 ) 385 Towson, J . C . ( 3 ) 140 T r a b o l d , P. ( 6 i ) 81 T r a v e , S. ( 2 ) 15 Trehan, S. ( 3 ) 90; ( 7 ) 34 Trimble, L.A. ( 3 ) 467; ( 5 ) 173 T r i p a t h y , P.K. ( 5 ) 218 T r o g l e r , W.C. ( 5 ) 229 Trombini, C. (1) 58; ( 3 ) 262; ( 4 ) 7.5; ( 6 i i ) 89 T r o s t , R.M. (1) 39, 50, 8 3 , 84, 8 9 , 116, 134; ( 3 ) 40, 427; ( 4 ) 240; ( 6 i ) 9 , 41, 68, 70, 71, 137, 149, 162; ( 7 ) 1 3 , 1 4 , 37, 38, 124, 125; ( 9 ) 19, 8 7 , 121 Troyansky, E . I . ( 5 ) 322 Trueblood, K . N . ( 5 ) 95 T r u j i l l o , J . M . (1) 123 Tsang, R . ( 4 ) 68; ( 7 ) 108
Tsay, Y.-H. ( 7 ) 9 ; (9) 120 Tscharnber, T. ( 3 ) 149 T s i p o u r a s , A. ( 9 ) 140 T s o t i n i s , A. ( 1 ) 74; ( 6 i i ) 165 Tsuboi, S. ( 4 ) 35 Tsubuki, M. ( 3 ) 341 T s u c h i h a s h i , G. (3) 250, 361, 399; ( 4 ) 22, 23, 109; (8) 55 Tsuda, T. ( 2 ) 40, 53, 54; (3) 124; ( 6 i i ) 139 Tsuda, Y. ( 4 ) 18 Tsuge, 0. ( 2 ) 64; ( 5 ) 450; ( 6 i i ) 180, 235; ( 7 ) 87; ( 9 ) 78, 79 Tsugoshi, T. ( 3 ) 8 6 ; ( 5 ) 234 T s u j i , J. ( 1 ) 9 , 93, 94; ( 2 ) 21, 92; ( 3 ) 188, 218, 228, 271, 391; ( 4 ) 105, 138, 231; ( 5 ) 294; ( 6 i ) 8 , 13, 8 5 T s u j i , M. (1) 47; ( 3 ) 165; ( 5 ) 351 T s u j i , Y. ( 3 ) 105; ( 6 i ) 83 Tsujimoto, K. (1) 78; ( 3 ) 267; ( 5 ) 227 Tsukamoto, G. ( 5 ) 261 Tsukamoto, M. ( 1 ) 1 4 Tsukamoto, T. ( 6 i i ) 292 Tsukube, H. ( 5 ) 84 Tsunekawa, H. ( 3 ) 269 Tsuruda, T. ( 2 ) 113; ( 6 i i ) 61 Tsurumaki, M. ( 3 ) 170 T s u t s u i , T. ( 5 ) 269 T s u t s u i , Y. ( 3 ) 230 Tsutsumida, J. ( 5 ) 98 Tuck, B. ( 3 ) 302 Tuckmantel, W. ( 1 ) 33; ( 6 i i ) 167, 226 Tunga, A. ( 3 ) 516 T u r n b u l l , M.M. ( 6 i ) 30 T u r n e r , A.T. ( 4 ) 180 T u r r o , N . J . ( 2 ) 63 Uchida, K. ( 6 i i ) 197 Uchida, K. ( 3 ) 139 Uchida, S. ( 6 i i ) 282 Uchikawa, M. ( 3 ) 45, 46; ( 4 ) 113, 114 lJchio, Y. ( 2 ) 143 Uch6a, R.R. ( 2 ) 46 Uda, H. ( 3 ) 193, 227; ( 4 ) 87, 116 Ueda, K. ( 3 ) 356 Ueda, M. ( 6 i i ) 62 Ueda, T. ( 3 ) 279
Ueda, Y. ( 5 ) 14 Uehara, H. ( 3 ) 113; ( 4 ) 206 Uehling, D.E. ( 2 ) 198; ( 3 ) 58 Ueki, M. ( 3 ) 526 Uemura, S. ( 3 ) 74; ( 5 ) 233; ( 6 i i ) 285; (9) 92 U e n i s h i , J. ( 4 ) 44 Ueno, A. ( 5 ) 501 Ueno, H. ( 3 ) 391 Ueno, K. ( 5 ) 450 Ueno, M. ( 2 ) 35, 36 Ueno, S. ( 6 i i ) 197 Ueno, Y . (1) 1; ( 3 ) 322; ( 4 ) 159, 224; ( 6 i i ) 200; ( 9 ) 1 4 Uggeri, F. ( 2 ) 118; ( 3 ) 82 Ugi, I. ( 5 ) 36, 37 U k a j i , Y. (3) 155, 175; ( 5 ) 134; ( 6 i i ) 24 Ulatowski, T.G. ( 3 ) 140 U l l e n i u s , C. ( 3 ) 109 Umani-Ronchi, A . (1) 58; ( 3 ) 262; ( 4 ) 75; ( 6 i i ) 89 Umekawa, H. ( 6 i i ) 218 Umemoto, T. ( 3 ) 111 Umezu, K. ( 3 ) 358; ( 6 i i ) 48 Undheim, K. ( 6 i i ) 185, 280 Uneyama, K. (3) 356; ( 4 ) 54 Uno, H. ( 3 ) 219; ( 5 ) 297; ( 6 i i ) 150, 156 Uno, T. ( 3 ) 128; ( 5 ) 261 Uozumi, Y. ( 6 i ) 84 Upthgrove, A . L . (3) 216 Urabe, H. (1) 62; ( 7 ) 107 Urano, K . ( 5 ) 312 U r a t a , Y. ( 4 ) 224; ( 9 ) 14 Urch, C . J . (1) 84 U s a m i , Y. ( 2 ) 59; ( 3 ) 176; ( 4 ) 99; ( 6 i i ) 62 Ushio, K. ( 3 ) 157, 162; ( 4 ) 36, 37 Ushio, Y. ( 3 ) 178; ( 4 ) 11 Utaka, M. ( 3 ) 32, 5 9 ; ( 4 ) 35, 39 Utimoto, K . (1) 33, 34; ( 3 ) 320; ( 4 ) 43, 190; ( 6 i i ) 144, 167, 205, 226, 254; ( 9 ) 4 Utz, R. ( 5 ) 252 Uyama, H. (3) 417 Uzawa, J. (5) 337
General and Synthetic Methods
698
Vaccara, W. ( 3 ) 470; ( 5 ) 153 Valderrama, . J . A . ( 5 ) 372 Valenzuela, B.A. ( 6 i i ) 233 V a l l e , L. ( 6 i i ) 233 V a l o t i , E. ( 3 ) 435; ( 5 ) 235 Van de H e i s t e e g , B.J.J. ( 6 i i ) 77 van d e r Baan, J . L . ( 6 i ) 24 Van d e r Does, T. ( 2 ) 91; ( 7 ) 127 v a n der Helm, D. ( 2 ) 75; ( 7 ) 43; ( 6 i ) 31 van d e r P l a s , H.C. ( 5 ) 20, 21, 441 Van Duyne, G. ( 1 ) 127; ( 5 ) 435 van E i j k , P.J.S.S. ( 5 ) 464 Van Engen, D. ( 5 ) 225 Vankar, P. ( 2 ) 154; ( 3 ) 307 Vankar, Y.D. ( 2 ) 138 van Leusen, A . M . ( 5 ) 344 Van Meerssche, M. ( 5 ) 211 van T h u i j l , J . ( 5 ) 380 van Veldhuizen, A. ( 5 ) 21 van Vuuren, G. ( 3 ) 118; ( 5 ) 394; ( 9 ) 6 Van Z y l , C.M. (1) 31; ( 2 ) 67; ( 7 ) 58; ( 6 i i ) 176 V a r i e , D.L. ( 6 i i ) 251; ( 9 ) 51 Varma, M. ( 5 ) 466 Varma, R.S. ( 5 ) 57, 466; ( 9 ) 73 Varney, M.D. ( 3 ) 379 V a s e l l a , A . ( 5 ) 135, 226, 368, 412 Vass, A . ( 5 ) 513 Vaughan, J. ( 5 ) 355 Vaughan, K. ( 5 ) 237, 500 V a u l t i e r , M. ( 3 ) 497; ( 5 ) 420; (6i-i) 20 V a v i l i k o l a n u , P.R. (2) 156 Vawter, E . J . ( 2 ) 185 Veda, T. ( 7 ) 44 Vedananda, T.R. ( 8 ) 5 3 Vedejs, E. ( 4 ) 8; ( 6 i i ) 180, 251; ( 9 ) 51, 67, 74, 75 Vederas, J . C . ( 2 ) 109; (3) 38, 467; ( 5 ) 173, 246 Vega, J . C . ( 3 ) 290 V e i t h , R. ( 7 ) 128 Venton, D.L. ( 5 ) 56
V e n t u r e l l o , C. ( 3 ) 7 ; ( 6 i ) 19 Venugopalan, B. ( 5 ) 461 Veoka, R. ( 3 ) 486 Verducci, J. ( 3 ) 448; ( 5 ) 170 Verh6, R. ( 5 ) 448 V e r k r u i j s s e , H.D. (1) 10; ( 6 i i ) 30 Verlhac, J.-B. ( 2 ) 124; ( 5 ) 190; ( 6 i i ) 214 Vermeer, P. ( 6 i i ) 67 Vernon, P. ( 9 ) 9 0 Veschambre, R. ( 4 ) 33 Veyrat, C. ( 9 ) 111 V i a l a , J. (1) 43 Vialaand, .J. ( 4 ) 108 V i a l l e , J. ( 3 ) 296 V i a l l e f o n t , P. ( 3 ) 448; ( 5 ) 170 V i a n i , F. ( 3 ) 338 Villemin, D. ( 6 i i ) 234 V i l l i e r a s , J. ( 3 ) 209; ( 4 ) 66 V i n c e n t i , M. ( 4 ) 208 V i n e t , V . ( 5 ) 14 V i s n i c k , M. (3) 336; ( 6 i i ) 28; ( 8 ) 21 Visser, R . (5) 464 V i t t , S.V. ( 3 ) 454 Vogel, C. ( 9 ) 110 V o l l h a r d t , K.P.C. ( 7 ) 80; ( 8 ) 22; ( 9 ) 119 Vollmar, A . ( 5 ) 366 Volodarsky, L.B. (5) 468 von K e r e k j a r t o , B. ( 3 ) 412 Voss, E. ( 5 ) 132 Voss, J . ( 3 ) 293 Vostrikova, O.S. ( 6 i ) 7 V o t t e r o , C. ( 2 ) 144 Vriesma, R.K. ( 3 ) 486 Vukicevic, R. ( 4 ) 152 Vuorinen, E. ( 5 ) 7 Wada, A. ( 6 i ) 66 Wada, E. ( 7 ) 87 Wada, F. ( 5 ) 8 3 Wada, M. ( 1 ) 59; ( 4 ) 46; ( 6 i i ) 245 Wada, T. ( 5 ) 263, 489; ( 6 i i ) 244 Wadman, S. ( 4 ) 112 Waespe-Sarcevic, N . ( 3 ) 149 Wagner, R. ( 6 i i ) 8 1 Waigh, R.D. ( 4 ) 253 Wakabayashi, S. ( 3 ) 355; ( 5 ) 320 Wakamatsu, K. ( 1 ) 33; ( 6 i i ) 167
Wakamatsu, T. ( 3 ) 425 Wakamiya, T. ( 5 ) 152 Wakasa, N . ( 3 ) 78 Wakbayashi, H. ( 5 ) 228 Wakefield, B . J . ( 6 i i ) 19 Wakita, Y. ( 6 i i ) 120 Waldner, A . ( 3 ) 179 Walker, J . C . ( 6 i ) 52, 56-58, 72; ( 9 ) 142, 143 Walker, T.E. ( 5 ) 175 Wall, A . ( 6 i i ) 272 Wallace, T.W. ( 6 i i ) 264 Walshe, N . D . A . ( 6 i i ) 27 Walt, D . R . ( 3 ) 496 W a l t e r , W . ( 5 ) 446 W a l t e r s , M.A. ( 6 i i ) 9 ; ( 9 ) 80 Walther, I. ( 3 ) 473 W a l t s , A.E. ( 1 ) 60; ( 4 ) 51; ( 6 i i ) 128 Wamhoff, H. (5) 445 Wamprecht, C. ( 5 ) 444 Wanat, R.A. ( 5 ) 435 Wang, J.-X. ( 3 ) 308 Wang, K. ( 3 ) 486; ( 6 i i ) 163 Wang, K.K. (1) 6 , 35, 72, 73, 104; ( 6 i i ) 101, 202; ( 9 ) 21 Wang, N . ( 4 ) 135 Wang, P.-C. ( 5 ) 405 Wang, Y.-F. ( 3 ) 174 Wanner, K.T. ( 2 ) 83 Ward, F.E. ( 3 ) 26 Warkentin, J. ( 9 ) 70 Warner, P. (5i) 54 Warner, S. ( 5 ) 66 Warren, S. (1) 11; ( 3 ) 233, 235, 251; ( 6 i i ) 231, 255 Warrener, R.N. ( 3 ) 382, 38 3 Warshawsky, A . ( 5 ) 241 Wartski, L. ( 2 ) 188, 189; ( 9 ) 111 Wasserman, H.H. ( 3 ) 90; ( 9 ) 28, 29 Watabiki, 0. (5) 1 9 Watanabe, H. ( 3 ) 182 Watanabe, I. ( 5 ) 318 Watanabe, K . ( 3 ) 155; ( 6 i i ) 24; ( 7 ) 92; ( 9 ) 128 Watanabe, M. ( 3 ) 322 Watanabe, N . ( 3 ) 486 Watanabe, Y. (1) 1; ( 3 ) 105, 188; ( 4 ) 159; ( 6 i ) 83, 200; ( 8 ) 32 Watson, R.A. ( 2 ) 184 Watt, D.S. ( 3 ) 392; ( 5 ) 481; ( 9 ) 102 Wayda, A . ( 4 ) 9 5
699
Author Index
Webb, M. ( 1 ) 63; ( 2 ) 71; ( 7 ) 46 Webb, N . J . ( 6 i i ) 204 Webber, S.E. (1) 131, 132 Weber, A.E. ( 3 ) 467; ( 5 ) 137 Weber, H.-M. ( 3 ) 134; ( 5 ) 442 Weber, J . V . ( 4 ) 248 Weber, T. ( 3 ) 464; ( 5 ) 154 Webster, A.E. ( 4 ) 82 Webster, F.X. (3) 22 Weedon, A.C. ( 3 ) 243 Wei, L. (5) 6 6 Wei, T. ( 2 ) 2 3 Weiberth, F.J. ( 5 ) 6 Weidmann, H. (3) 148; ( 4 ) 118 Weigel, L.O. ( 5 ) 136 Weil, J . A . (5) 396 Weiler, L. ( 7 ) 111, 112 Weinig, P. ( 4 ) 64; (6i) 41 Weinreb, S.M. ( 3 ) 331, 519; (5) 69, 205; ( 6 i i ) 196, 269; ( 9 ) 62 Weinstock, I. ( 6 i ) 55 Weinstock, L.M. ( 7 ) 100 Weisenfeld, R.B. ( 5 ) 9 3 Weiss, R. ( 2 ) 60; ( 3 ) 495; ( 5 ) 199, 200 Weiss, U. ( 7 ) 52 Weitzberg, M. ( 3 ) 137 Weitzerberg, M. ( 6 i i ) 265 Welch, J.T. ( 2 ) 160; (6ii) 8 Welch, S.C. ( 2 ) 74; ( 6 i i ) 221; ( 7 ) 64 Welker, M.E. ( 9 ) 141 Weller, D. ( 5 ) 281 Wemtrup, C. (5) 289 Wender, P.A. ( 1 ) 91; ( 7 ) 113, 118 Wengenroth, K . J . ( 2 ) 79 Wentrup, C. ( 5 ) 315 Werbitzky, 0. (5) 129 Werdman, H. ( 6 i i ) 8 0 , 8 4 , 85 Werner, 5 . 4 . ( 5 ) 490; ( 9 ) 17 Wersin, G. ( 3 ) 515 West, F.G. ( 6 i i ) 180; ( 9 ) 74 Wester, R.T. (3) 340 Weqtling, M. ( 5 ) 343 Wetzel, J.M. ( 4 ) 135 Whelan, J. ( 4 ) 241; ( 6 i ) 33 Whitby, R. ( 4 ) 112 White, D.H. (1) 127 White, F.H. ( 4 ) 223;
( 6 i i ) 54 White, J . D .
(1) 129;
(8) 53 Whitehead, J.W.F. ( 8 ) 28 Whitesell, J.K. ( 3 ) 33-35; ( 6 i i ) 269 Whitesides, G.M. (4) 41 Whiting, D.A. ( 8 ) 59 Whitney, R . A . ( 3 ) 169; ( 6 i i ) 93 Whitney, S.E. ( 2 ) 183 W h i t t a k e r , M. ( 3 ) 338 Whitten, J . P . ( 5 ) 336 Whittle, R.R. ( 6 i i ) 230 Wiberg, K.B. ( 3 ) 395; ( 7 ) 72 Widdowson, D . A . ( 3 ) 282; ( 4 ) 203; ( 6 i ) 48, 49 Widler, L. ( 3 ) 172 Wiehl, W. ( 5 ) 22 Wiemer, D.F. (2) 133, 134; ( 6 i i ) 237, 238 Wiggins, J . M . (3) 410 Wilchek, M. ( 5 ) 241 Wilcox, C.S. (3) 256 Wild, H. (3) 316 Wilde, R.G. ( 6 i i ) 251; ( 9 ) 5 1 , 67 W i l l f a h r t , J. ( 3 ) 473; ( 5 ) 165 Williams, A.D. ( 3 ) 200 Williams, D . J . ( 4 ) 225; ( 6 i ) 39; ( 9 ) 44 Williams, D.R. ( 4 ) 223; ( 6 i i ) 54, 55; ( 9 ) 50 Williams, I . D . ( 5 ) 66 Williams, I . H . ( 6 i ) 53 Williams, J.C. (5) 176 Williams, J.M. ( 3 ) 286 W i l l i a m s , M.D. ( 3 ) 443; ( 6 i i ) 26 Williams, R.M. ( 3 ) 472 W i l l i a r d , P.G. ( 2 ) 158 Wilson, G.S. ( 9 ) 52 Wilson, K.D. ( 3 ) 440; (5) 210 Wilson, W.S. ( 5 ) 373, 374 Wimmer, E. ( 5 ) 369; ( 6 i i ) 247 Winer, A.M. (5) 381 Wingbermuhle, D. ( 3 ) 263 Winkler, J. ( 5 ) 129; ( 7 ) 48; ( 9 ) 115 Winnik, M . A . ( 5 ) 109 Winstead, R.C. ( 4 ) 227; (9) 27 Wipf, P. ( 5 ) 248 Wirz, B. ( 2 ) 22 Wissinger, J.E. ( 7 ) 115 Wittenberger, S. ( 6 i i ) 251; ( 9 ) 51 Wlasislaw, R. ( 2 ) 46
Woell, J.B. (3) 104 Wojdan, T.S. (5) 395 Wolf, J.-P. ( 5 ) 40 Wolf, R. ( 4 ) 193 Wolff, S. (9) 28 Wollmann, T.A. ( 4 ) 27, 79; ( 6 i i ) 108 Wong, C.-H. (3) 486 Wong, S. ( 1 ) 102 Wonnacott, A. ( 6 i i ) 65 Woo, E.P. (3) 370, 371 Wood, C.Y. ( 9 ) 130 Wood, M.E. ( 3 ) 512; ( 4 ) 120 Woodward, R.W. ( 3 ) 477; ( 5 ) 259 Woolmann, T.A. ( 3 ) 289 Wright, B.T. ( 2 ) 85; ( 4 ) 210; ( 7 ) 122 Wright, C. ( 9 ) 94 WU, P.-L. (5) 113; ( 7 ) 114 Wu, Y. ( 4 ) 27; ( 6 i i ) 108 Wuerthwein, E.-U. (5) 455, 456 Wuest, M. ( 5 ) 122, 123 Wulff, G. ( 3 ) 481; (5) 453 Wulff, W.D. ( 1 ) 36; ( 3 ) 377; ( 6 i ) 33, 87 Wunsch, E. ( 3 ) 515 Wust, M. (7) 88 Wuts, P.G.M. ( 3 ) 4 , 397; ( 4 ) 42; ( 6 i i ) 132 Wynberg, H. ( 3 ) 486 Wynn, H. ( 3 ) 285; ( 5 ) 286, 287 Xia, J. ( 6 i i ) 241 Xie, L. ( 3 ) 135 Xu, Y. ( 6 i i ) 241 Yadav, J.S. ( 3 ) 6 5 Yadav, V.K. ( 4 ) 110 Yahata, N . ( 2 ) 191; ( 3 ) 196; ( 6 i i ) 60 Yamabe, K. ( 5 ) 279 Yamada, M. ( 2 ) 21; ( 4 ) 138 Yarnada, S. (1) 113; ( 3 ) 6 6 ; ( 5 ) 19 Yamada, T. (3) 141, 471; ( 4 ) 6 ; ( 5 ) 268; ( 6 i ) 18, 7 5 Yamada, Y. ( 5 ) 263; ( 6 i i ) 244 Yamagishi, A . ( 4 ) 251 Yamagishi, M. ( 5 ) 219 Yamaguchi, H. ( 6 i i ) 282 Yamaguchi, M. (1) 9 , 68,
General and Synthetic Methods
700 92, 95; ( 2 ) 97; (3) 9 , 45, 46, 136, 325, 326, 426, 444, 447; ( 4 ) 56, 57, 113, 114; ( 5 ) 169; ( 7 ) 22 Yamaguchi, S. ( 5 ) 327; ( 7 ) 74 Yamaguchi, T. ( 9 ) 108 Yamakawa, K . ( 1 ) 40; ( 2 ) 126-129; ( 5 ) 188 Yamakawa, Y . ( 4 ) 97 Yamamoto. A . (1) 55, 56; ( 3 ) 126, 439; ( 5 ) 232, 239; ( 6 i ) 1, 79, 8 0 , 108 Yamamoto, H . (1) 106, 109; ( 2 ) 58, 61; ( 3 ) 8 , 411; ( 4 ) 1, 5 3 , 72, 73, 109, 117, 234; ( 5 ) 375; ( 6 i i ) 133, 135, 138; ( 7 ) 126 Yamamoto, J. ( 6 i ) 66 Yamamoto, K. (5) 401 Yamamoto, M. ( 7 ) 109 Yamamoto, T. ( 3 ) 88; ( 5 ) 232; ( 6 i ) 80 Yamamoto, Y. (1) 108; ( 3 ) 106, 144, 248, 400, 468; ( 5 ) 51, 430; ( 6 i i ) 131; ( 9 ) 33 Yamamura, K . (1) 49; (5) 306, 310 Yamamura, S. ( 7 ) 74 Yamamuro, A . ( 4 ) 27 Yamana, Y. ( 3 ) 309 Yamanaka, S. (5) 101 Yamanishi, T. ( 6 i i ) 83 Yamanoi, T. ( 4 ) 219 Yamasaki, H . ( 3 ) 306; ( 4 ) 137 Yamasaki, N . ( 3 ) 288, 488; ( 4 ) 92; ( 5 ) 196 Yamasaki, Y. (1) 19 Yamashita, H. ( 2 ) 88; ( 3 ) 375; ( 7 ) 36 Yamashita, M. ( 8 ) 7 Yamashita, S. ( 1 ) 107; ( 3 ) 145, 230; ( 4 ) 45; ( 6 i i ) 219 Yamashita, T. ( 2 ) 143 Yamauchi, S. (4) 15 Yamauchi, T. ( 3 ) 74 Yamawaki, K . ( 2 ) 10, 11; ( 4 ) 156, 157; ( 6 i ) 20 Yamazaki, H. ( 5 ) 48 Yamazaki, S. (3) 274; ( 5 ) 134, 488 Yamochi, H. (5) 310 Yamoto, T. ( 4 ) 217 Yanada, K . (5) 414; ( 6 i i ) 282 Yanagihara, H. ( 3 ) 439; (5) 239; ( 6 i ) 79
Yanagihara, N. ( 3 ) 320 Yanai, T. ( 4 ) 244; ( 6 i i ) 250 Yang, D. (1) 36; ( 5 ) 390; ( 6 i i ) 33 Yang, J. ( 6 i i ) 269 Yang, Z.-Y. ( 6 i ) 15 Yano, T. ( 3 ) 103, 418 Yao, K . ( 2 ) 42; ( 6 i ) 42 Yao, Z. ( 5 ) 428 Yaozhong, J. ( 3 ) 455; ( 5 ) 157 Yasuda, A . ( 3 ) 139 Yasuda, H. ( 3 ) 8 6 ; ( 5 ) 234 Yasuda, K . ( 3 ) 186, 201, 390 Yasukouchi, T. ( 1 ) 97; ( 9 ) 81 Yasumura, M. ( 6 i i ) 256 Yasunaga, T. ( 6 i i ) 120 Yeates, C. ( 4 ) 112 Yeo, Y.K. (5) 11 Yeung, B . W . A . ( 5 ) 214 Y i , K.Y. (5) 292 Yoda, H. ( 3 ) 353; ( 6 i i ) 212 Yokote, S. ( 3 ) 509 Yon, G.H. (1) 4 ; ( 3 ) 122; ( 6 i i ) 82 Yoneda, N . ( 3 ) 182 Yoneda, R. ( 5 ) 288, 311, 317, 323; ( 8 ) 38 Yonekawa, Y. ( 3 ) 162 Yonemitsu, 0. ( 4 ) 130, 212; ( 5 ) 70; ( 9 ) 1 0 Yoneyama, K . ( 8 ) 36 Yoon, J. ( 6 i ) 29 Yoon, N.M. ( 4 ) 13 Yorke, S.C. ( 5 ) 5 5 Yorozu, K. (5) 450 Yoshida, J. (1) 54, 87; ( 6 i i ) 157; ( 9 ) 23 Yoshida, T. ( 2 ) 10, 11, 149; ( 4 ) 156, 157; (5) 258; ( 6 i ) 20 Yoshida, Z. ( 3 ) 265; (6$) 64, 90; ( 9 ) 8 9 Y o s h i f u j i , S. ( 8 ) 36 Yoshigi, M. ( 3 ) 8 6 ; (5) 234 Yoshihara, K . (3) 415 Y o s h i i , E. (1) 133; (3) 379, 380 Yoshikawa, K. (3) 80, 81; ( 5 ) 329 Yoshikawa, M. (5) 401 Yoshikawa, S. (3) 304, 305, 381; ( 4 ) 141, 142 Yoshikoshi, A . ( 4 ) 235 Yoshimura, N. (3) 178; ( 4 ) 11 Yoshino, K. (5) 261
Yoshino, T. ( 3 ) 486 Yoshioka, H. ( 4 ) 215 Yoshioka, T. ( 4 ) 130 Youda, A . ( 5 ) 94 Youn, I . K . (1) 4 ; ( 3 ) 122; ( 6 i i ) 82 Young, R.N. ( 3 ) 283; ( 4 ) 166 Youngs, W . J . ( 7 ) 6 Yousaf, T.I. ( 5 ) 116, 447 Youssefi-Tabrizi, M. ( 6 i i ) 76 Yu, S. ( 2 ) 148 Yu, X. ( 6 i i ) 241 Yue, B.Z. ( 8 ) 60 Yuhara, M. ( 1 ) 93; ( 5 ) 294; ( 6 i ) 1 3 Yukawa, H. ( 9 ) 97 Yura, T. ( 2 ) 130, 177 Yus, M. (1) 16; ( 2 ) 120; ( 3 ) 364; ( 4 ) 172; ( 6 i i ) 3, 34, 9 5 , 96 Z a b l o h s k i , Z. ( 5 ) 272 Z a c h a r i s , U. ( 3 ) 510 Zahner, H. (3) 478 Zago, P. ( 3 ) 171 Zahalka, H . A . ( 4 ) 100; (6i) 12 Zaim, 0. ( 2 ) 122 Z a p a t a , A . ( 3 ) 220; ( 6 i i ) 204 Zappi, G.D. ( 3 ) 72 Zappia, G. ( 5 ) 409 Zarak, E . A . ( 7 ) 6 Zard, S.Z. ( 5 ) 421 Zaslona, A . (8) 33 Z b i r a l , E. ( 3 ) 146 Zee, S.-H. ( 6 i i ) 115 Zehnder, M. ( 5 ) 102, lo? Zelle, R.E. ( 3 ) 406 Zellweger, D. ( 5 ) 492 Zervos, M. ( 2 ) 188, 189 Zhai, D. ( 3 ) 472 Zhang, P. ( 2 ) 98 Zhang, Y. (1) 63; ( 4 ) 107 Zhang, 2. ( 3 ) 8 3 , 84 Zhou, Q. ( 5 ) 114 Zhu, J. ( 6 i i ) 242 Z i e g l e r , F.E. (3) 340 Z i e l i n s k a , B. ( 5 ) 381 Zimmerman, J . ( 3 ) 156 Zimmermann, B. ( 3 ) 60; ( 5 ) 400 Zinke, P.W. ( 6 i i ) 124 Zocher, D.H.T. ( 9 ) 12 ZGlyoni, G. ( 5 ) 445 Zorc, B . ( 2 ) 18 Zschiesche, R. ( 2 ) 9 0 ; (7) 84 Z v i e l y , M. (9) 5 Zwierzak, A . (5) 34, 128
