Organophosphorus Chemistry
Volume 22
A Specialist Periodical Report
Organophosphorus Chemistry Volume 22
A Review of the Recent Literature Published between July 1 9 8 9 and June 1 9 9 0 Senior Reporters
D. W. Allen, Sheffield City Polytechnic B. J. Walker, Department of Chemistry, David Keir Building, The Queen's University of Belfast
Reporters
C. W. Allen, University of Vermont, U.S.A. R. Cosstick, University of Liverpool 0. Dahl, University of Copenhagen, Denmark R. S. Edmundson, formerly of University of Bradford C. D. Hall, King's College, London
ISBN 0-85 186-206-3 lSSN 0306-07 13 Copyright @ 1991 The Royal Society of Chemistry A II Rights Reserved N o part ofthis book mu?)be reproduced or transmitted in an-vform or by any rnecins - graphic. electronic: including photocopying, recording tqjing. or irlformution storage and retrieval systems - without written
pcwnission .from The Rqval Society of Chernistn
Published by The Royal Society of Chemistry, Thomas Graham House, The Science Park, Cambridge CB4 4WF Printed in Great Britain by Billing & Sons Ltd.. Worcester
Introduction
Volume 22 introduces one of us, David Allen, as a new Senior Reporter, although not as an author since David has contributed to Organophosphorus Chemistry since volume 7. David replaces John Hobbs, who we thank for all his hard work, not only as Senior reporter but also as author of the "Nucleotides and Nucleic Acids" chapter. We have been fortunate in persuading Rick Cosstick to take on the formidable task of writing this chapter and we welcome him. Unfortunately we have again not been able to include the "Physical Methods" chapter but we hope to do so next year. A highlight of the year covered by this volume was the XIth International Conference on Phosphorus Chemistry held in Tallinn, Estonia, during July 1989. This was not only an unusual and most enjoyable experience, it was also a most timely venue in view of the far reaching developments in Eastern Europe. We met many old, and made many new, friends and it is clear that the traditional strength of organophosphorus chemistry in the USSR is safe in the hands of excellent young chemists with modern ideas. We look forward to the XIIth International Conference at Toulouse in 1992. As measured by the numbers of publications the activity in all the areas covered has increased. The interest in the px-bonded area has increased again after last year's apparent decline. The results of a structural study of bis(bory1)diphosphines indicate a P-P bond length in the range normally reserved for P=P bonds. This suggests that the P-P bond shortening in diphosphenes, which has always been interpreted as being due to 3px-3px, may to some extent be a consequence of rehybridization. There have been a number of developments worthy of special mention in chemistry invoIving pentaco-ordinated compounds and intermediates. These include reports of molecular mechanics calculations to study the hydrolysis of cyclic phosphorus esters, further detailed studies of the reactions of tervalent phosphorus compounds with acetylene carboxylates and the first synthesis of a pentaco-ordinated phosphorus compound containing a three-membered (phosphirene) ring. There has also been further elegant work in the area of phosphatrane chemistry. Novel phosphine oxide cage compounds have been prepared from tris(4-hydroxypheny1)phosphine oxide and their structures have been determined by X-ray crystallography. High temperature thermolysis of
vi
lntroduction
dimethylphosphins oxide gives 2-phosphapropene via elimination of water; this is perhaps surpesing since it involves loss of the P=O bond. In tervalent phosphorus acid chemistry the main area of activity has again been the use of tervalent phosphorus acid derivatives for the preparation of phosphates or modified phosphates of biochemical interest. Apart from the nucleotide field, (vide infra), pentavalent phosphorus acid chemistry seems to be mainly in the doldrums; exceptions to this are the areas of myo-inositol phosphate and aminoalkylphosphonate chemistry where activity remains high. It is gratifying to observe that the nucleotide field continues to produce a large quantity of innovative phosphorus chemistry. The potential use of anti-sense oligonucleotides to control gene expression is now widely accepted and has been responsible for the explosive increase of activity in the synthesis of modified oligonucleotides. However, if the anti-sense therapeutic principle is going to fulfil its initial expectations and maintain momentum, exciting and widely reproducible biological activity will have to be demonstrated in the near future. Activity also remains high in the synthesis of non-radiolabelled oligonucleotides for use as hybridization probes. Many versatile procedures have been reported in the last year which enable oligonucleotides to be labelled with multiple reporter groups either during automated chemical synthesis or as a post-synthesis modification. Reports of the use in synthesis of the Wittig reaction, and the related methods involving phosphonate and phosphine oxide carbanions and iminophosphoranes, have, if anything, increased and many of these include useful innovations. New results and speculation on the mechanism of the Wittig reaction continue to be published by groups with well established reputations in the area. Activity in the phosphazene area has increased over that reported in volume 21 as indicated by an increase of fifty-five in the number of citations. Three particular areas deserve special mention. These are the use of the aza-Wittig reaction in the construction of heterocyclic rings, the structural diversity and solvent selectivity in macrocycles formed by reactions of long chain diamines (or oxodiamines) with N3P3C16 and lastly the synthesis of new heterophosphazene polymers by ring opening reactions of cyclic he terophosphazenes. D W Allen and B J Walker
Contents
CHAPTER
1
Phosphines and Phosphonium Salts By D.W. Allen
1
Phosphines
1
1.1 Preparation
1
1.1.1
From Halogenophosphines and Organometallic Reagents From Metallated Phosphines By Addition of P-H to Unsaturated Compounds By Reduction Miscellaneous Methods
1.1.2 1.1.3 1.1.4 1.1.5
2
7 7 9
1.2 Reactions
12
1.2.1 1.2.2 1.2.3 1.2.4
12 12 13 15
Nucleophilic Attack at Carbon Nucleophilic Attack at Halogen Nucleophilic Attack at Other Atoms Miscellaneous Reactions
Halogenophosphines
16
2.1 Preparation 2.2 Reactions
16 17
Phosphonium Salts
19
3.1 Preparation 3.2 Reactions
19 21
4
p,-Bonded
23
5
Phosphirenes, Phospholes and Phosphinines
30
References
34
3
CHAPTER
1 3
2
Phosphorus Compounds
Pentaco-ordinated and Hexaco-ordinated Compounds By C.D. Hall Introduction
48
Structure, Bonding and Ligand Reorganization
48
Acyclic Phosphoranes
50
Ring Containing Phosphoranes
53
4.1 Monocyclic Phosphoranes 4.2 Eicyclic and Tricyclic Phosphoranes
53 59
...
Contents
Vlll
5
CHAPTER
CHAPTER
3
63
References
69
Phosphine Oxide and Related Compounds By B.J. Walker Preparation of Acyclic Phosphine Oxides
71
Preparation of Cyclic Phosphine Oxides
71
Structure and Physical Aspects
74
Reactions at Phosphorus
77
Reactions at the Side-Chain
77
Phosphine Oxide Complexes
82
References
85
4
Tervalent Phosphorus Acids By 0. D a h l
1
Introduction
87
2
Nucleophillc Reactions
87
2.1 Attack on Saturated Carbon 2.2 Attack on Unsaturated Carbon 2.3 Attack on Nitrogen, Chalcogen, or Halogen
87 89 89
Electrophilic Reactions
92
3.1 Preparation 3.2 Mechanistic Studies 3.3 Use for Nucleotide, Sugar Phosphate, Phospholipid or Phosphoprotein Synthesis 3.4 Miscellaneous
92 95 95 103
Reactions involving Two-co-ordinating Phosphorus
106
Miscellaneous Reactions
106
References
110
3
4
5
CHAPTER
Hexaco-ordinated Phosphorus Compounds
5
Quinquevalent Phosphorus Acids By R.S. Edmundson
1
Phosphoric Acids and their Derivatives
114
1.1 Synthesis 1.2 Reactions 1.3 Uses of Phosphoric Acid Derivatives
114 128 133
Phosphonic and Phosphinic Acids and their Derivatives
134
2.1 Synthesis 2.2 Reactions
134 161
References
174
2
cot1ter1ts
CHAPTER
ix 6
Nucleotides and Nucleic Acids By R . Cosstick
1
Introduction
181
L
Mononucleotides
181
2.1 Nucleoside Acyclic Phosphates 2.2 Nucleoside Cyclic Phosphates
181 185
3
Nucleoside Polyphosphates
187
4
Oligo- and Poly-nucleotides
189
4.1 DNA Synthesis 4.2 RNA Synthesis 4.3 Oligonucleotides Containing Modified Phosphodiester Linkages 4.4 Oligonucleotides Containing Modified Sugars 4.5 Oligonucleotides Containing Modified Bases
189 199
5
217 223
Oligonucleotide Labelling, Conjugation and Affinity Studies
226
6
Cleavage and Sequencing Studies
234
7
Interaction of DNA with Metals and Small Molecules
238
Analytical and Physical Studies
241
References
244
8
CHAPTER
205
7
Ylides and Related Compounds By B.J. Walker
1
Introduction
252
2
Methylenephosphoranes
252
2.1 Preparation and Structure 2.2 Reactions of Methylenephosphoranes
252 254
2.2.1 2.2.2 2.2.3 2.2.4
Aldehydes Ketones Ylides Co-ordinated to Metals Miscellaneous Reactions
254 259 262 262
3
Reactions of Phosphonate Anions
269
4
Selected Applications in Synthesis
276
4.1 Carotenolds, Retenolds and Pheromones 4.2 Leukotrienes, Prostaglandins and Related Compounds 4.3 Macrolides and Related Compounds 4.4 Nitrogen Heterocycles 4.5 Miscellaneous Reactions
276 276 280 282 282
References
292
Contents
X
CHAPTER
8
Phosphazenes By C.W. Allen
1
Introduction
298
2
Acyclic Phosphazenes
298
3
Cyclophosphazenes
305
4
Cyclophospha(th1a)zenes and Related Compounds
312
5
Miscellaneous Phosphazene Containing Ring Systems Including Metallophosphazenes
315
6
Poly(pho8phazenes)
318
7
Molecular Structure of Phosphazenes
327
References
332
AUTHOR INDEX
343
Abbreviations
AIBN C IDNP CNDO CP DAD DBN DBU DCC DIOP DMF DMSO DMTr EDTA E.H.T. ENU FID g.1.c.-m.8. HMPT h.p.1.c. i.r. L.F.E.R. MIND0 MMTr MO MS-C1 MS-nt MS-tet NBS n.q.r. p.e. PPA SCF TBDMS TDAP TFAA Tf ,O THF Thf ThP TIPS t.1.c. TPS-C1 TPS-nt TPS tet TsOH
-
U.V.
*
bisazoisobutyronitrile Chemically Induced Dynamic Nuclear Polarization Complete Neglect of Differential Overlap cyclopentadienyl diethyl azodicarboxylate 1,5-diazabicyclo[4.3.O]non-5-ene 1,5-diazabicyclo[5.4.O]undec-5-ene dicyclohexylcarbodi-imide [(2,2-dimethyl-1,3-dioxolan-4,5-diyl)bis-(methylene)] bis(dipheny1phosphine) dimethylformamide dimethyl sulphoxide 4,4'-dimethoxytrityl ethylenediaminetetra-acetic acid Extended Huckle Treatment N-ethyl-N-nitrosourea Free Induction Decay gas-liquid chromatography-mass spectrometry hexamethylphosphortriamide high-performance liquid chromatography infrared Linear Free-Energy Relationship Modified Intermediate Neglect of Differential Overlap 4-monomethoxytrityl Molecular Orbital mesitylenesulphonyl chloride mesitylenesulphonyl 3-nitro-1,2,4-triazole mesitylenesulphonyltetrazole N-bromosuccinimide nuclear quadrupole resonance photoelectron polyphosphoric acid Self-consistent Field t-butyldimethylsilyl tris(diethy1amino)phosphine trifluoroacetic acid trifluoromethaneaulphonic anhydride Tetrahydrofuran 2-tetrahydrofuranyl 2-tetrahydropyranyl
tetraisopropyldisiloxanyl thin-layer chromatography tri-isopropylbenzenesulphonyl chloride tri-isopropylbenzenesulphonyl-3-nitro-l,2,4-tr~azole tri-isopropylbenzenesulphonyltetrazole toluene-p-aulphonic acid ultraviolet
Abbreviations used in Chapter 6 are detailed in Biochem. J., 1970,120, 449 and 1978,171,l
1 Phosphines and Phosphonium Salts BY D. W. ALLEN
1
PhosDhines
..
.-
rom HalOaenODhOSDhlneS and Oraanometallic Reaaenta Grignard procedures have been used to prepare phosphines bearing up to two adamantyl- or l-adamantylmethyl- substituents at phosphorus. Organolithium reagents nevertheless remain the reagents of choice in phosphine synthesis. Selective metallation of pendant thienyl groups of copolymers of 2-vinylthiophen and divinylbenzene, followed by treatment with chlorodiphenylphosphine, has given a polymer-bound heteroarylphosphine which has been used as a co-reagent in the halogenation of alcohols.2 Direct wmetallation of arylethers has been employed in the synthesis of the acyclic polyetherphosphine (l), the phosphonium salts derived therefrom giving high &-selectivities in Wittig reactions under salt-free conditions. A range of phosphines bearing bulky organolithium alkenyl substituents ( 2 ) has been prepared reagents generated by direct metallation at carbon adjacent to silicon.4 Metallation of imines at carbon alpha to the imino group has led to the synthesis of the functionalised phosphines Sequential trans( 3 ) , together with other products.5'6 metallation of 1,l'-bis(tributylstanny1)ferrocene with butyllithium has enabled the synthesis of new diphosphinoferrocenes ( 4 ) , and further examples of chiral ferrocenylphosphines, e. 9., ( 5 ) ,a have been prepared by nuclear lithiation of chiral aminoalkylferrocenes Direct followed by treatment with chlorodiphenylphosphine. metallation at the benzylic carbon of the 2,2'-dimethylbiphenyl system is the key step in the synthesis of a series of bidentate phosphines, e.g. , ( 6 ) l o Halogen-metal exchange of chiral 2,2'-diiodo-6,6'-dimethylbiphenyl with butyllithium has given a chiral diorganolithium reagent which, on treatment with
.
chlorodiphenylphosphine, provides the stable, chiral diphosphine (7).l1 In contrast, an earlier report12 that the reaction of
chlorodiphenylphosphine with 2,2'-dilithiobiphenyl yields the 1
Organophosphorus Chmrstrv
Me\
P
SiMe3 I
R’ R ~ -CH P
(3) R’ = Prior BU
I
CH=CHSiMe3
R2 = H or Me R3 = But or C6Hll
(2) R’,R2 = Ph or NMe2 CH(R)NMe2
VPPh2 &PPh2
&PR2
( 5 ) R = menthyl
Ph
(16) n = 1-3
P. “CPh2 PCI,
I
Cp2Ti=/t-Ph
PhP*Ph
I:
Phosphiries utid Phosphotiiurii Solts
diphosphine ( 8 ) has now been shown to be in serious error, the principal products being 5-phenyldibenzophosphole (9) and triphenylphosphine.l 3 Also of concern is a report that the repetition of the literature preparation14 of the trisheteroarylphosphine (10) (admittedly with minor modifications), leads to the the phosphinic acid ( 1 1 ) . l5 Organolithium isolation of reagents derived from O-protected phenols have been employed in the synthesis of the phosphines (12) bearing sterically-crowded phenolic substituents.l6 Lithiation at nitrogen of the pyridylamino-phosphine (13), followed by treatment with chlorodiphenylphosphine, has given the chelating diphosphine (14).17 Several reports have appeared of the application of unusual organometallic reagents in phosphine synthesis. Treatment of 2-lithiopyridine with anhydrous zinc chloride results in the formation of a 2-pyridylzinc reagent which can be used to introduce the 2-pyridyl group at phosphorus in a controlled manner. Thus, e.g., in its reaction with phenyldichlorophosphine, the 2-pyridyl(pheny1)chlorophosphine (15) is formed. This has then been converted the phosphide route into a new class of binucleating ligands ( 16). l 8 The sterically crowded dichlorophosphine ( 17) (accessible from the reaction of phosphorus trichloride with lithium diphenyl(2-pyridy1)methanide) is converted into the thermally stable phosphirane (18) on treatment with calcium, strontium or barium cyclooctatetraenide.l9 The reaction of phenyldichlorophosphine with the readily accessible titanacycle (19) affords a convenient route to the phosphetene (20).2o
a
3.1.2 2 .- The reactions of metallophosphide reagents with alkyl halides and sulphonate esters continue to be widely employed in the synthesis of new phosphine ligands, many of which are chiral and have obvious potential in homogeneous catalysis. Chiral substrates derived from simple carbohydrates have been used in the synthesis of chiral diphosphines, 1-23 e.g . , ( 21 ) ,23 although in some cases yields are poor due to elimination reactions. Among new chiral systems prepared using lithiophosphide reagents are the diphosphines (22),24 ( 2 3 1 and ~ ~ (24),26 the latter having a "natural bite" angle of 120", and able to occupy diequatorial positions in trigonal bipyramidal complexes. New optically-active di- and tri-phosphines, e.g., (25), have been prepared from optically pure lactones and carboxylic acids via intermediate tosylatee.2 7
>( PPh2
(25)
n
0. O”,l
,NH N(CH2CH2PPh2),
Ph2P
<-
PPh2
(26)
(27)Z = OMe or SPh Ph
Ph2PCH2CH20CH2CH20Me
(29)
Ph
(30)
I:
Phosphiries utid Phosphotiiurii Solts
Further examples of chiral diphosphines in the DIOP- and 2,4-disubstituted pyrrolidine- series have also been described.28-30 Lithiophosphide reagents have also been used in the synthesis of a wide range of new achiral phosphines. The addition of lithium diisopropy1arni.de to a solution of 1-bromo-3chloropropane and a primary or secondary phosphine in THF at -78'C provides a new, inexpensive, and time-efficient route for the preparation of 3-chloropropylphosphines in high yield, the latter being capable of further transformation the phosphide route to yield new polyphosphines 31 Among new chelating diphosphines prepared lithiophoephide reagents are the unsaturated system (26),32 the tripod-like hybrid ligand systems (27),33,34 and the cyclophosphamide derivative (28) 3 5 The lithiophosphidealkyl halide route has also provided an alternative approach to systems of type ( 6 ) 36 New polyetherphosphines e.9., ( 29 ) , have been obtained the lithiophosphide-mesylate route.37 Alkylation of diphosphide reagents with u,w-dihalides has been employed in the synthesis of five-, six-, and seven-membered ring cyclic diphosphines, e.g., (30), (subsequently separated into geometrical isomers),38 and also of new phosphorus-containing macrocycles involving oxygen and nitrogen atoms as ring-members, e.g. , (31). 39 Lithiophosphide reagents have also found application in the synthesis of phosphines bearing tetramethylcyclopentadienyl groups in potentially chelating positions, e.g., (32), thereby providing a new type of ligand system.40 A study of the generation of diarylphosphide reagents by the alkali metal-induced cleavage of triarylphoephines bearing electron-donating groups has revealed a rather confusing picture. In the case of phosphines bearing both phenyl- and p-dimethylaminophenyl substituents, the use of potassium in ether solvents results in the predominant cleavage of the most electron-donating group. In contrast, cleavage with lithium results in a scrambling of aryl substituente. A cleaner route to potassium bia(p-dimethylaminopheny1)phosphide ( 3 3 ) , a desirable reagent for the synthesis of new aminofunctional, acid-soluble, phosphines, is provided by the intermediate preparation of bis(p-dimethylaminopheny1)chlorophosphine followed by treatment with potassium.41 A related study of the sodium-induced cleavage of triarylphosphines bearing methoxyphenyl eubstituents has shown that as methoxy groups are introduced into the aryl system, the yield of the diarylphosphide cleavage product decreases, the extent of the decrease depending on the number and position of the methoxy subetituente 42
.
a
.
.
a
.
Nevertheless, applications of such substituted diarylphosphide reagents in the synthesis of new, chelating diphosphines continue to appear.43-45 Cleavage of phenyl groups from alkyldiphenyl phosphines using sodium in liquid ammonia, followed by treatment with ammonium chloride, has been used a s a route to secondary phosphines . 4 6 In related work, alkylation of the intermediate sodiophosphide reagents has also provided a route to potentially chiral phenyldialkylphosphines.47 The olefinic diphosphine ( 34 ) has been prepared by the reaction of sodium diphenylphosphide with 2,3-dichloropropene. On treatment of ( 3 4 ) with diphenylphosphine in the presence of potassium t-butoxide, the new diphosphine (35) is formed rearrangement of (34), rather than the expected triphosphine (36). However, the latter system can be obtained as a metal complex under appropriate conditions from the corresponding reaction of the metal complex of ( 3 4 ) . 4 8 A route to the water-soluble phosphines (37) is provided by the reactions of mixed sodium- and potassium diphenylphosphides with sultonee .4 9 A study of the photo-induced reactions of t-alkyl halides with sodium diphenylphosphide in liquid ammonia has revealed that chloroalkanes react the SRNl mechanism, whereas the related bromoalkanes suffer elimination. A route to primary phosphines is afforded by the selective alkylation of phosphine with alkyl halides in the presence of concentrated aqueous potassium hydroxide in DMSO, or in a two-phase system involving a phase-transfer catalyst.51-53 In related work, it has been shown that the alkylation of diphenylphosphine with dichloromethane under phase-transfer conditions provides chloromethyldiphenylphosphine in high yield.5 4 Interest has continued in the synthesis of organophosphido derivatives of main group elements. In addition to the first beryllium diorganophosphide (38) (in which the phosphorus atom still appears to have Lewis base properties),55 further examples of diorganophosphido derivatives of aluminium,56 gallium57‘58 and have been described. The synthesis and characterisation of diorganophosphino-8 ilanes6 o and - stannanes has also received further attention. A zirconium phosphido complex derived from l12-bisphosphinobenzenehas also been characterised.6 2 Tellurophosphinite anions (39) are reported to be formed in the reactions of elemental tellurium with diorganophosphides 63 Structural studies of lithiophosphides and their complexes with ether and amine ligands have a l s o continued to attract attention,6 4 - 6 7 together with related studies of phosphinomethanide reagents generated by metallation of phosphines at
a
.
I:
Phosphiries utid Phosphotiiurii Solts
7
carbon.68-70 1.1.3 Preoaration of PhosDhines bv Addition of P-H to UnsComPounda A third part of a review of P-H addition to unsaturated systems has appeared, covering addition to unsaturated ligands in the coordination sphere of a metal.71 Addition of diphenylphosphine to the free vinyl group of the [4+2]cycloadduct of 3,4-dimethyl-l-phenylphosphole and phenyldivinylphosphine (both in the form of metal complexes) has led to the unsymmetrical triphosphine (40), isolated as the related metal ~omplex.'~ A similar u.v.-induced addition to methyl(viny1)cyclotetrasiloxane has given a tetraphosphine which, on treatment with acid, forms an insoluble polysiloxane bearing pendant phosphino groups, useful as a support for metal complexes active as homogeneous catalysts.7 3 Free radical-induced additions have been used in the synthesis of a range of phosphines bearing other nucleophilic groups, e.g., (41), useful for specific peptide bond cleavage of proteins.74 A further example of the formation of the phosphorinanone system by addition of phenylphosphine to a divinyl ketone derivative has been described.75 Two reports have appeared of the addition of secondary phosphines to maleic anhydride and related activated olefins, to give functionalised tertiary phosphines, e.g., (42).76,77 A route to allylphosphines is provided by basecatalysed addition of secondary phosphines to 1,3-dienes.7 8
.-
2 1.1.4 Pre eduction.- Trichlorosilane continues to find application f o r the preparation of chiral phosphines from the corresponding chiral phosphine oxides. This route has been used in the synthesis of the chiral, nonracemizable phosphine (43),79 the first chiral phosphinocarboxylic acids (44)," and for both enantiomers of the biphenyl system (45).81 The chemoselectivity of this reagent has also been utilised in the synthesis of the diphosphine (46)82 and the 4-phosphinopyrazoles (47). 83 A number of applications of lithium aluminium hydride, eitheL as sole reagent or in combination with a co-reductant, have been described. As sole reagent, it has found use for the reduction of cyano- and thiocyanato-phosphines to primary and secondary phosphines,84 and for the reduction of phosphonate esters in the synthesis of the pyridylphosphine ( 48)85 and the diphosphines (49).86 However, it has been pointed out that attempts to prepare polyphosphines by the reduction of polyphosphine oxides or polyphosphinates using lithium aluminium
x
Organophosphorus C ’hemistry
(44) n = 2 or 3 (45)
0
PH2
(47)
MePH(CH2)”PHMe
0;””’ NH2
(49) n = 2 or 3
(50)
(48)
Ph2PCH2COCH3
CHCOCH3 Ph2Pz CH2COCH3
(53)
(54)
R12pXMe R12P OR2 (52) R~ = Pr or BU R2 = Et or Bu
PPh2
(55) 0
Ph2PCH2CH(R)OH (58) R = perfluoroalkyl
d!=%2 R’ (59) R’ = H or Me R2 = But or Me2N
gx
(rnenth~l)~P (PhCH=CH)3P (63)
(rnenth~l)~P 0
(64) X = 0, NPh, or NMe
I:
Phosphiries utid Phosphotiiurii Solts
hydride can give low yields due to complexation of the resulting polyphosphine by A13+ during aqueous work-up .87 In combination with sodium borohydride and cerium(II1) chloride, lithium aluminium hydride has been used for a one-pot conversion of phosphine oxides to the related phosphine-borane complexes, from which the free phosphine can be liberated with retention of configuration at phosphorus by treatment with either morpholine or diethylamjne.88 Aluminium hydride has been shown to be the best reagent for the chemoselective reduction of a-chlorophosphonates to primary The preparation of primary vinyla-chloroalkylphosphines phosphines on the gramme-scale has been achieved by the chemoselective reduction of the corresponding vinylphosphonates using dichloroalane in excess. Reduction of triphenylphosphine oxide to triphenylphosphine occurs when the oxide is heated with samarium(I1) iodide in the presence of HMPA in THF solution.” Reduction of q-aminophenyltriphenylphosphonium chloride with sodium naphthalenide offers a convenient route to the aminofunctional phosphine ( 5 0 ) . 92
.’’
..
5 Miscellaneous Methods of PreDarina PhosDhine8.- A range of new chelating phosphine ligands involving a polysilicon backbone, e.g., (51), has been prepared by coupling reactions of the organolithium or Grignard reagent derived from E-bromophenyldiphenylphosphine with appropriate polyfunctional chlorosilanes.9 3 The reaction of secondary phosphines with trialkylorthoacetates in the presence of boron trifluorideetherate has given the diphosphinomethanes ( 52 ) 9 4 Attempts to repeat the literature preparationg5 of the phosphine (53) from the reaction of trimethylsilyldiphenylphosphine and bromoacetone have led to the isolation of the stable phosphorane ( 5 4 ) , presumably as a result of rapid quaternization of the initially A range of 1inear formed phosphine , followed by deprotonation. and cyclic products has been obtained from the reactions of bis(trimethylsi1oxy)phosphine with 1 I 5-diketone8,97 and a related route to the 2-pho~phaadamantane-4~8-dionesystem (55) has been described.98 A general, one-pot , synthesis of 1 ,3-butadienylphosphines ( 5 6 ) has been developed.” Enaminophosphines, e.g . , ( 5 7 ) , are accessible the reactions of l-morpholino-cyclopentl-ene with halogenophosphines l o o A series of 2-hydroxyethylphosphines ( 5 8 ) has been prepared by the ring-opening of epoxides in their reactions with trimethylsilyldiphenylphosphine. In an extension of earlier work on metal-induced rearrangements of
.
.
Organophosphorus Chemistry
10
-o-haloaryl esters of P'acids,
it has now been shown that treatment of the PII'esters (59) with sodium or magnesium results in the formation of the q-hydroxyarylphosphines (60).l o 2 The effects of nickel(I1)-ion catalysis on the formation of tris(hydroxymethy1)phosphine in the reaction of phosphine with formaldehyde have been studied.l o 3 The familiar formation of aminomethylphosphines in the reaction of phosphine with formaldehyde and an amine has been applied in a reaction involving a coordinated polyamine, with the formation of a macrobicyclic aminoalkylphosphine.I o 4 Treatment of 3 ,5-di-t-butyl-4-hydroxybenzyldimethylamine with phosphine in the presence of tris(hydroxymethy1)phosphine has provided a route to the functionalised phosphine ( 61 ) Io5. A high-yield route to trimethylsilylphosphines has been developed which involves the reactions of phosphine (and primary and secondary phosphines) with trimethylsilyltriflate. lo' Condensation of salicylaldehyde with 3-aminopropyldiphenylphosphinehas given the phosphine (62), the structure being confirmed by an X-ray study.l o 7 Further reports have appeared of the direct synthesis of the phosphine ( 6 3 ) from red phosphorus and phenylacetylene under basic conditions,l o 8 ,l o g and of the reactions of silylphosphines with 2,3-dichloromaleic anhydride and related imides which have given rise to the diphosphines ( 64 ) . l o Reports of the chemistry of the dioxaboraphosphorinane system also continue to appear. 111-116 Full details have now appeared of the formation of the benzo-1,2,3thiadiphosphole system ( 6 5 ) . '17 The reaction of simple secondary phosphines with dibenzylmercury has been shown to proceed with the formation of P-P diphosphines. However, attempts to apply this reaction to the synthesis of cyclic polyphosphines from di(secondary phosphines) were frustrated by the predominant Phosphorus-phosphorus coupling formation of benzylphosphines has also been observed in the reactions of chlorodiphenylphosphine with thiourea derivatives, leading to the formation of tetraphenyldiphosphine monosulphide l 1 Interest continues in the synthesis of cyclopolyphosphorus systems, and, as usual, the main contributions have come from the groups of B a ~ d 1 e r l ~ O - l ~ ~ and Fritz.12*, 12' The unusual P2Si2 butterfly molecule ( 6 6 ) has been obtained in the reaction of white phosphorus with a sterically crowded disilene. 130 The synthesis of new phosphine ligands in the coordination sphere of a transition metal has a l s o continued to develop. 131-134
.
.
II :: Phosphiries Phosphiries utid utid Phosphotiiurii Phosphotiiurii Solts Solts
II
X
QT&7DX /!A
Ar2Si’ ISiAr, (66) Ar = Mesityl
R
(65) X = H or Me R = alkyl
H
CN
PPh3 (67)
+
CN
0,PPh3CI-
Ph3kR1=CR2R3 B r (68) R’,R2, R3 = H or alkyl
+
X-
RsPCF2X
*Pph3
CN
CN
H
PPh3
\
(737
(72)
‘PPh2 (76) n = 2 or 3
H(NMe& (79)
R
(70)
N=PPh3
Ph2P
BuP :C
l*:c
0:;
(69)
Ph2PM;Ph2
(71)
CN
Ar2C=N’
(74)
(77)
R
Ph
R PF2 (80) R = H or Me
(811
(82) Me Me
(86) X = CI or Br OMe
OMe
(90) P(CI)P(CI)
+
[Ph2P-PPh,CI]AI C,l
(92) (91)
PhP(CN)P(CN)Ph (93)
I:!
1.2
Reactions of Phosphines . . ucleoghrlic Attack at Carbon.- Ring-opening of N-acylaziridines occurs on treatment with triphenylphosphine with the formation of the ylides (67), thereby providing a route to a-substituted primary allylic amines via their h s i t y reactions with aldehydes.13' The reactions of triphenylphosphine with epoxides in phenolic media provide a new access to the vinylphosphonium salts (68).136 A route to l-hydroxyalkylphosphonium salts is provided by the reactions of trimethyl- or triethylphosphine with aldehydes or ketones in the presence of anhydrous acids. The related l-trimethylsiloxyalkylphosphonium salts can be isolated in the presence of trimethylsilyl chloride.137 Further Wittig-products have been isolated from the reaction of 1,2,3indanetrione with triphenylphosphine, 3 8 and I in related work, it has been shown that furoin is deoxygenated on heating with triphenylphosphine to form 2-furfuryl(2-furyl)ketone and triphenylphosphine oxide.13' The structure of the blue product from the reaction of triphenylphosphine with 2,3,5,6-tetracyano7-oxabicyclo(2,2,l]hepta-2,5-diene has now been shown by X-ray techniques to be the stable ylide (69).1 4 0
..
1.2.2 Nucleoph ilic Attack at Ha1oaen.- X-ray studies have finally established that the products of the reactions of triarylphosphines with N-chlorosulphonamide reagents in protic solvents are hydrogen-bonded adducts of the respective sulphonamide and phosphine oxide. 141,142 The enolphosphonium salt (70) is formed in the reaction of triphenylphosphine with 2,2',6,6'-tetrachlorocyclohexanone, undergoing subsequent methanolysis to form the phosphine oxide and 3-chloro-1I 2-cyclohexanedione . 143 Reductive dehalogenation also occurs in the reactions of a-chlorodicarbonyl compounds with triphenylphosphine in protic solvents.144 The phosphonium salts (71) are the first isolable intermediates in the reactions between tertiary phosphines and difluorodihalomethanes, but undergo dehalogenation in the presence of excess phosphine to form the related, unstable, dif luoromethylene ylides.145 Single electron transfer processes appear to be involved in the reactions of tributylphosphine with triphenylmethyl halides in apolar solvents, resulting in the formation of triphenylmethyl radicals.146 Triphenylphosphine-tetrahalomethane combinations continue to find new applications in synthesis, having been employed in a one-pot Bischler-Napieralski cyclisation in the synthesis of dihydroisoquinolines and R-carbolines, 147 in the
I:
Phosphiries utid Phosphotiiurii Solts
13
conversion of p-substituted benzoic acids into flavones, 4-quinolonesI and indenones,14* and f o r the synthesis of isothiocyanates from primary amines and carbon disulphide. 14' Conversion of primary alcohols to the related haloalkane in the presence of triphenylphosphine-bromotrichloromethane is the initial step of a one-pot, several stage, synthesis of primary amines.l5O Terminal alkynes are converted into the related bromoalkynes in the presence of the triphenylphosphine-tetrabromomethanesystem.15' The combination of triphenylphosphine with esters of trihaloacetic acids provides a reagent system for the stereo- and regio-selective conversion of alcohols into alkyl halides.15' The brominetriphenylphosphine adduct has been used at low temperatures (-5O'C in dichloromethane) f o r the removal of the tetrahydropyranyl protecting group from tetrahydropyranyl ethers derived from secondary and tertiary alcohols. 153 The reactions of tertiary phosphines (and other trivalent phosphorus compounds) with iodine in aprotic solvents have received further study, a range of species being identified.154 The first reported study of the reactions of trivalent phosphorus compounds with monopositive astatine has led to the identification of stable complexes with triphenylphosphine, trioctylphosphine, and triethylphosphite.155 1.2.3 N u c l e o a ilic Attack at Other Atoms.- Interest has continued in the synthesis of phosphine-borane adducts. Complexes of tetramethyldiphosphine with borane and various halogenoboranes have been used to generate a series of open-chain and cyclic phosphinoboranes 15' Adducts of 1,3,5-diazaphosphorinanes involving two or three moles of borane have been iso1ated.ls7 A bis-borane adduct involving the geminal phosphino- groups has been isolated from the reaction of the triphosphine (72) with the borane-THF complex. 15' An unstable adduct between triphenylphosphine and a photochemically-generated dimethylgermylene has been characterised The first 2 , 3-dihydro-l,3,2-A5spectrophotornetrically. 15' benzodiazaphospholes (73) have been formed in the reactions of triphenylphosphine with Q-benzoquinone di-imines stabilised by coordination.160 A complex of phenylnitrene with a tungsten pentacarbonyl acceptor has been trapped using triphenylphosphine. 16' A kinetic study of the reactions of diazoalkanes with triphenylphosphine, leading to the phosphazenes (74), indicates a biphilic mechanism, the dominant interaction in the transition state involving the diazoalkane as a net electron donor,
.
and the phosphine as a net electron acceptor.162 The Staudinger reaction also continues to find application in the synthesis of new phosphazenes, some of which are of interest as novel ligands 163-165 The reaction of p-azidobenzaldimines with tertiary phosphines in dichloromethane at O'C leads to the isolation of 2,3-diamino-2H-indazoles, via the Staudinger reaction followed by cyclisation of the intermediate phosphazene. 16' The phosphazene (75) has been characterised as an intermediate in the reaction of p-azidobenzoic acid with triphenylphosphine.167 A new range of phosphazene-like products has been isolated from the reactions of tertiary phosphines with tetrasulphur tetranitride.16* Tertiary phosphine-azodicarboxylate reagents continue to attract interest in synthetic chemistry, finding recent applications in the preparation of esters and ethers of the isomeric 5-norbornen2-018, 16' aryl ethers of ethynyl-carbinols,1 7 0 and cyclic The Mitsunobu esterification procedure has yielded lactams.17' mixtures of inversion and retention products when applied to a series of dicyclopentadienols, the stereochemical course being complicated by varying degrees of allylic rearrangement.172 The Miteunobu procedure has also been applied in a stereospecific synthesis of secondary amines from alcohols.173 In the presence of the di-isopropyl azocarboxylate-triphenylphosphine system, alcohols react with a pyridine-zinc azide complex to form alkyl a ~ i d e 8 . l ~31P ~ N.m.r. studies indicate that, at low temperatures, the only intermediate in the reaction of the diethyl azodicarboxylate-triphenylphoephine system with an alcohol and diethylphosphorothioic acid is the protonated form of the usual betaine. Above O'C, this reacts with the alcohol to form the alkoxyphosphonium salt which then interacts with the ambidentate thiophosphate anion to form the isomeric esters and triphenylphoephine oxide.175 The reactions of a,u -dithiols with the triphenylphosphine-diethyl azodicarboxylate system give rise to a mixture of cyclic and polymeric disulphides, the product distribution depending on the alkyl chain length and on conditions.176 The air-induced oxidation of trimethylphosphine has been followed in Y-type zeolites using solid state 31P n.m.r. techniques.177 The known chiral triphosphines (76) have been transformed into their monoxides and monosulphides y h protection of the diphosphinoethane moiety by coordination.17' A more detailed study of the reactivity of lt3,5-triaza-7-phosphaadamantane (77) has revealed that whereas protonation and
.
I:
Phosphiries utid Phosphotiiurii Solts
quaternization take place at nitrogen, complexation to "soft" metal acceptors occurs at phosphorus, which also displays its normal reactivity towards oxygen, sulphur, and selenium.17' In spite of its steric bulk, trimesitylphosphine exhibits normal behaviour in the oxidation reactions with oxygen and sulphur. However, a phosphine selenide could not be prepared. A detailed kinetic study of atom transfer between phosphines (and other group V ligands) and the related oxides, sulphides, and selenides, has appeared. Reversible insertion of tellurium into the phosphorus-phosphorus bond of tetra-ieopropyldiphosphine has been observed.l a 2 1.2.4 ~ c e l l a n e o u sReactipns of Ph0sDhines.- Full details have now appeared of Michael-type nucleophilic additions to the double bond of 1,l'-bis(dipheny1phosphino)ethene in its complexes with platinum( 1 1 ) halides,l a 3 and also of the free radical addition of diphenyl(trimethylstanny1)phosphine to alkynes and allenes 184 A comparison of the effects of attempted nitration of the triphenyl derivatives of the group V elements has revealed that whereae triphenylamine gives nitroarylamines, triphenylphosphine and its heavier cogeners, not surprisingly, are converted predominantly to the corresponding oxides, with only traces of the related nitroaryl oxides.l a 5 Trimethylphosphine has been oxidised to the dication [ Me3P-PMe3]2+ in the presence of copper ( I I ) hexaf luoro-phosphate (and also with other reagents) in acetonitrile.le6 The reactions of silylphosphines with sulphur, thionyl chloride, or sulphuryl chloride lead to either fission or insertion reactions involving the phosphorus-silicon bond. 187 A route to 0,O-divinyl-Otrimethylsilyl phosphates is provided by the reactions of bis(trimethylsi1oxy)phosphine with a-halocarbonyl compounds.la' The reactions of t-butylthioethylphosphinewith acid chlorides have Radical given a range of products, depending on conditions.18' cations have been characterised by e.6.r techniques following the gamma irradiation of diphosphinoalkanes. A study of the thermal decarboxylation of phosphinoacetic acids has shown that the presence of electron-withdrawing substituents at the alpha carbon leads to large increases in reaction rates, and that much higher decomposition temperatures are required in hydrogen-bonding solvents than, e.g., in toluene. As the related phosphine sulphides do not decarboxylate, the importance of the phosphorus lone pair is apparent, and a mechanism involving the formation of an intermediate ylide has been proposed. l g l Phosphines have been
.
shown to catalyse the reaction of carbon dioxide with a-ethynyl alcohols to form a-methylene cyclic carbonates. l g 2 The chiral phosphine (78) has been used as a reagent in the a-allylation of A solution of aldehydes, leading to chiral products. triphenylphosphine in hydrogen bromide has been used to cleave disulphide bonds in the synthesis of 8-mercaptoquinoline.lg4 In connection with the formation of modern electronic materials such as gallium phosphide, there have been a number of fundamental studies of the course of pyrolysis of t-butylphosphine. 195-198. In a related area, adducts of diphenylphosphine with trialkylgallium acceptors have been described. lg9 The bis(dimethy1amino)methyl group of the phosphine (79) is easily cleaved from phosphorus on treatment with electrophilic reagents.2 o o , 201 Examples of phosphorus-carbon cleavage in phosphines coordinated to transition metals continue to appear.202-210 Yet another route for the deactivation of phosphine-containing homogeneous catalyst systems has been revealed in the observation of the insertion of an alkene into the carbonmetal bond of a cyclometallated triarylphosphine, leading to the formation of coordinated Q-vinylarylphosphines l1 Tris (hydroxymethy1)phosphine forms water-soluble complexes with zero valent nickel, palladium, and platinum, which are catalysts for the addition of phosphine to formaldehyde.212 There appears to be a growing interest in reactions which lead to the modification of phosphine ligands coordinated to transition metals, a wide range of reaction types having been reported in the past year. 213-2l9
.
2.1 Prewaration- The reactions of organolithium reagents with chlorodifluorophosphine have been used to prepare a range of organodifluorophosphines, e.g., (80), (81), and (82).220,221 A detailed n.m.r. spectroscopic study of the well known reaction between diphenylamine and phosphorus trichloride has finally proved the intermediacy of the halogenophosphine (83) in the synthesis of phenophosphazine-10-oxide (84). However, the halogenophosphine(83) has still not been isolated in the pure state, appearing to be of low stability, and depositing unidentified yellow solids on situ“ for standing. However, it can also be prepared subsequent reactions by treating the oxide (84) with phosphorus trichloride.222 A convenient route to arylbromophosphines, e.g. , (85), is provided by the direct reaction of electron rich arenes
“a
I:
Phosphiries utid Phosphotiiurii Solts
17
with phosphorus tribromide in the presence of a base.223 A similar direct reaction of phosphorus trihalides with 1,3,3-trimethyl-2-methylene indoline has given the vinylic halogenophosphines ( 86 ) 224 A range of alkyl (phenyl) chlorophosphines has been prepared by the reaction between the related secondary phosphines and phosphorus pentachloride in toluene.225 The reaction of phosphorus trichloride with the organoaluminium reagent derived from the interaction of aluminium metal with dichloro- or dibromomethane affords a direct route to 1,2-bis(dichlorophosph~no)methane, although the product is contaminated with the halogenotriphosphine ( 87 ) .226 The dichlorophosphine (88) has been prepared by the reaction of phosphorus trichloride with tributyl (methylthiomethyl)stannane.227 Conditions for the reduction of intermediate organotrichlorophosphonium salts to dichlorophosphines have received further study, and the use of monoalkylphosphorodichloridites,228 or yellow phosphorus229 has been proposed. Whereas treatment of organobis(dialky1amino)phosphines with hydrogen chloride normally results in the cleavage of both amino groups to form the related dichlorophosphine, selective cleavage of only one amino group is possible if the aminophosphine is coordinated to a transition A similar cleavage reaction of a coordinated aminophosphine has been employed in the synthesis of the chlorophosphirane complex (89), which is much more stable than the free chlorophosphine.231
.
R e a c a n s of & L l O a e n O D h O s D h i n e s . On standing for several 2.2 days in deuteriochloroform solution, the difluorophosphine (90) undergoes an unusual disproportionation reaction to form the related aryltetrafluorophosphorane and the dihalogenodiphosphine (91).232 Phosphorus-phosphorus bond formation has also been observed in the reactions of chloro(pheny1)phosphines with aluminium chloride, with the formation of phosphinohalogenophosphonium salts, e.g., (92)233,234 and also in the reaction of dicyano(pheny1)phosphine with acetic acid, which reeulte in the formation of the dicyanodiphosphine ( 93 ) . 35 Various phosphine oxides have been isolated from the reactions of aluminium chloride complexes of chlorodiphenylphosphine with alkyl halides, following aqueous work up.236,237 The ester (94) is the intial product of the reaction of dichloro( pheny1)phosphine with ethylene oxide.238 In contrast, the reactions of iododiorganophosphines with cyclic ethers lead to the related phosphoryl halide and an a l k e ~ ~ e . ~ ~ ’
18
PhP(OCH2CH2C1)2
(94)
K
Ph2P+\fPPh2
0
fi
R2P-ON=CRCI
F3C CF3
(95)
21-
+
RP(NEt2)C12
K
PC16-
(97)
p Me P P h+ 2 M e
MePh2P +PPh2Me 21-
I-
MePh2P+ (1 03)
+ se R'
M ~2
R3
p l!;
(1 11) R', R2, R3 = H or alkyl
(1 14) X = halogen
Me36CH2CH(OMe)Ph BPh4 (112)
(115)
I:
Phosphiries utid Phosphotiiurii Solts
Attempted nitration of dichloro(pheny1)phosphine under mild conditions results only in oxidation at phosphorus. 2 4 0 The phosphinate esters ( 9 5 ) have been isolated from the reactions of chlorodialkylphosphines with 1 ,1-dichloro-1-nitrosoalkanes 241 Studies of the reactions of halogenophosphines with tetrahalogenomethanes have continued, P-halogenoylides being characterised among the products derived from di( t-buty1)halogenophosphines. 2 4 2 , 2 4 3 The cyclic phosphinate ( 9 6 ) has been isolated from the reaction of dichloro(methy1)phosphine with the ethoxycarbonylimine derived from hexaf luoroacetone.2 4 4 Treatment of trichloro( organo)phosphoniumhexafluorophosphate salts with dichloro(diethy1amino)phosphine results in the halophosphonium salts ( 97) .2 4 5 Some reactions of dichloro(-)menthylphosphine have been reported.2 4 6 As usual , nucleophilic displacement reactions of halogenophosphines have received attention as routes to new systems of interest as ligands.2 4 7 , 2 4 8 Of particular interest in this connection is a report of the synthesis of the phosphorus-functionalised calixarenes ( 9 8 ) . 2 4 9 Only one chlorine atom of dichloro(pheny1)phosphine is replaced on treatment with an excess of dicyclohexylamine, enabling the stepwise synthesis of the chiral aminophosphines ( 9 9 ) , described as air-stable solids.2 5 0 Remarkable diastereoselectivity has been achieved in the synthesis of dinucleoside methylphosphonates from the reactions of dichloro(methy1)phosphine with suitably protected nucleosides at low temperatures.251 Various phosphapolyboranes have been obtained from the reactions of dichloro(methy1)phosphine with polyborane anions.2 5 2 A high yield route to monodeuteriated trifluoromethylphosphine is offered v& -i the reaction of iodo(trifluoromethyl )phosphine with deuteriotrimethylstannane.2 5 3 Phosphorus(III) thioesters have been obtained from the reactions of halogenophosphines with benzylthio( trimethyl)silane.2 5 4
.
3
PhosDhonium S a l t s
3.1 Preparation- The role of 02p-and NZp- through space hypervalent interactions involving a developing phosphonium centre in quaternization reactions has been reviewed, together with their role in other aspects of phosphonium salt chemistry.2 5 5 Quantitative yields of alkylphosphonium salts are obtained in the reactions of primary alcohols with triphenylphosphine in 4 8 % aqueous hydrobromic acid.2 5 6 An unusual rearrangement occurs during the reaction of l,l,l-trifluoroisopropyl bromide with
Organophosphorus Chcmistrv
20
triphenylphosphine, which results in the salt ( 100). 2 5 7 Conventional quaternization procedures have been used in the preparation of both cyclic and acyclic salts! e . g . , (101) and (102), derived from 1,l’-bis(diphenylphosphinomethy1)ethene. Careful deprotonation of the latter using an ylide ha8 given the 1,3-bis(phosphonio)propenide salt (103), a useful model for the free ally1 anion.258 Direct quaternization has also been used in the synthesis of the heteroarylmethylphosphonium salts ( 1 0 4 ) ,259 and phosphonium salts bound to a polyoxetane polyether.260 Heterocyclic phosphonium salts, e.g., (105), have been prepared by the reactions of urea-bridged P,P-diphosphines with methyl triflate.261 Two edantiomeric iron carbonyl complexes of the butadienylphosphonium salt (106) have been obtained by the trapping of a complexed organic cation with triphenylphosphine.262 Further studies of the interaction of phosphines with pyrylium Cyclisation of the intramolecularly salts have appeared.263t264 coordinated phosphine-borane (107) with acetyl chloride has given the heterocyclic salt (108).265 Treatment of a,B-unsaturated ketones with triphenylphosphine in the presence of t-butyldimethylsilyl triflate results in the formation of the silylated enol ether phosphonium salts (log), which are useful intermediates for the synthesis of R-acylated enones.266 The reactions of alkenes , e.g., cyclopentene, with dimethylthiomethylsulphonium salts and triphenylphosphine have given a series of 2-methylthioalkylphosphonium salts, e.g., (110), which, on treatment with base, give vinylphosphonium salts in good yield.267 Allylic phoephonium ylides, on treatment with phenylselenyl bromide, undergo conversion to the 3-phenylseleno-l-alkenylphosphonium salts (lll), mild oxidation of which provides a route toa,B-unsaturated aldehydes.268 The salt (112) has been isolated from the reaction of phenyl acetylene with a trimethylphosphine-cobalt(1) complex in methanol, in what is claimed to be the first example of phosphonium salt synthesis by the reaction of a phosphine with a coordinated alkyne.269 The vinyl-phosphonium salt (113) has been obtained from the rearrangement of a coordinated ylide complex of platinum( 1 1 ) .270 A new class of zwitterionic dyes, (114), which are blue in colour, have been prepared by the reactions of triphenylphosphonium cyclopentadienylide with halogen-substituted g-benzoquinones 271 Phosphonium salts bearing new heterocyclic substituents, e.g., (115), are formed in the reactions of phosphino-substituted phosphonium ylides with halogeno-phosphines and -arsines.272, 273 The planar 2 ,4-diphospha-l,3-diphosphonia-
.
I:
Phosphiries utid Phosphotiiurii Solts
cyclobutane dication is present in the salt (116), formed on treatment of 2,6-dimethoxyphenyl(trimethyl)stannane with chlorodifluorophosphine.274 Further examples of effective coordination templates have been discovered in the metal ioncatalysed formation of arylphosphonium salts from phosphines and aryl halides under mild conditions. Thus, e.g., treatment of the benzaldimine derived from benzaldehyde and 1-amino-8-bromonaphthalene with triphenylphosphine in the presence of nickel(I1) ions in ethanol results in the formation of the salt (117).275 The reaction of chlorodiphenylphosphine with bromine, followed by an excess of a secondary amine, provides a new general synthesis of diaminodiphenylphoephonium salts.276 N-lithiation of triphenylphosphinimine, followed by treatment with one or two moles of an alkyl halide, results in monoalkyl- or dialkylamino-(tripheny1)phosphonium salts, alkaline hydrolysis of which gives a new route to primary or secondary amines 277 Diphenylaminophosphonium salts have been prepared by the reaction of N-phenyltriphenylphosphinimine with phenyldiazonium salts, this reaction also having been applied to the synthesis of polymer-bound phosphonium salts.278 Cleavage of dimethylaminophosphonium salts in liquid hydrogen chloride results in the formation of the related chlorophosphonium salts. 2 7 9
.
um Salt&.- The first direct and precise measurements of phosphonium salt acidity have been obtained from studies of the kinetics of proton transfer to an electrogenerated base, enabling a comparison with carbon acids of known PKa * 280 Phosphonium salts (and phosphine oxides) bearing at least two 2-pyridyl substituents, e.g., (118), give rise to 2,2'-bipyridyls and pyridines on treatment with acidic or neutral solvents, e.g. , aqueous ethanol.281 Alkaline hydrolysis of benzyltris(dialky1amino)phosphonium salts proceeds with exclusive loss of an amino group, with the formation of benzylbis(dialky1amino)phosphine oxides.282 A range of vinylphosphonium salts (119) has been prepared by nucleophilic addition to triphenylpropargylphosphonium bromide.283 The reaction of the latter with N-phenyltriphenylphosphinimine, followed by benzaldehyde, results in the formation of the salts (120), useful as precursors for azadiene synthesis.284 Further examples of cyclisation reaction6 of the phosphonio-imidoyl chloride salts (121), leading to new A~*~ phosphonium salts, e.g., (122), have been r e p ~ r t e d . ~ * ~ , one-pot reaction of allyltriphenylphosphonium salts with the sodium
+
ArP-PAr, +/
Ar2P-PAr
/
2Me3SnF2-
L
R\
Ph3$CH=C:
ci’
Me
+ C=NCH2PPh&I-
(121) R = Ar or But
(1 19) Z = MeO, PhS, PhNH, or R2N
s M T ; 0 3 . h J+ R (124) R Ph36-CZC-R1
2
XR3
(125) R’ = Me, Ph, or NPh2
(126) R’ = Me, Ph, or NPh2
Ph26(Me)CEC6R3
O II + R2P-CH-PPh3 i
= Ph Or
~ 1 -p =p
CH2Ph
ArP-E
ArP =EC5Me5
H ArP =PER3
1/1
E-PAr
ER3 = SnBu‘3 or SiPh3
(133) E = A s or Sb
E
CI (135)
PPh3
(130) R = Mesityl, PrLN or MesO
(132) Ar = 2,4,6-But3CsH2 (131) R’ = But or Ph E = As or Sb R2 = CF3, Me, But, or Ph
(134) Ar = 2,4,6-But3C~H2 or (Me3Si)3C
+&>+
Ph3P
(Pri2N)2P-P=P-R
X-
(129) R’ = alkyl or aryl R2 = CN, CONEt2, OTS, C02Et, or COR
-~2
x-
’
(127) R’ = Me, Ph, or NPh2 R2 = H or Me R3 = Me or Ph
R2
(l 28)
g
H
I I: : Phosphiries Phosphiriesutid aridPhosphotiiurii Phosp hori iurnSolts S a Its
23
salts of R-ketoesters, (in which the alkylphosphonium salt rearranges h to a 1-alkenylphosphonium salt) provides a route to alkyl 1-acyl-2-alkylcyclopropane carboxylates.287 An allylic rearrangement occurs in the room temperature transformation of the 1-alkoxyallylphosphonium salts (123) to the 3-alkoxyallyl salts (124).288 The course of the reactions of the alkynylphosphonium salts (125) with phosphonium ylides depends on the nature of the substituents present at the ylidic carbon. With methylenetriphenylphosphorane, the salts (126) are formed, whereas with C-substituted ylides, the 1,3-diphosphaa11y1 salts (127) result.289 The triple bond of the betaine (128) shows a lack of reactivity to 1,3-dipolar reagents, presumably as a result of eteric crowding.290 Studies of the tautomerism of the phosphoryl-substituted phosphonium salts (129) have continued.291-294 Laser flash photolysis of diarylmethyltriphenylphosphonium salts results in the formation of diarylmethyl carbocations 295 The trimesitylphosphonium radical cation readily abstracts a hydrogen atom from a variety of solvents to form the related triarylphoephonium cation.296 Further examples of phase transfer catalysis involving phosphonium salts have been described.297-299 Phosphonium bromides , both simple300 and polymer-boundl301 have found application as carriers of molecular bromine, and used in the bromination of organic compounds. Polymer-bound phosphonium salts have also been used for the trapping of photosensitive anions,3021303 and as catalysts for the regioaelective reactions of oxiranes with active esters.304
.
After last year's apparent decline, there has been a resurgence of activity in this area. Several reviews have appeared.305-308 In a theoretical contribution, & m t i o calculations have indicated that in terms of its ability to form pn-bonds, phosphorus is closer to carbon than to silicon.309 The influence of the electronegativity of substituents at phosphorus on bond angles in diphosphenes ha8 been investigated by M.O. calculations and the results compared with X-ray structural data on a range of compounds of the type (130).310 A new route to 2 ,6-di-t-butylbromobenzene has been developed, enabling the use of the 2,6-di-t-butylphenyl substituent as a sterically-stabilising group in diphosphene chemistry.311 The reactions of alkyl- or aryl-bis(trimethylstanny1)phosphines with dimethyl alkyl- or aryl-dithiophoaphonites
provide a new route to the unsymmetrical, reactive diphosphenes (131), which have been trapped as [2+4] cycloadducts with dienes.312 Structural studies of the coordination complexes of related diene adducts of bis(trifluoromethy1)diphosphene indicate that the original diphosphene had the trans-configuration.313 Photoirradiation of the stable unsymmetrical diphosphene (131, R1=meSityl; R2=2,4 ,6-tri-t-butylphenyl) results in the formation of a mixture of E- and z-isomers of the symmetrical diphosphene (131, R1=R2=2,4,6-tri-t-butylphenyl). The related dimesityldiphosphene was not isolated.314 On u .v.-irradiation, the phospha-arsenes and -stibenes (132) yield the bicyclo[l,l,O]butane analogues ( 133). 315 On gamma irradiation, sterically stabilised diphosphenes form the related radical cation, an electron being lost from a phosphorus lone pair. 316 Routes have been described for the synthesis of the diphosphenes (134) bearing triorgano-silyl or -stannyl substituents at phosphorus, both of which have potential as diphosphene transfer reagents.317,318 Studies of the reactivity of diphosphenes and phospha-arsenes which bear a complexed transition metal substituent at phosphorus (or arsenic) continue to appear.319-324 Aspects of the coordination chemistry of diphosphenes also continue to receive attention. 325,326 The phosphorus and arsenic analogues of cyclobutadiene, cyclo-P4 and cyclo-As4, have been stabilised as ligands at a niobium centre.327 328 The highly reactive phospha-alkene (135) can be generated by the action of bases on dichloromethylphosphine and trapped with various reagents, e.g., dienes, to give adducts, e.g., (136). Dehydrohalogenation of the latter leads to the dihydrophosphorin (137), also isolated by trapping. Thus, in this respect, dichloromethylphosphine is behaving as the synthetic equivalent of the phospha-alkyne, HC-P.329 Photoelectron spectroscopy has been used to compare bonding interactions in the phospha-alkene CH2=PC1 (generated by flash vacuum pyrolysis of dichloro(methy1)phosphine) and the related imine CH2=NC1.3 3 0 The first example of phospha-alkene synthesis yj& thermal dehydration is provided by thermolysis of dimethylphosphinous acid, resulting in the formation of 2-phoephapropene, CH3P=CH2. In a similar way, thermolysis of methylphosphinous acid gives HC-P.331 The thermal elimination of fluorotrimethylstannane from perfluoroalkyl(trimethylstanny1)phosphines has continued to be investigated as a route to phosphaalkenes bearing perfluoroalkyl substituents, e.g., (138), and further studies of the reactivity of these systems have been
I:
Phosphiries utid Phosphotiiurii Solts
GtH
+mN Ph3P--C-P(NPri2), + -
+.@={HzcH2
CH2N-
R X(1 47)
(145) X = CI or Br Ph3&C=PNPri2 R X-
xxcl
R-P=CX,
Ar-P-P-Ar
(149) X = CI or Br
(148) R = H or Me
(150) Ar = 2,4,6-But3C6H2
X = CI or Ph
X ArP=C: PAr
+p=c:;
C I P qH C o 2 M e
I
Bu (151) X = CI, Me, or Ph
(152) R’ = alkyl R2 = alkyl or Ph R’, R, = ( ~ ~ 2 Ph
(OC)~W
1 5
Ph
PhPmPPh
1
(153)
1
W(CO)5
(155)
X=P-N=Y (156) X = C(SiMed2 or 2,4,6-But3C6H2N
Y = CHPh,PR3, or CPh2
ArP=C=CHPh +p=c=p$)--R
(158) Ar = 2,4,6-BUt3C& At
(157) R = pentyl
P=C=C=C,
,R’ R2
(159) Ar = 2,4,6-But3C&i2
described. 332-335 A direct route to the stable phospha-alkenes (139) is provided by the reaction of 2,4,6-tri-t-butylphoephine with aromatic aldehydes in the presence of boron trifluoride.336 The phosphatriafulvenes (140), prepared by the reaction of di-t-butylcyclopropenonewith lithio(trimethylsily1)phosphide reagents, provide an interesting example of inverse electron density at the P=C bond, existing largely in the Hiickel aromatic zwitterionic form (141). Consistent with the stated polarity, nucleophilic attack at carbon, and electrophilic attack at phosphorus, is observed.337 Mathey's group has exploited the use of "phospha-Wittig"reagents, e.g., (142), for the synthesis of phospha-alkenes,astheir P-complexes. Such reagents are accessible from either the reaction of phosphines with 7-phosphanorbornadiene-P complexes338 or nucleophilic attack at phosphorus in phosphirane P-complexes 339 Treatment of the "phospha-Wittig" reagents with aldehydes at room temperature gives a general route to phospha-alkenes,338, 340 and has also been applied to the synthesis of 1-phosphadienes, (143), as their P-complexes.341 The reaction of cyanomethyllithium with 2,4,6-tri-t-butylphenyldichlorophosphine enables a one-step preparation of the functionalised phospha-alkene ( 144). 342 A new route to phosphaalkenes is provided by nucleophilic attack at the vinylic CH2 of the halogenophosphine (145), with displacement of halogen from phosphorus. Thus, with DABCO as nucleophile, the novel system ( 146) is formed.343 Treatment of the phosphino-substituted ylides (147) with Lewis acids results in the 2-phosphonio-1phospha-alkenee (148), reported to be sufficiently stable for X-ray analysis, but also undergoing various addition reactions.344,345 Routes to the dihalomethylene systems (149) have been developed which involve the reactions of halogenophosphines with tetrahalogenomethanes in the presence of phosphines,346r347 and also phosphine-induced dechlorinations of trichloromethylchlorophosphines. 348 Phospha-alkenes are also formed in the thermal decomposition of P,P-diphosphine monoimines . 349 Further derivatives of the enol forms of acylphosphines have also been described.350 Diphosphiranes (150), accessible by addition of carbene reagents to diphosphenes, undergo both nucleophilic and electrophilic ring-opening to form phosphino-substituted phosphaalkenes, (151).351,352 A range of phospha-alkenes (152) has been obtained from the reactions of alkylidenephosphoranes with monochloro (aryl)phosphines.353 Various routes to phospha-diene systems have been developed. Base-induced dehydrohalogenation of
.
I:
Phosphiries utid Phosphotiiurii Solts
allyldichlorophosphines has given isomers of the P-halofunctional phospha-diene (153), characterised by trapping with ethyl diazoacetate.354 The diphosphetene-complex (154) undergoes a reversible, conrotatory ring-opening on treatment with maleic anhydride or N-phenylmaleimide, to form the complexed diphosphadiene ( 155). 355 The reactions of P-halofunctional phospha-alkenes with N-trimethylsilylimines and related compounds have given a series of azaphosphadienes ( 156). 356 The first unsymmetrical 1 ,3-diphosphaallene (157) has been prepared.357 A phospha-allene of pseudoaxial symmetry (158) has been separated into its enantiomers by HPLC on a chiral column. However, racemisation occurs on exposure to light.358 A route to the phospha-butatrienes ( 159) has also been developed. 359 The first methylenephosphonium ion, (160), has been prepared. A structural study of the triflate salt shows that the double bond is twisted by 60". Attack by nucleophilic reagents occurs at phosphorus to generate ylides 360 Addition reactions of phospha-alkenes continue to be explored. The thermally unstable lt2,3,4-triazaphospholine system (161) is formed in the cycloaddition of phenyl- or benzyl-azides to phospha-alkenes bearing an amino-substituent at carbon, the adduct decomposing above room temperature with the generation of phenylphosphinidene. 361 The reaction of dihalogenomethylene phosphaalkenes with two equivalents of lithium trimethylsilylamides results unexpectedly in the formation of 1 I 2 , ~~-azaphosphoridines (162).362 Hydrozirconation of phospha-alkenes has given the three-membered ring system (163). 363 Addition of dicyclohexylborane to the phospha-alkene PhP=CHNMe2 results in the dimeric system (164),364 and in its reaction with an ethylsiloxane reagent, this phospha-alkene gives a mixture of aminomethylphosphines . 365 Several groups have reported addition reactions to P-halofunctional phospha-alkenes. With diazoalkane and related reagents, diazophosphole systems result.366, 367 Isomers of 2-chloro-l-thia-2-phosphiranes (165) have been formed in reactions with 5-methyl-1, 3 ,4-oxathiazol-2-onesI 368 and with phosphinidene precursors I the P-halogenodiphosphiranes ( 166 ) result. 369 Reduction of P-halogenophospha-alkenes with sodium or magnesium results initially in the diphosphadienes (167) which then isomerise to various isomeric diphosphacyclobutanes, e. g . , ( 168 ) 370 Phospha-alkenes continue to attract the interest of the coordination chemists and yet another mode of coordination has been discovered. 371 Oxidative addition of the halogen-phosphorus bond
.
.
25
Pr2N,+ /SiMe3 /P=c, Pr2N SiMe3 (162) R = SiMe3 or But
(161) R' = Ph or PhCH2 R2. R3 = H or Me
R /p\ CIP-C(TMS)z
ni
CII
(166) (165) R = TMS or Ph
R\
c,
R =P -P=C(
TMS TMS (167) R = Ph or TMS
R\ Mes2B'
R P-P<
ArP= Si=PAr BMes, (173) Ar = 2,4,6-But&H2
(172) R = Mes or Adamantyl
But
(174)
R2C=N -P=NAr (177) R = Bu'
(175) R' = R2 = But R' = But R2 = Mesityl
,P=NAr RN'P=NAr
(1 76)
Me @=s,
Me Me
/OSiMe3 Adamantyl
I:
Phosphiries utid Phosphotiiurii Solts
of P-halogenophospha-alkenes to zero valent metal(phosphine) complexes has resulted in phospha-alkenes bearing a complexed metal as P-substituent,372 and the chemistry of this class of compound has continued to develop.373-375 A new route to the phosphetane and 1,2-dihydrophosphete ring systems is provided by the [2+2) cycloaddition reactions of P-complexes of phospha-alkenes bearing electron-withdrawing substituents with electron-rich alkenes and alkynes.376 Interest in phospha-alkyne chemistry has also continued. Various trapping reactions of phospha-ethyne, MeCsP, have been described.377 The reaction of the phospha-alkyne (169) with a phosphinidene reagent has given the first l-H diphosphirene (170), described as an extremely air sensitive, deep red liquid.378 Heating the phospha-alkyne ButCzP in a sealed tube results in the formation of an air-stable cyclotetramer having the tetraphosphacubane structure (171).379 A series of polycyclic cage polyphosphines has been formed in the reaction of the phosphaalkyne ButCsP with an organoiron complex.380 Two groups have also reported the cyclodimerisation of this phospha-alkyne in the coordination sphere of a transition metal, with the formation of complexes of the 1 ,3-diphosphacyclobutadiene ligand.381 382 Other aspects of the coordination chemistry of phospha-alkynes have also received attention. 383 The chemistry of p,-bonded phosphorus compounds in which phosphorus is bonded to a p-block element other than itself or carbon continues to develop. Phosphorus-boron systems have been boron ,-interactions in the borylreviewed.384 Phosphorus phosphines H3-nP(BH2)nr (n = 1-3), have been explored by & initio calculations, and shown to be maximised at n=2.385 A structural study of the bis(bory1)diphosphines (172) has revealed that although these molecules are twisted about the P-P bond, the geometry about each phosphorus and boron atom is planar, implying n-type interaction. Significantly, the P-P considerable P: -B distance (2.11A) is the shortest P-P single bond recorded, being well within the reported range for P=P in diphosphenes. This result raises the issue as to how much of the observed bond shortening observed in diphosphenes is due to 3p,-3p, overlap, and how much is a consequence of rehybridisation.386 Evidence for the existence of the 1,3-diphoepha-2-sila-allene ( 173) ,387 and the related delocalised anions (174),3 8 7 t 3 8 8 has been presented. Two new germaphosphenes (175) have been prepared, one having been separated into two geometric isomers.389 As usual, the chemistry
-
of P=N systems has continued to attract attention. A further structural study has been reportedI3” and the steric course of addition of optically active alcohols and amines investigated. 3 9 1 Two reports of the synthesis of the halofunctional system (176) have appeared,3 9 2 , 3 9 3 together with studies of the course of nucleophilic displacement reactions at phosphorus which have led to the synthesis of a number of new systems, including the heterobutadienes (177),394 the 1 ,4-pentadienes ( 178) ,3 9 5 and a stable iminophosphene having a complexed metallo substituent at phosphorus. 3 9 6 Nucleophilic displacement of an aryloxy substituent from the phosphorus atom of a P=N system has also been studied.397 The reactions of lithio( trimethylsily1)phosphides with the chlorides of nitrous, phosphinic and sulphinic acids provide a general route to P=N, P=P, and P=S systems, e.g., (179).398 Interest has also continued in the chemistry of A3- h5 systems,399-401 and other low coordination phosphorus species, in particular phosphenium ions, R2P:+, and phosphinidenes, RP:. The reactions of phosphenium ions with isocyanides ,4 0 2 1 ,3-dienes and o-quinones,403 and amidines,404 have been investigated. The coordination chemistry of phosphenium ions also continues to stimulate interest.4 0 5 - 4 0 8 The thermal decomposition of phosphirene and phosphirane P-complexes provides a new approach for the synthesis of terminal phosphinidene complexes, e.g., (180), which can be trapped with a variety of reagents.409 Evidence of the formation of surface phosphinidene intermediates has been adduced in the heterogeneous dechlorination of alkyldichlorophosphines by magnesium metal at 600K. 410 5
PhosDhirenes. PhosDholes and PhosDhinines
The reactions of P-halophospha-alkenes with carbenes provide a new route to l-chloro-1H-phosphirines ( 181 ) . 4 1 1 Such compounds are highly reactive, and a study of nucleophilic displacement reactions at phosphorus has been facilitated by preparation of the related P-W(C0) complexes.412 The first pentacoordinate systems derived from phosphirenes, ( 1 8 2 ) , have been formed in the reactions of P-halo- or P-cyano-phosphirenes with tetrachloro-oquinone.4 1 3 Evidence has been presented for the rearrangement of P-chlorophosphirenium ions (183) to the vinylphosphenium ions (184).414 A new approach to the phosphole ring system is provided by the reaction of terminal phosphinidene complexes with electron rich
I:
Phosphiries utid Phosphotiiurii Solts
+
Et2N M
R%P(NPri2) Ph
Ph'
.
NEt2 e
0 Me
R
\W(C0)5
.
R2, R3 = H or Me
2g uFS
& CP2
PSiMe3
CI
Li+
Li
D
<
Ar
O T j NH H P h (1 99)
.
. Me
fq -
Ph2P.+ PPh2 v
(206)
R2N
P >Ar
(200)X = 0, S,Se, or NPh
Me2N NMe2
?-
Me2NA,%P\'NMe2 NMe2 Me2N
(207)
Me Pri!? P=P (201)
alkynes, which proceeds a formal [2+2+1] cycloaddition to give substituted phosphole complexes, e.g. , (185).415 The application of high pressure to the reaction between 1,3-dienes and organodichlorophosphines reduces the reaction time from days to hours, producing the intermediate P-halogenophospholenium salt in finely divided form, which readily undergoes elimination of hydrogen halide on treatment with an amine to give the p h ~ s p h o l e . The ~~~ influence of pressure on cycloaddition reactions of phospholes has also been studied.417 Full details have now appeared of the the synthesis of 2-aryl- and -heteroaryl-phospholes (186) initial reaction of phosphole P-W(CO)5 complexes with arenes or heteroarenes in the presence of aluminium chloride.418 Following an earlier report419 of the formation of new, unsymmetrical polydentate phosphines frortr Diels-Alder additions of phospholes and vinylphosphines, both present in the form of their palladium(I1) or platinum(I1) complexes, the same group has now shown that these reactions also occur under mild conditions with the related nickel(I1) bromide complexes, the advantage of the latter (apart from the cost) being that nickel is much easier to remove from the final product than are the other metals. The new tridentate phosphine (187) has been prepared in this way.42o The l-phosphanorbornadienes (188) are formed in the reactions of l-phenyl-3,4-dimethylphosphole with alkenes at 150", which proceed [4+2] addition of the alkene to an intermediate 2H-phospholer formed by thermal isomerism of the parent phosphole.421 Cycloaddition of diazomethane to phospholes is a key step in the synthesis of the homophospholes (189).422 A simple route to phospholyl anions is offered by the reaction of the zirconacyclopentadienide (190) with phosphorus trichloride, giving the intermediate chlorophosphole (191) which, on treatment with lithium metal, gives the related phospholyl derivative (192).423 The characterisation of phospholyl complexes has continued to attract attention.424-427 The reactions of bridging diphenylphosphido ligands with alkynes has led to the synthesis of n-complexes involving quaternized phospholes 428 Treatment of the dilithiophosphide reagent (193) with carbon dioxide in the presence of trimethylsilyl chloride results in the formation of the benzodiphoephole ( 194). 429 A related reaction of the diphosphide (193) with pivaloyl chloride gives the benzodiphospholyl complex (195), which on subsequent treatment with alkyl halides is converted to the benzodiphospholes (196).430 A new route to the lr3-diphospholide anion (197) has been developed, and applied in
a
a
.
I:
Phosphiries utid Phosphotiiurii Solts
the synthesis of a diphosphaferrocene.431 Both 1 ,3-diphospholide and 1,2,4-triphospholide anions are formed in the reactions of the phospha-alkyne ButCsP with sodium amalgam in monoglyme. 432 Oxidation of a mixture of the lithium salts of these anions with transition metal halides has given a new pentaphosphorus cluster cage system.433 Yet another new cage polyphosphorus system arises from the protonation of the 1,2 ,4-triphospholide ion.434 Various modes of coordination of lI3-diphospholide ions have been recognised.435 While development of the chemistry of the pentaphosphaferrocene system ( 198) has continued,436 a theoretical study suggests that the bis(pentaphospholy1)iron system ( "decaphosphaferrocene" ) , is unlikely to be isolable.437 The chemistry of heterophosphole systems has also continued to generate interest. New routes to benzophosphazoles, e.g., (199), have been developed,438 and further studies of the electronic structure of benzoheterophospholes and related systems have appeared. 439 1 440 A series of patents has been published which give details of various cyclocondensation reactions leading to a range of 1,3-heterophospholes (200) and 1 ,2-azaphospholes.441 The azadiphosphole (201) is formed in the pyrolysis of bis(diisopropy1amino)phosphine.442 Development of the chemistry of diaza- and triaza-phospholes, and related systems, has also continued.443-447 Routes to functionalised phosphinine systems, e.g., (202),448 and the phenolic systems (203) and ( 2 0 4 ) ~ ~ ~have ' been developed, the latter behaving as a genuine heterocyclic phenol. Whereas the 2-chlorophosphinine (205) is unreactive towards nucleophilic reagents, nucleophilic attack at phosphorus occurs in the related reactions of the P-W(CO)5 complex of (205).450 The synthesis of the partially delocalised lA5, 3A5diphosphabenzene system (206),451 and the 1 A5 ,3i5, 5X5triphosphabenzene system (207),452 ha6 also been reported. Interest has also continued in the chemistry of azaphosphinine systems, although many of these involve phosphorus in the ~5-state.453-460
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410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446
.,
H. BockandM. Bankmann, J.Chm. Soc.. Chm. Cmnam 1989, 1130. W. S c h n u r r and M. Regitz, 2kWahed.ron L e t t . , 1989, 3,3951. B- mchenps and F. Mathey, J, them., 1988, u, 755. M. Ehle, 0. Wagner, U. Bergstrhser, and M. Rsgitz, m utg. , 1990, 3429. S. A. Weissman and S. G. Baxter, Tetrahedron Lett 1990, . . a3,819. N. H. T. Huy and F. Mthey, P h o s ~ r u s .Sulfur and s 1990, 421 477. N. S. Isaacs and G. N. El-Din, Svnthesis, 1989, 967. N. S. Isaacs and G. N. El-Din, -Q, 1989, 7083. E. Deec+hanps and F. Mathey, J. Ora. Chem., 1990, 2494. J. A. Rahn, M. S. Holt, G. A. Gray, N. W. Almck, and J. H. Nelson, Inora. Chem 1989, 28, 217. L. S o l u j i c , E. B. Milosavljevic, J. H. Nelson, N. W. Alcock, ard J. Fiecher, Inora. 1989, 28, 3453. P. Le O f f , F. Mathey, and L. Ricard, J. Ora. Chm , 1989, 4754. D. Oebels and F . 4 . Kl-, Tetrahedron &I t., 1989, 3, 3525. T. Douglas and K. H. Theopold, &yew. Qwn., Ed * t 1989, 28, 1367. F. Nief, L. R i d , and F. Mathey, oraancmetalu,1989, 8 , 1473. F. Nief, F. Mthey, and L. Ricard, J. oraananet. Chqp 1990, 271. T. Douglas, K. H. Theopold, B. S. H a w r t y , and A. L. Rheinqld, -, 1990, 9 , 329. D. Belletti, A. Tiripicchio, M. T i r i p i c c h i o C a m e l l i n i , and E. Sappa, J. chan Soc Dalton m., 1990, 703. D. Braga, A. J. M. Caffyn, M. C. Jennings, M. J. Mys, L. Mmojlovic-mir, P. R. Raithby, P. Sabatino, and K. W. Woulfe, J. Qgn. Soc.. C h m m 1989, 1401. H. Schmidt, E. Leissring, and K. Issleib, Z. Chell!., 1988, 2 , 255 (Qlem.Ab81989, 39 463). K. Issleib, H. Schmidt, and E. Leissring, J. O r-. 1990. 382, 53. N. &grot, L. &card, C. Charrier, and F. Mathey, &gw. C h m. I Int. Ed. m a . , 1990, 2p, 534. R. Bartsch and J. F. N b n , Eplvhedron, 1989, 4, 2407. R. Bartsch, P. B. Hitchcock, and J. F. N h n , J. O r . 1989, 375, C31. R. Bartsch, P. B. Kitchmck, and J. F. N b n , J. Chm .I m., 1989, 1046. R. Bartsch, P. B. H i t c h a d , and J. F. N k n , J. * I am. m. , 1990, 472. 0. J. Scherer, T. BxUck, and G. Wolmershtiuser, 1989, 2049. J. A. chamim, M. R u i Z - M Z O n , R. Salcedo, and R. A. 'lb8cBRDI Inora, Chem 1990, 29, 879. H. Schmidt, E. Leissring, and C. Wirkner, Z. Chm., 1989, 2, 410. L. Nyulaszi, G. Ceonka, J. Reffy, T. V e s z p r m i , and J. Heinicke, J. t . Chm 1989, 373, 49. L. Nyul&tszi, G. Csonka, J. Reffy, T. Veszpr€¶ni, and J. Heinicke, .tJ . C h m 1989, 57. H. Hartmann and M. Weber, Ger. (ECast) 268,700; 268,701; 268,702; 268,703; Ab8W 1990, JJ2, 98 939; 98 840; 98 041; 98 842; 268,704 98 843). w. Gueth, T. Busch, W. W. Sctroeller, E. N i e c k e , B. Krebs, M. Darhnann, and P. Radmacher, New J. chem., 1989, 309. W. Schn~rrand M. RegitZ, SWItheSis, 1989, 511. T. A. Riley, S. B. Larsen, T. L. Avery, R. A. Finch, and R. K. R C b h , J. Med. then 1990, 3,572. . . w , 1990, 42, 173. J.-L. Zhang and W. XU, m I S l 8 .S U U J K and S G. Bacmlini, R. lhlpozzo, and E. Fkzzina, € & & X ? L U m Silicon, 1989, 2i5.
a,
.,
s, s,
.,
.,
.
a.
mt . .
.,
.
m,
.I
., u,
.,
.,
.,
m-
. m., mI
.,
.,
., (m. .,
m,
u,
.,
s,
I:
Phosphiries utid Phosphotiiurii Solts
447 448 449 450 451 452 453 454
J.-P. EIajoral, C. Rquee, M.-R. Mazitze8, J. Jaud, and M. Sanchez,
z,. 1989, 1496. m.
Anna, M. Regitz, and H. Kluge, W . , 1990, 935. M k k l and A. Kallnihzer, Jett., 1989, Zp, 5245. LR Floch, L. R i d , and F. Mathey, , 1990, 9 , 991. Schmidbaur, C. Paschalidis, 0. SteigelmaM, andG. MUller, 1990, 29, 516. E. Flu&, G. HeClanann, W. PlaSS, M. spahn, and H. BOITXWUI, 1 1990, 1223. , A. M. Kibardin, E. Ya. Wina, V. B. Mikhailov, Yu. B. Mikhailov, and A. N. m ik,&w. Nauk SSSR. Ser. E ~ *U I I 1988, 1943 ,.-( 1989, JJJ, 153 910). E. Ya. Levina, A. N. pudovik, Sh. K. Latip,.R. 2 . Musin, and A. M. Kibardin, Jzv. SSSR. Ser. IQu!, 1989, 490 (than.., 1990, 35 995). J. Barluenga, F. L q e z , and F. Palacios, J. Qlem. Soc.. , 1989, 2273. J. Barluenga, F. Iapez, and F. P a l a d o e , J. ' I 1990, 3 U I 61. T. Facklam, 0. Wagner, H. Heydt, and M. Regitz, J& Ed. 1990, 314. H. W. RDeaky, U. sdrolz, and M. Noltmeyer, 1989, 255. A. S C h i w , 1989, 3,24. T. Chiand M. N. S. Rm, 1989, 25, 40.
U. G. P. H.
,.--
.,
.
u,
455 456 457 458 459 460
-.
.-
a., a,
,-.
m,
V
s
v
n
t
h
.
,
m. e.,
2 Pentaco-ordinated and Hexaco-ordinated Compounds BY C. D. HALL 1. Introduction - The subject has received a stimulus this year from the publication of the proceedings of the XIth International Conference on Phosphorus Chemistry a t Tallinn, Estonia in July 1989.1 Among the huge variety of papers presented at the conference, there were numerous contributions in the field of hypervalent phosphorus chemistry, several of which are mentioned later in the article. A review on the chemistry of thio derivatives of trivalent phosphorus acids 2, which covers the literature to 1986, includes a section on pentacoordinate phosphorus compounds derived from addition to a-diketones and unsaturated systems activated to nucleophilic attack by electron withdrawing groups. Chemical bonding in hypervalent molecules has been discussed and qualitative bonding concepts developed to supersede the dsp3 and d2sp3 models. A review on the mechanism and stereochemistry of the Wittig olefination reaction inevitably includes a discussion of the equilibrium between betaine and 1,2-oxaphosphetane intermediate^.^ A correction has been published to reference 19 of Chapter 2 in SPR14, V01.21, concerning the Mitsunobu R e a ~ t i o n . ~
.
Structure. B
.U -
Further interesting information has emerged on the structure of pentaarylbismuth compounds. The fluoro derivative (1) is a dichroic violet solid with the now familiar squarepyramidal structure. In solution it has a reddish colour which again affords purple crystals. The very similar compound (2) has the same colour in solution but forms orange crystals which are trigonal-bipyramidal. It is clear from the colours in solution that both structures involved in the Berry pseudorotation mechanism are present in solution and the ratio of the visible absorption intensities does not change with large variations in the temperature. It follows, therefore, that the difference between the energies of the tbp and the sp forms must be close to zero and that the solid state structures must be determined by lattice energies. Ligand exchange cannot be frozen out on the 19F n.m.r.time scale, even a t the lowest achievable temperatures, which points to an energy barrier between the two structures of A G**20kJm01.-~.~Further work seems to indicate that in contrast t o P, As and Sb, sp geometry seems to dominate the solid state structure of pentaaryl bismuth compound^.^ The structures of gaseous tetrafluorohydridophosphane, HPF4, and trifluorodihydridophosphorane H2PF3, have been determined by electron diffraction. Both molecules adopt t b p structures with the hydrogen atoms occupying equatorial sites in conformity with CzV symmetry.8 Theoretical 2.
48
2.387
2.371
Et20
(C2F5)3PO
(9)
+
CSF
,OCs
CsF
,ocs (c2F5)2p\F
(c2F5)3p\ F (10) S3’P = -56.9 ’Clp~= 972 HZ 2JpF= 72 Hz
-c2F4
F
50
Organophosph0ru.v C 'hrtnis t n
calculations have shown that PLib, SLiq and SiLi6 challenge conventional notions of molecular structure and bonding. Thus, for example, the Cqv isomer (3)of PLi5 is found to be a true minimum and is slightly, but consistently more stable than the tbp structure (4).9 Ab initio calculations have shown that the transition states for pseudorotation of PH5, PH3F2 and a dioxaphospholane ( 5 ) approximate the sp structures envisaged by Berry, but some of the transition vectors show displacements in accord with a turnstyle process.1° A new set of parameters for 1-3 interactions around the pentaco-ordinate phosphorus atom adapted to Allingers' 1977 force field, have been tested on several phosphorane structures (6-8).11 Bond lengths and bond angles evaluated by this method compare favourably with the available experimental data. Molecular mechanics calculations have also been used to study the hydrolytic reactions of some cyclic esters of alkylphosphates and phosphonates. The calculations indicate that during hydrolysis, the ratio of the ring opening and retention products and the effect of ring size and the endocyclic substituents on the hydrolytic rate constants, are mainly controlled by the steric energy difference (AEor AAE) between the substrate and its pentaco-ordinated transition state. l2 3.
- A study of the acceptor properties of (CgF5),PC15_,
(1<
n < 3), (C6Fs)n P+C14,n (1< n < 3) and C6F5P+Br3 towards Lewis bases such as the chloride ion and uni- and bi-dentate pyridines, led to the isolation of several pentaco-ordinated and hexaco-ordinated phosphorus complexes which were characterieed by elemental analysis and in some cases i.r. and 31P n.m.r. spectroscopy. l3 Tris (perfluoroalkyl) phosphine oxides (9) react with caesium fluoride to form stable adducta (10) containing pentaco-ordinated phosphorus which gradually decomposes at 25OC to (ll).14The same paper reports the reaction of tris(perfluoroalky1)-difluorophosphoranes (12) with M+F- (M+= Cs+,K+or Na+) to form the phosphates (13) of the corresponding metals. The latter may, in turn, be used in a modification of the Schiemann reaction to convert aryl diazonium salts into aryl fluorides (14). The reaction of methyltriphenoxyphosphonium iodide (15) with dimethylformamide dimethylacetal(l6) gave tetraphenoxymethylphosphorane (17) which was converted to (18) by excess ethylene g l y ~ 0 l . lThe ~ reactions of aryltetraiodophosphoranes (19) with N-trimethylsilyl derivatives (20) have also been investigated and the products (which are all phosphonium salts) shown to depend upon the nature of the group R.16 For instance, with R=N-morpholine, aryldimorpholinoiodophosphonium triiodide(21) is formed whereas with R= PhNH, the aryltrianilinophosphonium triiodide (22) is produced. Studies of the oxaphosphorylation properties of diethoxytriphenylphosphorane (23)have been extended to include methyl a-D-glucopyranoside (24) which affords two isomeric dioxaphospholanes (25 and 26). Thermolysis of these phosphoranes in DMF at 4OoC in the presence of LiBr, affords the allopyranoside (27) in a regiospecific reaction17, whereas thermolysis in the absence of LiBr
(CZF~)~P + FM~+ F
ArF
+ N2 +
MCI
+
(C2F&PF
0 9 Me-b<'
2MeP(OPh)31 + (Me0)2CHNMe2 (1 5)
bg
(1 6)
+
4PhOH
(18) W H 2 W 2
1
2Mel
+
HCONMe2
+
MeP(0)(OPh)2 + MeP(OPh)4 (17) $'P, -53
ArPI4 (19)
+
-
RSiMe3 (20)R= 0-N
U
PhNH, Ph,P=N
I
+
ArR2PI 13-
or
+
-
ArR3P l3
Orgunoph osphorus C 'hen1imy
Ho\
HO
\
-:,
OH
OH
OMe
Ph3
IDy:ac"'
OH
"eH
OH
cy
0:::
HO'*'
OMe
I
OMe
0-CR3R4
F
Et2NP=CR1R2
R3R4C0
I
I
* (Et2N)2P,C/C*cHR5 R1/ 'R2
I
F
II II
0
0
(32)
53 Y3
R4 = CH2R5
(Et2N)2P-CR'R2
MeNHCNHCCH2CI
PCI3
I
-POCl3 -Pa3 -3HCI
I
OMe
-
K
MeN,
/NCC12CHC12
P CIS
(33)
gives a mixture of (27,4596) and (28,4096) plus 1596 of 3,6-anhydro-a-Dglucopyranoside. 4
. ..
1
-
4.1 Monocvclic -P A study of the spectral composition of lumineecence and of the kinetic8 of attenuation of chemiluminescence during the thermal decomposition of triphenylphosphite ozonide, ha8 shown that the emitter of chemiluminescence in the i.r. region is singlet oxygen whereas the emitter in the visible region is triphenyl ph08phate.l~ Four-membered oxaphosphetan rings are, of course, an integral feature of the mechanism of the Wittig reaction which has again received an exhaustive treatment during the The first two papere by Vedejs et aZ.19#20argue that kinetic (not equilibrium) factors are dominant in Wittig reactions of conjugated ylids and that the mechanism involvee an asynchronous cycloaddition process without participation of betaine intermediates. The third paper,21 examines the effect of metal ions in Wittig reactions and offers a general hypothesis for the mechanism. In most cases where lithium is present, the mixture is enriched with Z alkene whereas when sodium or potassium ions are present the E isomer predominates. These observations are alleged to support the concept that a spin-paired diradical is formed when potassium or sodium are preeent but that an ionic reaction occurs when lithium is the counter cation. The accumulated evidence, which involves aromatic, heterocyclic and aliphatic aldehydes reacting with benzylidenediphenylmethylphosphorane (PhCH= PPh2Me) or the preferred betaines in THF a t -78OC indicates, in common with Vedejs' work, that the Wittig reaction occurs under kinetic control without any significant degree of equilibration or Wittig reversal. In a continuation of an investigation of the chemistry of P-halogeno ylids, P-fluoro ylids (29) have been shown to react with aldehydes and ketones to form 2-fluoro-1,2A5-oxaphosphetans(30) which rearrange to alkylphosphonates (31).22 The pentaco-ordinated phosphorus compounds ( li3 lP= -41.W-56.0) were also characterised by l H and 13C n.m.r. A novel reaction of PCl5 with N-methyl-N-chloroacetylurea (32) leads to a compound (33) containing a diazaphoephetidine ring whose structure was determined by multinuclear (lH,13C and 31P) n.m.r.23 The dimerization of phosphimides (e.g.34) is an example of the fixation of different stages of nucleophilic subetitution at a phoephorus atom. If the leaving group X forms strong bonds (e.g. P-F or P-Cl) reaction stops with the formation of a pentacoordinated phosphorus compound (35). In the cases of the weaker P-Br or P-I bonds, the reaction goes further to form (36) or (37) depending upon the nature of the substituents R1,R2 and Y.% Triphenylphosphine (benzoy1)methylene(38) reacts with the phosphetan disulphide (39) to give a mixture of the phosphorane (42) and either (43) or (44) via intermediates (40) and (41).26 The available spectroscopic data was apparently unable to distinguish between (43) and (44)due to lack of solubility but
?'
X-P=NY A2
(34)
(35)
PhyO Ph36-CH-P-
E
Ph3&CH=C-O-T-SPh I
A
(40)
PhkO
R (41)
with (39 b-d) the only products obtained were those equivalent to the phosphorane (42) containing the thiaphosphetan ring; no 31P n.m.r. data were quoted. An interesting reaction of a-carbonylphosphonites (45a-c) with one mole of hexafluoroacetone (46) yielded, by insertion into the P-C bond, a series of phosphites (47a-c) which on reaction with a further two moles of (46) gave the conventional oxidative cycloaddition reaction to form the analogous series of phosphoranes ( 4 8 a - ~ ) Twofold .~~ oxidative addition of bisphosphines (49ab) to hexafluoroacetone gave different phosphoranes depending upon the nature of X.27With X= OSiMeg and X= NMe2, the products were the 1,3,2dioxaphospholane structures (50ab) but with X=Cl and n=3 (49c) the 1,4,3dioxaphospholane ring system (51) was formed. The latter, on heating above llO°C, rearranged UM (52) to the bisphosphorane (53) containing l,2i5oxaphosphetane ring structures. In the same arena, the reaction of the bisphosphonites (54) with a range of aliphatic aldehydes (55) gave high yields of 2,2-dialkoxy-1,4,2-dioxaphospholanes (56) which were stable at room temperature for 1-2 months.28 The reactivity and synthetic utility of 1,3,2~5-dioxaphospholanes are 1 The. abstract ~ ~includes discussed in a paper presented at Tallinn by Evans et ~ a summary of the kinetics of Lewis acid-mediated decomposition and a report on the use of dioxaphospholanes to prepare a-D-pyranosides mentioned in Section 3 (reference 17). Further reports have appeared on the reaction of trivalent phosphorus compounds with acetylene d i c a r b o ~ y l a t e s . ~ ~In * ~the first, alkyl diphenylphosphinites (e.g.57) are shown to react with dialkylacetylene dicarboxylates (e.g.58) in the presence of carbon dioxide to form 1,Z-oxaphosphol3-enes (e.g.59) which in the presence of excess phosphinite decompose uia (60) to give di-ylids (e.g.61). On the other hand, the phosphoranes (62) from phosphonites and phosphites react with a further phosphorus component to give the ylids (63) which are readily converted by treatment with alcohol into phosphonates (65) apparently via ketene intermediates (64) as evidenced by 13C and 2H isotopic tracer studies.30 In an extension of earlier work, Burgada et al. have also reported on the reaction of the cyclic phosphite (66) with dimethylacetylene dicarboxylate (58) in the presence of proton sources such as carboxylic acids, amide N-H bonds in ~ succinimide or phthalimide and amine N-H bonds in pyrrole or i n d 0 1 e . ~With carboxylic acids (67) a mixture of the ylid (68) and the cyclic phosphorane (69) was obtained and in some instances (e.g. with 2,4,6- trimethylbenzoic and p methoxybenzoic acids) the ylid and phosphorane were shown t o be in equilibrium. With amides as the proton source, ylids were generally formed although with N-methylbenzamide (PhCONHMe)a signal attributed to (70) was observed at 631P = - 52 p.p.m. which had disappeared by the end of the reaction through rearrangement to (71). With amines (e.g. pyrrole) the products were again a mixture of ylid (72) and phosphorane (73) and the entire set of results was rationalised in terms of HSAB theory and the symbiotic effect around phosphorus.
+
cF3T o \ P (0Et),OC(CF3),COX 0 ' CF3 CF3 (48 a-c) 8 ' P = -58
(45 a-c)
(46)
a) x = ~ r ' b) X = Bu' c) X = Me0
\
/
/
2 x (46)
(Et0)2POC(CF3)2COX (47 a-c)
(50a, b)
(49 a, b) a) X = OSiMe3; n = 2, 3 b) X = NMe2;n = 3
F3C CF3
V
4 x (46) D
0CH(CF3), OCH(CF&
(53)
-
(R’O)2 PCH2P(OR1)2 + 4R2CH0
(54) R’ = Et, Pr‘
Ph2POMe
+
OR’
R2
OR
OR’
(55) R2 = Me, Et, Pr’
MeO2C.CEC.CO2Me
OR’
P
0
(58)
(57)
Ph2POMe
(59)
51>
OMe 1
Ph2>e,C02Me C02Me
2 0
R’ R22P
R~O~C
R’R2,P
6Ph20Me c=o
I
C02R3
R’R~~P P
co2~3
0&C02R3
(62) R’ = Ph; R2 = Me0 or R’, R2 = Me0 or EtO R3 = Me or Et
R’R22pM C02Me
Q0
Me Me$>
P-OMe
+ (58)
Me
y02Me O--f;=CH-YH-O.CO
Me
OMe
C0,Me
I
Me
(68)
(67)
+
Me
I
-7'
,o.co =CHC02Me
OMe C0,Me (69) S3'P, -49.9
/
Me
I
Me0 CO,Me Me
(66)
+ (58)
-
O-P=S;-CH-N
I
Me0 CO2Me
A study of the reaction of N-arylhydrazides (74ab) with phosphorus pentachloride depends upon the molar ratio of the reactants and may lead to either the monocyclic phosphoranes (75ab) or spirophosphoranes (76ab) in which the P-C1 bonds may undergo a number of nucleophilic displacement reactions (e.g. by alcohols).32 Finally in this section, the coordinated o-benzoquinone diimine structure (77ab) has been shown to undergo a facile cheletropic reaction with triphenylphosphine to give 2,3-dihydro-1,3,2X5-benzodiazaphospholes (78ab) which equilibrate to the iminophosphoranes (79ab) in moderate yields.33
.
.
4.2. -P The first synthesis of a series of pentaco-ordinated structures (82a-d) containing a three-membered (phosphirene) ring has been achieved by the oxidative addition of tetrachloro-o-benzoquinone (80) to (81 a-d).34 The chlorine atom in (82a) may be replaced by azide ion and a
crystal structure of (82d) showed a highly distorted sp structure at phosphorus with the CN group in the apical position. Further contributions to the study of the interaction of trico-ordinated phosphorus compounds with carbonyl compounds have been reported by Pudovic et al. In the first of these,35 a phosphoroisocyanitidite (83) reacts with the two moles of hexduoroacetone (46) in ether at - 2 6 O to form the bicyclic phosphorane ( 8 5 ) via the ylid intermediate (84). Similar reactions occur with alkyltrifluoropyruvates ( CF3CO.CO2R , R= Me or Et) as substrates. In the second paper, the reaction of dimethyl alkynylphosphonites (86) with trifluoromethyl carbonyl compounds (e.g.46) in ether at -2OOC gave bicyclic compounds (89) by a similar mechanism involving intermediates (87) and (88).36An analogous reaction of (86,R=Meor Et) with alkyl esters of benzoylformic acid (90ab) leads to (91ab) and the same paper describes the reaction of (86) with benzoyl cyanide to form the monocyclic phosphorane (92).37 The fourth paper examines the successive insertion of chloral (94) into the P-Br bands of the cyclic phosphorane (93) t o form a series of stable phosphoranes (95a-c). Disproportionation of (95a) gives (96) which again undergoes insertion into the PBr bond by chloral to form (97).38 Throughout the whole of this work the proposed structures are supported by elemental analysis and multi- nuclear n.m.r. The contribution by Roschenthaler to the Tallinn Conference involved a survey of the reactions of acyclic and cyclic phosphites, (R0)2 PX where X= Cl,OH,OMe,OSiMe3or NCO with activated ketones (e.g. CFQCOCFQ)in order to study the influence of R and X on product formation. A new type of insertion, a 1,4 group migration and cycloaddition reactions yielding five-membered rings and bicyclic systems were observed.3g Structural and pseudorotational contributions t o the conference included an X-ray and variable temperature n.m.r. study of cyclic pentaoxyphosphoranes by Holmes et aL40 This work revealed a preference of six- and seven-membered rings for apical equatorial orientations within trigonal bipyramids with saturated six-membered rings preferring to adopt a boat conformation. Apical-equatorial ring pseudorotations
60
RCONHNHAr
+
(75 a, b)
PCI5
(74 a, b)
a) R = CF3; Ar = Ph b) R = Ph; Ar =Ph Ar Ar
(77a, b) a) R = H; b) R = Me
(79 a, b)
CI (80)
CI (81 a-d)
(82 a-d)
a) X = CI b)X=F c) X = Br d)X=CN
S3'P NMR, -82.2k126.6
P T C F 3 (CHF&FzCH20)2PNCO
+
(CHF2CF2CH,0)2T-N,
2(CF3)2CO
0
\
Et20/-20
\
"C
o e 3;
/
CF3
/
CF, (89) Ph (Me0)2PCECR1
+
2PhC0.C02R2
(90a, b)
(86)
I (MeO) P
a) R2 = Me b) R2 = Et 2PhCOCN
'Jb
p
CECR'
Ph p CN
C02R2 (91 a, b)
Organophm phorus C'h ern i.wy
(94)n = 1-3
(93)
(95a-c) a) n = 1 b)n=2 c)n=3
2 x (95a)
Br
I
OCHCCI,
(97)
(96)
were reported to be more facile for five-membered rings whereas ligand exchange via diequatorial ring placement was found to be easier for the larger rings. Hydroxyalkyliminophosphoranes (e.g.98) and their tautomeric pentacoordinated phosphoranes (e.g.99) were deprotonated by KH to give anionic pentaco-ordinated phosphoranes which on treatment with methylating agents gave the N-methyl compounds (e.g. 100). The structures as defined by single crystal X-ray analysis, revealed tbp structures with the N-Me group in an apical position and the ring oxygen e q ~ a t o r i a l . ~ ~ The spirophosphorane (101) hydmlyses to the phosphonate (106) whose structure, a s determined by X-ray analysis, is a reflection of the spirophosphorane (101) from which it originates. This remarkable observation was rationalised as shown in Scheme l.42 Reaction of the hydridophosphorane (107) with PhPC12 in the presence of triethylamine gave a new bisphosphorane (108). With (109) the reaction with (107) proceeded ta give the ring-opened product (110) but the bicyclic structure of (109) was retained during reaction with (111)to give the bis-phosphorane (l12).43 Further aspects of the chemistry of hydridophosphoranes (107 and 111)involving reactions with keto acids (113) were also reported a t Tallinn44 and typical reactions included the formation of either (114) or (116) the latter via (115). Some of the compounds are good models for pentaco-ordinate intermediates in the reactions of phosphoric esters of enolpyruvic acid. A single crystal X-ray structural evaluation of the hydrido-phosphorane (117) reveals that the compound lies on the Berry coordinate apparently 50% between tbp and rp structures with the oxygen atoms in apical positions45 and an 0-P-0 bond angle of 165.9O. The new phosphatrane (118) protonates to form the extremely weak acid (119, p G ca. 16) with a pentaco-ordinate structure. Oxidation of (118) followed by treatment with BF3 again leads to a phosphatrane (121) featuring five-coordinate p h o s p h ~ r u s .Apparently ~~ the BF3 moiety is capable of polarizing the phosphoryl oxygen of (120) suEciently to stabilize the chelated pentaco-ordinated structure. Reactions of the cyclophosphoramide Pt(I1) complex (122) were also discussed a t Tallinn and are summarised in Scheme 2.48 The formation of (125) again illustrates the ability of the cyclen ligand to alter the usual products and/or mechanisms at square planar Pt(I1) centres since the expected reaction would have led to either p-coordination of the alkyne or oxidative addition of the alkyne fragments to the metal.
P-rus (=omDounds- The first examples of diazadiphosphetidines (128) with phosphonium and 6-coordinate phosphate centres without halogen atoms on phosphorus were formed from the reaction of the spirophosphorane (126) with phosphonimidic diamides (127).49 Neutral hexaco-ordinate phosphorus compounds (131ab) are also formed by the reaction 5. W c o - o r w
of halophosphoranes (129ab) with carbodiimide (130h50 These compounds are air stable, moisture sensitive solids with very high field (-155/-205~.p.m.)~~Pn.m.r.
0 - -P-c, MeOYA H' o=c,
yH OMe
Scheme 1
MeN
+
(107)
CI-P(
I
NMe
I
NMe
Me N
EW
+o
N Me
0
0 h
H
+
(109)
VPh 0
(107)
+
RCH2CO.CO2H (113 a-c) a)R=H b) R = Ph C) R = CH2C02H
RCH2’
C
I ‘C02 6HEt3 OH
Et3N P
h7
I
HCECPh / NaBPh,
Scheme 2
(126)
(127) R’ = Me, R2 = Ph or R’, R2 = Et
(128)
S3’P, ca. + 31 and -1 15
hx
Orgunophosphorus Chhrmistrv
a) X = CI b) X = CF3
R = cyclo-C~H,1 or Pr'
(131 a, b)
+ C'F3
(135a)
(1 36a) F
(1 37) X = F or OCF(CF3)z
(138) X = F (1 39) X = OCF(CF3)z
chemical shifts whose stereochemistry was readily deduced from the l9FI3lP n.m.r. coupling constants. The cyclic phosphite (132) was oxidised by perfluoroisopropoxide anion (133)to give a mixture of S5a6-phoephites(134,135aband 136ab).51 The reaction mechanism is thought to involve a one electron redox reaction between (132) and (133) and suggested intermediates include fluorophosphoranyl radicals (e.g.137), the ketyl radical anion, [OCF(CF3)2l"and the fluorophosphoranes (138) and (139).
1. Phosphorus, Sulfur and Silicon, 1990,4W60. 2. O.G. Sinyashin, E.S.Batyeva and AN.PudoviL, Russ.Chem.Reue., 1989, W 4 ) , 352. 3. AE.Reed and P.von R. Schleyer, J.Amer.Chem.Soc., 1990,118, 1434. 4. B.E.Maryanoff and AB.Reitz, Ckm.Reu., 1989,89,863. 5. APautard-Cooper and S A E v a n s Jr., J.Org.Chem., 1989,64,4974. 6. A.Schmuck, P.Pykko, and KSeppelt, Angew.Chem., Znt.Ed.Engl., 1990.29 (21,213. 7. ASchmuck, D.Leopold, S. Wallenhauer and KSeppelt, ChemBer., 1990,183, 761. 8 . A.J.Down8, G.S.McGrady, E.A. Barnfield and D.W.H.Rankin, J.Chcm.Soc., Dalton Trans., 1989,646. 9. C.J.Marsden, J.Chem.Soc., Chem.Commun., 1989, 1356. 10. P. Wang, D.K.Agrafiotis, A.Streitwieser, and P.von R.Schleyer, J . C h e m . S o c . , Chem.Commun., 1990,201. 11. G. Robinet, M. Barthelat, V.Gasmi and J. Devillers, J.Chem.Soc., Chem.Commvn., 1989, 1103. 12. X.Liao, S.Li and C. Yuan, J.Chem.Soc., Perkin Trens.2, 1990, 971. 13. RAli and KB.Dillon, J.Chem.Soc., Dalton Tmns., 1990, 1375. 14. N.V.Pavlenko and L.M.Yagupol'shii, J.Gen.Chem. U.S.S.R., (Engl. tmnsl), 1989, 69, 469. 15. L.V.Nesterov and N.E. Krepysheva, J. Gen. Chem. U.S.S.R., (Engl. t m s l . ) , 1989,659,634. 16. T.V.Kovaleva, J.Qtn.Chem. U.S.S.R., (Engl. tmnal.), 1989,69, 2207. 17. N.AEskew and S.AEvans Jr., J.Chem.Soc.. Chem.Commun., 1990,706. 18. V.V.Shereshovets, S.S. Ostakhov, N.M.Korotaeva, G.L. Sharipov, V.P.Kazakov,V.D. Komissarov and G.A. Tolstikov, BuIIAcad. Sci. U.S.S.R.(Engl. traml.).1989, 30,2460. 19. E. Vedejs and T.J.Fleck, J.Amer.Chem.Soc., 1989, 111, 5861. 20. E.Vedejs and C.F.Marth, J.Amer.Chem.Soc., 1990,112, 3905. 21. W.J.Ward Jr., and W.E.McEwen, J.Org.Chem., 1990,56, 493. 22. 0.1. Kolodyazhnyi and D.B. Golokhov, J.Oen.Chem. U.S.S.R. (Engl. tmnsl), 1989,59, 262. 23. M.Yu Dmitrichenko, V.G. Rozinov, and V.I. Donskikh, J.Gen.Chem. U.S.S.R.(Engl. trans13,1989,69,632. 24. E.M. Tsvetkov and AAKorkin, J.Gen.Chem. U.S.S.R. (Engl. tmnsl.), 1989,69, 849. 26. N.M.Yousif, Phphorus, Sulfur and Silicon, 1989,46,169. 26. A.A.Prishchenko, M.V. Livantsov, N.V. Boganova a n d I.F. Lutaenko, J.Oen.Chem.U.S.S.R. (Engl. tmnsl.), 1989, 69, 2485. 27. N. Weferling and R Schmutzler, Chem.Ber., 1989,18e, 1465. 28. Z.S.Novikova, I.L.Odinets and I.F.Lutsenko, J . Gen. ChPm. U.S.S.R. (Engl.transl.), 1989, b,87. 29. W.T.Murray, A. Pautard-Cooper, NAEskew and S.AEvans Jr., Phosphorus, Sulfur and silicon, 1990,49mO,lOl.
30. J.C.Caesar, D.V.Griffitha, P.A. Griffiths and J.C.Tebby, J.Chem.Soc., Perkin Trans.1, 1989,2425. 31. B.Ben Jaafar, D.El Manouni, R.Burgada and Y.Leroux, Phosphorus, Sulfur and Silicon, 1990,47,67. 32. S.K.Tupchienko, 1.N.Duchenko a n d A.D.Sinitsa, J.Gen.Chem. U.S.S.R. (EngLtransl.), 1989,m, 1333. 33.E. Balogh-Hergovich and G. Speier, Phosphorus, Sulfur and Silicon, 1990,48,223. 34.M.Ehle, 0.Wagner, U.Bergstrasser and M. Regitz, Tetrahedron Letters, 1990,31(24),3429. 35. I.V. Konovalova, L.A. Burnaeva, E.K.Khustnutdinova, R.N.Kamaletdinova, a n d kN.Pudovik, J.Gen.Chem. U.S.S.R. (Engl. transl.), 1989,5@,238. 36. I.V.Konovalova, I S . Dokuchaeva, Yu G. Tristin, L.A.Burnaeva, V.M.Chistokletov and A.N.Pudovik. J.Gen.Chem. U.S.S.R.(Engl.trans1.) 1989,6@,1535. 37. R.N. Burangulova, Yu.G.Tristin, I.V. Konovalov, L.A. Burnaeva, V.N.Chistokletov, and kN.Pudovik, J. Gen. Chem. U.S.S.R.(Engl. transl.), 1989,6@,1773. 38. V.F. Mironov, T.N. Sinyashina, E.N.Ofitserov, P.P. Chernov, 1.V.Konovalov and A.N.Pudovik. J.Gen.Chem. U.S.S.R. (Engl. trans1.),1989, 69, 2583. 39, R.Francke, J. Heine, and G.-V.Roschenthaler, Phosphorus. Sulfur and Silicon, 1990,49/50, 377. 40. KC.K. Swamy, S.D. Burton, J.M.Holmes, R.O.Day, a n d R.R.Holmes, Phosphorus, Sulfur and Silicon, 1990,49/60,367. 41. B.Kol1, K.Totschnig, J . Vogel, P.Peringer, E.P.Muller, M. Fischer, a n d W.Petter, Phosphorus, Sulfur and Silicon, 1990,4060,385. 42. Y.Leroux, D.EI Manouni, L. Labaudiniere, R. Burgada, A. Safsaf, A. Neuman and H. Gillier, Phosphorus, Sulfur and Silicon, 1990,47,443. 43.L, Lamande and AMunoz, Tetrahedron, 1990,46,3627. 44.AMunoz and L. Lamande, Phosphorus, Sulfur and Silicon, 1990,49/M),373. 45. R. Contreras, A.Murillo and P.Joseph-Nathan, Phosphorus, Sulfur and Silicon, 1990,47, 215. 46. H.Schmidt, C.Lensink, S.KXi and J.G. Verkade, 2.Anorg.Allg.Chem.. 1989,678, 75. 47. H.Schmidt, S.KXi, C.Lensink and J.G.Verkade, Phosphorus, Sulfur and Silicon, 1990, 49/M),l63. 48.D.V.Khasnis, M. Lattman and USiriwardane, Phosphorus, Sulfur and Silicon, 1990,49/50, 459. 49. I.S.Zal'tsman, G.KBespal'ko, A.M.Pinchuk and A.P.Marchenko, J . Gen. Chem. U . S . S .R. (Engl. transl.), 1989,6@,1698. 50. D.K Kennepohl and R.G. Cavell, Phsphorus,Sulfur and Silicon, 1990,40/M), 359. 51.R. Bohlen and G.-V. Roschenthaler, Z.Anorg.Allg. Chem., 1989,678,47.
3 Phosphine Oxides and Related Compounds BY B. J. WALKER
1 Preparation of Acyclic Phosphine Oxides The rriphosphines ( 1 ) have been converted into their monooxide ( 2 ) and monosulphide (3) derivatives by complexation with nickel(I1) chloride followed by reaction of the single, uncomplexed phosphorus1 . The monooxide and monosulphide derivatives of bis- 1,2-(dimethylphosphin0)ethane ( 4 ) have been prepared by direct partial oxidation of the parent phosphine or its dihydrochloride salt2. A variety of symmetrical and unsymmetrical 1,3-diphosphoryl-substituted (Ej-propenes ( 6 ) and ( 7 ) are available from nickel(l1 j-catalysed reactions of 1 -acetoxyallyl-substituted phosphine oxides (51 with secondary or tertiary phosphorus ( I V ) compounds (Scheme l ) 3 . 2,3-Bis(diphenylphosphinyl)-1,3-butadiene ( 8 ) acts as the starting material for syntheses of the corresponding dicyclopropyl, phosphine oxide (9, X = O ) and sulphide (9, X = S ) and, through reaction with diazomethane, the dioxide (10) (Scheme 2j.4 Phosphine sulphides and thiophosphates have been converted into phosphine oxides and phosphates, respectively, by reaction with dimethyldioxirane (Il j . 5 Optically active secondary and tertiary phosphine sulphides have been prepared by the reaction of optically active phosphinodithioates (12) with butyllithium followed by treatment with electrophiles.6 Compounds ( 1 3, R=t-Bu, E = H ) a n d (13, R=l-naphthyl, E=H) prepared in this study are claimed to be the first reported examples of optically active secondary phosphine sulphides. A variety of bis(2-hydroxyary1)phenylphosphine oxides ( 1 5 ) have been prepared from diary1 phenylphosphonates ( 1 4 ) by based-induced double 1,3-migration of phosphorus from oxygen to carbon.7 4-Pyrazolylphosphine oxides ( 1 6 ) have been synthesised and their 13C, 1H and 3 1 P n.m.r. reported.8
2 Preparation of Cyclic Phosphine Oxides The dihydrophosphete oxide (18), although it has not been characterised, is suggested to be the major product of air oxidation of 1,2-dihydro-phosphete (17).9 A new route to 2-aryl and 2-heteroaryl 2,5-dihydrophosphole oxides (20) and sulphides (21) is available from arylation of the phosphole metal
71
Organoph asphorus Chemisirk
72
X
II
Ph2P I
Ph2P(CH2),CHCH2PPh2
Me2PCH2CH2PMe2
(1) X = lone-pair, n = 1, 2 (2)x = 0, n = 1 , 2 (3) X = S, n = 1, 2
(4)
OAc (5)
(7)
(6)
E
0
Reagents: i, R3R4FH,NiCI2, CH&N(SiMe3),
Scheme 1
0"
i
*
p h 2 p k X" PPh2
1
(9) x = 0
iv
ii, iii 1
(9)x = s
E
Reagents: i, MeS=CH2; ii, HSiCI3, Et3N; iii, S,; iv, CH2N2
Scheme 2
S Ph,ll R p- SMe
i, BuLi
ii, E+
-
Ph,ll
5
3: Phosphine Oxides arid Related Compounds
73
0 HO
-
Ph![C)@R]
LDA
“[@I2
PhP
2
+ (0C)sM’
‘R
ArH
i
-
N‘ R’
V
A
(0C)sM’
R ‘
r
iiiiv
s:”
+ Reagents: i, AIC13, CH2C12; ii, PyH Br3; iii,[;
.;p,
r
bR
;iv, H20;v, S8, PhMe
N Me
Scheme 3
?=JLr 0.
lv X .PA
*
R
74
Organophosyhorns C’hemisry
complex (19) followed by decomplexation under appropriate conditions (Scheme 3).lO A synthesis of phospho sugars (e.g. 23) from 1-methoxy-3phospholene 1 -oxides (e.g. 22) has been reported.] 1 2-Bromo-3,-methyl-1ph en y l p hos phol ane- 1 -oxide (24), obtained from the corresponding 2phospholene 1-oxide, has been converted into a range of glycosyl derivatives ( 2 5 ) by reaction with nucleophiles (Scheme 4). A variety of oxides (26) and sulphides (27) of 1-phosphanorbornenes have been prepared by cycloaddition reactions of alkenes with 2H-phospholes followed by oxidation.12 Although obtained in low yield, the oxide (28) is the major product from the reaction of tolyl methyl sulphide with phosphorus tric hloride/aluminium trichloride followed by treatment with acetyl chloride (Scheme 5). The oxide (28) was also obtained as one isomer by the oxidation of the corresponding phosphine. 1 3 The phosphine oxide e x o - e x o cages (30) and (31) and e x o - e n d o cages (32) and (33) have been prepared from tris(4-hydroxypheny1)phosphine oxide ( 2 9 ) and in two cases, (30) and (33), X-ray structural analyses were Compounds (30 to 33) all form 1:2 complexes with p carried 01.11.’~ n i trophenol.
3 Structure and Physical Aspects The conformational behaviour of 2-phosphoryl- 1,3-dioxanes and dithianes continues to be an area of interest. Molecular mechanics methods have been applied to 2-phosphoryl-1.3-dioxane (34), the corresponding dithiane (35) and 2-thiophosphoryl-l,3-dithiane (36).15 The relative stabilities of the axial and equatorial conformers in each case vary due to a combination of differing 1,3-axial interactions and anomeric effects. The conformer calculated to be the most stable for (34) and (35) is the structure given in each case. In the case of ( 3 6 ) the isomers are estimated to be of approximately equal energy. In a separate study the different steric requirements in (34) and (35) have been evaluated and it is claimed that it is these, and not different anomeric effects, which determine the conformational preference in each case.] 6 13C and 3 1 P n.m.r. data have been reported for a range of 5,lOdihydrophenophosphazine derivatives including a number of phosphine The secondary phosphine oxide (37, R = H ) undergoes oxides (37).1 7 disproportionation at 200OC to give the corresponding secondary phosphine and phosphinic acid. In the form of its anion (37, R = H ) can be used to synthesise tertiary phosphine oxide derivatives of (37). A comparison of 1 7 0 n.m.r. chemical shifts of a range of phosphine oxides with 31P chemical shifts of the corresponding phosphines shows a linear correlation.1 8 However there appears to be no correlation between 1 7 0 shifts and 31P shifts in phosphine oxides. A systematic study has been carried out on the
3: Phosphine Oxides and Related Compounds
75
Br..
(22) iv-vi
Me
t
Me
1;'s
0 Ph
Reagents: i, PC15, CCI4, OOC; ii, PhMgBr, THF; iii, NBS, CCb; iv, KOAc, CH3CN; v, Os04, NaC103; vi, Ac20, py; vii, Nu-, DMF Scheme 4
M0S
-
MeyJ--&--rJM Me
Reagents: i, PC13, AIC13; ii, MeCOCI, AIC13 Scheme 5
76
0
0
H
i \\
R O (37)R = H, Bu', CH2Ph OMe
?
(Me2Sn(CI)CH2CH2)2PPh
(39)
\
0m9
(40)
3: Phosphinr Oxides and Rrlurrd Compound
77
solvent and concentration dependence of the P=O stretching vibration of triethylphosphine oxide.19 The absolute configuration of 1- l e r t - bu t y 1p h e n y Iph o s p h i n y 1-2 methylphenylphosphinylethane ( 3 8 ) has been determined by X-ray crystallography and, through chemical correlation, related to the corresponding ethene.20 The oxide ( 3 9 ) has been synthesised and its structure investigated by n.m.r and X-ray methods.2 1 Surprisingly the phosphine oxide (40) is very soluble in water22; oxide (40) also forms stable hydroxyphosphonium salts with acids and stable 1:l adducts with amines. 4 Reactions at Phosphorus Phosphine oxides (41) bearing at least two 2-pyridyl ligands at phosphorus are known to form 2,2'-bipyridyl and pyridine on treatment with organometallic reagents.23 It has now been reported that a similar reaction takes place on treatment with acid or in neutral hydroxylic solvents.24 It is suggested that the reaction proceeds via a pentacoordinate phosphorus intermediate ( 4 2 ) and this is supported by the isolation of phenylphosphinic acid from one reaction. A kinetic study of alkaline cleavage of the phosphorus-carbon bond in phosphine oxides has been reported .25 Treatment of triphenylphosphine oxide or tribenzylphosphine oxide with sodium in liquid ammonia generates diphenyl-( 4 3 ) and dibenzyl-(44) phosphinite ions, respectively.26 When photostimulated the anions (43) and (44) react with aryl halides by an S R N ~mechanism to give aryldiphenyl- and aryldibenzylphosphine oxides (Scheme 6). In the case of (44), consecutive debenzylation with sodium in liquid ammonia followed by photostimulated reaction with aryl halides provides a route to unsymmetrical triarylphosphine oxides. Thermolysis of dimethylphosphine oxide at >770K leads to the elimination of water to give 2-phosphapropene (46).27 Cleavage of the normally stable P=O bond is explained by reference to an energy hypersurface calculated by MNDO methods. This suggests that there is an entropy-favoured dissipation of the activation energy stored in the isomerization intermediate ( 4 5 ) . '
5 Reactions at the Side-Chain Warren continues to extend his phosphine oxide-based method of stereoselective olefin synthesis. The previously published method of acyl transfer followed by borohydride reduction to give selectively the t h r e o hydroxyalkylphosphine oxide intermediate has now been applied to more complex examples carrying other chiral centres.28 Optically active butyl(2methoxypheny1)phosphine oxide ( 4 7 ) has been used to provide a chiral
18
Otgmophasp horns Chem is trv
(421
f
i
Z,P=O
t
Z,PNa
-
ii
0 II Z2PAr
(43) Z = Ph (44) Z = PhCH2
Reagents: i, Na, NH3(,);ii, ArX, h v, Bu'OH Scheme 6 H Me,P=O
[Me,P-OH]
*
(45)
MeP=CH2
+ HO ,
(46)
OMe
(47)
(63:37)
.SPh
0 '
Reagents:i, LDA, -95°C; ii,
(49)
(48)
; iii, MsCl, Et3N, 0°C; iv, 0 ~ 0 4v,; KOH, DMSO;
vi, Mg monoperoxyphthalate;vii, PhSLi, THF; viii, NaH, THF
Scheme 7
3: Phosphine Oxides and Related Compound,y
79
synthesis of (Z)-2-but y l i d e n e c y c l o h e x a n - 1 - 0 1 ( 4 8 ) and ( 2 ) - 2 butylidenecyclohex-1 -ylphenylsulphide (49) (Scheme 7).29 The chirality at phosphorus appears only to control the stereochemistry at the carbon adjacent to phosphorus, the stereochemistry at the two chiral centres produced by cis-hydroxylation with osmium tetroxide is controlled by the initially generated chiral carbon centre. The cyclohexanone (53), an intermediate for the synthesis of thromboxane antagonists, has been prepared by a combination of phosphine oxide- and phosphonium ylide-based olefinations.30 Reaction of the lactone (50) with methoxymethyldiphenylphosphine oxide anion gave a poorly characterized adduct (presumably ( 5 1)) which on reduction with sodium borohydride, followed by treatment with sodium hydride gave the vinyl ether ( 5 2 ) in 80% overall yield from (50) (Scheme 8). Further modification gave the required cyclohexanone (53). Olefination of aldehydes with the a -fluoroalkylphosphine oxide ( 5 4 ) provides a highly stereoselective route to the (2)-fluoroalkenes ( 5 5 ) (Scheme 9).31 A similar reaction with the corresponding phosphonate gave a 1:l mixture of ( E ) - and (Z)-alkenes. A new one-pot synthesis of 2(diphenylphosphinoy1)cycloalkanes ( 5 6 ) by the reaction of cycloalkanone enolates with chlorodiphenylphosphine followed by oxidation has been reported (Scheme lO).32 Attempts to synthesise sarkomycin methyl ester (58) via reaction of the anion of phosphine oxide (57) with formaldehyde were unsuccessful as were similar reactions with other aldehydes, although the corresponding phosphonate anion does undergo olefination reactions. An X-ray structural analysis of (57) is reported. Two reports of syntheses of the complex phosphine oxide ( 5 9 ) and its use in the synthesis of the C l O - c 3 4 fragment of FK506, a highly potent immunosuppressant macrolactam, have appeared.33>34 The phosphine oxide ( 6 0 ) has been prepared and used i n a convergent synthesis of la-fluoro-25-hydroxycholecalciferol and l a - f l u o r o 25-hydroxyergocalcifero1.3~ The related phosphine oxide ( 6 1 ) has been synthesised enantiospecifically from (R)-(-) carvone;36 (61) is a key A-ring synthon for the preparation of la,25-dihydroxy vitamin D3. Phosphine oxide-based alkene synthesis has been used to synthesise the hydrindanol (66), possessing the correct relative configuration at four carbon centres for the vitamin D structure.37 Reaction of the allylicphosphine oxide anion ( 6 2 ) with 2-methylcyclopent-2-enone gives the enolate (63) which reacts with a series of (3-sulphonyl vinyl ketones to give unsaturated diketones (e.g. 6 4 ) i n good yield. Further modification of ( 6 4 ) provides the t r a n s hydroindanone phosphine oxide (65) the anion of which, on reaction with a-methacrolein followed by hydrogenation, gives (66) (Scheme 11).
Organophosphorus Chrmisir?,
80
2
N
Reagents: i, Ph2P
Y
OMe, THF, -78°C; ii, NaBH4, EtOH; iii, NaH, THF,
[N9 H
Li
Scheme 8
f?
i, ii
Ph2PCHC02Et
CO2Et
I
F
H (55)
(54) Reagents: i, Buli, THF; ii, R2CH0
Scheme 9
n = 0 , 1,2
(56)
Reagents: i, LDA, -78OC, THF; ii, Ph2PCI,-78'C, THF; iii, 02, RT
Scheme 10 Me
Me
OMe OMe Me
OR (57)
(58)
(59)
3: Phosphinr Oxides and Reluted Compounds
81
0
(65) \ - v i i , f l
HO
$3
(66)
0 Reagents: i, -60°C, THF; ii, ~
~
s
o
2 ; iii, H2, p Pd/C; h iv, I OH, MeOH, 60°C;
0 v, DIBAL-H; vi, LDA, THF, -1OOC; vii,
Scheme 11
Attempts to use Horner-Bestmann oxidation of the complex phosphine oxides (67) and ( 6 9 ) to prepare the corresponding ketones (68) and ( 7 0 ) as intermediates in a synthesis of d,l-methynolide were only partially s u c c e s s f u l . 3 8 The oxide (67) can, with difficulty, be deprotonated and further reaction with oxygen gives (68). However, the oxide (69) could not be deprotonated, probably due to the preferred conformation in ( 6 9 ) placing the proton adjacent to phosphorus towards the sterically-demanding interior of the ring. Olefination of the aldehyde (71) with the dianion of the P-keto ester phosphine oxide (72) has been used to synthesise ( 7 3 ) , a key intermediate in a convergent synthesis of the fungal biochrome ( 5 )teneIIin.39 Allenyl phosphine oxides (75) have been prepared by the reaction of the enediyne alcohols (74) with chlorodiphenylphosphine. When heated at 37OC in the presence of 1,4-cyclohexadiene, (75) gave mixtures of aromatic compounds ( 7 6 ) , ( 7 7 ) and (78) (Scheme 12). Evidence for the biradical ( 7 9 ) acting as an intermediate was obtained by heating (75) i n perdeuterotetrahydr~furan.~o The enediyne alcohol (74, R = C H 2C H 2 0 A c ) shows DNA-cleaving activity which is presumably related to diradical formation .4 1 The effect of different Lewis acids on the Diels-Alder reaction of diarylvinylphosphine oxides with cyclopentadiene to give ( 8 0 ) has been inves tigated.42 Lewis acids were found to catalyse the reactions and to enhance endo-selectivity. The regiochemistry of the 1,3-~ycloadditions of nitrones to diphenylvinylphosphine oxide and sulphide43 and of nitrile oxides and nitrones to racemic methylphenylvinylphosphine oxide (81) 4 4 has been investigated. Reactions with ( 8 1) are regioselective to give phosphinyl-isoxazolines (82) and -isoxazolidines (83), respectively, in good yields. The reactions show substantial diastereofacial selectivity and possible transition state structures are discussed. In one case (82, R=Ph) t h e stereochemistry was confirmed by an X-ray crystal structure. Aliphatic and aromatic thiols have been added to (S ) methylphenylvinylphosphine oxide ( 8 4 ) to provide optically active 0 alkylthio- and P-arylthioethylphenylphosphine oxides (85).45 The reaction of the phosphine sulphide (86) with tetrachloro-o -benzoquinone gives ( 8 7 ) which undergoes further r e a ~ a n g e m e n t6. ~ 6 Phosphine Oxide Complexes Triphenylphosphine oxide forms stable 1 :1 complexes w i t h alkyl hydroperoxides and a 2: 1 crystalline complex with dihydrogen peroxide. Infrared and n.rn.r. spectroscopic data is given for each complex f0rmed.~7
83
Ab CH20Me
RO
H -'*&BEt u
A
X
Et
OTBS
?
5)
(69)X = Ph2P (70)X = 0
(67)X = Ph2P (68)X = 0
0
+ O
H
C
0
0
EtO&FPhz
r
(71)
/
NaH. THF, BuLi, 0°C
EtOw 5 5
(73)
Scheme 12
Ph P\
'0
(79)
Organophosphorus C‘hrmisrty
4
,<‘‘Me
!?,A+ ‘A+
0 P-CH2CH2SX PhO
Me,ii
(84)
(85) X = R, Ar
3:
XS
Phosphine Oxides ond Relurrd Compound,\
REFERENCES
1.
H. Bmnner, H-J. Lautenschlager, W.A. Konig, and R. Krebber, Chem. B e r . . 1990,
2.
P. Maeding and D. Scheller, Z. Anorg. Allg. Chem., 1988. 5 6 7 . 179 (Chem. Abstr..
3.
Y. Lu, X. Tao. J. Zhu, X. Sun. and J. Xu. Synrhesis, 1989, 848.
123, 847.
1990, 112, 21053). 4.
K. Dziwok. J. Lachmann, D.L. Wilkinson, G. Muller. and H. Schmidbaur. C h e m B e r . , 1990, 123, 423.
5.
F. Sanchez-Baeza. G. Durand, D. Barcelo, and A. Messeguer, Terrahedron
Letters,
1990, 31, 3359. 6.
T. Kawashima. S. Kojima, and N. Inamoto. Chem. Lett., 1989, 849.
7.
B. Dhawan and D. Redmore. 1. Chem. ResearchfS), 1990, 184.
8.
A.B. Akacha. N. Ayed. B. Baccar. and C. Charrier, Phosphorus Sulfur, 1988. 40, 6 3 (Chem. Abstr..
1989, 111, 134311).
9.
K.M. Doxsee and G.S. Shen. J. Am. Chem. Soc.. 1989, 111, 9129.
10.
E. Deschamps and F. Mathey. J. Org. Chem., 1990. 55, 2494.
11.
K. Ikai. A. Iida. and M. Yamashita, Synthesis, 1989, 595.
12.
P. Le Goff, F. Mathey. and L. Ricard, J. Org. Chem., 1989, 54, 4754.
13.
G. Baccolini and E. Mezzina, J. Chem. SOC., Perkin Trans.1, 1990, 19.
14.
B.P. Friedricksen and H.W. Whitlock. J. Am. Chem. Soc.. 1989, 111, 9132.
15.
M. Mikolajczyk, P. Graczyk. M.I. Kabachnik. A.P. Baranov, J. O r g Chem.. 1989, 54,
2859. 16.
E. Juaristi, A. Flores-Vela, and V. Lasbastida, J. Org. Chem., 1989. 54, 5191.
17.
J.J. Skolimowski. L.D. Quin, and A.N. Hughes, J. Org. Chem., 1989. 54, 3493.
18.
J. Szewczyk, K. Linehan, and L.D. Quin, Phosphorus Sulfur, 1988, 3 7 , 35.
19.
U . Mayer. H. Hoffmann, and R. Kellner, Monatsh. Chem., 1988, 119, 1207; i b i d ,
20.
K.M. Pietrusiewicz. M. Zablocka, and W. Wieczorek. Phosphorus Sulfur,
1223. 1990, 4 2 ,
183. 21.
M. Dargatz. H. Hartung, E. Kleinpeter, B. Rensch, D. Schollmeyer, and H. Weichmann, J. Organomet. Chem., 1989, 361, 43.
22.
M. Wada, H. Ohta. N. Hashizume. M. Kanzaki, K. Hirata, and T . Erabi, C h e m . Express, 1988. 3, 471 (Chem. Abstr., 1989, 111, 194868).
23.
B.J. Walker in 'Organophosphorus Chemistry', Ed. B.J. Walker and J.B.
Hobbs
(Specialist Periodical Reports). T h e Royal Society of Chemistry. London, 1990,
v01.21, p.77. 24.
Y. Uchida and H. Kozawa. Terrahedron Letters, 1989, 30, 6365.
25.
G. Aksnes, R. Gierstae, and E.A. Wulvik, Phosphorus Sulfur, 1988. 3 9 , 141 ( C h e m . Absrr., 1989, 111, 134294).
26.
E.R.N. Bornancini and R.A. Rossi. J. Org. Chem., 1990. 55, 2332.
27.
H. Bock and M. Bankmann, Angew. Chem. Int. E d . Engl., 1989, 28, 911.
28.
P.M. Ayrey and S, Warren, Tetrahedron Letters, 1989, 30, 4581.
Xh 20.
N.J.S. Harmat and S. Warren, Tetrahedron Letters, 1990. 31, 2743.
30.
P.J. Harrison, Tetrahedron Letters, 1989, 30, 7 125.
31.
E. Baader, W. Bartmann, G. Beck, P. Below, A. Bergmann, H. Jendralla, K. Kesseler,
and G . Wess, Tetrahedron Letters, 1989, 30, 5 1 1 5 . 32.
M. Mikolajczyk, P. Kielbasinski. M.W. Wieczorek, and J. Blaszczyk, J . O r g . C h e m . .
33.
R-L. Gu and C.J. Sih, Tetrahedron Letters, 1990, 31, 3283; ibid, 3287.
34.
T.K. Jones, R.A. Reamer, R. Desmond, and S.G. MiIls, J. Am. Chem. Soc., 1990. 112,
1990, 55, 1198.
2998. 35.
S-J. Shiuey. I . Kulesha, E.G. Baggiolini. and M.R.Uskokovic. J. O r g . Chem., 1990, 31, 2 4 3 .
36.
S . Hatakeyania, H. Numata. K. Osanai, and S. Takano, J. Org. Chem., 1989, 54, 3515.
37.
R.K. Haynes, S.C. Vonwiller, and T.W. Hambley, J. Org. Chem., 1989, 54, 5162.
38.
E . Vedejs, R . A . Buchanan, P.C. Conrad, G.P. Meier. M.J.Mullins, J.G. Schaffhausen,
and C.E. Schwariz, J Am. Chem. Soc., 1989, 111, 8421; E. Vedejs, R.A. Buchanan, and Y . Walanabe, J. Am. Chem. Soc., 1989, 111, 8430. 39. 40.
J . H. Rigby and M . Qabar, J. Org. Chem., 1989, 54. 5852. R. Nagata, H. Yamanaka, E. Okazaki, and 1. Saito, Tetrahedron Letters, 1989, 3 0 , 4995.
41.
R . Nagala, H. Yamanaka, E. Murahashi, and 1. Saito. Teytrahedron Letters, 1990, 31, 2907.
42.
M. Maffei and G . Buono, New J Chem
,
1988. 12, 923 (Chem. Abstr., 1990, 1 1 2 ,
98635).
43.
K.M. Pietrusiewicz and A. Brandi, Phosphorus Sulfur, 1989, 4 2 , 135 (Chem. Abstr.,
44.
A . Brandi. P. Cannavo, K.M. Pietrusiewicz. M. Zablocka, and M. Wieczorek. J. U r g .
1990. 112, 77357).
Chem., 1989, 54, 3073. 45.
46.
K.M. Pietrusiewicz and M. Zablocka. Phosphorus Sulfur. 1988. 40, 47.
M . Granier, A. Baceiredo, H. Grutzmacher, H. Pritzkow, and G . Betrand, A n g e w . Chem. lnt. Ed Engl., 1990. 29, 659.
1 -
41.
H . Kropf and S. Munke, J. Chem. Research(S), 1990, 26.
4 Tervalent Phosphorus Acids BY 0. DAHL
1 Introduction The main area of activity this year has again been the use of tervalent phosphorus acid derivatives for preparation of phosphates or modified phosphates of biochemical interest. Most of this work is reported in part 3.3 of this chapter. Proceedings of the 11th International Conference on Phosphorus Chemistry, Tallin 1989, have been published? They contain several interesting papers on tervalent phosphorusacid chemistry. Relevant to a more specialised group of researchers is the proceedings of the 8th International Round Table on Nucleosides, Nucleotides and their Biological Applications, Alabama, 1988.2
2 Nucleophilic Reactions 2.1 Attack on Saturated Carbon.- Dibutoxyphosphine (1) is able to displace an alkoxy group from (2) to give the previously unknown dialkylaminomethylphosphonites (3);3 a similar reaction with N,N-dimethylformamide dimethyl acetal (4) gave (5).4
Equimolar amounts of methyl iodide alkylates (3, R = Et) at nitrogen, but excess of methyl iodide gave the Arbuzov product (6); in contrast pivaloyl chloride gave the trivalent substitution product (7).3 Dialkyl alkylphosphonates (8) with identical alkyl groups are usually made by heating trialkyl phosphiteswith a catalytic amount of an alkyl iodide. A cheap and easy alternative is to use a catalytic amount of iodine i n ~ t e a dAminomethylphosphonous .~ acid (9) has been prepared in high yield from the easily available N-Arylaminomethylphosphonates(1 1) were obtained in good yields from trialkyl phosphites and N-(methoxymethy1)arylamines in the presence of titanium tetrachloride.’ A series of phosphoenolpyruvate analogues (12) has been prepared using Arbuzov reactions between halomethacrylates and trialkyl phosphites.8 Other phosphoenolpyruvate analogues (13) were obtained by Perkov reactions using the in part labile 87
xx (BuO)~PH+ B u O C H ~ N R ~ (1)
(1)
+
(B u O ) ~ P - C H ~ N R ~
t.
1.
(3) R = Me, Et, Pr
(2) 120 "C -.
(Me0)2CHNMe2
[(BuO)~P]~CHNM~~
(4)
(5) Me
Me
M
y
! ? I
I ( B u O ) ~ P - C H ~ + NI-E ~ ~ Me1
B u O P - C H ~ + N EI-~ ~ I
Me
(B u O )P ~-CH2NEt2
(6)
f (Bu0)2P-CBut
+ [CICH2NEt2]
(7)
!
I2
(R0)3P
R-P(OR),
A
+
95-99 70
( 8 ) R = Me, Et, Bu
N-CH2Br + (Me3Si0)2P--COOEt
0
f
i, A
ii, 6N HCI*
H2NCH2-P-H I
OH
(10) (9)
ArNHCHzOCH3
+
P(OR)3
Tic14 r.l.
!
ArNHCH2-P(OR)2 (11)
R12-f WH)2
R2
COOH
(Et0)2P-SR
0 II
OEt
,..=,,
f + BrCH2C-COOEt
COOEt
(14) R = Pr', Bu, Ph
(13)
(12) R'
Et3NH+H2P02-+ 2 Me3SiCI
Et3N
-
9 (Me3SiO)zPH
0
0
R2
ii, H30+
~
R'
H-zlyC~~~3 3
AH
R2
thiophosphites (14).9 2.2 Attack on Unsaturated Carbon.- A versatile route to phosphinic acids (15) is
the 1,4-addition of bis(trimethylsily1)phosphonite (16) to a$-unsaturated esters.
The
pyrophoric (16) was prepared in siru from triethylammonium phosphinate; silylation and 1,Qaddition can be repeated to give (17), or performed in one step if symmetrical phosphinic acids (17) are wanted. Tervalent phosphorus acid esters (18) react with dialkyl acetylenedicarboxylates in the presence of carbon dioxide to give 1,2-oxaphospholenes (19);l these reacted further with an excess of the phosphorus reagent to give different ylids, (20) or (21), dependant on the number of methoxy groups in (18). Dialkyl l-alkynylphosphonates (22) were formed in good to high yields by treatment of 1-alkynyliodonium tosylates (23) with trialkyl phosphites;’
the reaction is exo-
thermic with trimethyl phosphite but requires heating with triethyl or triisopropyl phosphite. The addition of trimethyl or triethyl phosphite to 3-alkylene-2-oxindoles (24) has led to new product types for a$-unsaturated carbonyl compounds, i.e. a stable trialkoxyphosphonium zwitterion (25),l and a C-alkylated phosphonate (26).l The thiophosphite (27) with acetyl chloride gave mainly the Arbuzov product (28) in methylene chloride, but the substitution product (29) was the main product in hexane or without solvent, probably because the intermediate is a phosphorane in the latter case.l
2-Acetylphenyl alkylphosphonamidites, phosphorodiamidites, or phos-
phoramidites (30) upon heating gave different cyclisation products (31)-(33) dependant on the substituents on phosphorus, and on the amount of amine hydrochlorides present in (30).l
2.3 Attack on Nitrogen, Chalcogen, or Halogen.- The stereochemistry of oxidation of two cyclic phosphites with 02/AIBN, 12/H20, and N204 has been shown to be clean retenti0n.l
The 02/AIBN reagent is recommended for introduction of oxygen
isotopes; there was no observable scrambling of the labelled atoms. The ability of a series of phosphites, phosphonites, and thiophosphites to destroy hydroperoxides has been studied kinetica1ly.l Tervalent phosphorus acid amides, 8.g. (34), with hydroxylamines or hydroxamic acids gave a mixture of oxidised products, 8.g. (35)-(37), which at least partly must have come from a primary substitution product (38), observed transiently by 31P n.m.r.l Phosphites are fairly easily oxidised to thiophosphates with sulphur in pyridinel
40
Organophosphorus Chrmistv
5;OOR Ph, P(OMe)s,
C
+
+
III
-
PhnP(OMe)s,P
c02
i?O ROOC COOR
5;COOR
(1 9)
(18)
Ph2(MeO)PHCOOR
+ ROOC
Ph, (MeO)snPO
P(OMe)Ph2
(211
(20)
R'CH-$(OR3)3
I
+
(26) (Et0)2P-SBu
+
5;'
+
MeCOCl
e. (EtO),P-COMe I
CI-
SBu
(27)
p
EtO, /P\ BUS COMe
(28)
+
EtCl
Z=ZZ
(Et0)2P-COMe I SBu
(Et0)2PCI
(29)
+
BuSCOMe
4:
Ttwalerti Phosphorus Aci&
91
(30)R = Me, Et, NEt2 OEt, OPr R = OEt, OPr
1
+
92
0rganophosphoru.s Chumisty
carbon disulphide, but the danger of precipitation of sulphur during automated DNA synthesis has stimulated a search for alternative sulphur-transferreagents. Three such reagents are (39),20 (40),21 and (41).21The reagent (39) is very soluble in acetonitrile, and anchimeric assistance during the sulphur transfer step makes the reaction very fast; the diacyl disulphides (40) and (41) reacted more slowly, but gave clean reactions without dealkylation products from attack of thioate ions on R1. The stable N-(alkyVaty1thio)succinimides (42) or -phthalimidesreact exothermicallywith phosphites to give simple access to a variety of thiophosphates (43).22 Trialkyl phosphites remove sulphur from phosphonodithioformates(44) to give the stabilized ylids (45) which can be further transformed to (46) or (47).23 Phosphorodiamidites, e.g. (48), and Nchloroamines (49) gave exclusively diamidochloridates, e.g. (50), in methylene chloride, whereas in petroleum ether some amidate, e.g. (51), was formed as The reactions of carbon tetrachloride with alkylbis(dialkylamino)phosphines (52) have been further studied this year.25 The remarkable rearrangement (53)to (54) occurs only with large isopropyl substituents on nitrogen, and with alkyl or hydrogen on the ylidic carbon.
3 Electrophilic Reactions 3.1 Preparation.- Trialkyl or triatyl phosphites and trithiophosphites (55) can be
obtained in 50-90% yields from white phosphorus, carbon tetrachloride, triethylamine, and the appropriate alcohol, phenol, or thiol in a polar aprotic solvent such as dimethylformamide.26 A series of racemic phenylbis(dialkylamino)phosphines(56) have been prepared in a one-pot synthesis as shown;27 the bulk of the dicyclohexylamino group prevents substitution of the second chlorine atom, and the products (56) are claimed to be stable to air and moisture. In a one-pot synthesis tns(diethylamin0)phosphine has been treated successively with three different alcohols to give a 89% yield of the thiophosphate (57) after oxidation with sulphur28 Several tervalent diphosphorus compounds (58)-(61) have been prepared from the disecondary phosphine (62) as shown.2g A number of compounds containing the new 1,3,2-0xathiaphospholen ring system (63) have been prepared from (64)30 or (65).31 Another study has been directed to the preparation of dihydro-l,3,2-OXa~aphosphonns, e.g. (66).32
4:
Tervalenr Phosphorus Acids
E
fl
93
+
(R10)3P + R2C-S-S-CR2=
-
T)?
(R10)3P-S--CR2
6
(40) R2 = Ph (41) R2 = PhCH2
(R10)3P=S
+
E f l
R2C-S--CR2
-S-CR2
(49)
CI
Cl
0
(EtZN)sP=O
II
(Et,N)2PCI
+
+
EtCl
Et3N
(50)
(R12N),P--CH2R2
+ CCI4
-
(52) P4
+
12 RXH
CI
Pi
RI
I
(R’&P=CHR2
(R12N)2P--CHR2 (54)
(53)
+
6 CCI4
+
6 Et3N
50-70 “C DMF
4 (RX)3P
(55)
+
6 CHC13
x = 0,s
+
6 Et3NHCI
94
Organophosphorus Chemisty
n n 0 N w wNM
n
(56) NR2= N(CH2),, n =4-6, N
v
rj-/
(57) R’OH = cis -9-octadecen-1-01 R20H= cholesterol R~OH = nonan-1-01
0
0
OSiMe3OSiMe3
I’ I’ MeP(CH2)nPMe I 1
I
Me2N-SiMe2
(58) n =2, 3
H
MeP(CH2)” PMe
I
NMe2 NMe2
I
H
I
MeP(CH2), PMe
I
(62) MeP(CH2)3PMe
I
I
/
Me2NH
I
MeP(CH2’3PMe (60)
Me-P-P+-Me
(59)
U
CI -
(61) SH 0 X-PCI,
+
I
II
RCH-CMe
Et3N
NHMe
+
X-Pfx
II
------RO-P(NEt2)2 Me
(63) X = CI, OR, NEt2 R=H,Me
(64) X = CI, OEt, NEt2
X-PCI,
0
R
I
0
II
MeC=CH-CMe
-
+ HSCH2CMe
(65) R = Me, Et, Bu
0
Me (66) X = OR, Ph
The ylid anion (67) with chloroaminophosphines gave the phosphino ylids (68) and (69), and a small amount of the product (70) arising from N-attack on (67).33 Both (68) and (69) with dichlorophosphines gave five-membered ring compounds, e-g. (71). The first air-stable a-diazophosphine (72) has been prepared and characterized by an X-ray crystal structure d e t e r m i n a t i ~ n . ~ ~ 3.2 Mechanistic Studies.- A number of substitution reactions of alcohols, phenols, or amines with 1,3,2-dioxaphospholans, e.g. (73), oxazaphospholans, and diazaphospholans have been followed by 31 P n.m.r. and shown to involve H-phosphoranes,
e.g. (74).35 The reactions are run in toluene or without solvent, and without addition of an acidic catalyst; in some systems, with 4-chlorophenol as the nucleophile, an equilibrium was established between an H-phosphorane (75) and a phosphonium salt (76), but the authors still favour (75) as the true intermediate. The equilibrium constants for a series of exchange reactions between (thio)phosphites (77) and (thio)phosphorodichloridites (78), and some analogous bromidites and a fluoridite, have been measured.36 The constants increase with increased electron donor ability of R. The reaction of a phosphonamidite (79) with a trifluoracetyl ester (80),to give a In phosphonite (81), has been shown to be catalysed by 4-dimethyIamin0pyridine.~~ contrast to an earlier report where a similar reaction proceeded with retention of configuration at p h o ~ p h o r u s the , ~ ~present system gave an equal amount of the two diastereomers (81). A mechanism is proposed which involves attack of an alkoxide, formed by de-trifluoracetylation of (80), on an equilibrating DMAP-intermediate (82). Another unusual substitution reaction is one between an alkoxyborane (83) and a phosphite (84).39 The phosphite was prepared in situ from acetylacetone and diethyl phosphorochloridite, and the substitution occurred under very mild conditions and gave high yields of phosphates after oxidation.
3.3
Use for Nucl eotide, Sugar Phosphate, Phospholipid, or
Phosphoproteln Synthesis.- Several reagents have been proposed this year which can be used to phosphitylate complex alcohols. The new phosphoramidite (85) gives allyl phosphates which can be deprotected with Pd(Ph3P)4 and ammonia; its usefulness was demonstrated by phosphorylation of several nucleosides and peptides.40 The allyl phosphorodiamidite (86) has been used to prepare nucleoside phosphoramidites containing allyloxycarbonyl protecting groups on the bases.41 After solid
Organophosphorns Chemistry
96
+
Ph$-&CN
Ph&-E=C=N
o o \ P - P h
'
-
+
Ph,k=C=N-P(NPr',),
I
Na+,
MeNH,
' 0
q y 0-P;;
H
QoH,phzPhP(NHMe)2 0-P,
I Ph NHM~ (74)
(73)
NHMe
(76)
(75) (RX)3P
(77)
+
140 "C
RX-PC12
2 (RX)2PCI
(78)
X = 0, R = C5Hllr Ph, H(CF2)&H2, CsF5 X = S, R = C4H9, Ph
4:
Trrvalent Phosphorus Acids
97
DMT*-P +
CF 3 C O O p T
DMTrOp
T
DMAP
OAc
(80)
(79)
DMT*v
OAc
(81)
'\PZN>NMe2 \ Me/
RO-BEt2
+
/
0EOW C *
(Et0)2P-OR
+
E t 20 i r--$ l e
0 (Et0)2P -
(83)
O Me f
Me
(84)
(CH2= CHCH20)2P-N Pr'2
CH2=CHCH2&P(
NP62)2
x\ o
>
P
0
-0PCI2 Me3%
-NEtp
Organophosphorus C’hrmi.wy
98
phase synthesis it is possible to deblock the oligonucleotide with a palladium reagerri without cleavage from the support.41 The new, cyclic amidite (87) is more stable and easier to purify than the analogous dibenzyl phosphoramidite and has been used to phosphitylate inositol
derivative^.^^
Dimethyl N,Ndiethylphosphoramidite (88) was
used to prepare Ophosphorylated Boc-tyrosine for use as a monomer in peptide synthesis.43 The di(4-chlorobenzyl) phosphoramidite (89) has been used similarly to phosphitylate serine, threonine, and tyrosine
derivative^.^^ The 4-chlorobenzyl groups
are easier to remove than methyl groups from the products, and are better than benzyl groups in withstanding the acid treatment necessary to remove N-Boc groups. The reagent (89) has also been used successfully for phosphitylation of a support-bound ~ e p t i d eA . ~cyclic ~ tripeptide containing a phosphordiester group has been made using A series of phospholipids (91) has been prepared using (92).47 An Ogeranyl (1-thio)diphosphate (93) was prepared employing (94) to introduce the thiophosphate group via an H-phosphonate i n t ~ r n e d i a t ethe ; ~ ~trimethylsilylethyl protecting group was removed with fluoride ions. Two papers have appeared this year about the use of
tris(hexafluoroisopropy1) phosphite (95) to prepare oligodeoxyribonucleotides via the H-phosphonate a p p r o a ~ h An . ~improved ~ ~ ~ ~ preparation of (95)is given,50 and a better catalyst found for the
coupling^.^^^^^
An improved synthesis of (96, B = T) and the synthesis of several 5-substituted deoxyuracil cyclic 3’,5’-phosphoramidates using tris(dimethy1amino)phosphine (97) have been published;51 the diastereomers were separated by HPLC on silica. Substitution of one amino group in tris(diethy1amino)phosphine (98) to give nucleoside phosphorodiamidites (99) is possible in nearly quantitative yields using an equimolar mixture of tetrazole and diethylamine as the catalyst;52 with tetrazole alone 26% of the bis(nuc1eoside) phosphoramidite (100) is formed. The diamidites (99) were used as monomers in oligonucleotide synthesis, and the resulting phosphoramidite linkage hydrolysed to H-phosphonates, or oxidised to phosphoramidates. The same group found that the morpholinoditetrazolide (101, X = tetrazolyl) was the most selective of several compounds (101 ) for monosubstitution with nucleosides, and that subsequently 3’,5’-dinucleoside phosphoromorpholidates could be prepared efficiently in
A series of substituted phenyl N,N,N’,N’-tetraethyl phosphorodiamidites (102) has been prepared and used to evaluate nucleoside aryl phosphoramidites (103) as monomers for oligonucleotide synthesis.54 As expected, the aryl phosphor-
4:
Tervalent Phosphorus Acids
99
(96) B = T, U, 5-R-U
DMTav +
P(NEt2hMDMTmpB
OH
r m r O P-NEt2 p
+
0-P(NEt2)2
(98)
n
ArONa
+
CIP(NEt2)2
0-
-
ArOP(NEt& (1 02)
I
o\ A
4P-SBU'
P-NEt2
d
N C V "
+ Bu'SH
Nc-o-p<
CI -0-PCI2 NC
SBu'
(ButS)2PCI+ (NC/\/0)2PCI
2
amidites coupled more slowly than the usual alkyl phosphoramidites, and none seemed very promising for oligonucleotide synthesis. The method to prepare oligonucleotidesby coupling of iodine-activated nucleoside thiophosphites (104), published a few years ago,55 has now been refuted.56 The alleged thiophosphorochloridite(105), used to prepare (1b4), is very unstable, and the monomers believed to be (104) were actually the 3’,3’-dinucleoside phosphites (106), formed from (107). These phosphites, and others like (108), are indeed activated by iodine to make coupling reactions with alcohols possible, but the reactions are not clean enough to be useful for oligonucleotide synthesis.56 A procedure has been developed for a solid phase synthesis of 2’,3’-branched oligonucleotides, using the diamidite (109) as a monomer to introduce the branch point;57 a good yield of the branched product was obtained provided a high-loaded support and a low concentration of (109) was used. A linker reagent (110), which allows multiple binding of e.g. biotin at the 5’-0nd of oligonucleotides, has been developed.58 After coupling and oxidation, the DMTr group may be removed and (110) again added to the liberated alcohol group; in this way a linker consisting of five units was attached to an oligonucleotide and labelled with biotin, after removal of the Fmoc groups, for use as a very sensitive hybridization probe. The reagent (111) was used to attach fluorescent compounds to oligonucleot i d e ~ and , ~ ~the reagent (1 12) to label oligonucleotides with biotin6O Preformed phosphoramiditereagents introducedthis year to attach reporter groups or other active groups to oligonucleotides include the biotin derivative (113),6l the anthraquinone derivatives (1 14) and (1 15)62 the fluorescein derivative (1 1 6 p 3 and several derivatives (117)64 Arabino oligonucleotides up to a hexamer have been prepared by solid phase synthesis using (1 18) as the m0nomer;6~the phosphoramidites (118) could be obtained rather pure without 2’-OH protection due to steric hindrance for phosphitylation at this position. Deoxyoligonucleotidescontaining flexible nucleoside analogues have been synthesized using (119)66 or (120)67 as the modified monomers; in both cases hybridizationwas greatly impeded. A series of O-thymidine-3’-ylthiophosphoramidites (121) have been prepared and evaluated for use to prepare dinucleoside phosphorodithioates (122).68 The S cyanoethyl derivatives (121) were less prone to oxidation than the S-2,4-dichlorobenzyl analogues, and the N,Ndimethylthioamidites (121) were sufficiently reactive to
4:
101
Tcmwktnt Phosphorus Acid.$
(112) B = T , I
102
Organophosph oms Chemistr?, NH(C H2)6NHR 2 f $N OAN
"""V
OL P -NPr', N C P O '
(1 17) R' = biotinyl, 2,4dinitrophenyl,
(118) B = AbZ, U
dansyl, pyrene-3-sulphonyl R2 = H, Me
DMTa-Lod \
P
OH
DMTa
4:
Grvalent Phosphorus Acids
103
couple within a few minutes upon activation with tetrazole. However biproducts were formed which were ascribed to the lability of the alkylthio group in the thioamidites and the intermediate thiophosphites. Ribonucleoside thiophosphoramidites (123),prepared in the same way as (121), have been used to obtain the first ribonucleoside phosphorodithioatedimers (124);69 these were very resistant to nucleases and, more remarkable, also to hydrolysis by conc. aq. ammonia. The nucleoside phosphoroditriazolides (125) have been used by two groups for the preparation of nucleoside Hphosphonodithioates (126).70*71 The latter were shown to give dinucleoside phosphorodithioates, either directly by iodine activation70 or via activation with pivaloyl chloride to give H-phosphonothioatesfollowed by oxidation with sulphur.71 An S-thymidine-3’-yl thiophosphoramidite (127) has been prepared and used to synthesize a dithymidine phosphorothioate(128) and the dithioate (129),72 as well as some oligonucleotides containing one phosphorothioate linkage.73 In order to overcome the low reactivity of (127) a stronger catalyst than tetrazole, 5-(4-nitrophenyl)tetrazole, was used, but like (121), side reactions occurred which were ascribed to partial displacement of the 34hiothymidine group upon activation. Deoxynucleoside methylphosphonate dimers have been obtained with up to 79% diastereomericexcess of the Rp isomer when the previously described coupling
with methykiichlorophosphine was carried out at -80°C.74 Deoxynucleoside phosphoramidate dimers (130) with the nitrogen atom at the 5’-linkage position have been prepared as shown;75 they could be used as dimer building blocks to incorporate such phosphoramidatelinkages in oligonucleotides. Another route to oligonucleotides containing phosphoramidateslike (130) was the coupling of a normal phosphoramiditeto
a support-bound oligonucleotide containing a 5’-amino group;75 the latter was obtained by using (131) as the monomer. An easy route to dinucleoside silyl phosphites (132) has been described employing (133) as the coupling agent;76 the dimers (132) were useful precursors to methylphosphonates, phosphoramidates, and Hphosphonates.
3.4 Ml8cellaneous.- Several oligoethylene glycols, or similar diols containing one or two amino groups, have been treated with diphenylchlorophosphineto give ligands,
8.9. (134) and (135), which were used as ‘ditopic” ligands that coordinate soft and hard metal ions ~irnultaneously7~ Similar ligands containing 1,3.2-dioxaphospholans or 1,3,2-diazaphosphoIans, e.g. (136),were also studied.78 The new ligands (137)79
DMTrov ?
0 OSiButMe2
R'S-P(
NR2,
-s
(1 23) B = APac,CbZ,GPx, U
OH
-!-OV HO OH
(124)B = C , G
C'\
3
NR22= NMe2, N RO
B
"OV
-
(1 26) R = DMTr, Pix
OH (128) X = O (129) X = S
4: Tervalent Phosphorus Acids
105
DMT*-v +
O-P(OMe),
OAc (132) B', B2 = Abz, T
Ph2P-
0 T O Pn O -PPh2
Ph2P-OANANnO-PPh2 I I
Me (134) n = 1-4
Me
(135)
* O--CH~H-CH~NP~'
I
I
PR2
(137) R = C y , Ph
(136) X = 0, NMe
Cy2P-0'
=U
I06
Orgml o p hosph oru.5 C ' h c w i 5 it-\,
and (138),80 for use in asymmetric hydrogenation catalysis, have been described.
4 Reactions Involving Two-co-ordinate Phosphorus A series of two-co-ordinated, conjugated compounds (139) was prepared by simple condensation as shown.81 Most of these were stable at O°C. Attempts to prepare a similarly conjugated compound (140) gave the dimer (141) instead.82 Phosphenium ions (142) with isocyanides gave the new 1,3-azaphospheten cations (143);83 with t-butyl isocyanide and larger substituents on the amino groups elimination of isobutene occurred to give cyanophosphines, e-g. (144). The reaction of chlorophosphenium ions (145) with silylated amidines gave the new 1,3,2-diazaphospheten cations (146).84 Several new phosphonium salts have been obtained from phosphenium ions and 1,3-dienes or o-quinones, e.g. (147).85 A series of phosphino substituted diphosphenes (148) has been prepared as shown and the structure of three examined by X-ray crystallography.b6 The P-P-P angle was less than 90° in two cases in agreement with expectations from ab initio calculations. The syntheses of the new, stable diphosphenes (149)a' (150),88 and (151 )89 have been described.
5 Miscellaneous Reactions The reaction of phosphorous acid with pivaloyl chloride in pyridine has been studied;90 three eq. of pivaloyl chloride gave the triacyl phosphite (152). Thiophosphinites or monothiophosphites (153) rearrange spontaneously to the thiophosphoryl isomer (154) in the presence of oxygen.91 The rearrangement was inhibited by the addition of radical inhibitors. Irradiation of a mixture of naphthalene or phenanthrene and trialkyl phosphites in the presence of 1,3-dicyanobenzene gave several isomeric monoph~sphonates.~~ The first phosphonia-alkene (155) has been prepared as shown;93 an X-ray crystal structure reveals a twist of 60° around the double bond! The diphosphinodiazomethane (156) upon heating in benzene gave (157) by carbene insertion into one of the isopropyl groupsg4 The first diphosphirene (158) has been prepared and
4:
li~walrtitPhosphorus Acids
+
X=P-CI
107
-
Me3Si-N=Y
X=P-N=Y
(139) X = C(SiMe3)2, N
Y = CR'R2, PR3 ( Me3Si)2CH,
Ph
-
I 2 [(Me3Si),CH-P=N-C=N-SiMe3]
I4 + 11
(140)
(R12N)2P+ + R2NC
-
+
(R12N)2P=C=N R2
p\'
N \pPh
(Me3Si)pCH°F-N'~i~e3 N\ C =N -SiMe3 Ph/
-
(141)
(R12N)2P-C&-R2
(142) R' = Me, Et, Pr'
R'PN,
NSiMe3
P+
+
R2-C,
CI'
//
-
N Rl2N--P/ ;&R2 N '
N(SiMe3)2
I
SiMe3
(145)
(146)
(R"P+
+
-
0
(R2N)2P,+ 0 /
O
h
(147)
Li
(Pri2N)2P-PC12 + R-P<
-
SiMe3
(P$2N)2P-P=P-R(Pri2N)2P-P(SiMe3)2 (148) R = Mes, NHMes, OMes,
G
+ RPCI2
, N(SiButMe2)2, N(SiMe3)N(SiMe3)2
I ox
Organop hosphomi C 'hcvnisrv
P=P
P=P
/
R
'
Ph3Si
F3C (151) R = C(SiMe3)3,
+
H3P03
3 Bu'COCI
-Py
(Bu'COO)~P (152) S
Rt2P-SR2
0 II -&+R12PR2
R' = EtO, R2 = CH2COOEt **
+
(Pri2N)2P-C-SiMe3
CF3S03SiMe3
-
(Pr'2N)26=C(SiMe3)2 CF3S03(155)
Pr',N,
P(NP$2)2
2 !
(Pri2N)2P-C-P(NPr'2)2
A
__c
Pr'' (1 56)
:$Me Me (157)
4:
Evvulent Phosphorus Acid.v
w
MeN ‘P’
I
MeN NMe \ / Me2N/%NSiMe3
NMe
NMe2 (161)
+
Me3SiN3 NMe
K
MeN
NSiMe3
\P’ Me2” ‘.\S
characterizedby an X-ray crystal structure d e t e r m i n a t i ~ n . ~ ~ In an attempt to prepare a phosphathiosemicarbazide (159) the diphosphine monosulphide (160) was obtained instead.96 This surprising result was explained by attack o! the dhlorophosphine at sulphur instead of at nitrogen as shown. Anothgr unexpected result was the attempted Staudinger reaction of trimethylsilyl azide with (161) which gave (162);97 the reaction is probably initiated by azide attack at the thiocartmnyl group in preferenceto the phosphorus atom.
References 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12 13. 14. 15.
16. 17. 18. 19. 20. 21.
A. Aaviksaar (ed.), Phosphorus, Sulfur and Silicon, 1990, 49-52, 1-975. J. A. Secrist 111 and J. A. Montgomery (eds.), Nucleosides Nucleotides, 1989, 8, 625-1178. A. A. Prishchenko, M. V. Livantsov, N. V. Boganova, and I. F. Lutsenko, J. Gen. Chem. USSR, 1989,59,2130. A. A. Prishchenko, M. V. Livantsov, N. V. Boganova, P. V. Zhut-skii,and I. F. Lutsenko, J. Gen. Chem. USSR, 1989,59,2132. V. K. Yadau, Synth. Commun., 1990, 20,239. 0.Grobelny, Synth. Commun., 1989, 19 , 1177. H.-J. Ha, G.4. Nam, and K. P. Park,Tetrahedron Lett., 1990, 31, 1567. H. G. McFadden, R. L. N. Harris, and C. L. 0.Jenkins, Aust. J. Chem., 1989, 42, 301. C. Despax and J. Navech, Tetrahedron Lett., 1990, 31, 1557. E. A. Boyd, M. Corless, K. James, and A. C. Regan, Tetrahedron Lett., 1990, 31,2933. J. C. Caesar, D. V. Griffiths, P. A. Griffiths, and J. C. Tebby, J. Chem. SOC., Perkln Trans. 1, 1989, 2425. J. S. Lodaya and G.F. Koser, J. Org. Chem., 1990, 55, 1513. R. K. Bansal, D. Sharma, and J. K. Jain, Indian J. Chem., 1988, 278, 610. M. R. Mahran, W. M. Abdou, N. M. A. El-Rahman, and M. M. Sidky, Phosphorus, Sulfur and Silicon, 1989, 45,47. T. Kh. Gazizov, L. N. Ustanova, andYu. V. Chugunov, J. Gen. Chem. USSR, 1989, 5 9 , 1712. F. S.Mukhametov, E. E. Korshin, V. M. Nekhoroshkov, and Yu. Ya. Efremov, J. Gen. Chem. USSR,1989,59,1159. W. G. Bentrude, A. S. Sopchik, and T. Gajda, J. Am. Chem. SOC.,1989,111, 3981. T. Kbnig, W. D. Habicher, and K. Schwetlick, J. Prakt. Chem., 1989, 331, 913. M. K. Grachev and E. E. Nifant’ev, J. Gen. Chem. USSR, 1989, 59, 1538. R. P. lyer, W. Egan, J. B. Regan, and S. L. Beaucage, J. Am. Chem. SOC., 1990, 112, 1253; R. P. lyer, L. R. Phillips, W. Egan, J. B. Regan, and S. L. Beaucage, J. Org. Chem., 1990,55,4693. P. C. J. Kamer, H. C. P. F. Roelen, H. van den Elst, G.A. van der Marel, and J. H. van Boom, Tetrahedron Lett., 1989,30,6757.
4:
Tmtalent Phosphorus Acids
111
22. 23. 24.
C. E. Milller and H. J. Roth, Tetrahedron Lett., 1990,31,501. A. Bulpin, S.Masson, and A. Sene, Tetrahedron Lett., 1990,31, 1151. T. Kh. Gazizov, L. K. Sal'keeva, and Yu. V. Chugunov, J. Gen. Chem.USSR,
25.
0.1.Kolodyazhnyi, J. Gen. Chem. USSR, 1989,59,285;0.1. Kolodyazhnyi and D. B. Golokhov, Ibld., 2194. L. Riesel, M. Kant, and R. Heibing, 2. Anorg. Allg. Chem., 1990,580, 217. T. Mohan, M. N. S. Rao, and G. Aravamudan,Tetrahedron Lett., 1989,30,
1989,59,1346. 26. 27.
4871. 28.
S. D. Stamatov and S. A. Ivanov, Phosphorus, Sulfur and Slllcon, 1989,
45,73. 29. 30. 31.
N. Weferling and R. Schmutzler, Chem. Ber., 1989,122, 1465. A. R. Burilov, 1. L. Nikolaeva, M. A. Pudovik, R. G. Musin, and A. N.'Pudovik, J. Gen. Chem. USSR, 1989,59,1493. A. R. Burilov, 1. L. Nikoiaeva, and A. N. Pudovik, J. Gen. Chem. USSR, 1989,
59,1492. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.
F. S.Mukhametov, R. M. Eliseenkova, and E. E. Korshin, J. Gen. Chem. USSR, 1989,59,277. H. Griltzmacherand H. Pritzkow, Chem. Ber., 1989,122, 141 1. A. Baceiredo, J. Organometal. Chem., 1989,372,201. B. Tangour, C. Malavaud, M. T. Boisdon, and J. Barrans, Phosphoru8,Sulfur and Slllcon, 1989,45,189. V. A. Chauzov, Yu. N. Studnev, L. 1. Ragulin, and A. V. Fokin, J. Gen.Chem. USSR, 1989,59,1 146. A. V. Lebedev, G. R. Wenringer, and E. Wickstrom, Tetrahedron Lett., 1990,
31,851. L. Homer and M. Jordan, Phosphorus and Sulfur, 1980,8,235. W. V. Dahlhoff and K. M. Taba,Z. Naturforsch., 1989,44b, 1260. W. Bannwarth and E. Kiing, Tetrahedron Lett., 1989,30,4219. Y. Hayakawa, S.Wakabayashi, H. Kato, and R. Noyori, J. Am. Chem. SOC.,
1990,112,1691. 42. Y. Watanabe, Y. Komoda, K. Ebisuya, and S. Ozaki, Tetrahedron Lett., 1990, 31,255;Y. Watanabe, T. Shinohara, T. Fujimoto, and S. Ozaki, Chem.Pharm. Bull. Tokyo, 1990,38,562. 43. E. A. Kitas, J. W. Perich, G.W. Tregear, and R. B. Johns, J. Org. Chem., 1990, 55, 4181. 44. H. B. A. de Bont, J. H. van Boom, and R. M. J. Liskamp, Recl. Trav.Ch1m. Pays-Bas, 1990,109,27. 45. H. 8. A. de Bont, J. H. van Boom, and R. M. J. Liskamp, Tetrahedron Lett., 1990,31,2497. 46. A. H. van Oijen, C. Erkelens, J. H. van Boom, and R. M. J. Liskamp, J. Am. Chem. SOC.,1989,111, 9103. 47. C. McGuigan and B. Swords, J. Chem. SOC., Perkln Trans. 1,1990,783. 48. D. S.Mautz, V. J. Davisson, and C. D. Poulter, Tetrahedron Lett., 1989,30, 7333. 49. 0.Sakatsume, H. Yamane, H. Takaku, and N. Yamamoto, Tetrahedron Lett., 1989,30,6375. 50. 0. Sakatsume, H. Yamane, H. Takaku, and N. Yamamoto, Nuclelc Aclds Res., 1990,18,3327.
I13
51. 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.
W. G.Bentrude, M. R. Khan, M. R. Saadein, and A. E. Sopchik, Nucleosides Nucleotider, 1989, 8, 1359. K. Yamana, Y. Nishijima, A. Oka, H. Nakano, 0. Sangen, H. Ozaki, and T. Shimidzu, Tetrahedron, 1989,45, 4135. H. Ozaki, S. Yamoto, S. Maikuma, K. Honda, and T. Shimidzu, Bull. Chem. SOC. Japan, 1989, 62, 3869; H. Ozaki, K. Yamana, and T. Shimidzu, Tetrahedron Lett., 1989,30, 5899. R. Eritja, V. Smirnov, and M. H. Caruthers, Tetrahedron, 1990, 46, 721. 0. Dahl, in 'Organophosphorus Chemistry",ed. B. J. Walker and J. B. Hobbs (Specialist Periodical Reports), The Royal Society of Chemistry, 1988, 19,104. H. Nagai, T. Fujiwara, M. Fujii, M. Sekine, and T. Hata, Nucleic Acids Res., 1989,17, 8581. M. J. Damha and S. Zabarylo, Tetrahedron Lett., 1989,30, 6295. P. S. Nelson, R. Sherman-Gold, and R. Leon, Nuclelc Acids Res., 1989, 17, 7179. R. Eritja, D. Johnson, J. P. Ziehlermartin, P. A. Walker, and B. E. Kaplan, An. Qulm. C Org. Blochim., 1989, 85, 80. M.-J. De Vos, A. Cravador, J.-P. Lenders, S. Hovard, and A.Bollen, Nucleosides Nucleotldes, 1990, 9, 259. A. J. Cocuua, Tetrahedron Lett., 1989, 30, 6287. K. Mori, C. Subasinghe, and J. S. Cohen, FEBS Lett., 1989, 249, 213. F. Schubert, K. Ahlert, D. Cech, and A. Rosenthal,Nuclelc Acids Res., 1990, 18, 3427. A. Roget, H. Bazin, and R. Teoule, Nucielc Acids Res., 1989, 17, 7643. M. J. Damha, N. Usman, and K. K. Ogilvie, Can. J. Chem., 1989, 67, 831. K. C. Schneider and S. A. Benner, J. Am. Chem. SOC.,1990, 112, 453. A. Wilk, M. Koziolkiewicz, A. Grajkowski, B. Uznanski, and W. J. Stec, Nuclelc Acids Res., 1990, 18, 2065. B. H. Dahl, K. Bjergarde, V. B. Sommer, and 0. Dahl, Acta Chem. Scand., 1989, 43, 896. K. H. Petersen and J. Nielsen, Tetrahedron Lett., 1990, 31, 911. W. K.-D. Brill, E. K. Yau, and M. H. Caruthers,Tetrahedron Lett., 1989, 30, 6621. G.M. Porrit and C. B. Reese, Tetrahedron Lett., 1989,30, 4713; Tetrahedron Lett., 1990,31, 1319. R. Cosstick and J. S. Vyle, Nuclelc Acids Res., 1990, 18, 829. R. Cosstick and J. S. Vyle, Tetrahedron Lett., 1989, 30, 4693. T. L6schner and J. Engels, Tetrahedron Lett., 1989, 30, 5587. M. Mag and J. W. Engels, Nuclelc Acids Res., 1989, 17, 5973. W. Dabkowski, J. Michalski, and W. Qing, Angew. Chem., lnt. Ed. Engl., 1990, 29, 522. J. Powell, M. R. Gregg, A. Kuksis, C. J. May, and S. J. Smith, Organometaillcs, 1989,8, 2918. J. Powell, A. Kuksis, C. J. May, P. E. Meindl, and S. J. Smith, Organometalllcs, 1989,8, 2933. H.-W. Krause, H. Foken, and H. Pracejus, New J. Chem., 1989, 13, 615.
-
80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97.
T. Yamagishi, S. Ikeda, T. Egawa, M. Yamaguchi, and M. Hida, Bull. Chem. SOC. Japan, 1990, 63, 281. A.-H. Caminade, C. Roques, N. Dufour, D. Colombo, F. Gonce, and J.-P. Majoral, Tetrahedron Lett., 1989,30, 6869. J.-P. Majoral, C. Roques,M.-R. Mazieres, J. Jaud, and M. Sanchez, J.Chern. SOC., Chem. Commun., 1989, 1496. C. Roques, M.-R. Mazieres, J.-P. Majoral, and M. Sanchez, J. Org. Chem., 1989,54, 5535. C. Roques, M.-R. Mazieres, J.-P. Majoral, and M. Sanchez,lnorg. Chern., 1989, 28, 3931. M.-R. Mazieres, T. C. Kim, R. Wolf, and M. Sanchez, Bull. SOC. Chlm. Fr., 1990, 127, 79. T. Busch, W. W. Schoeller, E. Niecke, M. Nieger, and H. Westermann, Inorg. Chem., 1989,28, 4334. M. Scholz, H. W. Roesky, D. Stalke, K. Keller, and F. T. Edelmann, J. Organometal. Chem., 1989, 366, 73. D. Hanssgen, H. Aldenhoven, and M. Nieger, J. Organometal. Chem., 1989, 375, c9. A. H. Cowley, P. C. Knuppel, and C. M. Nunn,Organometalllcs, 1989, 8, 2490. J. Stawinski and M. Thelin, J. Chem. SOC., Perkln Trans. 2,1990, 849. A. R. Burilov, T. Kh. Gazizov, L. N. Usmanova, M. A. Pudovik, Ya. A. Drozdova, and A. N. Pudovik, J. Gen. Chem. USSR, 1989, 59, 1494. M. Yasuda, T. Yamashita, and K. Shima, Bull. Chern. SOC. Japan, 1990, 63, 938. A. Igau, A. Baceiredo, H. Griitzmacher, ti. Pritzkow, and G.Bertrand,J. Am. Chem. SOC.,1989,111, 6853. M.-J. Menu, Y. Dartiguenave, M. Dartiguenave, A. Baceiredo, and G. Bertrand, Phosphorus, Sulfur and Silicon, 1990, 47, 327. E. Niecke, R. Streubel, M. Nieger, and D. Stalke, Angew. Chem., Int. Ed. Engl., 1989, 28, 1673. M. Gruber, P. G. Jones, and R. Schmutzler, Chem. Ber., 1990, 123, 1313. M. Gruber and R. Schmutzler, Chem. Ber., 1990,123, 289.
5 Quinquevalent Phosphorus Acids BY R. S. EDMUNOSON
The overall increase during the past year in the number of papers dealing with the chemistry of quinquecovalent phosphorus acids has been quite large and continues the trend observed during recent years in being concentrated on phosphonic and phosphinic acids and their derivatives. Topics relevant to the present Chapter are discussed in general reviews concerned with phosphorus-containing isocyanates, and with the synthesis and uses of organosilyl esters of phosphorus acids.
-ic
-
Svnthesis of A new route to phosphoryl fluorides involves the interaction of S-trifluoromethyl phosphorothioates with pyridine or triethylamine and (or) tetramethylammonium fluoride, the sulphur being eliminated as (SCF2)n; the reaction is not restricted to phosphoric acid derivatives but has been extended to those of both phosphonic and phosphinic acids. Free phosphoric acids are converted into phosphorofluoridates when acted upon by thionyl fluoride in the presence of Et3N, and the same reagents convert dithiophosphoric acids into thiophosphoryl fluorides. The first reported example of a reaction between a chloronitrosoalkane, MeCCl 2NO, and a quinquevalent phosphorus chloride, P0Cl3, has provided the phosphoryl dichloride ( 1 ) . The interaction of tris(trimethylsily1) phosphite and tribromoacetaldehyde leads to good yields of bis(trimethylsily1) phosphorobromidate (2) together with lower yields of the
1-1
Abbreviations used: Bn = benzyl; TBPP = tetrabenzyl pyrophosphate; mCPBA = meta-chloroperoxybenzoic acid; CPA = cyclophosphamide; MEM = [2-(methoxy)ethoxy]methyl; LDA = lithium diisopropylamide 114
5:
115
Quiny urvalent Ph osphomus Acids
?
?
?
C12PON=CCIMe
(Me3Si0)2POCH=CBr2
(Me3SiO)zPBr
(1)
(2)
(3)
(Me3Si0)2PH+ R’COCR2R3X
H
I
I
0
II 1
Me3SiOPOCR1 =CR2R3
(4)
R’ f: -CR2R3X OSiMe3 (6)
Me3SiOPOCR1=CR2R3
li
[
]
(Me,Si0)2POCR1=CR2R3
( MEI,S~O)~POCR’=CR~R~ -!%
-O-i;CR2R3X
0
It
Me3SiOP(OCR1=CR2R3)2 Reagents: i, Me3SiC1, Et,N
(5)
Scheme 1
O C O = p 0N E h
‘*‘OH OH
HO
OR’
(7)
MEMO’.
“OH
OMEM
“OBn OBn
1 I6
2 ,2-dibromovinyl ester ( 3 ) i tert-butyl catechol cyclic phosphite participates in an analogous reaction in which the five-membered ring is retained. Rather unusually, trialkyl phosphates have been prepared by the oxygenation of mixtures of alcohols and zinc phosphide containing Cu( 11) chloride. Trimethylsilyl vinyl phosphates have been obtained from the 1-bromocarbonyl precursors (4) in a sequence (Scheme 1) which leads mainly to the esters (5), but also to small amounts of the phosphonates (6); in certain cases, the latter become the main product as, for example, when R2 = R3 = X = C1, although for the corresponding reaction with tribromoacetaldehyde the product (5) is the more important. Direct phosphorylation of heavily fluorinated alcohols using P0Cl3 is catalyzed by HMPT, sulpholane, and also by tetramethylurea. lo Phosphorylations of similar alcohols by benzylic phosphoryl dichlorides are catalyzed by CaC12 or Mg, and have been recorded as affording the substituted-benzyl ether ;I1 the other hand, pentyl and 2,2,2-trifluoroethyl
on
phosphorodichloridates appear to react with the same benzylic alcohols in the expected manner.12 The course of the reaction between PhCH(CC13)0H and dialkyl phosphorochloridates, (R0)2P(0)C1, evidently depends upon the group R; when R = Me, the products are PhCH(CC13)C1 and MeOP02.py, but for R = Et, the expected triester is produced additionally together with the species ( EtOP02),. l3 The preparation of mixed phosphoric triesters by the nitrosation of dialkyl H-substituted phosphoramidates has been further explored, using isopentyl nitrite as the reagent of choice. l4 Last year's Report recorded most, at least, of the considerable increase in interest shown in the synthesis of many of the u - i n o s i t o l phosphates, IP,. This last year has seen no sign of a lessening in that interest and, indeed, the contrary seems to have occurred. An interesting feature of the work is the choice of starting materials. Syntheses have been described of the 1-phosphate the 4-phosphate ( l-IP1) :l5 the 2-phosphate ( 2-IP1) :l6 the l13-diphosphate ( 1,3-IP2 ) ;16 the ( 4-IP1) t-16,l7 18 1,4-diphosphate ( 1,4-IP2) il7 the 4,5-diphosphate ( 4,5-IP2)
5: Quinquevalent Phosphorus A c i h
I17
the 1,3,4-triphosphate ( 1,3,4-IP3 ) ;17 the l14,5-triphosphate 17-19,20-22 (1,4,5-IP3); the 2,4,5-triphosphate ( 2 ,4 ,5-IP3) l7 l8 and the 1 ,2,4,5- and 1,3,4,5-tetraphosphates (1,2 ,3 ,4-IP4)18 and (1,3,4,5-IP4)16 respectively. The 1,4,5-tris( thiophosphate) has also been prepared.l9 The subject has been reviewed. The single reported synthesis of D-(l-IP1) started from L-quebrachitol. The main problems were the stereospecific inversion of one OH group and the demethylation from oxygen. Phosphorylation of a benzylated intermediate was achieved using the cyclic phosphoramidite (7) as phosphitylating agent with subsequent oxidation by mCPBA and removal of the protecting groups by hydrogenolysis l5 The orthoformate (9; R1 = R2 = H) was the key intermediate in the preparation of both 2-IP1 and 4-IP1 from myp-inositol ( 8 ) , and was readily obtained from the latter in a conventional manner.16 Direct phosphorylation (TBPP) of (9) gave an intermediate (9; R 1 = (Bn0)2P(0), R 2 = H) from which 4-IP1 was obtained following debenzylation (H2, 10% Pd/C, DMF) and acidolysis (TFAA aq.). A sequence, consisting of metallation (NaH, DMF), benzylation (BnBr) to give the dibenzyl ether (9; R1 = R 2 = Bn), phosphorylation (TBPP) and full deprotection by hydrogenolysis, gave 2-IP1. An alternative plan of synthesis of the enantiomeric forms of 4-IP1 started with the racemic biscyclohexylidene derivative (10; R1 = R2 = H); this was converted into its monobenzyl ether (10; R1 = Bn, R2 = H) which was resolved using (S)-(-)-camphanic acid chloride. The separated D and L forms of (10; R 1 = Bn, R 2 = C10H 130 3 ) were hydrolysed and phosphorylated (TBPP); full deprotection afforded 4-IP1.17 The intermediates (10; R 1 = R 2 = H) and (10; R1 = Bn, R2 = CloH1303) were choice precursors to both the 17 racemic and resolved forms of 1,4-IF2. The intermediate (11) obtainable from benzene (see ref. 25) 18 was useful in the conversion of the latter into 4,5-IP2. The sequence starting with racemic (10; R1 = R 2 = H) ,
.
and consisting of allylation (allylBr, NaOH, PhH), loss of cyclohexylidene groups, further allylation and benzylation, and final removal of all three ally1 groups, afforded the tribenzyl ether
118
Organophosphorus Chemistv
(12); this, after phosphorylation (Naff, DMF, TBPP) and full hydrogenolytic debenzylation afforded racemic 1,'3,4-IP3.17
1r4r5-IP3 has been the most widely examined of the inositol phosphates from the synthesis point of view. Conduritol B derivatives have again been employed with the implication of total synthesis from benzene. Another route, through the phosphorylation (with (7) followed by mCPBA) of 2,3,6-tri-Q-benzoyl myQ-inositol was also feasible, and the use of sulphur in place of mCPBA provided the 1,4,5-tris( thiophosphate).I9 A third route involved the resolved forms of the biscyclohexylidene derivative (13; R1 = C10H1303, R2 = Bn); these were each converted into the corresponding (14; R1 = H, R2 = Bn) , phosphorylated (TBPP) and debenzylated to give the corresponding enantiomers of 1,4,5-IP3.17 Yet a further synthesis of the D-enantiomer (17) of 1,4,5-IP3 starting from (-)-quinic acid (15) proceeded through many steps yia the intermediate (16); the later stages of the synthesis 20 are illustrated in Scheme 2. In a sequence commencing with (18; R = H) the phosphorylation steps were performed with N,N-diphenylphosphorodiamidic chloride in pyridine. After the removal of the isopropylidene groups, the compound (19; R1 = (PhNH)2P(0) , R2 = H) was resolved through the use of a D-mannose ethylorthoacetate derivative. Further phosphorylation provided (19; R1 = R2 = (PhNH)2P(0) ) from'which the anilino groups were removed by nitrosation with pentyl nitrite, and the benzyl groups in the usual manner, to give laevorotatory 1,4,5-IP3.21 Reduction of the resolved forms of the cyclohexanone (20) with NaB[ 3H4 3 with a following sequence similar to those already outlined, led to tritium-labelled enantiomers of 1,4,5-IP3' 22 The racemic intermediate (13; R1 = R2 = H) also proved useful in the synthesis of 2,4,5-IP3. Following initial conversion into its dibenzyl ether, removal of the 4,5-Q-isopropylidene group was followed by allylation and removal of the 2,3-p-isopropylidene protection to give (21; R1 = R2 = H) which was then converted Selective into its tribenzyl ether (21: R1 = Bn, R2 = H) removal of the ally1 groups (10% Pd/C, p-TSOH, HeOH aq.),
.
5: Quinquevalent Phosphorus Acids
119
OH (1 5)
I iii, iv
Several steps
i, ii
c . -
H203p0v SEM = Me3SiCH2CH20CH2
HO'**
:
"OPO3H2
OH
(17)
Reagents: i, 03,CH&12/MeOH; Me2Sat -75 "C to r. t. ; ii, Bu'MezSiOTf, Et3N,CH2C12; iii,BH3, THF at r. t. ; alkaline H202; iv, Bu~N'F,HMPA;v, KH, TBPP, THF, 60 "C; vi, H2, PdC, EtOH Scheme 2
B "OBn
OR
n
O
R'O
q R2 "'OBn
OR'
phosphorylation (NaH, TBPP), and finally hydrogenolysis gave the target compound,l7 the synthesis of which has also been achieved through the use of the intermediate (11).l8 The key intermediate (11) was also the source of 1 ,2 ,4 ,5-IP418 whilst the 1 ,3 ,4 ,5-IP4 isomer may be prepared from the ortho ester (9). Allylation at the 4 position, followed by benzylation at the remaining free OH groups and removal of the ortho ester and ally1 groups provided (22; R1 = Bn, R2 = H) . Phosphorylation and debenzylation, both carried out in the usual way, provided the latter tetraphosphate.l 6 PseudolgQnas p u t l a converts benzene into the u-cyclohexadienediol (23) from which, through several steps, the epoxide (24) may be obtained. Reduction (LiA1H4) of the epoxide gave (25; R1 = Bn, R2 = X = H) which was phosphorylated (TBPP) and subsequently debenzylated to 6-deoxy-1,4,5-IP3 (26; X = H). The intermediate (24) proved useful in the preparation of other compounds with, for example, X = OMe, F, or Me.24 On the other hand, appropriate chemical (as opposed to biochemical) manipulation was employed to convert benzene into k.cmw-cyclohexadienedio1, the bisMEM ether of which, when acted upon by singlet oxygen, yielded (27); reaction of the latter with thiourea in MeOH gave the intermediate (28; R = H). Hydroxylation of the dibenzyl ether (28; R = Bn) afforded (29; R1 = Bn, R2 = H) The tri-MEM ether (29; R1 = Bn, R2 = MEM) was further benzylated and the MEM groups removed by acidolysis. Final phosphorylation (TBPP) and hydrogenolysis yielded racemic Cbiro-2,3,5-IP3 (30). The intermediate (29; R1 = Bn, R2 = H) can also be used to prepare racemic ~ - 1 , 2 , 3 , 4 - 1 P 425 . The 3,5,6-trideoxy derivative of myp-inositol-1monophosphate, viz, ( 1 ~ ) - p h o s p h o n y l o x y - ( 2 B , 4 S ) - dihydroxycyclohexane (32), has been synthesized from 4-hydroxycyclohexene and shown to be the most potent inhibitor of inositol monophosphatase yet identified.26 Within the general area of amino acid and peptide chemistry it has been reported that Q-phosphorylated serine,27 28
.
5:
Quinyurvulent Phosphoru.5 Acid5 R~OQ OR2
n
R~OQ OR'
"Oh
A110'-
R20"
~2
"OR'
OR2
OAll
0P03H2
OP03H2 (26)
"OH
MEMO-"
MEMO"' OMEM
OMEM
(28) HO..-@PO3H2 OH
HO..:c-""';OPO,H,
R10..:@R2 4
H203PO'*
"OH OP03H2 (30)
D
OR^
MEMO'.
OMEM
(29)
H,O,PO"
"OH OP03H2 (311
122
Organophosphorus Chemistry
threonine,28 and tyrosine2’ have been incorporated into peptide chains by solid state methodology. The zeotin (33a) metabolite (33b) is uniquely important in plant life. A recently reported synthesis of (33b) started from (34t R1 = NH2! R2 = H) and its initial reaction with (35; X = C1, R = 2-tetrahydropyranyl). Phosphitylation of the product from the latter reaction with the cyclic phosphorochloridite (36) and subsequent hydrolysis afforded the phosphinic acid (33c). Further reaction with I,Q-bis( trimethylsilyl ) acetamide/EtNPri2 converted the acid (33c) into the phosphorous acid bis(trimethylsily1) ester
(33d) from which appropriate oxidation steps gave the corresponding phosphoric (or thiophosphoric) ester: hydrolysis of the protecting groups gave (33b) (or the corresponding thfophosphoric acid). Attempts to perform the phosphorylation step with either pyrophosphoryl chloride or 2-cyanoethyl phosphate failed. 30 The reaction between (338) and morpholine in the presence of bis(2-pyridinyl) disulphide afforded (33f), subsequent treatment of 31 which with H3P04-Bu3N in DMF gave the pyrophosphate (33g). The cytokinin phosphate (33h; R3 = P 0 3 H 2 ) has been synthesized using the bis(benzotriazoly1) phosphoryl morpholide (37) as phosphorylating agent, although the final phosphorylation steps leading to (331) and (33j) were successfully performed with the participation of (36).32 Following the earlier discovery of the cyclic pyrophosphate (38) in 1 and certain
v, a new synthesis
of cyclic pyrophosphates, e.g. has been described which involves the NBS-mediated desulphurization of the bisphosphprothioates(39). Although the acyclic diphosphate (41) was the main product in this reaction, 33 nevertheless the yield of (40) was quite high. A successful synthesis of Q-geranyl thiopyrophosphate (42) employed 2-(trimethylsilyl)ethyl phosphorodichloridite as a phosphitylating agent. 3 4 The interaction of enol trimethylsilyl ethers and dialkoxyphosphoranesulphenyl halides yields S-(2-oxoalkyl) (40),
5:
Quinquevalent Phosphorus Acids
123
(33)a; R’ = R~ = H b; R’ = P03H2, R2 = H C; R’ = P(O)H(OH),R2 = 2-THP d; R’ = P ( O S ~ M E R2 ~ ~=) ~2-THP , 8; R’ = P(OSiMe3)2,R2 = H f; R’ = P(O)(OH)NCdHsO, R2 = H 9; R’ = P(O)(OH)OP(O)(OH)2,R2 = H
HO OH
HO OH
I24
Organophosphom C’hmii.uy
P,P-dialkyl phosphorothioates ( 43 ) ,3 5 also obtainable by more conventional means. 3 6 Similar compounds have also been prepared from dialkoxyphosphoranesulphenyl chlorides and diazoacetic 37 ester. Reactions between thiosuccinimides, or alternatively thiophthalimides, and trialkyl phosphites or tris(trimethylsily1) phosphite, have led to esters of the general type RSP(0) (OR1)2 for which the group RS is derived from the imide, and R1 = alkyl or Me3Si; the latter esters are particularly useful in the preparation of the free acids RSP(0) Scheme 3 summarizes some recently described reactions which illustrate useful interactions of organophosphorus and carbohydrate chemistries.39 The transformation of the D-glucal (44) into 3,4,6-tri-Q-acetyl-2-deoxy-D-arab~nohexopyranose ( 4 6 ) was made through the addition of Q,Q-dimethyl hydrogen dithiophosphate followed by Ag+-catalyzed hydrolysis (see also ref. 222) of the phosphorodithioate moiety from the intermediate (45; R = Me, X = Y = S). Further reaction with (49a) yielded ( 4 7 : (RO)2 = OCH2CMe2CH20, X = 0, Y = Se) which readily isomerized to (48; (R0)2 = OCH2CHe2CH20, X = 0, Y = Se) a step catalyzed by triethylammonium chloride and thought to proceed the chloride (51). The same product was also obtained following the reaction of (49b) with the bromide (50) with subsequent epimerization. While interest in the formation of metaphosphate intermediates in solvolysis reactions seems to have slipped from the limelight, probably momentarily, nevertheless the intermediacy of such species in a variety of other reactions still attracts considerable attention. Thus, the gas-phase pyrolysis of ethylene neopentyl phosphite evidently involves the elimination of the HOP02 species.41 When heated in boiling toluene, the phthalimide derivative (52; X = S), obtained from the oxygen analogue and P4Sl0, eliminates the phthalimido moiety, and generates a species capable of being trapped as the esters EtOP(S)(OR)OH by reaction with alcohols and hence thought to be Q-ethyl metathiophosphate (53); the same reaction may be brought about photolytically .42 Later references (180,181) should also be consulted for further discussion
5:
Quinquevalent Phosphorus Acids
(39)
AcO
-
AcO
AcO
X-P(OR), (44)
OH (46)
(45)
%
AcO AcO
iv
c--
X
AcO
II
X-P(OR),
Y -P II(OR)2 (48)
(47)
Reagents: i, (MeO),PS2H; ii, Ag' aq. ; iii, (49a), Et3N;iv, amb. temp. Scheme 3
)cOf O B
AcO* AcO
A AcO c
O
G CI
(49)a; A = Se, B = CI b; A = 0,B = SeNa
of this topic. Routes to H-cyanophosphoramidates and related compounds have been explored. The cyano group has been attached to phosphoramidate nitrogen in reactive phosphoramidates possessing the P(0)-NH-(0)P entity through reaction with BrCN-Et3N,43 or through the use of phosphoramidate sodium salts.44'45 The carbodiimides ( 5 4 ) are obtained from silver or potassium dicyanamide and the appropriate phosphoryl chloride, and also from Na2NCN or H2NCN/Et3N with N,N-dichlorophosphoramidates. 44 The peptide-like compounds (55) have been obtained following reactions between N-phosphorylated 2-pyrrolidinecarboxylic acid, activated as a mixed anhydride with diethyl hydrogen phosphate, and 2-pyrrolidinecarboxylic esters.46 Several 1,3,2-oxazaphosph(v)olidines and 1,3,2-thiazaphosph(v)olidines have been considered as potential insecticides, and attempts have been made to correlate their physiological activity with structure.47 For other such compounds, configurations have been explicitly assigned.48 The 2-chloro-1,3,2-oxazaphospholidine 2-oxides ( 5 6 ) are rather unstable 49 compounds and decompose fairly rapidly at room temperature. In a related area, 4-(3-pyridinyl)cyclophosphamides have been synthesized from 3-pyridinecarboxaldehyde in four steps, and the stereoisomers distinguished spectroscopically.5 0 The compounds (57; n = 0 or 1, X = 0 or S , R1, R2 = H or CH2CH2C1) have been prepared, and three diastereoisomers of (57; n = 1, X = 0 , R1 = H, R2 = CH2CH2C1) have been separated, and a fourth detected spectroscopically, and their conformations and 51 configurations discussed. The new compounds (58; X = 1.p. or 0) have been prepared from CPA and diphenylphosphine, together with some metal complexes. 5 2 Interaction of alkyl thiophosphoryl diisocyanates and 53 primary aromatic amines yields the triazaphosphorines (59). Examples of the two systems (60; R2 = H, and R22 = (CH2l4) are obtainable from aryl phosphorodichloridates and the appropriate cyclic h y d r a ~ i n e s . ~Several ~ phosphatranes (61; Y = l.p., 0, S, Se, N3Ph, or NPh) have been prepared.55 A full paper has appeared56 on the synthesis of nitrogen-containing macrocyclic compounds from phosphoric (as well as phosphonic) dihydrazides and
5: Quinquevalent Phosphorus Acids
127
138
n.
Orguttophosphorus c'hiw i ist
biscarboxaldehydes of the general type OHC-X-CHO, where X is a cyclic system e.g. phenylene or furanediyl. Structural studies have been carried out on the particular examples (62; X = 0, Y = H), (62; X = S , Y = NMe2) and (63).57
Reactions of f i -.Addition of alcohols (ROH) to diethyl [2,2-difluoro-l-(trifluoromethyl)vinyl]
192
phosphate yields the ether esters (64). 58 Other fluorovinyl phosphates (65; R1 = F or CF3, R = hexyl, cyclohexyl, or Ph) are cleaved by LiA1H4/CuBr or by LiA1H4/Br2 in THF at -78O to give the ketones (66); the same esters are also cleaved by diisobutylaluminane to furnish aluminium enolates in situ for further reaction.59 Diphenyl phosphorochloridate acts upon hydroxymethylsilanes to yield the esters (67; ,'R R2 = alkyl; R1 = Ph, R2 = Me); when heated at 200' these compounds rearrange to the silyl phosphates (68).60 The novel rearrangement, under photolytic conditions (254 nm), of ally1 diphenyl phosphate to 2-allylphenyl phenyl hydrogen phosphate (69), has been rationalized as indicated in Scheme 4 .61 Other rearrangements of allylic phosphates and pyrophosphates are of great importance biochemically. However, contradictions in experimental data have made structural assignments to the various proposed intermediates in such reactions rather uncertain. A study has been made of the hydrolysis of the allylic or OPh) derived from resolved phenyl phosphates (70; A, B = =O forms of the parent diol. The hydrocarbon skeleton is rigid and relative structural assignments were made on the basis of X-ray diffraction studies. In nitrobenzene at 145' the two diastereoisomers (those examined) equilibrated. The dihydro derivatives of (70; a,b) are fully resistant to solvolysis and racemization to give a product in which the phosphorus-containing ring is opened. The kinetic data indicate that the proximity of the phosphoryl bond to C=C in (70;a) facilitates an allylic rearrangement in the intermediate ion (71). The ratio, rate of racemization/rate of solvolysis, is greater for (70;a) than for (70;b) by the factor 1.7 because of the slower racemization of (70;b).62 The relation between the extent of ring opening or retention
5:
Quin y uevalent Ph osphoms Acids
129
0
0
II (Et0)2POC(CF3)=CF2
II
RO-/ROH c
(EtO)2POCH(CF,)CFz(OR) (64)
0
-
II
( Et0)2POCR'=CFCF2R2 (65)
0
11
R'CF2CHFCR' (66)
0
0
II
( Ph0)2POCH2SiR'2R2
200 "C
-
(68)
(67)
Scheme 4
(70)a; A = = O ,B = OPh b; A = OPh, B ==O
II
(Ph0)2POSiR'2CH2R2
130
Organophosphorus Chemistry
and structure in the hydrolysis of a series of cyclic phosphates (and phosphonates) has been considered from a theoretical viewpoint using molecular mechanics. The effects of structural features such as ring size and substitution on the rate of hydrolysis were interpreted in terms of differences in energy between the substrate structure and that of an appropriate pentacoordinate transition state. (see also references 211-2131.63 The reactivity of dialkyl 2-dimethylaminoethyl phosphates in aqueous solution has been examined. Unimolecular fragmentation to dialkyl 1,H-dimethylaziridinium phosphates or bimolecular isomerism to a zwitterionic derivative are each possible, the ultimate choice being dependent on experimental conditions such as nature of solvent and concentration.64 The alkaline hydrolysis of l,lO-phenanthroline-2-carbonyl phosphate is affected markedly by the presence of divalent metal ions: Cu(II), Ni(II), Co(II), and Zn(I1) can each increase the reaction rate by a factor of lo7. For Mg(II), catalysis is not so effective, the factor being lo4.6 5 Novel reagents for the catalytic cleavage of reactive phosphates include iodosobenzoate immobilized on solid supports of, for example, silica66 or 'Ti02167 or even nylon.67 These preparations are active against diphenyl 4-nitrophenyl phosphate and soman. Other reactive phosphates are cleaved by bis(a , w dimethy1amino)alkanes.68 The addition of 18-crown-6 to a mixture of a 4-nitrophenyl phosphoric triester (or of such an ester of a phosphonic acid) with alkoxide NaOR in ROH causes a catalytic dweleration in the solvolysis, whereas for the analogous thiophosphoryl compound a catalytic acceleration is to be ~bserved.~' The mechanism and kinetics of hydrolysis of Zn(I1) diethyl dithiophosphate have been studied using 31P n.m.r. spectroscopy.70 p,p,Q-Trialkyl phosphorothioates and selenoates are efficiently converted into the corresponding phosphates by trifluoroacetic anhydride in dichloromethane, a process rendered easier in the presence of pyridine. Cyclic thiophosphates yield cyclic phosphates with retention of configuration, and the reaction has been depicted as proceeding through a pentacoordinate intermediate of the type R3P ( SCOCF3) ( OCOCF3 ) ;71 another
5:
131
Quinquevalent Phosphorus Acids
useful reagent for such conversions is dimethyldioxirane.72 The use of HPLC and ms allowed the separation and identification of unstable intermediates produced during the oxidation of Q,P,P-trisubstituted phosphorothioates with mCPBA. In particular, the polysulphides (R0)3PSn were detected, although it was not always possible to distinguish these from the corresponding (R0)3P02Sn-1 as n increased. Such intermediates breakdown into trialkyl phosphate and the yellow HS-, or (R0)2P(0)SnH.73 A less detailed study of the oxidation of dialkyl phosphorothioic acids at - 6 0 ° , also by mCPBA, led to the detection, by 31P n.m.r. spectroscopy, of a species thought to be a phosphorothioxoperoxoic acid, (Et0)2P(S)SOH. A scheme was elaborated to account for its conversion into triethyl phosphate in the presence of EtOH, together with diethyl hydrogen phosphate and, a pentacoordinate intermediate, through thione-thiol isornerization.74 During alkylation by alkyl halides in the presence of bases, S-(2-oxoalkyl) phosphorodithioic esters have been found to undergo rearrangements of the general types (72) -> (73). The overall outcome is influenced both by experimental conditions as well as by the nature of other alkoxy groups attached to phosphorus. Thus, Q,Q-dimethyl S-(2-oxo-2-phenylethyl) phosphorodithioate undergoes thione-thiol isomerization (72) -> (73a) in addition to dithiophosphate to thiophosphate rearrangement, (72) --> (73b), whereas the corresponding diethyl ester undergoes only the second of these processes. 75 In a new study relevant to the Todd-Atherton reaction, alkylammonium salts of monoalkyl phosphonates have been shown to react with the usual CC14-CHC13 medium. The results show that their anions play a more important role thah do the frequently suggest& dialkyl phosphonate anions.76 The hydrolysis of the 4-hydroxy-CPA derivatives (74; b-d) and subsequent ring reclosure of the corresponding ( 7 5 ) are qualitatively related to the same steps for 4-hydroxy-CPA (74;a) itself. However, (74;a) and (74;d) undergo general acid-catalyzed ring opening, whereas for (74;b) and (74;c) the reaction is spqcifically base-catalyzed. A difference in behaviour is also to be
a
noticed in their reactions with sodium 2-mercaptoethane sulphonate; here, (74;a) and (74;d) react readily whereas (74;b) and (74;c) fail
Orgunophosp horus Chemist r?,
RO !, S
ii
P-OCR2=C( SR3)R’
RS’
0
II
(73a)
(R0)2PSCHR’C R2
5
II
( RO)pP-OCR2=C(SR3)R’
(73b)
f
R’ NH-T-NR2(CH2CH2CI) OCH2CH2CHO (74) a; R’ = H, R2 = CH2CH2CI b; R’ = CH2CH2CISR2 = H C; R’ = CH&H&I, R2 = CH2CH2CI d; R’ = Me, R2 = CH2CH2CI
R=Me
(75)
?
(Me0)2P-N(CN)SiMe3
0
II
(R0)zPNHCN (76)
fl
(Ph0)2P-N(CN)SiMe3
(77)a; A = CI, B ==S b; A==S, B = C I
+
f!
(Ph0)2P-N=C=NSiMe3
S:
Quinquevalent Phosphorus A c i h
133
to do A study of the kinetics of the decomposition of isophosphoramide in aqueous solution and is reactions with other nucleophiles e.g. mercaptoethanol, has been reported. 78 The reactions between 3-trifluorophenylhydrazine and various halides of both tetracoordinate phosphorus (including thiophosphoryl halides, and MeP(S)C12) and acyclic and cyclic chlorides of tricoordinate phosphorus, react regiospecifically at the unsubstituted nitrogen atom. 79 However, subsequent reactions between the same reagents and the initial products can occur at either nitrogen atom. Thus, ( Et0)2P( OH)N1HN2HPh reacts with Me3SiC1 or ( EtO) 2PC1 at N1, whereas ( EtO) 2P( S)NHNHPh reacts with the same reagents on N1 and N2 respectively.80 The outcome of reactions between chlorotrimethylsilane and the pcyanophosphoramidates (76) may depend on more than one factor yiLzL nature of the group R and choice of base component.81 Finally, the ability of a tetracoordinate phosphorus compound to undergo electron capture and so provide free radicals has been linked with the stereochemistry of the substance; (2B,4S,58)-2-chloro-3,4-dimethyl- 5-phenyl-1,3,2-oxazaphospholidine 2-sulphide (77;a) undergoes ready electron capture in contrast to the corresponding (2s) compound (77;b).82 1.3
of -Acidvaw.-
The resolution of the
cyclic phosphoric acid (78; X = OH), prepared from 2,2-dihydroxy-1,l-binaphthylr affords a means of obtaining the latter in resolved forms. 83 Optically active forms of the corresponding chloride (78; X = C1) may be employed to determine the chirality of 84 secondary alcohols. 1-Cyanoalkyl phosphates, readily obtainable from aldehydes or ketones with diethyl phosphorocyanidate and LiCN, are good precursors to nitriles through subsequent reactions with Sm12 in tert-butyl alcohol at room temperatureb5 or by reduction with Li/NH3( 1) .86 Applications of cyanohydrin phosphates in organic synthesis have been reviewed. 87 Phenyl phosphorodichloridate in DMSO, which participates chemically, converts benzylic amines into carbonyl compounds, R2CHNHR3 -> R2COAr.88 The synthetic potential of phosphoryl isothiocyanates has
Organophosphorus Chem istty
134
been extended to include the use of (O)P(NCS) in the conversion of carboxylic acids into acyl isothiocyanates.a9 The cyclic phosphoryl chloride (79) has been recommended as a phosphorylating agent for oligonucleotides.
2.1
-.-
S Y n u m a b of
4
A comprehensive review of the additions of P(II1) compounds to sp2-carbon containing systems has been published. 91
Reactions between phosphorous acid and cyclic ethers in the presence of acetic anhydride yield cyclic hydrogen phosphonates, 1 ,3 ,2-dioxaphosphacycloalkane 2-oxides. 92
i In addition to .the decomposition of trifluoromethylthio esters3 and the use of SOF2/Et3N in conjunction with free acids14 both of which processes have already been mentioned in relation to phosphoric acids, but which are also applicable to phosphonic and to phosphinic acids, phosphonic fluorides have been prepared from tetraf luorophosphoranes by reaction with hexamethyldisiloxane 9 3 FeC13 catalyzes the reactions between butyl difluorophosphite and 1-halogenoalkyl ethers, 9 4 and also between alkyl dichlorophosphites and Br3CNC0 to give C12P(0)CBr2NC0.g5 a*,-Hydroxy(cyc1o)alkylphosphonicdichlorides have been reported to be produced when aldehydes or ketones interact with PC13 in acetic acid, water, or H3P03. The structure of the cyclohexyl compound was verified by an X-ray analysis. 96 ib) 1 AcFQS.- The interaction of dialkyl hydrogen phosphonates and diazo compounds in the presence of Cu(acac)2, a more effective catalyst than the normally used CuS04, provides dialkyl (branched - alkyl) phosphonates. 97 Scheme 5 illustrates
.
the usefulness of diethyl [(1-trimethylsilyl)v~nyl]phosphonate (80) as a starting point for the synthesis of a range of compounds through the participation of the carbanion (81) and leading to esters of
.
branched-chain phosphonic acids ( 82 ) 98 The use of (1-1ithioalkyl)phosphonic or -phosphinic acid derivatives allows considerable modifications to be made in the preparation of a wide variety of structural types. Interaction of
5:
Quinquevulent Phosphorus Acids
13.5
?
(EtO)2PTSi (Et0)2!ib
-
!R2
ii
___)
Me3Si
Me3
R’
1
iii
Reagents: i, RLi (R = Me, Bu, But, or Ph) or RMgBr (R = Et or Ph); ii, R2X; iii, Bu4N+F;iv, R3CHO; v, R4COCI Scheme 5
Bu‘OOC-
/ R
136
Organophosphorus Chemi.vm,
such lithiated species with crotonic esters yields mixtures of & (85) and syll (86) products, of which the former are the main diastereoisomers.99 structurally similar anions were used to prepare (1-phosphonylalky1)sulphoxides (87; R = alkoxy or Me2N) for chiroptical studies'" whilst with alkyl isocyanates, R2NC0, a-phosphonylated carboxamides were obtained.101 A sequence starting with methylenebis[phosphonic acid] tetraester carbanions, and consisting of alkylation with an appropriate 3-substituted-propyl halide, side-chain modification, and cyclization, ultimately affords the tetraalkyl esters of cyclopropane-1,l-bis[phosphonic acid], and from which the free acid has been obtained. The reaction between 1 ,2-dibromoethane and ethyl (diethoxyphosphinyl) acetate or ethyl (ethoxymethylphosphiny1)acetate in the presence of K2C03 in DMSO yielded the derivatives ( 8 8 ; R = OEt or Me) of cyclopropane1-carboxylic acid.103 Trimethylsilyl esters of dialkylphosphinic acids have been prepared from alkyl halides and bis(trimethylsily1) phosphonite in the presence of Me3SiC1-EtjN; final ethanolysis gave the free acids.lo4 The same phosphonite also adds to crotonic esters (with the formation of the phosphinic acids (89)) as does H3P02 itself, in a reaction from which several products are isolable but which can be made to lead ultimately to the asymmetrical phosphinic acids (90) (Scheme 6).lo5 fc\ A w l . B;LhYnvl. and Aromtic Aci&i.- A s illustrated in Scheme 5, 1,2-disubstituted vinylphosphonic esters are preparable from the €-silylated carbanions (81) using Wittig procedures.98 Those
esters of type (80) were themselves prepared from dialkyl hydrogen phosphonates and Re3SiCX=CHR1 (X = halide) in the presence of Pd(PPh ) -Et3N with evident retention of geometry at the double bond. 1 k 4 Vinylphosphonic and vinylphosphinic acid esters result from the methoxide-induced elimination of nitrous acid from appropriate ( 2-nitroalky1)phosphonic or -phosphinic acid derivatives.lo7 The action of an aldehyde RCHO upon diethyl vinylphosphonate in the presence of DABCO affords a high yield of a diethyl High yields of a [ 1-hydroxyalkyl)vinyl Iphosphonate (91) . mixture (s;ra. 1:l) of the two propenebis[phosphonic acid] tetra esters
5:
Q u inq uevalenf Ph osph oms Acids
I37
liii, iv
0
R2
R300CN!+COOR2OH R'
(90) Reagents: i, R1CH=CR2COOR3;ii, Me3SiCI/Et3N;iii, R300CCH=CH2; iv, H30+
Scheme 6 0
II
(EtO),PY=CH, CH(0H)R (911
OAc
(93)
(92)
0
0
II
II
(Et0)2P--CH2C--P(OEt)2
II
CH2 (94)
0
0
II
II
(Et0)2P-CH=CMe P(OEt)2
(95)
(92) and (93) result from the Ni(I1)-catalyzed additions of hydrogen PhosPhonates to dialkyl [ (1-acetyloxy)allyl]phosphonates. For each of (92) and (93), the predominant isomer possesses the (E)-geometry. The isomeric propenylbis[phosphonic acid] tetraethyl esters (94) and (95) were obtained from triethyl phosphite and diethyl (1,2-propadienyl)phosphonate, the latter itself conveniently prepared from triethyl phosphite and trimethyl(2-propyny1)amonium bromide. 'lo Moderate to high yields of 1-alkynylphosphonates have been obtained from trialkyl phosphites and alkynylphenyliodonium tosylates.111 A one-pot procedure for the synthesis of arylphosphonic acid monoalkyl esters (the hexyi esters were chosen in practice) started with aryl bromides, the interaction of which with triethyl phosphite is also catalyzed by Ni(I1) salts;ll2 various (trifluoromethylpheny1)phosphonic acids have been obtained by the hydrolysis of aryltrichlorophosphonium tetrafluoroborates.l1 Phenylphosphonic acid has been successfully sulphonated with SO3, and the 3-sulphonic acid (96) isolated by fractional precipitation of barium ~a1ts.l'~ Treatment of diary1 esters of phosphoric acids (97; R 2 = alkoxy, aryloxy), phosphonic acids (97; R2 = Me, But, or Ph) , or phosphonic amides (97; R2 = NMe2 or NC4H80) with sodium in dioxane, or with magnesium activated by anthracene in THF, affords the bis(2-hydroxyary1)phosphinic acid derivative (or phosphine oxide) (98) following a carbanionic rearrangement.'15 The LDA catalyzed rearrangement of dialkyl aryl phosphates (99) to dialkyl (2-hydroxyary1)- phosphonates has been known for some time and the use of the di-tert-butyl esters, now reported, offers advantages in the ease of preparation of the respective free (2-hydroxyary1)phosphonic acids. The sequence (Scheme 7) has also been extended to include further phosphorylation and rearrangement steps to yield the 2,6-bis(dialkoxyphosphiny1)phenols (100).l16 New 3-(dialkoxyphosphinyl)pryrroles (101) have been 117 prepared. f dl P h o s D h o l a n e s PhosDhorinanes, and ' b l r oxa UIdJUUriva-.(Methyl 2,3-Q-isopropylidene- e - 0 - w pentopyranoside)-4-~lose, /102), after conversion into its p-toluenesulphonylhydrazide (as a mixture of E and forms) and .
a
5: Quinquevalent Phosphoms Acids
139
0
0
Ij
(99)
Reagents: i, LDA; ii, (R30)2P(0)Cl/Et3N
Scheme 7
?
0
COOEt
(Et0)2P
II
v C 0 2 E t
(Et0)2PCHCICMe
+
II
w
0
&Me
NNHR
I
NHR (101)
OM0
O
NHNHTos
MeO'
0 5 07
K OMe
I40
subsequent reaction with dimethyl hydrogen phosphonate, afforded a mixture of the (4S)-phosphonate (103; R = OMe) and its phosphorus epimer (104; R = OMe), accompanied by smaller amounts of other compounds including the bicyclic 1,2-oxaphospholane (105; R = OMe). A similar sequence with methyl hydrogen phenylphosphonate yielded (4S)-(103; R = Ph) together with its phosphorus epimer (104; R = Ph) but unaccompanied by oxaphospholane (105; R = Ph). Removal of the hydrazide group from the main epimer (103; R = OMe) gave methyl 4-deoxy-4-(dimethoxyphosphinyl)-2,3-Qisopropylidene-B -D-ribopyranoside (106; R = OMe) and the a-L-compound (107; R = OMe) in the ratio 85:15; when (104; R = OMe) was similarly treated, the ratio of the products (106) and (107) was almost the same. Each of the methoxyphenylphosphinyl compounds ( 1 0 3 ; R = Ph) and (104; R = Ph) afforded the same ratio 88:12, of each of (106; R = Ph) and (107; R = Ph). The compounds (106; R = OMe or Ph) were each reduced by sodium dihydrobis(2-methoxyethoxy)aluminate to the corresponding primary (from the series with R = OMe) or secondary phosphine (108; R = H or Ph). By acidolysis and peroxide oxidation the phosphines were transformed into the tetrahydroxyphospholane l-oxides ( l o g ) , characterized as their tetra-Q-acetates.'18 On the principle that blocking the incorporation of 3-deoxy- 13 -D-manno-octulopyranosonic acid (110) in the biosynthesis of the outer membrane in Gram-negative bacteria might lead to new types of antibacterial agents, the l,2-oxaphosphorinane analogue (111) was chosen as a suitable target compound for attempted Treatment of 2,3 :5,6-di-Q-isopropylidene-D-mannose synthesis.'19
a.
with lithium diethyl phosphite gave (112;a) which, on treatment with thiocarbonyldiimidazole followed by reduction with tributyltinhydride, was transformed (112;b) into (112;~). Removal of the ester Et group with Me3SiBr, followed by treatment of the product (112;d) with oxalyl chloride led to the cyclic phosphonic chloride (112;e) as stereoisomeric mixture; further reaction with PhSH under basic conditions gave (112;f), also as a mixture of stereoisomers. The (2s) form of (112;f) reacted with vinylmagnesium bromide to give the 2-vinyl derivative, a step which
a
failed, however, with the (2B) epimer. Attempts to oxidatively cleave the vinyl group and so generate a compound having a carbonyl
5: Quinquevalent Phosphorus Acids
141
A
(112)a; X = O H , R = O E t b; X = OCS.Im, R = OEt C ; X = H, R = OEt d; X = H, R = OSiMe3 0; X = H, R = Cl(2S) + ( 2 R ) 1; X = H, R = SPh (2s) + ( 2 R ) g; X = R = H ( 2 5 ) + ( 2 R ) h; X = H, R = COOBn
OH
HO
CI
H (1 14) a; X = CH(OR5)Me
b; X = PC12
0
0
II
II
(Et0)2PCF2CH2CR1=CR2R3
(E~O)ZPCF~CH~C~H~R
(1 19)
0
II
(EtO)2PCBrFS02Na
(1 20)
0
II
0
II
( Et0)2PCBrFCBrFP(0Et) 2
0
II
0
II
(R0)2PCF=CFP(OR)2
moiety directly attached to phosphorus by the sp2 carbon, all failed. Attempts to convert (112;c) into the thiophosphoryl analogue using Lawesson’s reagent, followed by desulphurization by, for example, Ph3P, also failed, and this precluded a second synthetic approach involving P(II1) intermediates. Reduction of ( 1 1 2 ; ~ ) with sodium dihydrobis(2-methoxyethoxy)aluminate gave a ring-opened primary phosphine, treatment of which with hydrogen peroxide yielded (112;g); removal of the isopropylidene groups from this again resulted in ring opening. When treated with hexamethyldisilazane, (2-E)-(112;9) afforded the cyclic trimethylsilyl phosphonite which reacted with benzyl chloroformate to give the P-epimer of (112:h); removal of the protecting groups from this compound proved impossible without conversion into ring-opened compounds. In contrast to much earlier data which has demonstrated little diastereoselectivity in reactions leading to cyclic phosphorus esters or amides, the reaction between methylphosphonic dichloride and (B)-1,1,2-triphenyl-lI2-ethanediol in pyridine led to a 9:l diastereoisomeric control in favour of the B p q product (113).
120
Reactions between the ethers (114;a; R1 = Et, R2 = alkoxy) and PC13 afford the corresponding (114;b) which can be cyclized to the 1,3-dioxa-2,4-diphospholane oxides (115); when R 3 = H and R4 = Me, the latter react with PC15 to give (114; R1 = Et, R2 = Cl). When R1 = R2 = alkoxy, and R3 = H I the reaction with PC15 provides the phosphorodichloridate (116) through an intermediate related to (115) (See also reference 137 for additional information on 1,2-oxaphospholane 2-oxides.) m v l Acids.- Replacement of the lel -kvl hydroxy groupin a (hydroxyalky1)phosphonic acid through reaction with 123 SoCl2122 is sometimes accompanied by dehydration particularly in systems already unsaturated. Regiospecific ring opening of (2,3-epoxyalky1)- phosphonic esters (117) with HC1123 or NaCN124 leads to ( 3-chloro-2- hydroxyalkyl)phosphonic or (3-cyano-2-hydroxyalkyl)phosphonic acid esters (118; X = C1 or CN) respectively. A useful synthesis of ethyl (diethoxyphosphiny1)fluoroacetate has been described.125 The dibromination and dichlorination of tetraalkyl methylenebisphosphonates with NaXO
5: Quinquevalent Phosphorus Acids (X
=
143
Br or Cl), and reductive monodehalogenation of the products with
Na2S03, have been used to prepare a wide range of mono- and mixed di-halogenated products.126 Compounds of types (119) and (120) have been prepared from the cadmium reagent derived from diethyl (bromodifluoromethyl)phosphonate, and the properties of (119; R1 = R 2 = R3 = H) exploited to provide a wide range of compounds.127 128 When treated with Fe(II)-H202, the phosphonylated sulphinic acid salt (121) is converted into the tetra ester (122) which, when acted upon by zinc dust, is debrominated to (123).I2' Both (122) and (123) can be converted into the free acids following initial reaction with Me3SiBr. An alternative approach to the (1,2-difluoroethenediyl)bis-(phosphonic acid) esters (123) consists in initial interaction of trifluorovinylmagnesium bromide and a suitable dialkyl chlorophosphite; subsequent oxidation of the products with Mn02 or SeOZ yields dialkyl (trifluoroviny1)phosphonates; these are then acted upon with trialkyl phosphite. This results in the loss of one of the m-difluoro atoms to give mixtures of E and Z-(123).l3' Abstraction of fluorine from such a grouping in a phosphate ester by reaction with a P(II1) triester has been employed elsewhere to prepare both dialkyl and bis(trimethylsily1) esters of ( 1-fluoro-2-trifluoromethyl) alkenylphosphonic acids. Other heavily fluorinated compounds recently described include (124; R = H or alkyl; n,m = 2 or 4 , and X = H, S02F, S02Na, S03Na or S03H)132 and (125; Rf = CF3 or C3F7), the latter being obtained from dialkyl hydrogen phosphonates and the appropriate perfluoro carboxylic anhydride.133 When acted upon by ylides at -78', the same carboxylic anhydrides lead, &l the depicted phosphonium salts, to esters of the (1-perfluoroalkylalken-1-y1)phosphonic acids (126) (the main products) together with, in some cases, the (1,2-epoxyalkyl)phosphonic esters (127).134
i f ) Hvdroxvalkvl. MercaPtoalkvl. and related Ac-
.-
The rearrangement of a carbanion following reaction between the epoxides (117) and a trace of E t O - may well play an important role in the formation of the (3-hydroxy-1-propeny1)phosphonic acid esters
4-XCsH4CHO
0 0 ?R2
/ \II
X = H, NO2
P-CHAr
-
(134)(132;R2 = H)
(132)R2 = Me3Si
0 (R1,d2 ‘POSiMe3
‘O/ 0 0 ?R2
(1 31 )
/ \II
(R12Fo/P-y-P No,:
(R’,Y2 ,PCOR3 0
~
/O\
II\
3
(CR12)2- (135)(133;R2 = H)
o0/
(1 33) R2 = Me3Si
(1 39)
I
R4U
? YR4 (R10)2P-C-Li+ I
SR2
XR4
H~O+ c
! I (R10)2P-CH
‘S R2 (141)
S: Quinquevalenr Phosphorus Acids
145
(128).123 (1-Hydroxyalky1)phosphonic acids, and also the related phosphinic acids, are normally obtained from hydrogen phosphonates and aldehydes or ketones. The reactions between perfluoroacetone and mixed dialkyl hydrogen phosphonates are noteworthy in that the expected products (129) may be accompanied by the phosphoric triesters (130). 135 Trimethylsilyl alkylene P( 111) triesters (131) are also useful starting materials; when acted upon by aromatic aldehydes or by (1-oxoalky1)phosphonic acid esters, the initial products are the silyl ethers (132) and (133) respectively, and these may be hydrolysed to the corresponding hydroxyalkyl compounds. Mixed dialkyl hydrogen phosphonates react with 1,1,1,5,5,5hexafluoropenten-2,4-dione (in its enol form) to give the phosphonic esters (136). In certain cases these were isolable, but they were generally allowed to undergo further transformations yiir pectaoxyphosphoranes to give a series of 3,5-bis(trifluoromethyl)1,2-oxaphospholane 2-oxides ( 137). 137 (Phenylacety1)phosphonates resulting from the reactions between trimethyl phosphite or 2-methoxy-4,4,5,5-tetramethyl-1,3,2dioxaphospholane and phenylacetyl chloride, exist with the ( 1-hydroxyalkenyl) phosphonate structure.138 Dialkyl [(trialkoxy)methyl]phosphonates (138) have been prepared from sodium dialkyl phosphites and (R'O) 3+BF4- and 1 139 from tetraalkyl pyrophosphites with C ( O R 14-BF3.Et20. Ylides are the postulated intermediates in reactions between phosphonodithioformates (139; X = S) and trialkyl phosphites; the ultimate products are the esters of (alky1thio)methylenebisfphosphonic acids] (14O).l4O The compounds (139; X = S or Se) also react with lithiumalkyls in THF at -78' to yield the compounds (141; X = S or se). When (141; X = S ) was treated with EtMgBr, however, a new condensation reaction, not observed with the lithium reagent, provided (142) and (143), the former in quite appreciable yield.141 Reference 171 should also be consulted for a synthesis of (1-hydroxalky1)methylphosphinic acids structurally analogous to phosphinothricin in terms of overall carbon skeleton although lacking amino and carboxyl groups (Scheme 12). A&&.The synthesis of examples of such compounds la) 1possessing perfluoroalkyl groups attached directly to the epoxide
I46
0 SEt II
I
y2
( R10)2P-y-S-y-P(OR’)2
SMe
SMe
(142) R 2 = H (143) R2 = SEt
0 II (EtO),P-R’
H J)j)0, ,
i,ii, iii
R’
1.
0 (EtO)*!+LR2
w
N@
(144) (R2 = alkyl)
-
R2
i v
R’ M,,,EtI2
R’
0 (144) R 2 = H
(145)
; pyrrolidine, C6H6; v, R~ X; Reagents: i, BuLi, THF, -78 OC;ii, DMF at -78 OC; iii, H ~ o + iv, vi, oxalic acid on wet SO2 Scheme 8
(Et0)2i4(
mT
*(4!2)0tE(
X (146)
I
OAr (147)
1
NNHR’
2,E ,(t
(148) X=OAr
+
X (148) In2CyCOR3
I
E
t
0 NNHR’ ) 2 R2 i 4 0 (149)
\
~
3
( E t 0 ) 2 ! q R 3
+
:A2 (150)
(Et0)2P
R3
I
NHR’ (151)
0
5: Quinquevulent Phosphorus Acid5
147
ring has already been referred to,134 but other (epoxyalky1)phosphonic acid esters have been prepared more conventionally using trifluoroperoxyacetic acid and the appropriate unsaturated phosphonic acid derivative123 or through the use of the Arbuzov reaction.124 ih) 0xod.kvl Ac&.(1-0xoalkyl)phosphonic acids bis(trimethylsily1) esters have been prepared from acyl halides and tris(trimethy1-silyl) phosphite. Their hydrolysis to the free acids and subsequent reaction between their silver salts and 2-oxoalkyl halides yields bis(2-oxoalkyl) esters of (1-oxoalky1)phosphonic acids, (R~COCH,O)2 ~ ( ~ ) 142 ~ ~ ~ 2 . The uses of 1-silyl phosphonocarbanions, referred to in Scheme 5, have been extended to include the preparation of esters of ( 2-oxoalkyl)- phosphonic acids ( 84).143 Alkylation, effectively at a carboxaldehyde group, is the result of the regiocontrolled metallation, alkylation, and subsequent hydrolysis of enamine phosphonates (144) to give (2-oxoalky1)phosphonic esters as outlined in Scheme 8.144 The direct conversion of (1-halogeno-2-oxopropy1)phosphonic esters (146; X = Br or C1) into the (1-aryloxy-2-oxopropyl) compounds (147) by reaction with ArO- has not been achieved, and the lengthier route carbonyl-protected compounds (148; R1 = COOMe) must be employed: a similar procedure has to be adopted in the case of the (3-aryloxy-2-oxopropy1)phosphonic acid derivatives (153), using the enamines (152).145 Ensuing reactions between (148) and the ketones, afforded the (2,4-dioxoalkyl)phosphonic acid derivatives (150) or the (pyrrolylmethy1)phosphonic diesters (151) by way of the intermediates The use of (1-halogeno-2-oxopropyl) compounds in the (149). '17 synthesis of (3-pyrroly1)phosphonic acid diesters has already been referred to under (2.1.c.L: compounds (147) and (153) have received attention and find similar application in the preparation of 145 the (benzofuran)phosphonic acid derivatives (154) and (155). Phosphorylation of the cyclic ketones (156), pretreated with LDA, leads to the cyclic enol phosphates (157) for which the isomeric structures a and b are possible, and which, under the influence of more base, rearrange to pphosphorylated cyclic ketones (158). 3,3-Dimethylcyclohexanone led to a product having the structure
a
Organophosphorus Chemistry
148
0
II
6
W W 2
i, LDA c ii, (R0)2P(O)Ci
LDA
(159) 0
OP(OEt)2 i, LDA ii, (EtO)2P(O)CI
LDA
5: Quinquevalent Phosphorus Acids
149
(158;b) rather than (158;a) a result which, taken together with other data, was deemed to be an indication of the participption of an allylic anion with migration of the phosphoryl group to an ally1 terminus decided on by steric resistance to migration. 3-Methylcyclohexanone might similarly be expected to favour the formation of type (158;b) at the expense of (158;a). In practice, products with the structure (158;a) and (158;b) were obtained in the ratio 2:l. Rearrangement of the dienol phosphate (159) gave (160) as the sole product, reduction of which provided the C-phosphorylated cyclohexanone. Such a rearrangement is less dependent on ring substitution than that of a monoenol phosphate. The regioselectivity
in therearrangementof cyclohexadienyl phosphates can thus be used with advantage to prepare phosphonoketones which might otherwise be difficult to obtain. The procedure is useful for five- and six-membered ring ketones, but ketones with larger rings can undergo other reactions; cycloheptanone, for example, yields a hydroxyphosphonate through a l12-phosphoryl migration. 146 The LDA-induced rearrangement of enol diethyl phosphates (162) derived from lactones is an alternative to the more traditional Arbuzov approach to the compounds (163) and is applicable to compounds with rings containing up to 13 member atoms. Cyclic ketones of similar ring size very often undergo unusual reactions, sometimes leading to hydrocarbons having either fewer carbon atoms, or consisting of condensed dimers. The procedure is also applicable to acyclic carboxylic esters although, because of steric factors, not with the same overall success.147 The evident importance of the rearrangement of en01 phosphates leading to C-P bond formation, under biological conditions should be mentioned. The occurrence of enzymes responsible for C-P bond formation in Tetrahvmena and S t r e D t o m v w h v w o s c oDicus has already been established, and new systems have now been reported. The conversion of carboxyphosphonoenolpyruvate (CPEP) (164) into phosphinopyruvate (165) has been shown to be catalyzed by a CPEP phosphonomutase. 148 Phosphoenolpyruvate( PEP)-phosphomutase is another enzyme which also catalyzes C-P bond formation and appears to play a central role in the biosynthesis of (2-aminoethy1)phosphonic acid. Possible mechanisms for the formation of the C-P bond under biological conditions through this latter role have been considered
I so
Organophosphorns Chonistty
in the light of results recently obtained during a study of systems incorporating 180-labelled enol thiophosphate.14’ Previously considered mechanisms for the rearrangement of PEP itself were (i) a stepwise double displacement route, (ii) a concerted sigmatropic phosphoryl migration, and (iii) a stepwise cyclization-ring opening path Y h an oxaphosphetane intermediate. The isomerization of PEP to the HOOCCOCH2P03H2 occurs with configurational inversion at phosphorus. Mechanisms (i) and (iii) should lead to retention of configuration. Inversion is apparently possible only with mechanism (ii), although corrections to assigned configurations make the final choice of pathway somewhat uncertain. This continues to be a very lil W k v l m related Aci&.active area, with many new syntheses and further modifications to old, well-tried, reactions. Thus, (1-aminoalky1)phosphonic acids have been prepared from triphenyl phosphite and symmetrical alkanebiscarboxamides or phydroxycarboxamides, followed by hydrolysis,150 and by the condensation of the same phosphite with aliphatic aldehydes and N-phenylthiourea and subsequent decomposition of the intermediate with HBr in HOAc.151 The reactions beween a P(II1) ester and pmethoxymethylarylamines in the presence of TiC14 yield diesters of (N-arylaminomethyl) phosphonic acids. 152 Reactions between p-benzyloximes and Pel3 in HOAc at room temperature lead to Q-benzyl derivatives of [(1-hydroxyamino)alkyl]phosphonic acids.153 The mechanism of interaction with PC13 with amides and carbonyl compounds in HOAc has been investigated with particular reference to those intermediates which are generated before P-C bond formation.154 The use of phenylphosphonous dich1ori.de in the preceding reactions leads to derivatives of the [(1-aminoalkyl)phenyl]phosph~nic acids. Oximes of (1-oxoalky1)phosphonic acids react with Ph2PC1/Et3N to give 1-(diphenylphosphinoyliminoalky1)phosphonates (166) by spontaneous rearrangement of the intermediates. Reduction of the imines and acid hydrolysis yielded ( 1-aminoalky1)phosphonic acids esters ( 167) Syntheses from hydrogen phosphonates ( RIO),P( O)H, include reactions with aldehydes, R’CHO and benzyl carbamate to give the intermediates (168),156 and additions to the intermediate (169). In the latter case, removal of aluminium with acetic acid
5:
Quinquevalent Phosphorus Acids
151
COOH (1 65)
PEP
0
II
(Et0)2PCHRN=CPh2 (172)
152
Orgariaphosphorus C h mistrv
leads to only moderate yields of esters of the desired acids from alkyl cyanides.157 A synthesis of Pphosphorylated aziridines commenced with the interaction of lithiated (chloromethy1)phosphonic diesters and aldimines in a highly stereoselective process yielding mainly (95%) the stereoisomer (171). Incorporation of CC14 into the reaction system afforded a -chloro derivatives of the aziridines, a result which led to the assumption that the reaction proceeded the intermediate anion (170).158 The N-diphenylmethylene derivative of diethyl (aminomethyl)phosphonate (172; R = H) can be alkylated (solvept systems not required) and the product selectively hydrolysed (10% HC1 as.) to (167).15' Alkylation of the Schiff base derived from an (aminoalky1)phosphonic acid and (S)-(-)-2-hydroxypinan-3-one (as a the chiral agent) leads to dextrorotatory acids H2NCHRP(0)(OH)2; same paper describes a new method for the column chromatographic resolution of racemic ( u -aminobenzyl)phosphonic acid using its Schiff base with the aforementioned chiral reagent.160 Optically active (1-aminoalky1)phosphonic acids have also been obtained using a methodology based on the chemistry of 1,3,2-oxazaphospholidines (Scheme 9 ) . The diastereoisomers (173;a) and (173;b) afe separated by column chromatography, then alkylated and hydrolysed to the ( S ) and ( B ) acids (174).161 A detailed study of the synthesis of N-(phosphonomethy1)glycine has been made using c.m.r. and 31P n.m.r. spectroscopy. When sodium glycinate, HCHO and dimethyl hydrogen phosphonate react together, the yield of the desired compound is low, and the main products are H3P03, (hydroxymethy1)phosphonic acid, U-methyl-N-(phosphomethyl)glycine, and H,N-bis(phosphonomethy1)glycine. New dialkyl (H,N-dialkylaminomethyl)phosphonates have been listed;163 H-alkylated derivatives of (2-aminoethy1)phosphonic diesters have been prepared by conventional means. 164 Addition of secondary amines to dialkyl (1-phenylviny1)phosphonates yields the compounds (RO)2P( O)CHPhCH2NFt1R2; 165 an alternative reaction, namely that of dealkylation at oxygen, occurs when the phenyl group is in the 2 position.166 A synthesis leading to esters of (2-aminoethy1)phosphonic acids (175) involves the treatment of
5: Quinquevalent Phosphorus Acids Me
153
Ph
H
MeN,
H R
ii
0o
-(173)a;
1
R=alkyl
H2N
P03H2
(174a)
II
A 1 7 2 : NHCOPh H
PhCONHCH2PCl2
\ Me)-(ph ii MeN, /O -(173)
b; R = alkyl
-
R H
1
H2N P03H2 (174b)
RYp-+o NHCOPh (173) b; R = H
Reagents: i, (-)-ephedrine/Et3N; ii, a, BuLi, THF at -70 OC, b, RX at -70 "C; iii, a, conc. HCI, b, propylene oxide Scheme 9
R'CH=CR%OOM~
-
0
II
(Et0)2PCHR'CHl?COOMe
0
0
II
II
(H0)2PCHR1CHF?NH2
(Et0)2PCHR1CHF?CONH2
(175) Reagents: i, (Et0)2P(0)H, NaOEt; ii, NH3; iii, PhIO-HCOOH or PhI(OH)(OTs);iv, H30+; v, propylene oxide Scheme 10
-
R'
BocNH BocNH4 HC O O M e
U ~ O M C I ) ~ii iii
0
H2N
0
Reagents: i, (Me0)2P(0)CHR2Li,THF, -78 "C; ii, Me3SiBr; iii, MeOH Scheme 11
0
0
154
Organophosphorus Chemisrry
3-phosphonopropanoamides with hypervalent iodine compounds (Scheme 10). 167 Bis(benzotriazoly1) (2-bromoethy1)phosphonate has been offered as a new reagent for the synthesis of H-substituted (2-aminoethy1)phosphonates derived from carbohydrates by reaction at the primary hydroxy group. 168 ( w -Aminoalkyl- w '-aminoalky1)phosphinic acids have been prepared from ( W -aminoalkyl)phosphinic (phosphonous) acid derivatives by aminomethylation and additions to acrylonitrile. 16' A simple preparative route (Scheme 11) provides (3-amino-2-oxoalkyl)phosphonic acids as novel inhibitors of D-alanine- D-alanine ligase. 170 Analogues of phosphinothricin lacking amino and carboxyl groups, have been prepared from the intermediates (176; R = H or C1) using the routes outlined in Scheme 12. Using the intermediate (178), similar routes led to (179; R1 = SiMej, R2 = Et) from which the protecting groups could be selectively removed as illustrated in Scheme 13. The racemic hydroxy compound (180; = H) is a powerful inhibitor of glutamine ~ynthetase.'~~ The intermediate (181) proved to be a good starting point for the synthesis of various other compounds of potential biological interest and fairly closely related to phosphinothricin, e.g. with amino and phosphoryl groups separated by three carbon atoms (Scheme 14) .170 Other (4-aminoalkyl)phosphonic acids (181) have been prepared as outlined in Scheme 15.l~' A new and more amenable synthesis of 2-amino-5-phosphonopentanoic acid consists in reaction between diethyl (3-bromopropy1)phosphonate and the Schiff base from benzophenone and ethyl glycinate, with subsequent removal of the diphenylmethylene protecting group and concomitant hydrolysis of the phosphorus ester
R1 = R2
groups with 6M HC1 a ~ 4 . l ~ ~ 2-Amino-7,7-difluoro-7-phosphonoheptanoic acid has significantly less antagonistic activity towards N-methyl-D-aspartic acid (rJMDA) than the parent dedif luoro compound. 173 In an investigation into the relative spatial requirements of phosphono and amino groups in (aminoalky1)phosphonic acids and phosphinic acids vis-a-v
their behaviour towards NMDA, several Q-,
5:
Quinquevalent Phosphorus Acids
0 II,Me R
= CI
%Et
i
0
(1 76)
1
R P H iii ii
(177) R = H I
lv
OR
(177) R = Me3Si
Reagents: i, MeP(OEt)2,PhMe, heat; ii, HOAc, EtOAc, Pt02/H2; iii, MeP(O)H(OEt), MeCON(SiMe&, CH2CI2;iv, EtOH aq. ; v, Me3SiBr,CH2C12;THF aq. Scheme 12
BnOOC (179) R’ = H, R2 = Et
NHCOOBn (178)
li
0
iI,Me BnOOCyyp\0R2 BnOOCNH
OR’
(179) R’ = Me3Si, R2 = Et
/ K
I
iv
(180) R’ = H, R2 = Et
0 ll,Me
Hooc\fyp\oR2 NH2 OR’ (180) R’ = R2 = H
Reagents: i, MeP(O)H(OEt), MeCON(SiMe&, CH2C12; ii, HF, MeCN aq. ; iii, Me3SiBr, CH2C12; iv, H2, PdC, EtOH aq. Scheme 13
156
Organophosphorus Chemistry
R’ i
H
1
1
HO iv
iv
iii
OH
1” H2N&P03H2 OH ; (Me0)2P(O)CHLi;iv, a, MeSSiBr b, Me0 Reagents: i, CH2[P(0)(OEt)d2;ii, Bu’OOH, 0 ~ 0 4iii, Scheme 14 R’ R’ (181) 1 BocNH
2
BocNH
0
OH
iv, v
H2N&po3H2
BocNH
0
0
(1 82)
Reagents: i, H2C=CHMgBr, Et20; ii, (COC1)2,DMSO;iii, Me3SiOP(OMe)2;iv, Me3SiBr; v, MeOH Scheme 15 H2N HOOC (1 83)
Q”
(1 84)
5: Quinquevalent Phosphorus Acids
157
m-,
and p-substituted (phosphonoalky1)phenylglycines and -phenylalanines (183) have been synthesized and compared with the series (184) in respect of their behaviour as competitive NMDA inhibitors. 174
These compounds were prepared by standard synthetic
routes from, for example, (185); this provided p ( 1 8 3 ; n = m = 0 ) and ~ ( 1 8 3 ; n = 0 m = 2). Two compounds, p-(183; n = 0, m = 1) and ~ ( 1 8 3 ; n = 1, m = 2) showed an antagonistic activity comparable to that o f 2-amino-7-phosphonoheptanoic acid.
a.
Last year's Report included mention of the synthesis of various 0 -3-(and 2-)-carboxypiperidinylalkylphosphonic acids with biological activities similar to that referred to in the previous paragraph. More examples of such compounds have now been described; their synthesis commenced with (4-pyridinylmethy1)phosphonic acid diethyl ester and developed with processes of chain extension, introduction of, and subsequent modification of, nuclear CN, and finally reduction of the pyridine nucleus. 175 Physiologically, the most interesting compound proved to be (186). Attention has also turned to related 2-piperazinecarboxylic acid-based phosphonic acids.176 Here, one of the most highly active competitive antagonists of the NMDA subtype-of glutamate receptor is 4-(3-phosphonopropyl)-2-piperazinecarboxyl~c acid (187). In a new synthesis from 2-piperazinecarboxylic acid, the blocking of the amino function a to the COOH group was achieved simply through Cu chelation (Scheme 16), although the use of other protection groups was also successful. The complexing abilities of (aminoalky1)phosphonic acids have been reviewed. 177 fi\ -S S e l - - c v . Greater than 89% configurational retention has been observed in the reactions between
. .
phosphinothioic acids RPhP(0)SH (R = But or 1-naphthyl) and Lawesson's reagent, followed by alkylation (MeI) 17' E-Chiral thioxaphosphoranesulphenyl chlorides, R1R2P(S)SC1, have been synthesized as a unique probe for the study of nucleophilic displacement reactions at a dicoordinate sulphur atom. The key intermediate in their preparation was the
.
amide (188; R = L-menthyl) the diastereoisomers ofxwhich were readily separated; in their ensuing reaction with Me3SiC1 each afforded the corresponding sulphenyl chloride; each of the latter
Orgunophosphorus Chetnistrv
1%
H
(CH2)3P03Ef2 i, ii
N
- (
C ‘:(OOHH
(tH2)3P03H2
iii, iv
(N ~ c o o H
l c 5 0
HON
I
H
CU-0
(187)
Reagents: i, CuC03*Cu(OH)2;ii, I(CH2)3P03Et2;iii, H2S;iv, 6M HCI Scheme 16
Me
Me
OEt
+ I -CHCOR~
Ar’
I CH-S
\
(195)
! , o l .
t
,P -CN HR3 R~NH’
5: Quinquevalent Phosphorus Acids
159
was readily convertible. back into the chiral sulphenamide by reaction with morpholine. The species (53) was also eliminated, and the phosphindole (189) formed when (190; X = S) was heated. The latter was obtained when the corresponding dioxide (190; X = 0) was treated with Lawesson's reagent: the dioxide was itself obtained through reactions based on the dimeric forms of 1-ethoxy-3-methyl-laphosphole 1-oxide or 1-sulphide with mCPBA. In the course of synthesis of (190; X = S), a new compound was isolated. This, although sensitive to water, had good thermal stability and was shown by X-ray diffraction techniques to possess structure (191), the first known compound to possess the 1,3,2,6-oxathiadiphosphorin ring system. '
Two new types of compounds are the products obtained when the pyridiniumacylides (192) are treated with dithiadiphosphetane 2,4-disulphides. The overall and relative yields of the 1,4,2-thiazaphospholes (193) and the 1,3,2-oxathiaphosphole betaines (194) evidently depend particularly on the group R1 .182 /k) P-N Bo&ed C-.The dihydro-1,2-azaphospholes (195) have been prepared from the oximes of dialkyl (1-oxoalky1)phosphonates carbanion formation and subsequent reaction with the aldimines
a
Ar1CH=NAr2. 183 Interaction of the analogous R2R3CHCH=NFt4 with (R'O) 2PI afforded the 1 ,3,4-diazaphospholidines (196). 184 1,3,2,4-Diazadiphospholidines (197; X = 1 . p . ) have been obtained as indicated, being readily modifiable through addition of S or 0, the latter by using DMSO. 185 The synthesis of the benzodiazaphosphorine (198; R2 = H) started with isatoic anhydride. Reactions between the former (R1 = alkyl or CH2COOEt) and isothiocyanates, R3NCS in the presence of base, gave (198; R2 = (CSNR3)-) initially: these, in simple steps could be made to yield the
[1,4,3]thiazaphosphorino[3,4-b] [1,3,2]-benzodiazaphosphorine 12-oxides (199; X = NR3) in which the P = 0 and C = N bonds are trans and axial. A similar reaction with CS2 gave (199; X = S ) together with the dimer (200). 18' 11) C o m s of bioloqical inter&.-
Recent years have seen a
large increase in interest in the synthesis of the various phosphates of myp-inositol, but little, if any, attention devoted to
160
Organophosphorus Chemist@
0
0
x
B
B
R
I
OH
(203) R = OH, 6 = Guanine (204) R = OP03H2, B = Guanine
\OH (207) B = Cytosine
(205) B = Guanine
(206)
(Et0)2P(O)X (208) a; X = CH20(CH2hBr b; X = (CH2)@r C; X = CH~SCH~CH~OMS d; X = CH20CH2CHRMe (R = I, OMS) e; X = CF2(CH2)#I (R = I, OMS)
B = MeO, or amino acid, or protected uracil or adenine (209)
0 (210) X
II
CH2CHZP(OEt)2
Y=JJS
0
II
(21 1) X = CH2CH2P(OEt)2
s-
I
5: Quinquevalent Phosphorus Acids
161
phosphonates based on the same system. A racemic myQ-inositol-1-phosphonic acid has now been synthesized starting from the bisisopropylidene derivative (201; R1 = R2 = H) which, when benzylated (NaH, DMD, BnBr), afforded a mixture of monobenzyl ethers, from one of which the compound (201; R1 = ButMe2Si, R2 = H) could be obtained. Oxidation (N-chlorosuccinimide) of this alcohol gave the corresponding cyclohexanone which was then acted upon by dimethyl methylphosphonate carbanion, and the resulting alkene reduced (H2, Pt02), de-esterified (Me3SiBr, MeOH), and deprotected (TFAA) to give the phosphonic acid (202).187 Ganciclovir (203) is an extremely potent agent active against herpes viruses, being metabolised to the monophosphate (204). A synthesis of the phosphonate isomer (205) is.based on the regiospecific addition of diethyl (hydroxymethy1)phosphonate to the enol ether (206; B = protected guanine) under oxidative ( S )-1- [ 3-Hydroxy-2- ( phosphonylmethoxy)propyl ] conditions. cytosine ( 2 0 7 ) has been synthesized and shown to be even more active 189 against herpes simplex virus than the guanine derivative. Several guanine-based phosphonic acid derivatives have been synthesized from the phosphonic acid esters (208; a-e) and suitably protected (benzyloxy, or 2-methoxyethoxy) guanine, with conventional modification procedures in the later stages. Irradiation of mixtures of amino acid or the carbohydrate (209; B = MeO, protected uracil, or protected adenine) and bis(2-pyridinyl) disulphide (a combination initially providing acylated N-hydroxy-2-thiopyridones (209; X = COOY)), in the presence of diethyl vinylphosphonate yields the addition compounds (210) (43-65%) which can be reduced to (211) using BugSnH. In some cases, rearrangement products e.g. (209; X = 2) (20-36%) are formed.lgl The chemistry of phosphonylalkyl and phosphonylalkoxyalkyl 192 derivatives of purine and pyrimidine bases has been reviewed.
Dienophilic reactivity has been observed in the Diels-Alder additions of esters of (2-methyl-1-propeny1)phosphonic acid to cyclopentadiene to give (bicyclo[ 2.2.1 ] hepten-2-yl )phosphonic acid derivativeslg3
162
Organophosphorus Chemistry
and in the additions of acetylenecarboxylic esters to
(1,2,4-pentatrienyl)phosphonic diesters.
In the latter case, the
final products are mixtures of the benzylphosphonic diesters (212) and (213) resulting from prototropic rearrangements within the initial adducts. lg4 Similar reactivity has been demonstrated in the reaction between (214) and PhCCl=NNHPh in the presence of Et3N, when the formation of (215) has been ~1aimed.l’~ The first examples of the Pd-promoted decarbonylation and metathesis reactions of acylphosphonic diesters have been reported. In the presence of [PdMe2(PMePh2)2], diethyl benzoylphosphonate is degraded during minutes and with quantitative yield, into diethyl phenylphosphonate; (1-oxoalky1)phosphonic esters suffer a similar fate but the process may take several hours under the same conditions. When mixtures of aroylphosphonic diesters and esters of (1-oxoalky1)phosphonic acids are brought into contact with the catalyst in boiling toluene, exchange occurs prior to decarbonylation ( Scheme 17 ) , and complex product mixtures can result.lg6 In the reactions between the halogenated dialkyl (2-oxoethy1)phosphonates (216; X = halogen) and aryldiazonium Salts in aqueous sodium acetate, loss of the CHO group occurs when X = C1 or Br, but for X = I, CHO is retained at the expense of the halogen atom. l g 7 A study of the kinetics of these reactions suggests initial, fast deprotonation of the phosphonate followed by coupling and subsequent loss of formic acid. The overall reaction rate increases with increasing pH. N.m.r. and i.r. spectroscopic studies on the nature of the carbanionic species from alkylphosphonic diesters, and the relevance of their structure to the stereoselectivity of their aldol type reactions, have been reviewed. lg9 Whereas alkylphosphonic diesters react readily with lithium or organomagnesium reagents with the formation of the metallated phosphonate carbanions, the reactions between such esters and the metals themselves result, by contrast, in dealkylation of the ester groups involving both C-0 and P-0 cleavage; traces of unsaturated hydrocarbons, even including alkynes and aromatics, are thought to be formed by radical-induced reactions.2 o o Benzonitrile and the E-oxime (217) are the isolable products
163
QQ
O’/‘OEt
R’COP(O)(OR‘)2
1
+
cat.
R2COP(0)(OR2)2
R1COP(0)(OF?)2 + R2COP(0)(OR’)2
cat.
R‘P(O)(OR’)2
’
R2P(0)(OF?k
1
1
cat.
cat.
R2P(0)(OR’ )2
R P(0)(OF?)2
Scheme 17 Me 0 II (R0)2PCHXCHO
0
II
/O\
(Et0)2P(CH2),-C ---CHR’
i
Me
MeX;(,Ph
Me
-
(218)
N
‘OH
0
II
(Et0)2P(CH,), COCHXR’
(219) n =Oor1 R‘ = H or ~e X = CI or Br
164
Organophosphorus Chemistqi
following the reaction between 2 - b e n z o y l - 2 - o x o - 4 , 4 , 5 ~ 5 - t e t h y l 1,3,2-dioxaphospholane and hydroxylamine, suggesting the rapid preferential dehydration of the H-oxime under the experimental conditions.201 It has been reported both that the oxime of dimethyl benzoylphosphonate is stable to formic acid, and that it readily converts into benzonitrile without any evidence of rearrangement. In a new study of the decomposition of oximes of other diethyl aroylphosphonates in acetic acid, two reactions have been discerned.
The first reaction is the expected dehydration to
the nitrile by attack of acetate at phosphorus: the second reaction is one of rearrangement leading to diethy; N-aroylphosphoramidate, demonstrating a higher migratory aptitude of the phosphonyl group over Ar. Which of these two processes predominates depends upon the substituent on the aryl group. 202 The chlorination, or brornination, of 2-(2-chloro-1,2-alkadiene)-l,3,2-dioxaphospholane 2-oxide results in ring enlargement to 2-halogenoethyl-2-oxo-5,6-dihydro1,2-oxaphosphorin. 203 The base-catalyzed rearrangement of diary1 phenylphosphonates to bis(2-hydroxyary1)phenylphosphine oxides has been examined. 204 The trif luoroperoxyacetic acid oxidation of alkenephosphonates with a halogen atom at the double bond yields the c-phosphorylated a-halogenated carbonyl compounds by 1,2-shift of chlorine; examples of such shifts are shown in (218) -> (219), (220) --> (221), and (222) -> (223) + (224).205 The migration of a benzyl group (indeed of any group other than phenyl) has been observed for the first time in Lossen-like rearrangements of H-phosphinoylated Q-sulphonylhydroxylamines, although the process occurs less readily than that for aryl groups directly bonded to phosphoryl phosphorus. With methoxide or ethoxide the phosphinic amide (225) yields only 25-35% of the rearrangement product (226), the main products being the ester (227; R = Me or Et) and the amide (228), but with isopropoxide or tert-butoxide, the rearrangement product (226) accounts for 70-80% of the total reaction yield. The use of tert-butylamine as base leads t o (229). rearrangement, in the present instance, is of mechanistic
The
significance since it demonstrates that the migration can be based
5: Quinquevalent Phosphorus Acids
165
0
-
II O/ ,
(Et0)2PCH-CCIBut
0
I1
0
II
(Et0)2PCHCICOB~t
0
II
Ph2PNHOPPh2
L
OR 0=PCx
I
CF&HCIN=CHPh
(233)
CF3CH=NCHP h
.OR 0=PCx
120-1300c_ CF,CH,N=CPh
1
(235)
(234)
0=P(OR1),
1
P
CF&H N=CH Ph
(238)
I hh
upon an sp3 carbon and that the new N-C bond can be formed without the involvement of r, electrons.206 Methoxide acts upon (230) causing degradation, but following treatment with tert-butoxide (230) undergoes rearrangement to the mixed anhydride (231), and although this was not isolable, it was characterized following its preparation by an alternative route. Under the same experimental conditions, the corresponding methanesulphonyl derivative afforded (232) in almost quantitative yield (a 5% yield was experienced from the phosphinoyl derivative). 207 C-Phosphorylation of the imidoyl halide (233) by reaction with dialkyl fluorophosphite results in the formation of the rearrangement product (234; X = F) which, at a higher temperature, rearranges prototropically and irreversibly to the phosphonate (235; R1 = Et or Pri) On the other hand, the ester (234; X = OR1 = OPri) rearranges rather more slowly than the diethyl (236), ester at the same temperature. The tautomer of (233), reacts with trialkyl phosphite (R1 = Pr' or Me3Si) to give (237) initially which rearranges irreversibly under the reaction conditions to give (238; R1 = Prl or Me3Si). 208 The esters (239), obtained analogously, are isolable, and are quite stable at 209 room temperature, but at higher temperatures, also rearrange, the corresponding trimethylsilyl esters particularly easily.210 In the last case, an even higher temperature results in phosphoryl migration thus affording the phosphonate (240). In a series of papers Chinese authors have reported on (a) the effects of changes in solvent on the hydrolysis of a series of 2-propyl- and 2-isopropyl-l ,3,2-dioxaphospholane 2-oxides,211 (b) a theoretical treatment, by molecular mechanics, of the hydrolysis of alkylphosphonic estes and alkylphosphonic dichlorides,212 and (c) a similar treatment of substituent effects in the alkaline hydrolysis of esters of alkylphosphonic and dialkylphosphinic acids.213 In respect of the last two studies, it was concluded that using steric constants derived from work on carbon compounds led to poor correlations. However, the steric effects of substituents on rates of hydrolysis correlated well with the quantity A A E, representing the difference, calculated by molecular mechanics, between the energies of the tetracoordinate ground state of the substrate and of
.
a.
5:
Quinquevalent Phosphorus Acids
7 Bu'C=NCH~P~
O = (OR),
167
160-1 70 "C
O =r;(OR),
BdCHN=CHPh
(239)
I
R = MesSi 160 "C
O=P(OSiMe3)2
I
BdCHN=CHPh
180-200
OC-
O=P(OSiMe3), I ButCH=NCHPh (240)
Ho;k
0
II
0
(241) a; R = Ph, X = Y = CH2 b; R = Ph, X = 0, Y = CH2 C; R = P h , X = Y = O d; R = Et, X = Y = CH2 e; R = Et, X = 0, Y = CH2
HO
(242a)
(242)
(EtO)(MeO)P(O)Ph
(EtO)(MeS)P(O)Ph
(247)
(246) EtO, p+S Ph' 'SMe
0
the transition state - assumed to possess pentacoordinate geometry. In (b), the correlation was good for branched chain alkyl groups, but less S O for unbranched alkyl groups, presumably because steric effects then play a reduced part in the overall substituent effect. The results of a study of conformational preferences on the rates of alkaline hydrolysis of the diphenyl and diethyl phosphonic esters (241)214 follows the appearance, last year, of those of a similar study on diphenylphosphinic esters. A mechanism involving both penta- and hexa-coordinate intermediates has been proposed to account for the asymmetric induction (1-14%) achieved during the displacement reactions from the racemic MePhP(0)X (X = F, C1, CN, OC6H4N02-4) by alcohols in the presence of resolved forms of 1-phenylethylamine, N,N-dimethyl-1-phenylethylamine, or nicotine.215 The structures of the various cyclic and acyclic products obtained through 1,2- and 2,3- additions, both E and Z, of sulphenyl halides to dialkyl (1,2-alkadiene)phosphonates have been verified by 216 chromatographic and n.m.r. spectroscopic studies. Some reactions of 1,2-oxaphosphol-3-ene 2-oxides have been reported. When brominated under free radical conditions, 3,5-di-tert-butyl-l,2-oxaphosphol-3-ene 2-oxide (242) gave the extremely labile 5-bromo derivative (242; R = Br) which, with MeOH, gave the 5-methoxy derivative. The 2,5-dihydroxy compound was obtained by hydrolysis; its reaction with diazomethane gave dimethyl 8-(2,2,6,6- tetramethyl-3-oxohept-4-en-5-yl)phosphonate indicating a tautomeric equilibrium between the cyclic (242; R = OH) and acyclic (242;a) structures for the acid. The methyl ester of (242; R = MeO) undergoes slow ring opening in the presence of base, a feature immediately reversed on neutralization, and the same compound is inert to methoxy exchange except in the presence of excess HBr at an elevated temperature.217 The inability of (1,2-propadienyl)phosphonic acids (243; R1 = ~2 = OH, R4, R~ = H or alkyl) to form 1,2-oxaphosphol-3-ene 2-oxides under the influence of concentrated acids has been attributed to the failure to produce stable ‘tertiary’ cations of type (244;a; E = H). On the other hand, those phosphonic acids which would be predicted to form stable carbocations, e.g. R4 and R5 are alkyl, react readily, presumably then because of steric
5:
Quinquevalent Phosphorus Acids
169
resistance within the carbocation to rotation to (244;b). Since cyclization of compounds other than free acids occurs with electrophiles other than H+, the possibility of cations of type (244;c) cannot be excluded when E = H. A recent development is the catalysis of cyclization, by Ag+, of allenephosphonic acids which can provide only a secondary carbocation i.e. either R4 or R5 is alkyl, but not both. The cyclization of phenylpropadienylphosphinic acid is similarly catalyzed by Ag+. From the practical standpoint, the catalysis enables the cyclizations to be achieved in hours at room temperature rather than over even more extended periods at l o o o . 218
Dialkyl (2-methylamino-1-propeny1)phosphonates exist as the enamine tautomer in CC14 solution, but are acylated to give the B-acyl derivatives. 219 Competitive displacement of the Me0 and MeS ligands from Q,S-dimethyl phenylphosphonothioate, when the latter is treated with NaOEt in EtOH, results in the formation of p-ethyl S-methyl phenylphosphonothioate (246) and preferentially, Q-ethyl Q-methyl phenylphosphonate (247), both with inversion of configuration; each displacement is accompanied by racemization resulting from simultaneous and competitive displacement of EtO groups. Further displacements by EtO- lead, in each case, to diethyl phenylphosphonate. The racemization of (246) is 22 times faster than that of (247), whilst the displacement of MeS from (246) is 65 times faster than the displacement of Me0 from (247). The conclusion reached was that the displacement of MeS does not occur Y k i an inversion pathway simply because a retention pathway, as recorded in 220 earlier literature, is blocked energetically. In another study, reactions of the ( € 3 ) p ( 3 ) p , - ( mixed +) anhydride (248) were examined.221 For each of (a) alkaline methanolysis, (b) acidic methanolysis, (c) alkaline hydrolysis, and (d) ammonolysis, displacement occurred preferentially at the phenyl-phosphonyl centre with inversion of configuration. The treatment of (248) with KSH (followed by MeI) yielded racemic Q-ethyl S-methyl phenylphosphono- dithioate (249) by attack at the phosphonyl phosphorus, together with (B)-(-)-Q,S-dimethyl Q-PhenYl phosphorodithioate (250) by attack at the phosphoryl phosphorus. Q-Ethyl (B)-phenylphosphonochloridothioate (251) and (B)-Q-ethyl
PhBu'P(S)OSO2CF3
[Bu'PhP=S]+[C F,SO,]-
(254)
PhBu'P( X)OSiMePh (C OH7- 1)
(255) x2
-
(256)
But\ 00 /p\+ R S-Me
>k
X-
-
x2
-x2
.p
But\ /p\+ Fc SMe X3-
>:
(257) a; R = Ph
X
But,+
P ' R' \SMe
Scheme 18
5: Quinquevalent Phosphorus Acids
171
Q-phenyl phosphorochloridothioate (252) were each obtained when (248) was acted upon by Pel5; here, inversion still predominated although the extent of racemization was greater than that found for the alcoholysis and hydrolysis reactions. The displacements were considered in terms of pentacoordinate intermediates. The behaviour of tert-butylphenylphosphinothioic chloride towards Ag’ contrasts markedly with that of the corresponding iodide. In MeN02, the chloride is unreactive, but the iodide affords a mixture of phosphorus-containing products. Tert-butylphenylphosphine sulphide was notable in its absence. The phosphine sulphide (253) was obtained when the reaction involving the iodide was carried out in anisole. Both the iodide, preparable from the mixed anhydride (254), and the latter itself, react with MeOH-Ag+ to give Q-methyl tert-butylphenylphosphinothioate with configurational inversion. The mixed anhydride (254), which also furnished (253) in anisole, was considered, mechanistically, as reacting through structure (255). 222 Such results are in contrast to those obtained during a study of displacement reactions involving the compounds (256; X = l.p., 0, S , or Se). Attack by 0, S , N, or C nucleophiles is directed essentially at silicon rather than at phosphorus, and yet the course of the reactions depends on X , proceeding with predominant configurational retention at Si for X = 1.p. or 0, but with 223 predominant inversion when X = S or Se. A very detailed study (Scheme 18) of the bromination and iodination of the S-methyl phosphinothioate esters (257) has been reported using mainly spectroscopic techniques, but accompanied by gc/ms methods and chemical isolation.224 (Work on the chlorination of the same esters was reported earlier; see ‘Organophosphorus 170.) Both phosphonium and sulphonium Chemistry’, 1988, u, intermediates are involved extensively in the scheme. For X = I, the first part of the Scheme is displaced towards the starting materials. The reactions between (257; a and b) and iodine or bromine (the latter being the faster) are slow, both halogens being weakly nucleophilic, and reaction content studies were extended over 489 days for X = I, and for up to 56 days for X = Br. The main products obtained from (257; a) and I2 were (258;a), (260:a) and (261;a).12 but the phosphinic iodide (263;a) was not formed. Using
/
\
- 2 [R2PS2] Scheme 19
S P
5:
Quinquevalent Phosphorus Acids
I73
bromine, the bromides (263; a) and b ) were both obtained., The stereochemical course of the sequence, investigated using ester (257;a) is naturally of particular interest. When halogenation involves sulphonium salts, as in the sequence (257) --> adduct --> (258)/(259) -> (263), the outcome is one of inversion. When the favoured reaction is (258)/(259) --> (260) -> (263) + (257), the net stereochemical outcome for (263) is configurational retention because of double concurrent inversions in the reactions between (257;a) and (258;a) and between ( X - ) and (260;a), and these proposals explain satisfactorily the experimental facts although the configurations at the P atoms in (260) have not yet been confirmed. The configuration of each phosphorus atom in (261;a) can be established by direct synthesis. Thus, ( R ) - ( + ) - (257;a) with bromine gave almost racemic
-
(263) + (-1 (2611, the (B)p(s)(s)p(o) stereoisomer being the main component. Considerable racemization occurred in the reactions between (257) and bromine leading to (263; X = Br), a feature explained by the formation of the latter two routes, namely,
a
+
(258) -> (260) + (263), and (259) --> (263). N.m.r. spectroscopic evidence has been provided to suggest the dissociation of relatively simple lt3,2,4-dithiadiphosphetane 2,4-disulphides (i.e. those with non-bulky groups) in solution: this (257)
evidence comprises the observed inversion at one of the phosphorus interconversion) and the exchange reactions atoms (i.e. &/trans occurring on admixture of two symmetrical compounds (Scheme 19) .225 An X-ray examination of the product from the interaction of (2~,4~,5~)-(-)-3,4-dimethyl-2-phenyl-1,3,2-oxazaphospho1id~ne 2-oxide with an aryl Grignard reagent has demonstrated that ring opening occurs with retention of configuration at phosphorus in accord with Inch's work, but at variance with that of Koizumi, and also in stereochemical opposition to that displayed by acyclic analogues (Mislow). Acid catalyzed alcoholysis of the acyclic phosphinic amide product yields alkyl esters of arylphenylphosphinic acids with high e.e. 226
I74
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g,
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5, 112,
z,
112,
30,
111,
31,
I
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175
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2,
I
112,
111,
19,
I
S,
I
_
S,
5: Quirtyur~wlerirPhosphorus Acids
177
101. Tay, M. K., About-Jaudet, E., Collignon, N., and Savignac. P., Tetrahedron, 1989, 5, 4415. 102. Hutchinson, D.W. and Thornton, D. M., Synthesis, 1990, 135. 103. Kazakov, P. V., Kovalenko, L. V., Odinets, I. L., and Mastryukova, T. A., Izvest. Ekad. Nauk. SSSR, Ser. Khim. Nauk., 1989, 2150; Chem. Abstr., 1990,, 112, i79213. 104. e e w s k i , P., Phosphorus, Sulfur, Silicon, Relat. Elem.. 1989, 5 , 151. 105. Boyd, E. A., Carless, M., James, K., and Regan, A. C., Tetrahedron Lett., 1990. 31. 2933. 106, Chang, K., Ku, B., and Oh, D. Y., Bull. Korean Chem. SOC., 1989, lo, 320; Chem. Abstr., 1990, 112, 56096. 107. Yamashita, M., Tamada, Y., Iida, A., and Oshikawa. T., Synthesis, 1990, 420. 108. Amri, K., El Gaied, M. M., and Villigras, J., Synth. Commun., 1990, 20, 659. 109. Lu, X., Tao, X., Zhu, J., Sun, X., and Xu, J.. Synthesis, 1989, 848. 110. Abramyan, T. D., Torgomyan, A.M., Panosyan, G. A., Ovakimyan, M. Zh., and Indzhikyan, M. G., J. Gen. Chem. USSR, 1989, 2, 499. 111. Lodaya, J. S. and Koser, G. F., J. Org. Chem., 1990, 2 , 1513. 112. Yuan, C. and Feug, H., Synthesis, 1990, 140. 113. Klumpp, E., Eifert, G., Boros, P., Szulagyi, J., Tmaas, J., and Czira, G., Chem. Ber., 1989, 122, 2021. 114. Montoneri, E., Galluzzi, M. C., and Grassi, M., J. Chem. SOC. Dalton Trans,, 1989, 1819. 115. Heinicke, J., Kadyrov, R., Kellner, K., Nietzschmann, E., and Tzschach, A., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 3 , 209. 116. Dhawan, B. and Redmore, D., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 2 , 177. i.17. Haelters, J.P., Corbel, B., and Sturtz, G., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 44, 53. 118. Hanaya, T. and Yamamoto, H., Bull. Chem. SOC. Jpn., 1989, 62, 2320. 119. Molin, H., Noren, J. 0 . . and Claesson, A., Carbohydr. Res. 1989, 194,209. 120. Brodesser, B. and Braun, M., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 44, 217. 121. Gazizov, M. B., Zyablikova, T. A,, Khairullin, R. A., Musin, R. Z., Chernov, A. N., and Il'yasov, A. V., J. Gen. Chem. USSR, 1988, 58, 1592; Gazizov, M.B. and Khairullin, R. A., J. Chem. SOC. Chem. Commun., 1989, 1549. 122. Cabioch, J. L., Pellerin, B., and Denis, J. M., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 44, 27. 123. Ryabov, B. V., Ionin, B. I., and Petrov, A.A., J. Gen. Chem. USSR, 1988, 58, 859. 124. I., Bou, A., Lalo, J., Maffrand, J. P., and Frehel, D., New J. Chem., 1989, 13, 507. 125. Elkik, E. and Imbeaux, M., Synthesis, 1989, 861. 126. McKenna, C.E., Khawli, L. A., Ahmad, W-Y., Phuong, P., and Bongartz, J-P., Phosphorus Sulfur, 1988, 37, 1. 127. Chambers, R. D., Jaouhari, R., O'Hagen, D., J. Fluorine Chem., 1989, 3. 2.75. 128. Chambers, R. D., Jaouhari, R., and O'Hagan, D., Tetrahedron, 1989, 5 , 5101. 129. Su, D., Guo, C. Y., Willett, R. D., Scott, B., Kirchmeier, R. L., and Shreeve, J. M., J. Amer. Chem. SOC., 1990, 112, 3152. 130. Kadyrov, A. A., Rokhlin, E. M., and Galakhov, M. V., Bull. Acad. Sci. USSR, Div. Chem. Sci., 1988, 1686. 131. Heine, J. and Roeschenthaler, G., Chem.-Ztg., 1988, 112, 246. 132. Su, D., Cen, W., Kirchmeier, R. L., and Shreeve, J. M., Can. J. Chem., 1989, 67, 1795. 133. Aleinikov. S . F.. Krutikov. V. I., Golovanov, A. V., Lebedev, V. B., Zorin, 8. Ya., and Lavrent'ev, A. N., J. Gen. Chem. USSR, 1988, 58, 2013. 134. Shen, Y,, Liao, Q., and Qiu, W., J. Chem. SOC. Perkin Trans. 1, 1990, 695. I
.
~
ZCO,
178
Organophosphorus C'hemisrty
135. Heine, J. and Roeschenthaler, G. V., Chem.-Ztg., 1989, 113, 186. 136. Ovchinnikov, V. V., Safina, Yu. G., Cherkasov, R. A., Karataeva, F. Kh., and Pudovik, A. N., J. Gen. Chem. USSR, 1988, 58, 1841. 137. Francke, R. and Roeschenthaler, G. V., Chem.-Ztg., 1989, 113, 115. 138. El-Manouni, D., Leroux, Y., and Burgada, R . , Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 42, 73. 139. Prishchenko, A. A., Livantsov, M. V., Boganova, N. V., and Lutsenko, I. F., J. Gen. Chem. USSR, 1988, 58, 1932. 140. Bulpin, A., Masson, S., and Sene, A., Tetrahedron Lett., 1990, 31, 1151. 141. Bulpin, A., Masson, S., and Sene, A., Tetrahedron Lett., 1989, 30, 3415. 142. Iyer, R . P., Phillips, L. R., Biddle, J. A., Thakker, D. R., Egan, W., Aoki, S., and Mitsuya, H., Tetrahedron Lett., 1989, 30, 7141. 143. Hong, S., Chang, K., Ku, B., and Oh, D. Y., Tetrahedron Lett., 1989, 30, 3307. 144. zeckmann, R. K., Walters, M. A., and Koyano, H., Tetrahedron Lett., 1989, 0 , 4787. 145. Haelters, J. P., Corbel, B., and Sturtz, G., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 42, 85. 146. Gloer, K. B., Calogeropoulou, T., Jackson, J. A., and Wiemer, D. F., J. Org. Chem., 1990, 55, 2842. 147. Jackson, J.A., Hammond, G. B., and Wiemer, D. F., J. Org. Chem., 1989, 54, 4750. 148. Hidaka, T., Seto, H., and Imai, S., J. Amer. Chem. SOC., 1989, 111,8012. 149. McQueney, M.S., Lee, S., Bowman, E., Mariano, P. S., Dunaway-Mariano, D., J. Amer. Chem. SOC., 1989, 111. 6885. 150. Yuan, C., Yuan, Q., and Xie, X., Youji Huaxue, 1989, 2, 136; Chem. Abstr., 1989, 111, 232995. 151. Kudzinx. H., Mokrzan, J., and Skowron/ska, R . , Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 2 , 41. 152. Ha, H-J., Nam, G.-S., and Park, K. P., Tetrahedron Lett., 1990, 1, 1567. 153. Elhaddadi, M., Jacquier, R., Petrus, F., and Petrus, C., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 45, 161. 154. Soroka, M., Liebigs Ann. Chem., 1990, 331. 155. Krzyzanowska, B. A d Pilichowska, S., Pol. J. Chem., 1988, 62, 165. 156. Yuan, C., Wang, G., and Chen, S., Synthesis, 1990, 522. 157. Kudzin, Z.H. and Majchrzak, M. W., J. Organomet. Chem., 1989, 376, 245. 158. Coutrot, P., Elgadi, A., and Grison, C., Heterocycles, 1989, 28, 1179. 159. Genet, J.P., Uziel, J., Touzin, A.M., and Juge, S., Synthesis, 1990, 41. 160. Cho, S. K. and Kim, Y . J., Tachan Hwahakhoe Chi, 1989, 33, 257; Chem. Abstr., 1990, 112, 35997. 161. Sting, M. and Steglich, W., Synthesis, 1990, 132. 162. Stranin, B. P. and Khizbullin, F. F., J. Gen. Chem. USSR, 1988, 58, 1992. 163. Charandabi, M. R. M. D., Ettel, M. L., Kaushik, M. P., Huffman, J.H., and Morse, K. W., Phosphorus,Sulfur, Silicon, Relat. Elem., 1989, 2 , 223. 164. Xu, Y., Jiang, X., and Yuan, C., Synthesis, 1990, 427. 165. Karimov, K. R., Shakhidoyatov, Kh. M., and Alovitdinov, A. B., J. Gen. Chem. USSR, 1989, 59, 904. 166. Gubnitskaya, E. S., and Peresypkina, L. P., J. Gen.Chem.USSR, 1989, 59, 492. 167. Wasielewski, C., Topolski, M., and Domkowski, L., J. Praktische Chem., 1989, 331, 507. 168. van d e r l e i n , P. A . M., Dreef, C. E., van der Marel, G. A., and Van Boom, J. H., Tetrahedron Lett., 1989, 30, 5473. 169. Maier, L. and Diel, P. J., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 45, 165. 170. ChakroGrty, P. K., Greenlee, W. J., Parsons, W.H., Patchett, A. A., Combs, P., Roth, A., Busch, R. D., and Mellin, T. N., J. Med. Chem., 1989, 32, 1886.
171. Walker, D. M., McDonald, J. F., Franz, J. E., and Legusch, E. W . , J. Chem. SOC. Perkin Trans. 1, 1990, 659. 172. bnstein, P. L., Org. Prep. Proced. I n t . , 1988, 20, 371.
5: Quinquevalent Phosp h ~ n i As c'ids
179
173. Bigge, C. F., Drummond, J. T., and Johnson, G., Tetrahedron Lett., 1989, 30, 7013. 174. Egge. C. F., Drummond, J. T., Johnson, G., Malone, T., Probert, A. W., Marcoux, F. W., Coughenour, L. L., and Brahce, L. J., J. Med. Chem., 1989, 32, 1580. 175. Hutchinson, A. J., Williams, M., Angst, C.. de Jesus, R., Blanchard, L . , Jackson, R . H., Wilusz, E.J., Murphy, D. E., Bernard, P. S., Schneider, L., Cambell, T., Guida, W., and Sills, M. A., J. Med. Chem., 1989, 32, 2171. 176. Bigge, C. F., Hays, S. J., Novak, P. M., Drummond, J. T., Johnson, G., and Bobovski, T. P., Tetrahedron Lett., 1989, 0 , 5193. 1729. 177. Kabachnik, M. I. and Polikarpov, Yu. M., J. Gen. Chem. USSR, 1988, 178. Kawashfma, T., Kojima, S., and Inamoto, N., Chem. Lett., 1989, 849. 179. Lopusinski, A., Luczak, and Michalski, J., J. Chem. Soc.Chem. Commun., 1989, 1694. 180. Quin, L. D . , Osman, F. H., Day, R. 0 . . Hughes, A. N., Wu, X. P., and Wang, L. Q., New. J. Chem., 1989, 13, 375. 181. Quin, L. D., Osman, F. H., Sadanani, N. D., Hughes, A. N., and Day, R. O., Phosphorus, Sulfur, Silicon, Relat. Elem.. 1989, 41, 297. 182. Yousif, N. M., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 44, 249. 183. Liorber, B. G., Pavlov, V. A . , Khamatova, Z. M., Musin, R . Z., Chernova, A. V., Zyablikova, T. A., and Il'yasov, A. V., J. Gen. Chem. USSR, 1989, 59, 94. 184. Gvikova, Z. S., Kabachnik, M. M., and Lutsenko, I. F., J. Gen. Chem. USSR, 1988, 58, 1809. 185. Chen. R. and Cheng, L . , Phosphor 193; Chen, R. and Cheng, L . , Sci. China, Ser. B, 1989, 32, 1300; Chem.Abstr. 1990, 112, 235438. 186. Chen, R. and Bao, R., Synthesis, 1989, 618; 1990, 137. 187. Kulagowski, J. J., Tetrahedron Lett., 1989, 30, 3869. 188. Kim, C. U., Misco, P. F., Luh, B. Y., and Martin, J. C., Tetrahedron Lett., 1990, 31, 3257. 189. Bronson, J. J., Ghazzouli, I., Hitchcock, M. J. M., Webb, R. R., and Martin, J. C., J. Med. Chem., 1989, 32, 1457. 190. Kim, C. U., Luh, B. Y., Misco, P. F., Bronson, J. J., Hitchcock, M. J. M., Ghazzouli, I., and Martin, J. C., J. Med. Chem., 1990, 33, 1207. 191. Barton, D. H. R., Gero, S. D . , Quichet-Sire, B., and Samadi, M., J. Chem. SOC. Chem. Commun., 1989, 1000. 192. Holy, A. and Rosenberg, I., Nucleosides Nucleotides, 1988 (19891, 8, 673. 193. Krolevets, A. A., Popov, A. G., and Adamov, A. V., J. Gen. Chem.USSR, 1988, 58, 2189. 194. MondesEa, D., Tancheva, C., and Angelov, C., Chem. Ber., 1990, 123, 1231. 195. Sedqui, A., Lakhlifi, T., Laude, B., and Amaudrut, J., Bull. SOC. Chim. Belg.. 1989, 98, 865. 196. Nakazawa, H., Matsuoka, Y., Yamaguchi, H., Kuroiwa, T., Miyoshi, K., and Yoneda, H., Organometallics, 1989, 8, 2272. 197. Buzykin, V. I., Sokolov, M. P., and Ivanova, V. N., J. Gen. Chem.USSR, 1989, 59, 631. 198. Sokolov, M. P., Mavrin, G. V., Gazizov, I. G., Ivanova, V. N., and Zyablikova, T. A . , J. Gen. Chem. USSR, 1989, 59, 45. 199. Seyden-Penne, J., Bull. SOC. Chim. Fr., 1988, 238. 200. Koch, P., Rumpel, H., Sutter, P., and Weiss, C. D., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 44, 75. 201. Breuer, E., Karaman, R., Gibson, D., and Goldblum, A., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 41, 433. 202. K a u s h i l C h e m . Ind.(London), 1989, 389. 203. Khristov, V. and Angelov, Kh., Dokl. Bolg. Akad. Nauk., 1988, 41, 73; Chem. Abstr., 1989, 111,194873. 204. Dhawan, B. and Redmore, D., J. Chem. Res.(S), 1990, 184. 205. R abov B. V., Ionin, B. I., and Petrov, A.A., J. Gen. Chem. USSR, 1989, 55, 233. 206. Harger, M.J.P. and Smith, A., J. Chem. Soc.Perkin Trans.1, 1990, 1447.
z,
Organophosphorus Chemistry
180
207. Harger, M. J. P., Tetrahedron Lett., 1990, 31, 1451. 208. Onys'ko, P. P., Kim, T. V., and Kiseleva, E . I., J. Gen. Chem. USSR, 1989, 2, 1123. 209. Onys'ko, P. P., Kim, T. V., Kiseleva, E. I., and Sinitsa, A. D., J. Gen. Chem. USSR, 1989, 2, 1129. 210. Onys'ko, P. P., Kim, T. V., Kiseleva, E . M . , Povolotskii, M . I . , and Sinitsa, A. D., J. Gen. Chem. USSR, 1989, 2, 1496. 211. Liao, X . , Li, S., and Yuan, C., Phosphorus, Sulfur, Silicon, Relat.Elem., 1989, 42, 53. 212. Li, S., Liao, X . , and Yuan, C., J. Phys. Org. Chem., 1989, 2, 146. 48. 213. Yuan, C., Li, S., and Liao, X . , J. Phys. Org. Chem., 1990, 214. Koole, L. H., Olders, E. A. T. A., Opresnik, M., and Buck, H. M., Rsc. Trav. Chim., 1990, 109, 55. 215. Weidert, P. J., Geyer, E., and Homer, L., Phosphorus, Sulfur, Silicon, Relat. Elm., 1989, 44, 255. 216. Mondeshka, D. M., Tancheva, C. N., Angelov, C. M . , and Spasov, S. L., Phosphorus, Sulfur, Silicon, Relat. Elem., 1989, 2, 61. 217. Rardon, D. and Macomber, R. S., 218. Mualla, M. and Macomber, R. S., Synth. Commun., 1989, 2,1997. 219. Sakhibullina, V. G., Polezhaeva, N. A., Bagoutdinova, D. A., and Arbuzov, B. A., J. Gen. Chem.USSR, 1989, 59, 865. 220. DeBruin, K.E., Tand, C. W., Johnson, D. M . , and Wilde, R. L., J. h e r . Chem. SOC., 1989, 111, 5871. 221. Tang, C., Tand, Y . , and C h e T R . , Sci. Sin., Ser. B.(Engl. Edn.), 1988, 31, 649; Chem. Abstr., 1989, 111,174214. 222. zrzypczyhki, Z . , J. Phys. Org. Chem., 1990, 3, 23, 35. 223. Wozniak, L., Cypryk, M., Chojnowski, J., and Lanneau, G., Tetrahedron, 1989, 45, 4403. 224. Gawlecka, B. and Wojna-Tadeueisk,, E., J. Chem.Soc. Perkin Trans. 2, 1990, 301. 225. Ohms, G., Grossmann, G., Buchta, B., and Treichler, A., 2 . Chem., 1989, 29, 138; Ohms, G., Treichler, A., and Grossmann, G., Phosphorus, Sulfur, Silicon Relat. Elem., 1989, 45, 95. Russell, M . J. H., Tetrahedron, 1990, 46, M . , Carey, J. V., 226. Brown, 4677.
-
i.
6
Nucleotides and Nucleic Acids BY R. COSSTICK AND A. M. COSSTICK
1.
Introduction
Whilst DNA synthesis has not yet reached perfection and automated RNA synthesis is still far from routine, much of the recent effort in chemical laboratories
has
oligonucleotides.
been
directed
Undoubtedly
towards
it has
the
been
the
synthesis
modified
of
potential rewards
of
the
anti-sense approach to the control of gene expression that has stimulated this work and the explosion of papers in this area is best exemplified by reference to oligonucleotides containing phosphorodithioate linkages.
Prior to 1989 only
three comrmnications on these analogues had appeared vet in the subsequent 18 months the total number has swelled to almost 20.
A number of novel and
interesting internucleotide linkages have been prepared, many of which do not contain phosphorus and there
is one report of a stable linkage in which
manganese is directly bonded to phosphorus. A plethora of methods are now available for labelling oligonucleotide probes for hybridisation experiments. Many of these procedures are compatible with automated DNA synthesis and the introduction of multiple reporter groups provides a means of amplifying the signal from the probe. A long awaited text book on the chemistry and molecular biology of nucleic acids has
appeared'
and
major
recent developments have
been
reviewed in
symposium reports.2 2 . Mononucleotides
2.1
Nucleoside
Acyclic
Phosphates.
2-Chloro-2,4-dioxo-3-methyltetrahydro-
3,2-As-thiazaphosphole (1) has been used as a programned phosphorylating agent in
a
one-pot
synthesis
of
dithymidine
5'-~-dimethoxytrityl-2'-deoxythymidine
with
monophosphate.3'4
(1)
in
pyridine
Reaction
of
gives
the
intermediate thiazaphosphole ( 2 ) which can be opened with cleavage of the phosphorus-nitrogen bond by 3'-~-acetyl-2'-deoxythymidine in the presence of a nucleophilic catalyst. The resulting phosphorothiolate triester ( 3 ) is readily deprotected using
a
solution of
aqueous
iodine.
The
transformation of
3'-fluoronucleosides into their 5'-monophosphates has been accomplished using whole cells of the bacteria Erwinia herbicola and 4-nitrophenyl phosphate as a phosphate donor.'
Additionally, convt rsion of
the monophosphates to
the
triphosphates has also been achieved enzymatically using cells of Saccharomyces
181
I X’
Tro TrovTh ?
HO-PI
OH OAc
(3)
HO
OH (4) 0
“
O
V
T 0
h
Y
OAc
(5)
6: Nucleotides and Nucleic A c i k cerevisiae.
183
The enzymatic synthesis of nucleoside 5'-phosphates labelled with
carbon-14 or tritium has been reviewed.6 Adenosine
5'-g-monophosphate has
E-1-oxide (4) (53% yield) solution at pH 8 . 0 . 7
been
using potassium
oxidised
to
the
corresponding
hydrogen persulphate in aqueous
Interestingly, this oxidation can also be performed on
poly(rA) to give a polymer which is about 60% modified.
It is noteworthy that
the enzymatic digestion of the modified polymer is about 20 times slower than that of poly(rA).
The influence of sugar and base substituents on the stability
of the N-glycosyl bond towards acid catalysed hydrolysis of nucleosides and nucleotides has been reviewed.'
Nucleoside 5 ' -
and 3'-phosphates are both
hydrolysed at a slower rate than the parent nucleoside and this effect is chiefly attributed to conformational changes in the sugar ring, A
trinucleoside monophosphate (5) has
been
prepared
in 96% yield
by
phosphorylation of 5'-G-trityl-2'-deoxythymidine with salicylchlorophosphine (6) and
subsequent
treatment with
excess
3'-~-acety1-2'-deo~ythymidine.~The
continuing search for effective anti-viral agents has maintained the interest in the synthesis and study of nucleotide triester analogues as potential pro-drugs. A series of novel bis(nucleosid-5'-yl)phosphate
triesters have been prepared
based on 9 - [ (2-hydroxyethoxy)methyl]guanine (acyclovir) (7) and (E)-5-(2-bromovinyl)-2' -deoxyuridine (BVDU) ( 8 ) and their ability to release the biologically active nucleotides has been examined in vivo."
The lability of the aryl group
(R) to hydrolysis can be modulated by varying the substituent on the phenyl ring and at pH 7.7 a convenient rate of hydrolysis (half-life 1 7 hours) was observed for the 4-(methylsulphony1)phenyl esters.
The resulting dinucleoside diesters
are substrates for phosphodiesterases and enzymatic hydrolysis produces the nucleoside and
nucleoside 5'-monophosphate.
Toxicity studies on the BVDU
analogue suggests that BVDUMP is released after the compound has penetrated into the cell.
A range of phosphate triester analogues of the anti-viral nucleosides
9-0-D-arabinofuranosyladenine"
(9)
(=-A)
9-~-D-arabinofuranosylcytosine1z(=-C)
and
the
anti-cancer
drug
(10) have been prepared by reaction of
the unprotected nucleosides with the appropriate dialkylphosphorochloridates. Both sets of compounds are highly resistant to hydrolysis at physiological pH, but show
& vitro activity that was directly related to the lipophilicity.
These results suggest that cellular penetration by the phosphate triesters is followed by intracellular hydrolysis, by an unspecified mechanism, to the free nucleoside
(P-0-nucleoside cleavage) or
dialkylphosphinate derivatives of %-A unprotected nucleoside with
the
nucleoside 5'-phosphate.
The
(11) were prepared by reaction of the
dialkylphosphinic ch10rides.l~
These compounds
still retain a significant inhibitory effect on DNA synthesis even though they cannot serve as a source of =-AMP.
But since the activity is reduced in
Organophosphorus Chemistry
184
OR
R
OH (11) R = Bu", BzI
OH (9) B = adenin-9-yl; R = Et, Pr", Bun, n-C~H11 (10) B = cytosin-1-yl; R = Me, Et, Pr", Bun,n-C5H11
t
HO-P-0 HO i
0-Gua
TGu HO
HO
'i7
OS02Me
(EtO),-P-0
0
0
II
OCNPh2
HO (18)
comparison to the phosphate triesters ( 9 ) ,
the latter compounds would appear to
be acting by release of both the free nucleoside and nucleotide. A
stereoselective
synthesis
of
a
phosphonate
AZT 5'-monophosphate has been accomplished."'
(12)
isostere
of
The bulky t-butyldiphenylsilyl
group was used to protect the 3'-hydroxy group of the uronic acid derived from 2'-deoxythymidine (13).
A key step in the synthesis involves the generation of
the 4'-radical and subsequent reaction with diethylvinylphosphonate gives the nucleoside phosphonate ( 1 4 ) as a single diastereoisomer. The stereospecificity of the conversion is controlled by the bulk of 3'-protecting group which dictates that
reaction occurs at
the upper
9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine
anti-herpes agent that is
face of
the
sugar
radical.
(DHPG) (15) is a potent and selective
known to exert its biological effect following
conversion to the monophosphate by HSV thymidine kinase.
Phosphonate analogues
of DHPG are therefore potential pro-drugs against viruses that do not specify
their own thymidine kinase.
(~)-9-[4-Hydroxy-3-(phosphonomethoxy)butyl]guanine
(16) has been prepared by alkylation of the mesylate ( 1 7 ) with the sodium salt of 2-amin0-6-chloropurine.~~ The final product is obtained after elaboration of
the
heterocycle and
cytomegalovirus.
deprotection, and
shows
potent
activity
against
A closely related isostere (18) has been synthesised through
the intermediacy of the enol ether (19).16
Conversion to the epoxide. in situ
reaction with dimethylhydroxymethylphosphonate and deprotection gives (18). variety
of
N-[2-(phosphonylethoxy)ethyl]
pyrimidine bases have
been
prepared
derivatives
(20)
of
purine
A
and
from 2-chloroethoxyethylphosphonate by
reaction with the sodium salts of heterocyclic bases.17
Deprotection of the
resulting diethyl esters was achieved with trimethylsilyl bromide.
The chemical
synthesis of phosphonate analogues of acyclic nucleotides has been reviewed.'* An
unusual
dephosphorylation
reaction
has
been
observed
in
which
a
phosphorylated 1',2'-seconucleoside ( 2 1 ) was converted to a tetrahydrofuranyl derivative ( 2 2 ) in 78% yield under transfer hydrogenation conditions.lg Papers which report the synthesis of dinucleoside monophosphates or their analogues as model studies for oligonucleotide synthesis are covered in section
4. 2.2
Nucleoside Cyclic Phosphates.
Neutral derivatives of nucleoside cyclic
3',5'-phosphates have proved to be useful probes in the study of enzyme active site mapping and as possible anti-tumour and anti-viral agents. A potentially straightforward route
to
cyclic
phosphoramidates from
hexamethylphosphorus
triamide has been reexamined.20 The reaction gives yields of up to 77% with a variety
of
5-substituted-2'-deoxyribonucleosides
and
the
intermediate
phosphoramidites can be converted to a range of cyclic phosphate analogues. The
Organophosphorus Chemistry
186
HO
OH
(25) n = 1, 2, 3
HO
OH (26)
Me2N
HO (27) B = adenin-9-yl (28) B = guanin-9-yl
OH
6: Nuc-leotides und Nuclric Acids
187
(%Iand (%)-diastereoisomers
of 9-(6-deoxy-a-L-talofuranosyl)adenine
cyclic
3',5-phosphoramidate (2312' and the closely related (9)and (*)diastereocyclic 3',5'-phosphoramidate isomers of 9-(6-deoxy-@-D-allofuranosyl)adenine (24) have been reported.22 In both cases the compounds were ,prepared from the cyclic 3',5'-phosphate by activation with phosphoryl chloride followed ammonolysis.
by
The products were obtained in about 30% yield as a mixture of
diastereoisomers which could be separated by chromatography. Extensive n.m.r. studies have been performed to examine the conformation of the dioxaphosphorinane ring and these results have been used as evidence for the stereoelectronic control of their acid catalysed hydrolysis. propy1)guanine
and
Yoshikawa-type
phosphorylation
The cyclic phosphates of DHPG,
(g)-
9 - ( 3-hydroxymethyl-4-hydroxybutyl)guanine,
and
tested
(2)-9 - ( 2,3- dihydroxy-
and
(S)-9-(3,4-dihydroxybutyl)guanine
for
have been their
prepared
by
substratelinhibitor
properties on a wide variety of nucleases.23 2'.3'-Cyclic
phosphates of adenosine and guanosine are regioselectively
cleaved to 2'-phosphates at pH 11.0 using @ - and y-cyclodextrins as catalysts.24 In the case of adenosine 2',3'-cyclic phosphate the ratio of 2'-phosphate to 3'-phosphate was greater than 7:l.
Regioselectivity is ascribed to the forma-
tion of an inclusion complex in which the heterocycle is located in the cavity and results in very different environments for 0-2' and 0-3'.
Interestingly,
the regioselectivity is the reverse of that observed for a-cyclodextrin where
P-0-2' bond cleavage is almost exclusively favoured. A significant increase in both the selectivity and the rate constant for the P-cyclodextrin catalysed hydrolysis of adenosine 2',3'-cyclic phosphate was observed in the presence of sodium, potassium, rubidium and cesium ions.2 5
This catalytic enhancement is
probably due to coordination of alkali metal ions with the 0 - 3 ' atom facilitating P-0-3' bond cleavage. At pH 11.0 a-cyclodextrins have also been shown to induce regioselective cleavage of 3',5'-phosphodiester linkages in dinucleotides.26
Cleavage of CpA, CpC, CpG and CpU gave 96-97% of cytidine 3'-mono-
phosphate together with A ,
C, G and U
respectively.
In the absence of
a-cyclodextrin hydrolysis (pH 11.0) of the same dinucleotides gives about 50X of cytidine 2' -monophosphate. (H,O)]z+
is
a very
The cobalt complex
[Co( triethylenetetramine)(OH)
efficient catalyst for the
hydrolysis of
adenosine
2',3'-cyclic phosphate to adenosine and gives a rate enhancement of about lo6 under mild conditions (pD 7.0, 20°C).27
This remarkable catalytic effect is
believed to result from both the attacking hydroxide ion and the 2',3'-cAMP coordinating to the same Co(II1)
species so that the reaction is effectively
intramolecular. 3 . Nucleoside Polyphosphates A very mild method has been described for the preparation of nucleoside
3',5'-bisphosphate~.~~Under tetrakistriazolide
reacts
strictly
with
anhydrous
nucleosides
to
conditions
form
pyrophosphoryl
a pyrophosphate
structure which bridges the 3 ' - and 5'-hydroxy functions.
ring
Hydrolysis of this
intermediate in the presence of triethylamine opens the pyrophosphate to form the 3',5'-bisphosphate. The procedure is particularly suited to the preparation of
acid
labile
nucleotides
and
has
been
applied
to
the
synthesis
of
bisphosphates derived from N_-2,3-etheno-2'-deoxyguanosine,e-2-ethyl-2'-deoxythymidine and ~-4-rnethyl-2'-deoxythymidine. Multigram quantities of CTP, GTP and UTP are available through a convenient enzymatic procedure."
Treatment of CMP with adenylate kinase, pyruvate kinase,
phosphoenolpyruvate and a catalytic amount of ATP gives CTP in 92% yield.
GTP
is prepared from GMP in 85% yield in a similar reaction, but with guanylate kinase replacing adenylate kinase.
In both procedures the relatively expensive
phosphoenolpyruvate can be generated in situ from the much cheaper D-3-phosphoglyceric acid.
Whilst UTP is also available from UMP through a purely enzymatic
synthesis it is most efficiently prepared (>95% yield) by deamination of CTP using sodium nitrite in acetic acid at 4°C. Bis(adenosin-5-yl) di-, tri- and tetraphosphates ( 2 5 ) have been synthesised by
metal
ion
catalysed
pyrophosphate
bond
formation
yield) were obtained with Mnz' and Cd"
between
adenosine
Best results (up to 60%
5' -phosphorimidazolide and adenosine nucleotides. 3 0
using a 3 fold excess of the imidazolide
over the nucleotide in 0.2 M N-ethylmorpholine-HC1 buffer at pH 7.0.
The exact
role of the metal is unclear, but most probably promotes pyrophosphate bond formation through coordination to the nucleotide andlor the imidazolide. The & of adenylated bis(nucleosid-5'-yl) tetraphosphates (Ap,N) has
vivo synthesis
been studied in strains of E.coli that overproduce aminoacyl-tRNA synthetases.31 Overproduction of any of the studied synthetases was accompanied by a significant increase in intracellular Ap,N
concentrations and the results establish
that aminoacyl-tRNA synthetases are
involved
in Ap,N
biosynthesis during
exponential cell growth and heat shock. Small nuclear RNAs (snRNAs) such as U1, U2, U4 and U5 possess a unique hypermethylated NZ,NZ-7-trimethylguanosine
cap structure
containing
(m3Z'2'7G) at their 5'-end. Several derivatives of
this cap structure have been
synthesised using
S-phenyl-Nz,N2-7-trimethyl-
guanosine 5'-phosphorothioate (26) as the key intermediate.32
Activation of
( 2 6 ) with iodine in the presence of the bis(tetrabuty1amnonium) salt of ADP or
GDP
gave
the
capped
nucleoside
triphosphates
M3'"'7G5'
ppp5'A
(27)
and
M32'2'7G5'pppS'G ( 2 8 ) respectively in about 50% yield. In an attempt
to
facilitate the uptake pyrophosphate
have
exploit of been
the mannose-6-phosphate receptor
nucleotides, nucleoside prepared.
adducts of
system to
D-mannose-6-
P1-(5-Iodo-2'-deoxyuridine)-5',P'-D-
6:
Nudeorides and Nuckeic Acids
189
mannose-6-pyrophosphate (29) was synthesised D-mannose-6-phosphate with
in 40% yield by
reaction of
S-iodo-2'-deoxyuridine 5'-phosphorom0rpholidate.~~
The adduct did not show any activity against strains of herpes simplex virus deficient in thymidine kinase and these results are indicative of pyrophosphate bond cleavage taking place prior to cellular uptake. 2',3'-Dideoxynucleoside S'-O_-(a-thio)triphosphates have been prepared by a one-pot synthesis from the precursor dideoxynucleosides and used in Sanger's dideoxynucleoside sequencing method.34
Sequencing reactions performed
with
these dideoxynucleoside analogues give chain termination products which are resistant to hydrolysis with exonuclease I11 and this enzyme can therefore be used to remove DNA fragments resulting from adventitious chain termination which
5'-0-
could otherwise interfere with the interpretation of the sequence data. Phosphorothioate analogues
of
5',5'-dinucleoside
oligophosphates
have
been
synthesised'fromthe 5'-G-phosphorothioate derivatives of 2',3'-2-isopropylidene adenosine.35 Activation of the phosphorothioate monoester with diphenylphosphorodichloridate followed by
reaction with the appropriate nucleoside
5'-2-mono-,di- or triphosphate and subsequent removal of the isopropylidene group with a strong acid ion exchange resin gives the required products in good yield.
Assignment of absolute configuration at the phosphorothioate centre was
performed on the pure diastereoisomers of the isopropylidene protected dinucleoside oligophosphates that had been separated by h.p.1.c. These products can be degraded to ADP(aS) by successive treatment with sodium periodate (pH 10.51,
a strong acid ion exchange resin and alkaline phosphatase and
the
configuration of the ADP(aS) can then be determined by the retention time on reverse-phase h.p.1.c. A
variety of interesting nucleoside imidophosphates have recently been
reported.
Reaction
of
N-methylimidodiphosphate
with
Sa-2-toluenesulphony1-
adenosine gives adenosine 5'-(a,P-N-methy1imido)diphosphate (30) which can be phosphorylated with phosphocreatine and
5 -(a, 0-N-methylimido)triphosphate
creatine kinase to give adenosine
(31).
5' - (0, y -!-methylimido)
Adenosine
-
triphosphate (32) has also been prepared from adenosine 5'-monophosphate and N-methylimidodiphosphate 5'-(a.0-imido)diphosphate
to
that
described
for
by Michelson's p r o ~ e d u r e . ~ ~ 2'-Deoxythymidine (33) has been synthesised using a procedure analogous
(30)
and
was
shown
2' -deoxythymidine 5' -2-phosphoramidate over Adenosine S'-(a,P-irnido)diphosphate
a
to
undergo
period
of
decomposition several
to
days. 3 7
has also been prepared and its Properties
studied. s a
4.1
4. Oligo- and Polynucleotides Synthesis. Several review
DNA
articles on
protecting groups used in oligonucleotide synthesis"
DNA
synthesis
have appeared.
'*
and
In some
190
(29) 0 Me0
0 Me0 II
I
II
A&
I HO HO-P-N-7-0 HO
OH I HO
I
II
II
t
OH I
AH
0 Me0 II
I
OH I
bH
OH I
wA
OH
HO
OH
(31)
(30)
HO-P-N-P-0-P-0
II
HO-P-0-P-N-P-0
v!?
Ad0 HO-P-N-P-O I HO
Hb
yoy HO
HO
(33)
(32)
Hov 4
,c=o
\
N ,CH,CONHO
V B 0, ,OMe
I
R
7N(Pri),
(34)
(35) R = H (36)R = Me
CPG
6: Nucieotides and Nucdeic A c i A
191
cases reviews have concentrated on more specialised aspects of the area such as the use of ally1 protecting groups
41'42
and the synthesis of oligonucleotides
based on organometallic chemistty.43 The
development
of
new
nucleoside protecting groups
and
procedures continues to be an important part of DNA synthesis.
al.
have reported that in the presence of
protection
Bleasdale g
2,6-di-t-butyl-&-methylpyridine,
nucleosides are rapidly and very efficiently tritylated at the 5'-position using the tetrafluoroborate salts of either 4-methoxytrityl or 4,4'-dimetho~ytrityl.'+~ Standard solid-phase procedures for the synthesis of oligodeoxyribonucleotides necessitate repeated and in some cases prolonged exposure to acidic conditions for the deprotection of the 5'-hydroxy function.
The acidic conditions can
cause depurination of 2'-deoxyadenosine and for this reason DNA synthesis using nucleoside methoxyphosphoramidites containing the base labile S'-O-fluorenylmethoxycarbonyl (FMOC) group (34) has been examined.45
The 5'-FMOC group is
removed rapidly using a 10% solution of 1,8-diazabicyclo(5.5.O)undec-7-ene (DBU) in dichloromethane.
Unfortunately the use of DBU in conjunction with the
methoxyphosphoramidite necessitates two additional changes to the standard procedures. Firstly, the conventional linker (35) which is used to attach the 3'-terminal nucleotide to the controlled-pore glass support is unstable to the DBU treatment and about 1% of the oligonucleotide is cleaved from the support during each deprotection. The cleavage is believed to result from deprotonation of the nitrogen a i d e with DBU which cyclises by intramolecular nucleophilic attack on the ester carbonyl function; this adventitious oligonucleotide cleavage from the support is eliminated using the sarcosine derived linker ( 3 6 ) . Secondly, the N-3 position of 2'-deoxythymidine requires protection to avoid methylation at this position by reaction of the deprotonated nitrogen atom with the phosphite triester. The 2-(t-butyldiphenylsilyloxymethyl)benzoyl
(SiOHB) group (37) has been
used to protect the exocyclic amino groups of the 2'-deoxyribonucleosides of adenine, cytosine and guanine.4"
Treatment of the SiOMB protected nucleoside
with fluoride ion releases the benzylic hydroxy group which cyclises to liberate the nucleoside. The relatively fast and quantitative removal of this blocking group is attributed to a strong hydrogen bond formed in the transition state between the fluoride ion and the amino proton.
The utility of the SiOMB group
has been demonstrated by the preparation of a deoxyribonucleotide hexamer on solid-phase. Protection of the exocyclic amino groups of 2'-deoxyadenosine and 2'-deoxycytidine has also been accomplished with the 9-fluorenylmethoxycarbonyl group and this protection strategy in combination with phosphoramidite chemistry has been used for the synthesis of a 12-residue fragment of the human insulin @-chain gene.47 Surprisingly, it has been shown that in dry pyridine at 50°C,
a-phenyl cinnamoyl chloride reacts selectively with the exocyclic amino function of 2'-deoxyadenosine, 2'-deoxycytidine and
2'-deoxyguanosine with negligible
reaction with the sugar hydroxy functions.
Deprotection of the resulting
N-a-phenyl cinnamoyl nucleosides is readily achieved with the conventional treatment with concentrated aqueous amonia.
Additionally, the bulk and hydro-
phobicity of the phenyl cinnamoyl group confers resistance to acid catalysed depurination of 2'-deoxypurine nucleosides. been demonstrated
in the synthesis of
The application of this group has
a dodecanucleotide using both
the
phosphoramidite and phosphotriester approaches. A new strategy for the synthesis of oligodeoxyribonucleotides has been presented using a set of nucleoside 3'-(2-cyanoethyl)-~,~-diisopropylphosphoramidites in which the 4-nitrophenylethoxycarbonyl (NPEOC) group is used €or protection of the amino group."g The amide function of 2'-deoxyguanosine is additionally protected by the 4-nitrophenylethyl (NPE) group (e.g. 3 8 ) .
The NPE
and NPEOC groups as well as the cyanoethyl group are removed by treatment with
0.5 M DBU in acetonitrile for 6 hours.
Interestingly, when this strategy is
used in conjunction with a support containing a 1,6-bismethylaminohexane linker (391, all the protecting groups can be removed without cleaving the oligodeoxy-
ribonucleotide from the support.
Cleavage from the support is achieved with
concentrated aqueous m o n i a to give the crude oligodeoxyribonucleotide free of by-products.
A similar strategy has been employed by Noyori and co-workers
using allyl and allyloxycarbonyl groups to protect the internucleotide linkages and nucleoside bases respectively (e.g. 40).50 Synthesis was performed by the phosphoramidite approach on controlled-pore glass with a succinyl linker.
The
allyl protecting groups were efficiently removed by treatment with a mixture of tris( dibenzylideneacetone)dipalladium(O)
-
chloroform complex, triphenylphos-
phine, butylamine and formic acid at 50°C for 1 hour.
Once again cleavage of
the oligodeoxyribonucleotide from the support is accomplished with aqueous ammonia.
The efficiency of
this procedure has been
demonstrated in the
preparation of a 60-residue oligomer of unprecedented purity.
oligodeoxyribonucleotide synthesis on a soluble polymeric support combines aspects of traditional solution methods with solid-phase synthesis and
is
particularly suited to the preparation of intermediate quantities of small and medium sized oligorners. A high efficiency liquid-phase procedure has been developed using polyethylene glycol as the soluble support.5 1 5' -2-Dimethoxytrityl-2'-deoxynucleoside-3'-succinates can be attached to the polymer using
standard protocols and oligodeoxyribonucleotides of up to 8
residues were
synthesised by the phosphotriester approach using l-(2-mesitylenesulphonyl)-3nitro-l,2,4-triazole
(MSNT)
generally in excess of 9OX
and
N-methylimidazole.
Coupling
yields
were
and polymer bound oligodeoxyribonucleotide was
5:
Nuclrorides and Nuclcic Acids
DM 0
1
~ S i - - O C H 2 - C H - C H 2 0 C O N - ( C H 2 ) 16 - N - C O C H1 2 C H 2 C ~ I OAc CH3 CH3
(39)
0 H O - C H 2 - C H 2 - ~ ~ C H 2 - C H 2 d acetate - ~ ~ >
0
0
Organophosphorus Chemistry
194
separated from excess monomer and coupling agents by precipitation into ether followed by two crystallisations from ethanol.
Cellulose acetate fmctionalised
4-(2-hydroxyethylsulphonyl)dihydrocinnamoyl
with
similarly used
for
liquid-phase synthesis."
substituents
(41)
This
is
polymer
has
been
soluble
in
pyridine, but insoluble in ethanol and is therefore particularly well suited to the phosphotriester approach. exemplified
by
the
The effectiveness of this procedure has been
preparation
an
of
octadeoxyribonucleotide
and
an
undecadeoxyribonucleotide in quantities in excess of 10 mg. Whilst the phosphoramidite approach is, in general, the method of choice for
automated DNA
synthesis very
solution synthesis.
little has been reported on
its use for
Beiter and Pfleiderer have described the synthesis of all
16 of the fully protected di-2'-deoxyribonucleoside phosphotriesters and their thiophosphotriester analogues.53 the
The syntheses were performed by activation of 3'-[4-(nitrophenyl)ethyl]phos-
5'-O_-dimethoxytrityl-2'-deoxyribonucleoside
42) in the presence of the appropriate 3'-g-benzoyl-2'-
phoromorpholidites (e.g.
deoxyribonucleoside. Yields for the coupling reaction were generally about 60% prior
to
5'-~-Dimethoxytrityl-Z'-deoxyribonucleoside
oxidation.
diethylphosphoramidites
(e.g.
43)
have
been
prepared
by
3'-g-bis-
reaction
of
5' -2-dimethoxytrityl-2'-deoxyribonucleosides with tris(diethy1amino)phosphine the presence activated
of
with
tetrazole and
diisopropylamine."
5-(4-nitrophenyl)tetrazole
d(CCTAGCTAGG) on a solid-phase support.
and
The
have
coupling yields are
by
tetrazole
in excess of
been
used
to
in
can be prepare
The initial product of the reaction is
a dinucleoside phosphoramidite linkage (44) which corresponding Z-phosphonate
bisamidites
the
can be
converted to the
catalysed hydrolysis.
97% and once the
The average
synthesis is
complete
oxidation to the required phosphodiester linkages is achieved using an aqueous solution of
iodine.
amidite with
Alternatively, oxidation of
t-butylhydroperoxide can
be used
the dinucleoside phosphor-
to generate a phosphodiethyl-
amidate linkage.
Tris(1,1,1,3,3,3-hexafluoro-2-propyl)phosphite,
which
is
an
effective
reagent for the preparation of 2'-deoxyribonucleoside g-phosphonates,55'56 has been prepared by
an
improved procedure from PC1,
1,1,1,3,3,3-hexafluoro-Z-propoxide. 5 7
In
addition,
1,3-dimethyl-2-chloroimidazolinium chloride agent
for
oligonucleotide
Coupling efficiency was
synthesis
y&
(DMCI) the
and the lithium salt of it
is
has an
been
shown
efficient
that
coupling
H-phosphonate
indistinguishable from that achieved using pivaloyl
chloride, but DMCI has the advantage that it is a stable crystalline compound and has
good solubility in organic solvents.
preparation
of
A
simple procedure for the
2 ' -deoxyribonucleoside H-phosphonates
has
been
developed.
''
Reaction of phosphonic acid with a condensing agent (either pivaloyl chloride or
195
6: Nudeorides and Nucleic Acids
"
"
'
O
W
0 d (43)
(42)
DMTowB 3
l
r*
f
!
H
H
HO-Y-O-Y-OH
0.
P
-
O
v
(45)
B
DM &
o\ P-OMe
P--OCHZCHzCN
MeO'
2
(46)
Q
0 11-
BzO
(47)
S - C e O M e
OBz (48)
0-7-0OH
~ - S - - S - - ( C H ~ ) ~ ~ - - N 0 (49)
d(AAAACGACGGCCAGTC)
5,5-dimethyl-2-oxo-2-chloro-l,3,2-dioxaphosphorinane) gives the pyrophosphonate
(45) which reacts smoothly with a suitably protected nucleoside to give the desired 3'-!-phosphonate
in yields greater than 85%.
The mechanism of inter-
nucleotide bond formation and the nature of unwanted side reactions for the H-phosphonate approach have been studied in detail."
Side reactions that occur
on activation can be minimised by using acetonitrile-quinoline ( 4 : l ) as solvent. This improvement to the procedure has been exemplified in the synthesis o f
n
38-residue deoxyribonucleotide. has
Surprisingly, it
been
shown
that
upon
activation
with
iodine,
phosphites (e.g. 46) can b e used f o r
bis(deoxyribonucleosid-3'-yl)-2-cyanoethyl
the synthesis of dinucleoside phosphates on a solid-phase support.Ga These results led
the authors to investigate the .utility of deoxyribonucleoside
3'-dimethylphosphites (e.g. 47) for oligonucleotide synthesis. However, whilst (47) could be activated with iodine and reacted with a 5'-hydroxy group of an otherwise protected nucleoside to give the fully protected dinucleoside methyl phosphitetriester in good yield, the accumulation of side reactions produced poor yields of oligonucleotides on solid-phase synthesis.
The
solid-phase
synthesis of oligodeoxyribonucleotides by iodine activation of (47) has also been investigated by Potapov, and the overall yield for the synthesis of dT,, was 11%after deprotection and isolation.61 An ingenious procedure for the combined purification and phosphorylation of oligodeoxyribonucleotides has been developed that relies upon the use of a 2',3'-~-dibenzoyl-3-undecyluridine 5'-(2-cyanoethyl)-kJ,l-diisopropylphosphorami-
dite (48).62 This residue is introduced in the final coupling step and after deprotection the thiol function can be released by treatment with silver nitrate followed by dithiothreitol
The thiol containing oligonucleotide can then be
coupled to controlled-pore glass also bearing thiol functions through a disulphide bridge ( 4 9 ) .
After separation of the support and washing, the required se-
quence is liberated with sodium periodate and triethylamine to give the 5'-phosphorylated oligonucleotide.
Bis(allyloxy)(diisopropylamino)phosphine
(SO) can
also be employed for the 5'-phosphorylation of nucleosides and oligodeoxyribonucleotides.b3 Activation with tetrazole in the usual manner and reaction with a nucleosidic 5'-hydroxy group followed by oxidation with m-chloroperbenzoic acid gives a fully
protected 5'-phosphate in excellent yield.
The ally1
protecting groups are removed with tetrakis( triphenylphosphine) palladiwn(0). Reverse-phase h.p.1.c. purification of
very
has
long
oligodeoxyribonucleotides."
been
(88-143
The
demonstrated to be bases)
isolated
effective for the
5'-~-dimethoxytrityl-derivatised
yields
were
superior
to
those
obtained using electrophoresis followed by electroelution. A fast procedure has been reported for the
purification of
oligodeoxyribonucleotides of varying
197
6: Nucleotidrs and Nucleic Acids
Cl (51 )
5‘ HO-protected
oligodeoxyribonucleotide
I
duplex
5’ 5’ 3’
1
T T T T T
I
A-T A-T A-T A-T A-T
I
O
F
T
? O=P-OH
h
Y
15
- linker
T-A T-A T-A
T T T
T-A
T
?
O=P-OH
c--Gc
bTh
0 I
Organophosphorus ChrmistT
198
lengths (10-40 bases) by anion exchange h.p.1.c. using volatile buffers.65 Several interesting strategies have appeared for the synthesis of cyclic oligodeoxyr-ibonucleotides.
A versatile solid-phase procedure has been developed
in which fully protected nucleoside phosphate triesters were attached to a polyacrylamide support & y
the heterocyclic bases (exocyclic amino groups of dA
dC or dG and N-3 or 0-4 of T e.g. 51)." the
5'-position, after
Chain extension can occur from either
treatment with
3'-terminus following removal of
trichloroacetic acid,
the cyanoethyl
or
group with
from
the
triethylamine.
Cyclisation is performed by deprotection of both 5'- and 3'-ends followed by treatment with (MSNT) and subsequent cleavage from the polyacrylamide resin is achieved
by
standard
aamonolysis.
hexadeoxyribonucleoiides
Cyclic
have been prepared
phosphotriester approach."
di-,
tri-,
in solution
tetra-, by
penta-
the
and
filtration
A key part of the strategy involves the use of
nucleoside 3'-(2-chlorophenyl) (2,4-dinitrobenzyl) phosphates as a 3'-terminal building block (e.g.
52).
Once the oligodeoxyribonucleotide has reached the
desired length the dinitrobenzyl (DNB) group is removed by a brief treatment with toluene-4-thiolate ions and the resulting 3'-tenninal phosphate diester cyclised to the 5'-hydroxy group with MSNT in anhydrous pyridine.
The yield for
the combined steps of DNB removal and cyclisation were generally greater than A less rigorous approach to cyclic oligodeoxyribonucleotides has been
60%.
adopted cyclised
by
g &. "
3' ,5 ' -Unprotected
bifunctional
phosphorylating
Capobianco using
a
linear precursors reagent
were
2-chlorophenyl
bis-~,~-(l-benzotriazolyl)phosphate. The procedure is particularly amenable to the synthesis of millimolar quantities of relatively short cyclic oligonucleotides.
A topologically more complex DNA structure in the form of a specific
quadrilateral has
been prepared. "
Four different
three-am
branched
DNA
junctions, each composed of two oligodeoxyribonucleotides were synthesised and covalently linked
together by
enzymatic ligation.
The product
is a
DNA
quadrilateral with sides of 16 base pairs long (approximately 1.5 turns of the helix).
Each individual junction is closed by a hair-pin loop and topologically
the four junctions form two intersecting DNA circles which are linked 6 times. A bidirectional pyrimidine oligodeoxyribonucleotide which contains a 3'-3' phosphodiester linkage with an abasic nucleoside (as in 53) has been synthesised by
an
automated
2'-deoxynucleoside.
procedure
starting
from
a
5'-O_-support
bound
The oligodeoxyribonucleotide is able to bind to adjacent
purine tracts on alternate strands of a Watson-Crick duplex through triple-helix formation. The abasic nucleoside acts as a linker between the adjacent strands. This work extends triple-helix formation to the recognition of (purinelm NN (pyrimidine)n sequences. Triple-helix formation has also been used to develop a chemical method for the ligation of two pyrimidine oligodeoxyribonucleotides.
6: Nucleoiides and Nucleic Acids
199
The double-stranded DNA serves as a template to align the reactive termini of the pyrimidine oligonucleotides (54).7'
The pyrimidine sequences are complemen-
tary in a Hoogsteen sense to the purine strand and the 3'-hydroxy function of oligonucleotide A is thus proximal to the 5'-phosphate of oligonucleotide B. Ligation is brought about by activation of the phosphate with cyanogen bromide in the presence of imidazole and NiC1,.
A pyrophosphate linked analogue of polycytidylic acid has been prepared from Ij-4-diphenylacetyl-2'-deoxycytidine phosphorothioate (SS).72
3'-O_-phosphate S'-O_-(S-4-methylphenyl)
Activation of (55) with iodine in a non-nucleophilic
solvent followed by removal of the diphenylacetyl groups with aqueous ammonia gave the 3',5'-pyrophosphate linked oligomers (56) and the cyclicpyrophosphate (57).
After fractionation, oligomers with a chain length greater than 16
residues (average length approximately 20) were used to catalyse the template directed
oligomerisation
of
3',5'-bisphosphoimidazolide
4.2
RNA Synthesis.
the
complementary
monomer
2'-deoxyguanosine
(58).
The chemical synthesis of RNA and its application to
molecular biology has been reviewed.73 The choice of a permanent protecting group for the 2'-hydroxy function is of paramount importance in oligoribonucleotide synthesis.
The 2-nitrobenzyl
group has been effectively used for the protection of this position and can be quantitatively removed by photolysis after chain construction.7 4
However, in
some instances deprotection is less than quantitative and yields are not improved by further irradiation. Model studies have shown that in the presence of
oxygen,
photolysis
Z'-O-(Z-nitrobenzoyl) conditions.75 the
with
long
derivatives
W
wave
which
are
light
can
stable
to
give the
rise
to
irradiation
These oxidative side reactions can be eliminated by performing
photolysis
at pH
l-(2-chloroethoxy)ethyl
3.5
in
solutions
purged
with
nitrogen.
The
(CEE) group has been used as an acid labile blocking
group for the 2'-hydroxy function and is presented as an alternative to the tetrahydropyranyl (THP) group.76
It is more resistant to acid cleavage than THP
ethers and therefore allows repeated removal of a DMT group without concomitant deprotection of the 2'-position,
The CEE group has been used in combination
with
(e.g.
phosphoramidite
chemistry
59)
for
the
preparation
of
a
integrity
of
dodecaribonucleotide on solid-phase. A
detailed
n.m.r.
oligoribonucleotides
study
prepared
has
been
by
the
procedure with Z'-O-t-butyldimethylsilyl
undertaken automated
on
the
cyanoethylphosphoramidite
The n.m.r. studies in
conjunction with enzymatic digestion (ribonuclease T,) demonstrate that the oligoribonucleotides contain entirely 3',5'-phosphate linkages and chemically
Organophosphorns Chemisrty
200
duplex 3' 5' C-GC T-A T T-A T T-A T C-GC
T-A T T-A T T-A T T-A T G - G C T-A T C - G C
I I
A
B (55)
I (54)
I
440 /p\
"O
OHO,? Y
C
9
PI
IU-\
HO
/O
6: Nucleotides and Nucleic Acids
20 1
prepared AGCU was essentially indistinguishable from the same sequence prepared using
polynucleotide
phosphorylase.
and/or 3'-5'
containing 2'-5'
Sequence
defined
oligoribonucleotides
phosphodiester linkages have
been
using 5'-protected ribonucleoside 2',3'-cyclicphosphoramidites
synthesised
(e.g 60).'8
activation with 5-(4-nitrophenyl)tetrazole (60) can be coupled to a support bound ribonucleoside and on oxidation (aqueous iodine) a mixture of the 2l-5' and 3'-5'
linked dinucleotides are formed (61).
of 2'-5' and 3'-5'
After deprotection, the ratio
linkage isomers could be quantified by h.p.1.c.
and the ratio
was found to be dependent on the heterocyclic bases present. The
1,1,1,3,3,3-hexafluoro-2-propyl
(HFP)
group has been
used
phosphate protecting group for oligoribonucleotide synthesis.'g phosphoryl chloride with 1,1,1,3,3,3-hexafluoro-2-propanol
as a new
Reaction of
in the presence of
aluminium chloride gives the hexafluoro-2-propyl phosphorodichloridate Phasphorylation nucleosides with
(62).
~-acyl-5'-~-dimethoxytrityl-2'-~-tetrahydropyranyl
of
(62) in the presence of triazole and subsequent hydrolysis
yields the phosphodiester monomer
Short segments of RNA have
(63).
been
prepared from (63) by the phosphotriester approach using 8-quinolinesulphonyl chloride and N-methylimidazole as coupling agents.
Removal of the HFP group is
achieved with a standard o x b a t e treatment. An improvement has been reported to the synthesis of oligoribonucleotides by the 1-hydroxybenzotriazole-activated The activated intermediates (e.g. 64) are extremely
phosphotriester approach.
sensitive to moisture and readily hydrolysed.
Additionally, the hydroxybenzo-
triazole generated on hydrolysis can cause partial removal of the DNT group. The addition of dicyelohexylcarbodiimide
stabilises the intermediates towards
hydrolysis and does not cause untoward side reactions.
This modified procedure
has been applied to the synthesis of two oligoribonucleotides r(GCGAAAGC) and r(CGAAAGC). 297
24 RNA Fragments corresponding to the hop stunt viroid (total of
residues)
approach.'l
have
been
synthesised
by
9-Phenylxanthen-9-yl (pixyl) and
(Hoxyl) groups
were
used
nucleosides respectively.
for The
5'-protection
the
cyanoethyl
phosphoramidite
9-(4-methoxyl)phenylxanthen-9-y1 of
the
purine
tetrahydropyranyl group was
and
pyrimidine
utilised
in
the
blocking of the 2'-hydroxy function and the bases were protected as shown in (65).
Average coupling yields were in the order of 95% using a solid-phase
procedure on CPG.
A series of oligoribonucleotides (6-29 residues) have been
prepared in yields up to 44% using N-acyl-5' -_O-dimethoxytrityl-2' -g-tetrahydropyranyl 3'-!-phosphonates mixed
DNA-RNA
activated with pivaloyl chloride.82
oligomers has
deoxyribonucleoside
been achieved
phosphoramidite
phosphoramidite intermediates."
and
on a
Synthesis of
solid-phase support
2'-silylated
using
ribonucleoside
Deprotection was accomplished using standard
procedures for oligoribonucleotides and the mixed oligomers have been used to
302
DMTov (59)
DMTowB 0,o
DM DMTo O\\dO OTHP HO” ‘OCH(CF&
I P -N(PTi)2 R / NCCH2CH20 (65)
B = N 6-benzoyladenin-9-yl; R = H B = N*-propionyl-O 6diphenylcarbamoylguanin-9-yl; R = H B = N 3-anisoyluracil-l -yl; R = OMe B = N4-anisoylcytosin-1-yl; R = OMe
6: Nucleotides and Nucleic Acids study
RNA
catalysis.
203 Strategies
oligoribonucleotides formed
in the
for
the
synthesis
of
branched
pre-mRNA splicing reactions have
been
c~mpared.~' Phosphite triesterk and phosphate diesters are relatively stable to attack by a vicinal hydroxy group under neutral and mild acid conditions and therefore synthetic methods attractive.
involving
these intermediates are particularly
A strategy based on the use of ally1 protecting groups has also
been used in the regiocontrolled synthesis of branched oligoribonusleotides.85 In a monumental work Reese and co-workers have reported the synthesis of the 37-residue 3'-terminal half
( 6 6 ) of
phosphotriester approach in solution.'6'87
alanine tRNA from yeast using the The protecting group strategy for a
solution synthesis of this complexity is particularly important and previous work on the synthesis of a 3'-terminal nonadecaribonucleoside had established the need for protection of 0-6 on guanine and 0-4 on uracil.'' earlier
studies,
guanine
bases
were
Based on these
protected
as
the
6-0_-(3-chlorophenyl)-2-~-phenylacetyl derivatives (67); 0-4 on uracil bases was
blocked by the 2.4-dimethylphenyl group (68) and the amino functions on adenine and cytosine bases were simply protected as the 4-(t-butyl)benzoyl
(69) and (70) respectively.a6 The modified base pseudouridine
(Y)
derivatives
was protected
at the N-1-position with the 4-bromobenzenesulphonyl group whilst 5-methyluracil
(T) was protected
as
the g-4-phenyl derivative.
The methoxytetrahydropyranyl
group was used for the permanent protection of the 2'-hydroxy functions. in'tial
strategy was to use the 2-(dibromomethy1)benzoyl
The
(Dbmb) group for the
temporary blocking of the 5'-hydroxy function.
However, removal of this group
using silver perchlorate in collidine became
increasingly inefficient with
increasing chain length and the Dbmb group was successfully replaced with the 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt) group (71) which was rapidly removed
with mercury I1 perchlorate under similar conditions. The oligoribonucleotides were
assembled
in
solution
by
the
phosphotriester
approach
using
the
2-chlorophenyl group to protect the internucleotide linkages and MSNT. as the condensing agent. three
step
The final 37-residue oligoribonucleotide was deprotected in a
procedure
using
sequentially
E-2-nitrobenzaldehyde
concentrated aqueous annnonia and 0.01 M hydrochloric acid.
oximate,
The total synthesis
of yeast tRNAAla by a combination of chemical and enzymatic methods has also been completed." A 35-residue oligoribonucleotide constituting the 5'-end of the initiator tRNA from B.subtilis has been synthesised on solid-phase using phosphoramidite chemistry in combination with 2'-0_-t-butyldimethylsilyl protection."
For the
protection of the exocyclic amino functions of the bases the phenoxyacetyl group was used for adenine and guanine whilst acetyl was preferred for cytosine. These comparatively acid labile acyl groups can be removed using relatively mild
204
Organophosphorus Chemistry
3' A C C A C C C G C U C AGGCC u UCCGG T C U G
G A G A G G
a
0
u
A
w
C
G
CI
6: Nurleotides and Nurleic Acids
205
conditions in the annnonia deprotection step and enable 5,6-dihydrouridine, which is present in the sequence and is sensitive to alkaline conditions, to be successfully incorporated into the oligoribonucleotide. The synthesis of aminoacyl oligoribonucleotides that mimic the role of the tRNA 3'-terminus has attracted considerable attention and recently Hagan and '
Chladek have synthesised ~henylalanine.~' The
' GGA3
I
aminoacylated at
oligoribonucleotide
was
the 2'(3')-position
assembled
by
the
with
stepwise
phosphotriester approach using (72) as the building block for the incorporation of
guanosine.
Aminoacylation
of
the
2- ( 4 4 ' -biphenyl)- 2- ( propyloxycarbony1)
trinucleotide protected
presence of l-(2-mesitylenesulphonyl)tetrazole. the 2'(3')-g-(L-phenylalanine)
was
performed
L- phenylalanine
using
in
the
Complete deprotection to give
trinucleotide was accomplished
by a
standard
oximate treatment followed by a removal of acid labile groups in 80% form.. acid at 0°C for 30 minutes.
A
hybrid
dinucleotide
pdCpA
has
L-phenylalanine to give pdCpA-Phe.92
been
chemically
aminoacylated
with
The aminoacylated dinucleotide can be
used in an enzymatic ligation (T4 RNA ligase) and attached to the 3'-terminus of a truncated (3'-terminal CA residues missing) amber suppressor tRNACUA. resultant
chemically
aminoacylated
tRNA
can
be
used
L-phenylalanine in response to an amber nonsense coding.
The
incorporate
to
This procedure can
potentially be used for the site specific incorporation of an unnatural amino acid
into proteins.
The use of deoxycytidine at position 75
in the tRNA
greatly simplifies the synthetic chemistry and does not appear to affect the efficiency of the tRNA. E.coli
tRNAfMet
in
Ogilvie and co-workers have prepared a DNA analogue of which
all
the
uridine
residues
are
replaced
by
2'-deoxythymidine and all residues are deoxyribonucleosides with the exception of the 3'-terminal riboadenosine."
This tRNA analogue can be aminoacylated by
E.coli methionyl-tRNA synthetase and the results support the hypothesis that aminoacylation of tRNAfMet does not depend on the presence of 2'-hydroxy groups with the exception of that in the 3'-terminal nucleotide. Catalytic activity of ribonucleic acid has been reviewed"
together with
its implications for the origins of life." 4.3
Oliaonucleotides Containing Modified Phosphodiester Linkages.
synthesis of
oligo- and
polynucleotides
containing modified
Whilst the
phosphodiester
linkages dates back to the 1960'~,'~ the knowledge that these analogues can both inhibit
and
interest in
activate this
gene
area, and
anti-sense oligonucleotides.
expression given
has
rise
to
dramatically a
new
increased
therapeutic
research principle;
The s y n t h e s i ~ ~ and ~ ,propertiesg7 ~~ of anti-sense
oligonucleotides have recently been reviewed.
Orgunophasphomv <'hemimy OCHZCH~CN I
207
6: Nucleotides and Nucleic Acids
The phosphorothioate modification is probably the most studied and most useful of all the oligonucleotide analogues and is readily accessible through the phosphoramidite approach by oxidation of the phosphite triester intermediate with elemental sulphur.
In practice, however, the poor solubility of sulphur in
common solvents can cause problems in automated synthesis. trialkylphosphites
react
with
phenacetyl
trialkylphosphorothioates and not the Arbusov product. dichloroethanelcollidine has
been used
for the
It is known that
disulphide
give
to
Phenacetyl disulphide in
sulphurisation of phosphite Two phosphorothioate
triester intermediates in oligonucleotide synthesis.sg
containing hexanucleotides have been prepared using this procedure and f.p.1.c. has demonstrated that none of the non-phosphorothioate-containing hexamer was present
in
triesters
the has
crude also
product. been
Sulphurisation
accomplished
of
using
dinucleoside
phosphite
3-~-1,2-beneodithiole-3-one
1,l-dioxide (73) in dry acetonitrile at room temperature.'OO
This reagent does
i
not appear to cause any base modification and because of its good solubility in organic solvents and rapid reaction kinetics it is ideally suited to solid-phase synthesis.
Relatively
containing
large
oligonucleotides
H-phosphonate
quantities
have
approach.'"l
intermediates
is
been
Because
accomplished
in
(0.1-1.0
prepared
on
g)
of
sulphurisation
one-step
after
phosphorothioate
solid-phase of
the
using
the
H-phosphonate
assembly
of
the
oligonucleotide is complete, this procedure is attractive for the synthesis of s s S labelled oligonucleotides.
Using elemental sulphur enriched with "S,
Zon
and co-workers have used this strategy for the preparation of ssS phosphorothioate labelled oligodeoxyribonucleotides of very high specific activity.'02 Oligodeoxyribonucleotides containing a single phosphorothioate group can be labelled on the sulphur atom by incubation in an aqueous buffer with a reporter molecule containing a suitable electrophilic functionality.103
Yields of the
labelled oligodeoxyribonucleotide were generally greater than 85% after reaction for 24 hours at 50°C. PROXn
spin
label
"his procedure has been used for the introduction of a
(74) and
a
dansyl
fluorophore
(75).
In general
the
introduction of the label does not noticeably alter the melting temperature of the oligonucleotide and the phosphorothiolate triesters are relatively stable in aqueous conditions ( pH 7-8) with less than 5% hydrolysis occurring over a 24 hour period. prepared
with
Phosphorothioate containing oligodeoxyribonucleotides have been an
acridine
chromophore
at
the
5'-end
(76).'"'
The
oligonucleotides were initially prepared with a S'-mercaptopropanol linker and then treated with N-9-kridinyl maleimide.
Whilst oligonucleotides in which an
acridine moiety was attached to the Sl-end
a pentamethylene chain had
previously demonstrated increased duplex stability,"'
the acridine-maleimide
linker showed no stabilising effect. This is attributed to steric hindrance of the maleimide group which reduces the flexibility of the linker and prevents intercalation. The stereospecific synthesis of individual
(RJ, RJ)-
and
(9, S~)-thymidylyl(3'-5')-
diphosphorothioate has been accomplished from the
thymidylyl(3'-5')thymidine
diastereoisomers
of
5'-~-monomethoxytrityl-2'-deoxythymidine
3 ' -0- [~-~4-nitrophenyl~-~-~2-nitrobenzyl)phosphorothioate] (77).
lo6
The prep-
aration of (77) was achieved by treatment of 5'-~-monomethoxytrityl-2'-deoxythymidine with ~-(4-nitrophenyl)-~-phenylamidochloridateYsubsequent conversion of the
resulting diastereomeric phosphoranilidates to the phosphorothioates
using carbon disulphide and sodium hydride and finaily alkylation of the crude phosphorothioate
epimers
diastereoisomers could
with
be
2-nitrobenzyl
resolved by
bromide.
The
chromatography.
individual
Activation of
the
S'-hydroxy group of 3'-~-acetyl-2'-deoxythymidine with t-butylmagnesiwn bromide enables internucleotide bond formation by displacement of the 0-aryl group on (77) with inversion of configuration. The 2-nitrobenzyl group was removed with thiophenoxide and the rate of deprotection is about 150 times faster than observed with
the methyl protecting group.
2',5'-adenylate
dimers,
trimers and
combination of
chemical and
Phosphorothioate analogues of
tetramers have
been
prepared
The
enzymatic techniques.l o 7
(RJ,RJ)
by
a
trimer
triphosphate (78) was the most potent inhibitor of reverse transcriptase (50% inhibition at a concentration of 0.5 pM). thioate-containing, abasic 1,2-dideoxyfuranose (79) in
that
contain
either
or (f)-butane-lY3-diol ( 8 0 ) replacing the deoxyribose
sugar has been described. considerably reduced
The synthesis of two phosphoro-
oligonucleotide analogues
The anti-HIV activity of both compounds was comparison to
the
homo-oligomer S-dC,,
(composed
entirely of phosphorothioate linkages) which is known to be a potent inhibitor of HIV replication.
Oligodeoxyribonucleotides containing phosphoroselenoate linkages have been prepared by an automated solid-phase technique using potassium selenocyanate to oxidise
the
intermediate phosphite
triester.log
The
phosphoroselenoate
linkages are slowly hydrolysed (half-life about 30 days at amblent temperature and neutral pH) to the natural phosphodiester linkages.
A
comparison of the
thermal melting temperature of Se-dT,,, 0-dT,, and S-dT,, with poly-rA revealed that the stability of the duplexes increased in the order phosphoroselenoate < phosphorothioate
< phosphate.
Additionally, a 17-residue phosphoroselenoate
oligodeoxyribonucleotide was shown to be a sequence specific inhibitor of rabbit a-globin synthesis in wheat germ extracts and in injected xenopus oocytes. However, in in vitro HIV assays the phosphoroselenoate oligonucleotides compared unfavourably with the analogous phosphorothioate compounds, being both less active and more toxic.
6: Nucleotides and Nucleic Acids
209
Hov fl " O V c C V
OH
(79)
210
Organophosp horns C 'htvni s t l y A
synthetic
procedure
has
been
developed
which
enables
the
(&)-
diastereoisomer of dinucleoside methanephosphonates to be prepared in up to 79% diastereomeric excess.11o
Reaction
of
dichloromethylphosphine with
the
3'-hydroxy function of an otherwise protected nucleoside at -80°C gives the chloromethylphosphine (81) as a 1:l by 31P n.m.r.
mixture of diastereoisomers as determined
Stereochemical induction therefore occurs in the subsequent
reaction with a S'-hydroxy group of the second nucleoside, since the final step in which the phosphinic ester is oxidised with t-butylhydroperoxide, is known to occur with
retention of
methanephosphonate
configuration.
linkages
on
The
duplex
effect of
stability
oligodeoxyribonucleotides by, Lesnikowski et al.
'
configuration of
has
been
studied
in
Two diastereomeric mixtures
of octathymidine methanephosphonates have been prepared in which one mixture (mixture
R)
contains methanephosphonate groups
of
a)-
essentially the
configuration (RpRpRpRpRpRpRpRp + RpRpRpSpRpRpRpRp) whilst in the other (mixture
S) the methanephosphonate groups are essentially of the &)-configuration (SpSpSpSpSpSpSpSp
+
A
SpSpSpRpSpSpSpSp).
comparison of the thermal melting
data for the duplexes formed between mixture R or mixture S and pentadecadeoxyriboadenylinic acid clearly indicates that the &)-configuration methanephosphonate group (&)-diastereoisomers
forms the
of
methylphosphoramidites
the of
more
stable
duplex.
of the (&)-
The
and
5'-~-dimethoxytrityl-2'-deoxynucleoside-3'-~-
N-6-benzoyladenine,
N-2-isobutyrylguanineS
N-4-benzoylcytosine and 2'-deoxythymidine have been separated by chromatography on
silica
Pre-treatment of
the silica with
1%
a
solution of
triethylamine in chloroform was essential to prevent hydrolysis and oxidation of the phosphoroamidite. The separation of the diastereoisomers is proposed as the initial step in the development of a stereospecific synthesis for oligodeoxyribonucleoside methanephosphonates; however, it should be noted that the same strategy has proved unsuccessful in the synthesis of phosphorothioate analogues due to tetrazole-induced epimerisation of the reactive phosphine intermediate.'13 Bis(v-diisopropy1amine)trimethylsiloxyphosphane
has been used to prepare
3',5'-dinucleoside trimethylsilylphosphites (e.g. 82) by sequential reaction with nucleosides
containing
diisopropylanrmonium
free
3'5'-hydroxy
tetrazolide."'
These
groups,
in
the
dinucleosides
presence are
of
versatile
intermediates that can be converted to methanephosphonates by a MichaelisArbuzov-type reaction with methyl iodide, to H-phosphonates by hydrolysis and to dinucleotide azolides by reaction with oxalylazolides. Similar reactions have been performed
on
3',5'-dinucleoside phenylphosphites (e.g. 8 3 )
intermediates can be
hydrolysed to H-phosphonates using
and
these
5-(2-nitrophenyl)-
tetrazole and ZnBr, and can also be converted to methanephosphonates with methyl iodide, although the reaction is less than quantitative.'15
A new procedure
21 1
6: Nucleorides and Nucleic Acids
DM DMTo O'P-Me CI
'
TBDMSO
vBDM ~DMT (84)
(83)
DMTo
YT 0, ,Me
hy
P S" \OCH2CH2CN
MTo
vT hy
has been applied to the synthesis of dinucleoside methanephosphonates which involves a nucleoside
(DMAP) catalysed
4-N,N-dimethylaminopyridine
and
3'-~-methylphosphonoarnidite
The
acetyl-2'-deoxythymidine.
4-tj,N-dimethylaminopyridyl
reaction
is
reaction between a
5'-e-trifluoroacetyl-3'-g-
believed
to
via
go
a
intermediate (84) which reacts with the 5'-hydroxy
function of the second nucleoside unit; gives the desired methanephosphonate.
oxidation with aqueous iodine then
This procedure has the advantage that
the coupling reaction is less sensitive to trace amounts of water than the standard tetrazole catalysed route, but unfortunately, the reaction is slower. The same DMAP catalysed coupling procedure has been used in the synthesis of the diastereoisomers of
a
2'-deoxythymidine 3'-~-methylphosphonothioate (85).'17
Following separation of the diastereoisomers by h.p.1.c. cyanoethyl group, the
lithium salt
of
the
alkylated with 2',5'-dideoxy-5'-iodo-3'-e-acetylthymidine
(9)-or
pure
(&)-diastereoisomer
of
and removal of the
methylphosphonothioate can to give either
be the
5'-dimethoxytritylthymidylyl-(3'-5' ) -
methylphosphono-5'-thio-3'-~-acetylthymidine ( 8 6 ) .
One mechanism by which anti-sense oligodeoxyribonucleotides can promote hybrid-arrest of translation is through RNase H activity. an endonuclease to destroy the RNA in DNA-RNA hybrids.
This enzyme acts as Unfortunately, hybrids
with fully methanephosphonate substituted oligodeoxyribonucleotides do not serve as
substrates
for
RNase
H.
Oligodeoxyribonucleotides
with
different
arrangements of methanephosphonate linkages have been examined for their ability to form RNase H sensitive substrates with complementary RNA. ' l a
Three or more
contiguous internal phosphodiester bonds in the oligodeoxyribonucleotide hybrid are shown to be sufficent to render the RNA strand of the duplex susceptible to RNase H cleavage.
In a comparative study 14-residue oligodeoxyribonucleotides
containing all natural phosphodiester linkages, alternating phosphorothioate and phosphodiester linkages, and up to 6 methanephosphonate linkages alternating with phosphodiester groups have been hybridised to human a-globin pre-mRNA and the resulting duplexes tested for their susceptibility to cleavage by RNase H from E.Coli or
HeLa cell nuclear extract."'
The natural sequences or
those
containing phosphorothioate residues gave duplexes that were substrates for cleavage whilst the oligomer with 6 methanephosphonate residues produced a resistant duplex and the susceptibility to cleavage increased in parallel to the reduction of the number of methanephosphonate linkages present. Anti-sense oligodeoxyribonucleotides containing either phosphorothioate or natural linkages have been shown to inhibit the replication and expression of human
immunodeficiency virus
cells).'20
already
growing
in
tissue
culture
(MOLT-3
The efficiency of inhibition is much greater than that observed
with random and homo-oligomers of the same length and reinforces the concept
6: Nucleotides and Nucleic Acids
213
that specific base pairing is a crucial feature of oligonucleotide inhibition of
HIV. The phosphorothioate containing oligomers were up to 100 times more potent than the analogous natural sequences. The formation of a triple-helix with dAl,.dTl,.dTl, has been studied in which one of the homo-pyrimidine oligodeoxyribonucleotide strands is replaced with the analogous strand containing all methanephosphonate linkages.lz1
In
contrast to a previous report there was no evidence for triple-helix formation. Phosphorodithioate quantitative
triesters
yield
(87)
have
been
prepared
in
essentially
5'-~-dimethoxytrityl-2'-deoxythymidine
from
3'-0-(2-
by treatment with either 4-chloro or
cyanoethyll-N,N-diisopropylphosphoramidite
2,4-dichlorobenzylmercaptan-tetrazole and subsequent oxidation with elemental sulphur. l Z 2
Conversion to the required phosphorodithioate diester ( 8 8 ) was
achieved
P-elimination of
by
acetonitrile.
Subsequent
the
3'-g-acetyl-2'-deoxythymidine S'-S-phosphorothioate
cyanoethyl
activation gave
(90)
in
the
the
group with MSNT
with
triethylamine
in
phosphorodithioate
ratio
75:25.
A
(89)
more
in
presence of
the
and
the
chemoselective
activation of the oxygen atom was achieved when triisopropylbenzene-sulphonyl chloride and
imidazole were
used
in the coupling
reaction.
Under
these
conditions the reaction proceeded to completion within 2 hours and the ratio (as determined
31P
by
n.m.r.)
5'-Q-Pixyl-2'-deoxythymidine
was
generally
in
excess
of
97:3.
3'-g-phosphonodithioate (91) has been synthesised
in 75% yield by reaction of a putative thymidine tris(l,2,4-triazolyl)phosphine (92)
with
hydrogen
temperature.lZ3 reaction
sulphide
Activation
with
in
of
the
presence
of
triethylamine
at
low
(91) with pivaloyl chloride and subsequent gives
3'-g-acetyl-2'-deoxythymidine
the
dinucleoside
phosphonothioate (93), which can be oxidised in situ with elemental sulphur to give
the
fully
protected
dinucleoside
phosphorodithioate
in
72%
yield.
Alkylation of the dithioate with 2,4-chlorobenzyl chloride gave the dithioate triester (94), which following removal of the 5'-pixy1 group could be elaborated to the trinucleoside diphosphorodithioate by reaction with (92) and repetition of
the
oxidation
and
alkylation
steps. lZ4
The dinitrobenzyl
group
was
efficiently removed by treatment with thiophenol/triethylaine at a rate of about 2 orders of magnitude greater than that observed for the 2,4-dichlorobenzyl group.
To aid
converted
to
characterisation
the
corresponding
quantitative
yield
Dinucleoside
phosphorodithioates
by
reaction
the
trinucleoside diphosphorodithioate
trinucleoside with can
iodine also
be
diphosphate in
aqueous
prepared
in
in
was
essentially
N_-methylimidazole. 57%
Yield
from
deoxyribonucleoside 3'-g-phosphonodithioates by oxidative coupling with one equivalent of iodine in the presence of 3'- ~ - a c e t y l - 2 - d e o x y t h y i d i n e l. Z 5 This procedure can also be applied to the synthesis of phosphorodithioamidates.
DMTo
wT-DM hy
s
o
NCCH2CH2O"'S
I
X
I
S\
P
X
HO/ P\ S - C H 2 b Y
-CH2 &Y
(87) X = H, Y = CI or X = Y = C I
MTo
vTh OAc (89)
+
px pxovT H
O
'P'
\
SH
21s
6: Nucleotides and Nucleic Acids
pxovT vT 4 hy
NO2 pxo
.,s /o /P\
P CH2-S' ' 0 y o 7 T h
02N
O
V
T
OAc
h
s+ /o
Y
y
OAc (94)
(93)
DMToYB Q 0
I
OTBDMS
RS-P,
NMe2
+ CI
R = -CH2CH2CNor - 4 H 2
(97)
-CI
-5"/"%I ( Go
oc
07T
co
hY
Organophosphorus Chrmisrry
216
Nucleoside 3'-g-phosphonothioates (95) are also useful synthetic precursors for phosphorodithioate-containing oligonucleotides and can be prepared
in 80-902
yield by reaction of a suitably protected nucleoside with phosphinic acid in the presence
of
pivaloyl
chloride
and
subsequent
oxidation
with
elemental
sulphur.lZ6 ~,~-Bis(3,4-dihydro-4-oxobenzotriazin-3-y1)-~-4-~hlorobenzyl phosphorodithioate (96) has been used to prepare dinucleoside diphosphorodithioate
triesters
using
method.12'
a
strategy
Dealkylation
analogous
of
the
to
van
protected
2-carbamoyl-2-cyanoethylene-l,l-dithioate and
cleavage of the 5'-phosphotriester bond; pronounced
when
deprotection
I
was
Boom's
dimer was
hydroxybenzotriazole
was
accomplished
accompanied
by
using
about
3%
internucleotide bond cleavage was more
performed
Diribonucleoside phosphorodithioates have
with
been
thiophenol/triethylamine.
prepared
from
ribonucleoside
phosphorothioamidites (97) by activation with tetrazole and subsequent reaction with the 5'-hydroxy group of an otherwise protected ribonucleoside."' ~-(2-cyanoethyl)phosphorothioamidites
were
used
in
preference
The to
the
S-( 2,4-dichlorobenzyl) derivatives which were more susceptible to oxidation and could not be purified by column chromatography. 5'-O-Dimethoxytrityl dithymidine phosphomorpholidate has been prepared in a one-pot procedure by thymidine
with
sequential treatment
of
5'-~-dimethoxytrityl-2'-deoxy3 ' -2-benzoyl-2' -deoxy-
bis( tetrazoly1)morpholinophosphine and
Oxidation of the resulting phosphoramidite was accomplished with
thymidine.lz9
t-butylhydroperoxide and the diastereomeric phosphoramidates separated by column chromatography.
Absolute configuration of the individual diastereoisomers has
been assigned on the
basis of
'H
n.m.r.
A new method for
experiments.
generating phosphonate linkages in oligonucleotides has been investigated that involves the reaction of a fully protected dinucleoside phosphite triester with [Pe(q5-Cp)(CO),(q
Z-C,H,)].130
An Arbusov-type dealkylation of the inter-
mediate with sodium chloride gives the (dicarbonyl) ( (ethy1)phosphonate
s -cyclopentadienyl)iron
(98) which is stable under the conditions of oligonucleotide
A novel internucleotide linkage in which manganese is directly
synthesis.
bonded to phosphorus has been synthesised by reaction of the same dinucleoside phosphite triester with [Mn(q '-MeCp) (CO), This adduct
(THF)] to yield the adduct (99).131
is stable to the conditions used
to construct and
deprotect
oligodeoxyribonucleotidesprepared by the phosphoramidite procedure.
Oligodeoxyribonucleotide
analogues
non-ionic, achiral spacers are of
containing
flexible
aliphatic,
interest as potential anti-sense agents.
Analogues containing the 3'0-5'C oxyacetamide linkage were first reported in 1974, and
an
published.13'
improved procedure
for their preparation
has
recently
The pyridinium salts of 5'-azido-3'-2-carboxymethyl
been
nucleosides
6: Nucleorides and Nucleic Acids can
be
condensed
217
with
5I-amino
nucleosides
in
dicyclohexylcarbodiimide and g-hydroxybenzotriazole.
the
presence
of
Reduction of the 5I-azido
function of the resulting dinucleotide analogue (100) using triphenylphosphine allows the elongation process to continue.
Carbamate linked oligodeoxyribo-
nucleosides derived from 5'-amino nucleosides have been characterised by mass spectrometry techniques and their fragmentation a n a 1 y ~ e d . l ~ ~More unusual carbamate-linked nucleoside oligomers which contain a morpholino unit replacing the sugar (101) have been prepared and studied.'34
The synthesis of building
blocks suitable for the preparation of non-ionic oligonucleotide analogues in which
the
phosphodiester
groups
(-0-PO,-0-)
are
replaced
by
sulphone
(-CH,-SO,-CH,-) groups has been recently described.135 A trimer of thymidine containing formacetal linkages has been attached to a solid-phase support (102) and incorporated at the 3'-end of a 15-residue oligodeoxyribonucleotide using chemistry.lS6
solid-phase procedures
from
taken
disaccharide
The formacetal linkages are chemically and enzymatically stable
and the modified 15-mer hybridises to a complementary strand with a tm (59.0"C) that is only 0.5"C less than that observed for the analogous unmodified sequence.
4.4
OliRonucleotides Containing Modified SuRars.
tides
a-Anomeric oligoribonucleo-
have been prepared on a solid-phase support from
a-rU, and a-rU,,
2 ' - ~ - t - b ~ t y l d i m e t h y l s i l y l ~ ~or ~
2'-~-l-(2-chloro-4-methylphenyl)-4-methoxy-
piperidyl13" protected a-uridine phosphoramidites. a-rU,, Formed a duplex with poly 0-rA, but the melting temperature (16°C) was significantly lower than that previously
measured
considerable
phosphodiesterases. radiolabelled
for
resistance
P-rU,,-P-rA,, to
Methods
digestion have
32P or
(either
by
been
35S)
(25°C) a
The
a-uridylates
variety
developed
for
of the
a-oligonucleotides of
showed
nucleases
and
preparation
of
high
specific
activity. A combination of n.m.r.
studies and molecular mechanics calculations have
shown that the parallel stranded duplex a-d(TCTAAAC).P-d(AGATTTG) right-handed duplex
in
solution with Watson-Crick base
glycosyl linkages on the P-strand display an the a-strand are
SJJ I.
both sugar anomers.
A 3'--
anti
adopts a
pairing.14'
The
conformation whilst those on
pucker of the deoxyribose ring is observed f o r
The anti-sense properties of the a-oligodeoxyribonucleo-
tides have been investigated and at a concentration of 1 pM a-dT,, produces 50% inhibition of reverse transcriptase activity in a poly(rA) directed HIV reverse transcriptase assay primed with natural P-dT,,.,,.
14'
A more detailed kinetic
analysis revealed that a-dT,, is a competitive inhibitor with respect to the natural primer fi-dT,,.
Organophosphoms Chemisrty
2 19
6: Nucleotides and Nucleic Acids
2'-~-Methyloligoribonucleotides are valuable anti-sense probes as they form
stable duplexes with
complementary RNA.
g.,
Sproat
have
reported
a
versatile route to 2'-~-methylpurineribonucleoside 3'-~-phosphoramiditesthat uses a sterically hindered strong organic base, 2-t-butyl-imino-2-dimethylamino-l,3-dimethylperhydro-l,3-diazaphosphorin (BDDDP) and methyl iodide to
effect the methylati~n."~
Key intermediates are 3',5'-e-(tetraisopropyldisil-
oxane-1,3-diyl)-2,6-dichloropurineriboside
(103)
disiloxane-1,3-diyl)-6-chloropurineriboside
(104), which after methylation can
be
subsequently
elaborated
2'-g-methylguanosine and
to
suitably
and
3',5'-G-(tetraisopropyl-
protected
phosphoramidites
2'-G-methyladenosine respectively.
The
of
automated
synthesis of 2'-~-methyloligoribonucleotides has also been achieved using the €j-phosphonate approach f o r oligomers containing 6-15 residue^.'"^ A potentially attractive route to 2-methylnucleosides is based on the use
of the [ [ 2-(methylthio)phenyl]thio]methyl and secondary hydroxy functions.'"
group for the protection of primary
This protecting group is stable under both
acidic and basic conditions and functions as a latent 9-methyl group. example,
5'-~-[[[2-(methylthio)phenyl]thio]methyl]-2'-deoxyth~idine (105)
readily converted into 5'-2-methylthymidine in 68% yield by tributyltin hydride and azobis(isobutyronitri1e).
For
is
treatment with
Alternatively, deprotection
to give thymidine can be accomplished using mercury (11) chloride in aqueous acetonitrile. Abasic sites are formed in DNA from the spontaneous loss of purine bases as a result of chemical modification and as intermediates in the normal course of DNA repair mechanisms involving glycosylases.
The study of the structures and
properties of abasic sites is important with regard to DNA repair mechanisms and a
variety
of
procedures
have
been
developed
for
oligodeoxyribonucleotides containing abasic residues.
the
synthesis
of
2-Deoxy-D-ribose has
been converted in 3 steps into a phosphoramidite building block bearing a TBDMS protecting group on the anomeric centre of the furanose sugar."5
Silylation
of 2-deoxy-5-~-dimethoxytrityl-D-ribofuranose with TBDMSCI in THPlpyridine in the presence of silver nitrate gives an anomeric mixture of the 1-2-silylated furanoses
in
which
the
main
component
is
the
a-anomer.
Following
oligonucleotide synthesis and removal of the base and phosphate protecting groups, the TBDMS group was removed by hydrolysis at pH 2 . 0 .
Attempts to
remove the TBDMS group using fluoride ion resulted in strand cleavage due to p-elimination of the 3'-phosphate group.
(106) has
been
incorporated
into
automated synthesis procedures.'46
l-(P-D-2-Deoxyribosyl)-2-pyrimidone
oligodeoxyribonucleosides using
routine
This nucleoside undergoes facile acid
catalysed hydrolysis and can thus be used to generate an abasic site at a pre-determined position.
At pH 3.0 hydrolysis of the pyrimidone nucleoside is
220 extensive and
is accompanied by a m i n i m amount of depurination.
procedure has been used to prepare d(CGCGUTTSGCG)
This
(S represents an abasic
site), the tm for this duplex is 20.3"C which is considerably lower than that measured
for
the native
duplex in
which dC
replaces S.
The partially
depurinated dinucleotides derived from d(ApA) namely d(SpA) and d(ApS) have been prepared and only the
latter isomer was shown to be a substrate for T4
polynucleotide kinase.'*'
Since dinucleotides of the type d(NpS)
are the sole
abasic site-containing products of fully digested DNA, a procedure using 32Plabelling of the fully digested DNA with polynucleotide kinase can be used to assay for abasic sites in DNA. The enzyme W endonuclease V participates in the removal of abasic sites from DNA by cleavage of the phosphodiester bond on the 3'-side of an aldehydic abasic residue &y
an elimination reaction.
The
stereospecificity of
the
hydrogen abstraction step has been studied using a damaged abasic polymer in which the pro-S 2'-H atom is replaced by tritium ( 1 0 7 ) . ' * "
The damaged polymer
was prepared by enzymatic incorporation of specifically tritiated dUTP into poly(dA*dU) and hydrolytic removal of the uracil using uracil-DNA glycosylase. The W
endonuclease V
from bacteriophage T4
is
shown
to
effect a
P-elimination of the pro-2 2'-H atom which proceeds from an open chain form of the abasic site.
Further evidence for this mechanism has been produced from
n.m.r. studies on W endonuclease V treated oligodeoxyribonucleotides in which the abasic residue contains 13C labels at the 1 ' - and 3'- positions.lbg A
series
of
2'-5'-linked
oligoribonucleotides
composed
9-(3-azido-3-deoxy-~-D-xylofuranosyl)adenine residues have been prepared
The NPE and NPEOC groups were used to protect the
phosphotriester route.'50
phosphotriester and amino groups respectively. fully
of
via the
deprotected
trinucleotide
Catalytic hydrogenation of the gave
the
9-(3-amino-3-deoxy-~-D-xylofuranosyl)adenine 2',5'-trimer
corresponding
(108).
Cytotoxic and
anti-viral nucleosides have been incorporated at the 2'-end of 2'-5'-linked oligoribonucleotide trimers. l S 1 potential pro-drugs
and
nucleosides
biological
nucleosides,
showed
possibly
The oligoribonucleotides can be regarded as
screening
of
activity
indicating
their
the
trimers
containing
closely
related
release
by
to
anti-viral the
enzymatic
parent
cleavage.
2'-5'-Linked oligoadenylates have been prepared by solid-phase synthesis using the phosphoramidite approach in combination with t-butyldimethylsilyl protection
of the 3'-p0sition.'~~ A series of analogues of the decamer d(GGGAATTCCC)
have been prepared in
which the nucleosides are sequentially replaced by (+)-butan-1,3-diol to give
oligodeoxyribonucleotides that position.15j
lack the
deoxyribose moiety
at
the
chosen
The diol unit was converted into the phosphoramidite derivative
6: Nucleotides and Nucleic Acids
22 1
(109) and used under routine conditions of automated oligonucleotide synthesis. The positioning of the diol unit towards the centre of the decamer resulted in decreased stability of the duplex.
Replacement of any of the nucleosides
Eco. R1
recognition sequence resulted in duplexes
within the central d(GAATTC)
that were not substrates for the analogue
derived
from glycerol
oligodeoxyribonucleotides.15"
Eco R1 endonuclease. has
been
A flexible nucleoside
incorporated into
a number
of
The required monomer (110) is available in 6
steps starting from (~)-3-(benzyloxy)-l,2-propanediol.
Melting studies on a
series of duplexes containing this modification demonstrate that the tm is lowered by 9-15°C for each glyceronucleoside incorporated.
The decrease in
stability of these oligodeoxyribonucleotides is greater than that predicted on the basis of entropy. Dithymidine
3'-S-phosphorothiolate (111)
has
been
prepared
from
the
phosphorothioamidite by activation with 5-(4-nitrophenyl)tetrazole and oxidation
of the intermediate dinucleoside phosphorothioite with the tetrabutylanrmonium salt of either periodate or oxone.lss
Whilst (111) is relatively resistant to
hydrolysis by nuclease P1, the phosphorus-sulphur bond is rapidly cleaved by aqueous solutions of iodine or silver nitrate.
The dithymidine 3'-S-phosphoro-
dithioate (112) has also been prepared by oxidation of the phosphorothioite with sulphur and absolute stereochemistry has been assigned to the diastereoisomers of (112) by comparing their chemical and physical properties to those of the
dinucleoside
phosphorothioates.
Additionally,
a
penta-2'-deoxythymidine
tetraphosphate analogue containing a central 3'-thio-2'-deoxythymidine residue has been prepared on a solid-phase ~upport."~ Sund and Chattopadhyaya have investigated the synthesis and stability of diribonucleosides containing a 3'-O-PO2-S-5'linkage.15' phosphorothiolate
(113)
was
prepared
from
the
The fully protected
triethylanrmonium
salt
of
0-(2-cyanoethyl)-S-5' -( 3-E-benzoyl-2' ,3' -di-g-acetyl-5' -deoxyuridyl)phosphoroth-
iolate (114) and 6-~-benzoyl-2'-~-pixyl-5'-~-toluoyladenosine by condensation with MSNT in dry pyridine.
After removal of the 2-cyanoethyl group with
triethylamine, controlled removal of the labile 2'-e-pixyl group was attempted using silica gel in a mixture of acetonitrile and water (pH
-
5) and although
the 2I-deprotected product could be identified by jlP n.m.r. it could not be isolated.
These results demonstrate that the
ribonucleoside-3'-0-PO,-S-5'-
ribonucleoside linkage is very labile due to the participation of the vicinal 2'-hydroxy function. Dinucleotides containing a S'-N-phosphoramidate linkage have been prepared by reaction of 5'-g-dimethoxytrityl-2'-deoxythymidine bis(methoxy)phosphine
and tetrazole.15*
with N,Ij-diisopropylamino-
The intermediate phosphite triester
was treated with a 5'-azido-2',5'-dideoxynucleoside
and in the presence of
222
Organophosphorus Chern i s t y
To'oY w!J Hx'p\o O\\ /s
NCCH2CH20' o\\Pp\S
OH
(111) (112)
x=o x=s
OPiX
AcO
Bz
OAc
6: Nucleotides and Nucleic Acids
223
lithium chloride the initial phosphite imine is converted to the phosphoramidate by
a
Michaelis-Arbuzov reaction.
incorporated
The
phosphoramidate linkages can
trityl)amino-2',5'-dideoxynucleoside monomers (115).
trityl
group
be
longer oligodeoxyribonucleotides using 5'-N-(monomethoxy-
into is
cleaved
1.5
only
to
2
Since the N-monomethoxy-
times
more
slowly
than
the
9-dimethoxytrityl group, these monomers can be used in a standard automated procedure.
The internucleotide 5'-N-phosphoramidate linkage has also been
prepared by reaction of nucleoside 3'-Q-methyl-~-phosphonates with 5'-aminonucleosides
in
the
presence
of
carbon
tetrachloride, triethylamine and
pyridine.15% The pyridine serves as a catalyst and the reaction is thought to proceed through the highly reactive pyridinium salt (116). dinucleoside phosphoramidate (117) nucleotide using
The resulting
has been incorporated into a pentadeca-
either H-phosphonate or
phosphoramidate chemistry.
The
presence of the phosphoramidate linkage in the oligodeoxyribonucleoside was confirmed by selective hydrolysis with mild acid. 2'-Deoxy-2'-fluorouridine has been chemically incorporated at the 3'-end of a
hexadeoxyribonucleotide using
phosphoramidite
chemistry.
Under
the
anrmonolysis conditions necessary to remove the acyl protecting groups the 2'-deoxy-2'-fluorouridine
residue was
partially converted
to
=-U.
The
oligodeoxyribonucleotides containing either g - U or 2'-fluorouridine could be distinguished by a solid-phase chemical sequencing technique.
Interestingly, if
the 2'-fluorouridine residue is incorporated in any other position in the oligonucleotide so that
the 3I-hydroxy group is
phosphorylated, then no
hydrolysis of the carbon-fluorine bond is observed.
Oligodeoxyribonucleotides containing (+I-carbocyclic 2'-deoxythymidine have been
prepared
Synthesis&I
by
chemical
synthesis as
potential anti-sense agents.16'
the phosphotriester and €J-phosphonate approaches unexpectedly gave
low coupling yields, but a coupling efficiency of 95% was achieved using phosphoramidite chemistry oligonucleotides are
and
enabled
the
synthesis
susceptible to hydrolysis with
of
C(dT),,.
These
snake venom phospho-
diesterase and can be characterised by partial hydrolysis and h.p.1.c. analysis.
4.5
OliRonucleotides containing Modified Bases.
6-2-Alkylguanine residues
formed by the alkylation of DNA are thought to play an important role in the carcinogenic activity of N-nitroso compounds.
The effect of 6-O_-alkylguanine
residues on DNA structure has been
studied through the incorporation of
6-9-methylguanine,
and
6-9-ethylguanine
6-2-i-propylguanine into
62 complementary dodecadeoxyribonucleotides.'
phenylacetyl group for the protection of the
self-
The use of the very base labile 2-!-amino
function enabled base
deprotection to be carried out with mild ammonolysis, thus preyenting formation
224 of
Orgunophosphoms Chrnt i . q the
2,6-diaminopurine nucleoside.
6-2-a1kylG.C base pairs had
Oligodeoxyribonucleotides containing
lower melting temperatures than the unmodified
duplexes, but only i-propy1G.C pairs resulted in a significant reduction in hypochromicity.
A
variety
of
oligodeoxyribonucleotides
containing
6-2-methylguanine have been prepared by the phosphoramidite procedure.lb3 In general it was found that all base pairs containing 6-2-methylguanine are weaker than those containing guanine and the most stable base pair was formed with cytosine. These results are in agreement with those obtained by detailed n.m.r. studies
on
the
6-2-ethylguanine*thymine pairing"'
and
the
6-e-ethyl-
guanine*cytosine pairing.lb5 It has also been shown that replacement of guanine
by g6-methylguanine causes asymmetric single-strand cleavage of DNA by some restriction enzymes. l b 6 4-~-i-Propyl-2'-deoxythymidine
dinucleotides d(i'TpT)
(i'dT)
and d(Tpi4T).lb7
has
been
incorporated
into
the
In contrast to the monomers the two
isopropyl methyl groups are magnetically nonequivalent and give rise to separate 'H and 13C n.m.r. signals. pucker for the i'dT
Coupling constant data also indicate a 3'-endo sugar
residue.
A new Watson-Crick base pair (118)
with a different hydrogen bonding
pattern from that found in G*C or A * T base pairs has been incorporated into RNA and DNA and expands the genetic alphabet from 4 to 6 letters.lb8 A primed oligodeoxyribonucleotide template containing the 2,6-diaminopyrimidine derivative
K
was used for run-off transcription with T7 RNA polymerase and it was
demonstrated that xanothosine was incorporated into the enzymatically produced
RNA strand.
In a similar experiment DNA polymerase (Klenow fragment) was used
to incorporate 2'-deoxyxanthosine into a DNA strand with high-fidelity. Base pairs containing *-cytosine
and *-guanine
(119) have also been incorporated
into nucleic acids.lb9 Incubation of a primed template containing 2'-deoxy-*cytidine with dNTPs and the Klenow fragment of DNA polymerase only produced the full length product in the presence of 2'-deoxy-&-guanosine the insertion of &-guanine neighbour
analysis.
3,4-dihydro-3Ij-pyrimido
opposite &-cytosine
A
nucleoside
analogue
[4,5-~][1,2]0xazine-7-one
incorporated into oligodeoxyribonucleotides.'71
triphosphate and
was established by nearest base'70
containing (120)
has
the been
This pyrimidine analogue has
been designed to have a tautomeric constant close to unity so that it should be able to form base pairs of comparative stability with either A or G and thereby remove the TIC degeneracy. The use of this nucleoside greatly simplifies the design of probes for DNA sequences derived from protein sequence data. A review on hydrogen bonding interactions in nucleosides and modified nucleosides has recently appeared.
6: Nucleotides and Nucleic Acids
225
H
H‘”
-o+fN-sugar
ANNNyNH
N y N O H --0
K
‘H
NH2
I
N N ‘ y F N HN -(CH2)lo-NHCSNH
OnN-f-O
HOOC HO OH
~NHCO--(CH2)~S-S-(CH2),--CONH-(CH2)~DMT (123)
'26 The bases 2-thiothymine (S'T),
4-thiothymine (S'T)
and 5-methyl-2-pyrimi-
done (H4T) have been incorporated into a self-complementary dodecadeoxyribonucleotide containing the
Eco RV recognition site [d(GATATC)].173
H'T
and SZT
were incorporated without any base protection, but the thione function in S'T was protected with 2-sulphenylmethyl group which can be removed by reduction with dithiothreitol.
All three of these modified bases show some degree of
reactivity with the ammonia solution used in the deprotection, and these side reactions complicate and reduce the efficiency of the syntheses.
7-Deaza-2'-
deoxyadenosine has been incorporated into oligodeoxyribonucleotides using the formamidine protecting group and phosphoramidite chemistry.l7'
Oligodeoxy-
ribonucleotides in which tracts of adenine bases were interrupted by 7-deazaadenine exhibited reduced bending.
A variety of 6-N_-methylatedanalogues of
adenine have been incorporated into oligodeoxyribonucleotides using phosphoramidite chemistry.17'
In alternating d(A.T),
sequences, the duplex destabilis-
ation introduced when dA was replaced entirely with 2'-deoxy-6-bJ-methyladenosine was reversed by the incorporation of 8-aza-7-deaza-2'-deoxy-6-N_-methyladenosine whereas 7-deaza-2'-deoxy-6-N-methyladenosine decreased the T A
pentadecanucleotide of
furanosyl)-1,2,4-triazole-3-carboxamide]
phoramidite approach.'76
further.
the anti-viral agent ribavirin has
been
prepared
[(l-P-D-ribo-
by
the
phos-
The oligomer is terminated at the 5'-position with a
6-aminohexyl linker and bears a 2'-deoxythymidine 5'-phosphate residue at the 3'-end.
The oligonucleotide was shown to be resistant to ribonuclease A, but
was cleaved completely by ribonuclease T,.
Compounds of this type are of
potential interest since in theory they can be conjugated to a monoclonal antibody and selectively targeted to virally infected cells.
Absorption of the
immunodrug-conjugate into the cell followed by cleavage of the oligomer by phosphatases or nucleases would release ribavirin 5'-phosphate.
5.
Oligonucleotide Labelling, Conjugation and Affinity Studies.
conjugates of
oligonucleotides and
related
compounds
has
A review on
recently
been
published. The synthesis of 2'-deoxyadenosine nucleotides which contain an aminoalkyl chain at the 8-position covalently attached to fluoroscein and their subsequent incorporation into nucleic acids provides a route to fluorescent DNA probes. 8-(lO-Aminodecyl)amino
S'-dAMP
was treated with fluoroscein isothiocyanate in
aqueous buffer at pH 9 to give the fluorosceinylated monophosphate in good yield."'
The
labelled triphosphate was most
efficiently prepared by an
analogous reaction of the phosphoromorpholidate with fluoroscein isothiocyanate
6:
227
Nucleotides und Nucleic Acids
tb give (1211, which was subsequently converted to the triphosphate in 24% yield by
reaction with tetra-n-butylammonium pyrophosphate in DMSO.
A similar
strategy has been used for the attachment of a biotin label onto dGTP.179 Reaction of 8-bromo-2'-deoxyguanosine S'-monophosphate with 2-mercaptoethylamine under oxidative conditions generates a disulphide with a free alkylamino group. Subsequent
reaction
with
8-biotinyl-6-aminohexanoic
triphosphate (122).
a acid
water and
soluble N-hydroxysuccinimide ester phosphorylation gave
the
of
biotinylated
This labelled analogue of dGTP could be incorporated into
DNA using DNA polymerase 1 from E.coli and detected using biotin specific reagents. Oligodeoxyribonucleotides complementary to oxytocin mRNA and to the human N-ras gene were labelled at the 3'-end with 5-bromo-2'-deoxyuridylate by tailing with
terminal
deoxynucleotidyl transferase."'
The hybrids were
detected with a monoclonal antibody raised against 5-bromo-2'-deoxyuridine. A universal controlled-pore glass support has been prepared which gives rise
to oligonucleotides with a 3'-thiol function after the final deprotection step.
Treatment of the commercially available 3-aminopropylated controlled-
pore glass with a 10-fold excess of 3,3'-dithiobis(~-succinimidyl propionate) in the presence of triethylamine and, following washing, further reaction with a S-fold excess of 4,4'-dimethoxytrityloxypentylamine gave the desired support (123).
Coupling yields were greater than 98% using the phosphoramidite approach
and after synthesis the thiol-containing oligomer (e.g. 124) is released by ammonia deprotection in the presence of dithiothreitol. 3'-hino derivatised oligonucleotides have been prepared by a similar approach using an aminohexanol linker immobilised to a solid support y&
a carbamate linkage (125).la2
After
assembly of the oligonucleotide the alkylcarbamate linkage can be cleaved from the support by treatment with aqueous ammonia and dithiothreitol to generate the 3'-amino derivatised oligomer. The amino function can be labelled with electrophilic reagents and this procedure has been used to derivatise oligonucleotides with acridine reporter groups.
A biotin derivative of S'-g-dimethoxytrityl-
4-8-(6-aminohexyl)-2'-deoxycytidine (126) has been prepared from 5' -g-dimethoxytrityl-4-thio-2'-deoxyuridine by displacement of the sulphur atom with excess
diaminohexane in ethanol at 6OoC and subsequent reaction with biotin-E-hydroxysuccinimide.le3 Following conversion to the phosphoramidite, (126) has been used for the incorporation of up to 20 biotin molecules into an oligodeoxyribonucleotide. Oligodeoxyribonucleotides with sequences 5 ' -d(GCAC*TCAG)
5'-d(GCACT*CAG) (T* = 128) have been prepared."'
(C* = 127) and
The primary amino functions
of these oligonucleotides can be reacted specifically with the lj-hydroxysuccinimide ester of 4-carboxy-4'-methyl-2,2'-bipyridine and further treatment with Ru(bpy),(H,0),2'
gives oligonucleotides which are covalently attached to
Organophosphorus Chemistry
228
!
~'-CGGATCCGCGGATCCG-O-T-&(CH~),TNHCOCH~CH+~H HO
(124) ~NHC&(CH2)2-C02-(CH2)2-!3-S-(CH2)2-OCONH-(CH2)6-OH (125)
HN-(CH,)G-NHCO-(CH2)4
HNKNH 0 OH
OH
(129) n =1 (130) n =2
(131 1
6: Nucleotides and Nucleic Acids
229
the fluorescent and redox-active Ru(byp),*' thymidine analogues (129) and
label.
(130) have been
The spin-labelled 2I-deoxyincorporated into the self
complementary dodecamer 5 ' -d(CGCGAATFCGCG) in place of the outer 2 ' -deoxythymidine re~idue."~ In both oligonucleotides the 5'-alkynyl chain resides in the major groove and does not appreciably perturb the double-helix. The e.p.r. spectrum of the dodecamer bearing residue (129) correlated with the expected global tumbling of the molecule, whilst the oligonucleotide-containing residue (130) gave a spectrum that was consistent with free rotation of the nitroxide label relative to the DNA. The difference in probes (129) and (130) is probably explained by the variation in mobility of the nitroxide labels.
For the monoyne
(129) the nitroxide bearing ring is closer to the sugar phosphate backbone and is likely to experience restricted rotation, whilst the addition of two more carbon atoms in (130) allows unrestricted rotation of the nitroxide group.
Oligodeoxyribonucleotides in
which
specific
adenine
bases
have
been
labelled with the fluorescent dansyl group have been prepared using the prelabelled monomers 6-~-benzoyl-8-(w-dansylaminoalkylamino)-5'-~-(4,4~-dimethoxytrityl)-2' -deoxyadenosine
3 ' -g- (2-chloropheny1)phosphate
(131).
ln6
Greater
fluorescence was obtained when the dansyl group was attached to a short alkyl chain (n=2) and situated at the centre of the oligomer.
4-!-(6-Hydroxyhexyl)-
5-methyl 2'-deoxycytidine has been incorporated into an oligodeoxyribonucleotide using phosphoramidite
This nucleoside serves as a branching
monomer which enables "fork" or "comb" structures to be prepared.
When the DMT
group is employed for the protection of both the aminohexanol and S'-hydroxy groups, simultaneous coupling of two identical nucleoside phosphoramidites is achieved leading to "fork" structures.
When
levulinoyl protection of the
aminohexanol linker is utilised then selective coupling at either of the hydroxy functions
is
possible
enabling
the
preparation
of
"comb"
structures.
Oligodeoxyribonucleotides of this type are of potential utility to amplify signal output in non-radioisotopic DNA probe assays. A
labelling strategy has been developed in which one or more specific
internucleotide linkages are modified
to
produce
aminoalkylphosphoramidate
residue^"^ by oxidation of an H-phosphonate internucleotide linkage with
-N-1-trifluoroacetyldiaminohexane in
the presence of carbon tetrachloride.
The
oligodeoxyribonucleotide can then be extended using either phosphoramidite or H-phosphonate chemistry and once synthesis is complete deprotection with aqueous annnonia gives the aminohexylphosphoramidate oligomer.
The amino Fiunction can be
labelled with the biotin-N-hydroxysuccinimide ester to give the two diastereomeric biotin adducts.
A pentadecadeoxyribonucleotide analogue containing all
methanephosphonate linkages and complementary to the 5'-end of human U2 small nuclear RNA "maxi-transcript", has been synthesised from nucleoside 3I-methyl-
'30
Orgutiophosp horus
C 'hemistry
phosphonamidite~.'~~The 5'-terminus was functionalised by performing the last coupling step with 2-~9-fluorenylmethoxycarbonyl)aminohexanol-(~,~-diisopropyl)methylphosphonamidite (132). ethylenediamine gave
the
Deprotection with aqueous ammonia followed by crude 5'-amino-derivatised oligomer which
purification could be labelled with biotin.
after
The labelled oligonucleotide has
been used to isolate the maxi U2 RNA:ribonuclear protein complexes from nuclear extracts of cultured human cells by affinity chromatography of the oligomer hybrid on streptavidin agarose.
The same experiment with a phosphodiester
containing oligonucleotide probe was unsuccessful due to cleavage of the RNADNA hybrid by endogenous RNase H activity present in the cell extracts. 5'-~-[2-(4-Biphenylyl~isopropyl-2-oxycarbonylamido-6-hexylamidocarboxy]
nucleosides
(133)
have
been
incorporated
at
the
5'-end
of
oligodeoxyribonucleotides using automated phosphoramidite chemistry.lgl The (4-biphenylyl)isopropyloxycarbonyl group is sufficiently acid labile that it can
be removed on the synthesiser under the standard conditions used for removal of the DMT group.
Biotinylation of the resulting S'-aminoalkyl oligomer can be
accomplished either on the support or in solution using a water soluble biotin ester.lg2
A
biotin
labelled
29-residue oligodeoxyribonucleotide
has
been
prepared entirely on a solid-support and used for the specific detection of human papilloma virus DNA. N-(9-Fluorenylmethoxycarbonyl)-l-~-dimethoxytrityl-2-~-cyanoethoxydiiso-
propylaminophosphinyl-3-aminopropan-l,2-diol has
been
used
to
construct an
oligodeoxyribonucleotide probe complementary to M13mp18 DNA containing 5 primary amino functions attached to the 5'-end.lg3 The amino groups can be labelled with biotin and the resulting probe has been used to detect as little as 0.5 ng of the target M13mp18 DNA using a dot-blot hybridisation assay with colourimetric detection.
PCR has been used to amplify DNA segments using fluorescently labelled oligodeoxyribonucleotide primers.lg4
fluorescent primers the DNA
After amplification and removal of the
segments are separated by
visualised in test tubes under uv light. can be used directly for diagnosis.
electrophoresis or
The colour or combination of colours
The use of radioactively labelled DNA
probes has been facilitated by binding the DNA to small nylon membranes prior to radioactive labelling.'95
The labelled DNA is readily removed from unin-
corporated nucleotides and probes prepared in this manner are just as efficient in detecting DNA as those prepared in solution.
5-[(4-Azidophenacy1)thioJuridine 5'-triphosphate ( 1 3 4 ) has been prepared by alkylation of 5-thiouridine S'-triphosphate with 4-azidophenacyl bromide.
This
analogue is a substrate for E.coli RNA polymerase and once incorporated into RNA can be used to study RNA-protein or RNA-nucleic acids interactions by photoactivated cross-linking.lg6 Unlike other photoaffinity labels the cross-linking
6: Nucleotides and Nucleic Acids
23 1
N3
H40gp30 0
HO
OH
(1 34)
HO
OH
OH
process can be reversed by treatment with Raney nickel.
Esterification of
N-(4-azido-2-nitrophenyl)-P-alanine with 2-azidoadenosine S'-triphosphate using
carbonyldiimidazole gives a bifunctional photoactivatable nucleotide (135).lg7 This ATP
analogue has
arrangement of photoaffinity
been applied
to the
a multisubunit ATPase by labelled
ADP
analogue
investigation of
photoaffinity
(136)
was
the
spatial
cross-linking.
prepared
by
The
reaction
of
4-azido-2-nitrophenylphosphate with adenosine 5'-monophosphoromorpholidate and has been shown to be a competitive inhibitor of glucose-6-phosphate dehydrogenase with respect to NADP. l g 8 prepared from either ["'C]AMP
Radiolabelled derivatives of (136) can be
or iodination of 4-azido-2-nitrophenol. has
Adenyl-(2'-5')-adeny1-(2'-5')-8-azidoadenosine
been
prepared
by
the
phosphotriester approach from building blocks containing a 3'-2-(4-nitrophenyl)The trinucleotide has been used to label RNase L
ethylsulphonyl group (137).lg9
in L929 cells by uv irradiation in cell culture. A review on the photoreactions of nucleic acids and their constituents with amino acids and related compounds has recently been published.z00 The affinity analogues of CAMP, 2-[(4-bromo2,3-dioxobutyl)thio]adenosine 3',5'-cyclic monophosphate (138) and 8-[(4-bromo2,3-dioxobutyl)thio]adenosine 3',5'-cyclic phosphate (139) have been prepared in
4 and 3 steps respectively from C A M P . ~ O ~ Whilst (138) was a competitive inhibitor of the high-affinity human platelet CAMP phosphodiesterase, (139) showed irreversible activation of this enzyme. 4,5',8-Trimethylpsoralen
has
been
attached
to
the
C-8
position
of
2'-deoxyadenosine via a sulphur atom and a 5 carbon alkyl chain.202 resulting
modified
deoxyadenosine
oligodeoxyribonucleotides, using
the
(140)
has
been
phosphoramidite
incorporated approach.
The into
When
the
modified base was positioned directly 3' or 5' to a thymidine residue and hybridised to a complementary oligodeoxyribonucleotide efficient cross-linking ( 90%) could be achieved by irradiation for one hour at 345
cross-linking was
observed
if
the psoralen
adduct was
nm.
Very little
separated by
one
A n oligodeoxyribonucleotide containing
nucleoside residue from a TA sequence.
psoralen attached to the 5'-end through a disulphide linker (141) has been used to
deliver
this
intercalator to
a
specific uridine
residue
in
P-globin
pre-mRNA.z03 The oligonucleotide sequence was chosen so that the RNA has one unpaired nucleotide adjacent to the targeted uridine; this arrangement enhances the
intercalation
of
the
RNA-oligonucleotide complex
psoralen
moiety.
is reacted with DNase
dithiothreitol to give the RNA-psoralen adduct.
After
1
irradiation
in the presence
the of
This procedure can be used to
provide valuable information on the secondary structure of the pre-mRNA.
A
review on the application of psoralen derivatives as probes for the study of nucleic acid structure and function has recently been p~blished.~" Interstrand cross-linking has also been
achieved between
a
synthetic
6: Nucleotides and Nucleic Acids
HO“0
233
OH
234
Organophosphorus C'hrmisiy
oligodeoxyribonucleotide containing an iodoacetamide linker attached to the 5-position of a pyrimidine base (142) and a target DNA sequence.205 The 6 atom chain bridges the major groove to alkylate the N-7-position of a guanine residue one base pair removed (143) and the degree of cross-linking increases with both time and temperature up to 37°C. A method has been developed for the synthesis of peptide- or more generally
polyamide-oligonucleotide conjugates.206
The
synthesis
is
performed
on
controlled-pore glass and involves the assembly of the polyamide on the support, conversion of the terminal amino function to a protected primary aliphatic hydroxy group by reaction wifh an a,w-hydroxycarboxylic acid derivative and finally,
oligonucleotide
synthesis
from
the
hydroxy
function
using
phosphoramidite chemistry. The utility of this procedure has been demonstrated in the
synthesis of
oligodeoxyribonucleotides containing multiple
lysine
residues which serve as sites for the attachment of non-radioactive reporter groups such as biotin or fluorescent labels.207 Probes containing 10 biotin labels gave a
detection limit of
approximately 5
attomoles.
Anti-sense
oligodeoxyribonucleotides prepared with a 3'-adenosine residue have also been conjugated to
polylysine via
a
N-morpholino ring
after
oxidation with
periodate.208 The conjugates were shown to effect specific protection against vesicular stomatitis virus at concentrations lower than 1 pole.
Water soluble
oxysterols (144) have been prepared by conjugation to nucleotides through a phosphodiester bond.
6. Cleavage and Sequencing Studies Sequence selective cleavage of duplex DNA has been achieved by a hybrid nuclease consisting of
a
short oligonucleotide selectively fused
disulphide bridge) to staphylococcal nuclease.
lo
(v&
a
The oligonucleotide-enzyme
adduct is able to hybridise to partially denatured double-stranded DNA via D-loop formation and both strands of the substrate DNA were then efficiently cleaved (Scheme 1).
Staphylococcal nuclease has also been used to effect site
specific cleavage as part of a hybrid protein with A-repressor.21'
A truncated
A-repressor protein was constructed lacking the C-terminal domain and engineered to contain a unique cysteine (ser 32 -> domain. a
cys 32) in the 102 residue N-terminal
The mutant cysteine was attached to the staphylococcal nuclease through
flexible methylbis[3-[3-~2-pyridyldithio)propionamido]propyllamine
tether.
The resulting hybrid specifically cleaved supercoiled plasmid DNA containing a A-repressor site (OR1) adjacent to this site. The interaction of the anti-tumour antibiotic bleomycin with DNA under conditions of limiting oxygen results in the production of a free nucleic base and an oxidatively damaged sugar-lesion. Studies on d(CGCTGCGT)
demonstrate
6: Nucleotides and Nucleic Acids
235
0 3’Hkligodeoxyri bonucleotide-0-P-N
It I
0
H-(CH2)TS-S-(CH,)2
-C” I
NMe
HO
I
(y2h
? 0
3’
5’
I
CH,I
0
HO
I
O=P-OH
DNA-nuclease adduct
target strand
-
target DNA
Scheme 1
I t
modified strand
+=
Organophosphorus Chemistry
'36
that the predominant pathway for base release is the result of initial oxidation at the 4I-position to generate a 2-deoxy-4-pentulose moiety
(145) and the
Additional studies
stoichiometric generation of a free nucleic acid base. '12
using either "0 labelled oxygen or water have established that the oxygen in the 4'-keto function of (145) is derived from the solvent.213 Upon activation with thiol, neocarzinostatin (NCS) has been shown to degrade DNA through the formation of a putative biradical species which is able to abstract hydrogen from C-5' (Scheme 2 , route A).
A detailed study on d(CGTACG)
demonstrates that
a competitive mechanism, involving hydrogen abstraction and subsequent hydroxylation at C-4' can also occur (Scheme 2 , route B).214 The copper-binding tripeptide Gly-Gly-His has been attached to the amino terminus of the DNA-binding domain of
recombinase.2'5
The modified protein
is capable of binding to DNA-containing the 13 base pair Hin recognition sites and is able to cleave at the same sites in the presence of Ni(OAc), monoperoxyphthalic acid.
and
Kinetic studies using DNA containing [4'-'H]thymidine
demonstrate that hydrogen abstraction from the 4'-position occurs at the rate determining step of the cleavage and suggests that the mechanism is similar to that reported for Pe(I1)-bleomycin.
The Fe(II)-EDTA
catalysed cleavage does not
discriminate between typical single-stranded and double-stranded regions of RNA and is therefore a useful probe for the examination of the tertiary structure of RNA.2'6
The
interaction of
porphyrins with
DNA has
been
reviewed with
particular emphasis on DNA binding and cleavage by cationic porphyrins.'l'
The
ultrasonic degradation of DNA has also been reviewed.218 Interstrand cross-linking in DNA
is believed to account for the cyto-
toxicity of many bifunctional alkylating agents. has been
A simple and general method
developed for determining the base sequence preferences of DNA A DNA duplex was cross-linked between a
interstrand cross-linking drugs. 'l9 single 5' -d(TA)
sequence using 4'-(hydroxymethyl)-4,5' ,8-trimethylpsoralen and
selectively radiolabelled at the recessed 3'-end (146). subjected to Pe(I1)-EDTA
The product was
cleavage and scanning densitometry of the polyacrylamide
gel electrophoresis autoradiograph. The cross-linked DNA yielded radiolabelled fragments that terminated at the site of cross-linking, whilst the native sequence produced the complete cleavage pattern.
This method has been used to
demonstrate the preferred site of cross-linking with mitomycin C and a pyrrolizidine alkaloid.
The same technique has been utilised for the study of
cross-linking reactions nitrogen
mustard
between
oligodeoxyribonucleotide duplexes and
mechlorethamine
the
[l-~-methylbis(2-chloroethyl)amine].220
Cross-links are formed through distal guanine residues with a preference for 5'-GNC sequences of 5 I - N over 5'-CG.
6: Nucleotides and Nucleic Acids
237
d c G T = oHA yThy
R’
’I NCS, 0 2
OpACG RSH
I”””
J““
Route A .OH
w
dCGpO
Route B
VTh
dCGpO
H0”
~ ~ A C G
OPACG
I
.”Ur OpACG
dCGpO
hy
OpACG
+ dCGp
+thymine
Scheme 2 5’-CCCCGGG:AGGCGGGC*G
’1
3’-GGGGCCCATCCGCCCGCAG (147) n = 4 , 5 o r 6
7. Interaction of DNA with Metals and Small Molecules The two major adducts formed between the anti-cancer drug c&-diamminedichloroplatinum(I1)
( S - D D P ) and DNA are
intrastrand cross-links between
either two adjacent guanine residues or between adjacent adenine and guanine residues.
It has been demonstrated that cyanide is able to remove most, but not
all, of the bound platinum under physiological conditions and importantly the kinetics of the removal are strongly dependent on DNA conformation.221 Cyanide can therefore be used as a probe to examine the conformation of DNA modified by
cis-DDP.
Reaction
d(CCTCGAGTCC)
of
the
inactive
trans-DDP with
the
single-stranded
gives, as the major product, a 1,3-intrastrand cross-link between
two N-7-atoms of the dG nucleosides.222 A model for the platinated oligonucleotide is structurally very different from that obtained when --DDP
modifies DNA
and may explain the different biological activity of the two DDP isomers. simple
procedure has
been
developed for
cross-linking two
A
complementary
oligonucleotides.223 One of the oligonucleotides is first converted to its 5'-phosphorothioate using polynucleotide kinase and ATPyS and then hybridised to a complementary sequence in the presence of trans-DDP. Interstrand cross-links result from platinum bridging the sulphur atom of the 5'-phosphorothioate and presumably a N-7 atom of a purine nucleoside. obtained in 40-50% yield.
The cross-linked products are
The interaction of novel bisplatinum complexes (147),
which are potentially new anti-cancer drugs, with short DNA fragments has been studied
by
polyacrylamide gel
electrophoresis.224
These
complexes
are
potentially tetrafunctional and interstrand cross-links are about 250 fold more frequent than in adducts derived from &-DPP. The novel ruthenium complex Ru( bpy) (dppz)'
+
shows no photoluminescence in
aqueous solution at ambient temperature, but displays intense photoluminescence in the presence of double-helical DNA.225 The complex binds very strongly to DNA and the sensitivity of its excited state properties to the surrounding environment make it an excellent probe for examining nucleic acid tions. With B-DNA (poly[d(GC)*d(GC)]
conforma-
and calf-thymus DNA) the complex shows an
emission maximum at about 230 nm, whilst with the 2- and A-forms the maximum is shifted to longer wavelength and also exhibits large differences in the emission intensity. Ru(bpy),(dppz)2'
is potentially able to act as a "light switch" in
response to changes in DNA conformation.
The interaction of chromium (111) and
chromium (VI) with the phosphate groups of nucleoside di- and triphosphates has been studied by 31P n.m.r.226
Chemical shifts indicative of Cr-nucleotide
complexes were only detected with Cr(II1)
species.
Additionally, experiments
with a radioisotope of chromium (51Cr) demonstrated that only Cr(II1) bound to DNA. The structure of the Ni2+*ATP complex has been determined in heavy water solution using neutron diffraction.227 The results provide the first structural
239
6: Nucleotides and Nucleic Acids
ion is directly bonded to ATP between either the a- and
evidence that the Ni"
p- or p- and y-phosphates. Metal-nucleotide interactions have recently been the subject of a review.z28 A multifunctional receptor molecule (148) has been designed for nucleotide
binding which has 3 functional subunits; a macrocyclic polyanmonium moiety for binding phosphates, a catalytic amino group within the macrocycle and an acridine side-chain for stacking interactions with a nucleotide base.229
The
receptor accelerates the hydrolysis of both ATP and ADP by factors of 9 and 3 respectively.
The reaction occurs
via nucleophilic catalysis involving attack
of the secondary amino group on the terminal phosphate, thereby proceeding through
the
formation
of
a
phosphorylated
macrocycle
intermediate.
A
bisguanidinium derivative has been designed to serve as a ditopic host for 2'-deoxythymidine 5'-mon0phosphate.~'~ Changes in the 'H n.m.r. chemical shifts for the aromatic signals of the host are consistent with a 1:l binding model. The guanidinium N-H bonds point to the corners of a distorted tetrahedron and thereby favour the complexation of tetrahedral anions. The naturally occurring antibiotic (+)-CC-1065
(149) binds to the minor
groove of DNA and bonds covalently to N-3 of selected adenines by reaction at the cyclopropyl ring.
Dimers (150) of the spirocyclopropyl alkylating moiety of
CC-1065 have been prepared in which the alkylating functions are separated by an alkyl chain.231
Both the cross-linking efficiency and cytotoxicity of the
dimers was strongly dependent upon chain length and the most effective compounds contained 3-5 methylene groups in the bridging alkyl chain.
The unnatural
enantiomer of (+)-CC-1065 has been synthesised and its interaction with DNA compared to that of the natural product.Z32 Although (-)-CC-1065 also forms a covalent adduct in which the cyclopropyl ring was bonded to the N - 3 atom of adenine and the resultant strand cleavage of the DNA parallels that seen for the (+)-isomer, it binds in the opposite direction along the minor groove and also exhibits different sequence specificity. The chemical structures of the principal adducts formed from calf-thymus DNA upon reaction with 4 optically active bay-region 3,4-diol 1,2-epoxides of dibenz(a,j}anthracene
have
been elucidated.233
The site of attachment is
between the benzylic C-1 of the diol epoxide and the exocyclic amino groups of adenine, guanine and cytosine.
Aflatoxin B, is a most potent mutagen and is
implicated as a human carcinogen; toxicity requires activation and the epoxide (151) is thought to be the active mutagen. with d(ATCGAT),
oligonucleotide duplex.23' give a 1:l
The adduct of aflatoxin B, epoxide
has been prepared by direct reaction of the epoxide with the Reaction occurs at the N-7 position of guanine to
adduct in which only one strand is modified.
increased duplex stability and spontaneous, but
The adduct has
slow, depurination of the
Organophosphotus C’hemisrrv
240
q 0
(1 50) n = 3-5
0::: I
H
‘
OMe
6: Nucleotidus and Nucluic Acids
24 1
modified dG residue is observed.
The limiting 1:l
stoichiometry of the adduct
suggests that the aflatoxin moiety is orientated such that the complementary strand is inaccessible to further attack by the epoxide.
An investigation of
DNA methylation with N-methyl-N_-nitrosoureaand related methylating agents has demonstrated that all the reagents show the same pattern of N-7-methylguanine formation, which is consistent with the formation of a common DNA methylating intermediate being generated outside the helix.235 A 6-8 fold variation between methylation at different guanine residues strongly suggests sequence dependent changes in nucleophilicity that may be a consequence of subtle conformational changes. A
topologically novel
bifunctional DNA
intercalator
(152)
has
been
synthesised which is derived from the bisintercalator spermidine bisacridine
(153). 2 3 h
Studies conducted using uv spectrophotornetry and viscometric analysis
demonstrate that ( 1 5 3 )
is able to intercalate calf-thymus DNA.
Modelling
studies suggest that the best fit between DNA and (153) involves a catanated complex in which the long-axis of the acridine moieties and the base pairs are aligned in the normal manner.
The formation of this unusual complex would
require two base pairs to open.
8. Analytical and Physical Studies The
structure
of
(~)-2'-deoxycytidyl-(3'-methanephosphonate-5')-2'-
deoxyguanosine has been determined by X-ray diffraction.237 Two dinucleotides form a duplex with Watson-Crick hydrogen bonding and a right-handed helical sense.
Based on this structure a mechanism has been presented for the B-Z
transition in alternating d(GC)*d(GC)
sequences. Very high field n.m.r. studies
have shown that phosphate methylated di(deoxyribonuc1eotides)
d(CpC) and d(TpC)
form a parallel mini-duplex exclusively for the (%)-configuration.238
This
configuration corresponds to the outward orientation of the methyl group, The parallel duplex structures involve C-C and/or T-T base pairs; the C-C pairing leads to a parallel duplex only in the case of the (%)-configuration, the T-T base pair can also accommodate the (&)-configuration. structure for the photoadduct of combination of
one- and
d(TpA)
(154)
two-dimensional n.m.r.
has
whereas
A solution
been derived from a
techniques and
molecular
modelling.239 The results confirm that the cyclobutane ring is formed between the thymine C6-CS and adenine C5-C6 bonds and has a trans-syn arrangement. The conformations about the glycosidic bonds are
a and anti
for 2'-deoxythymidine
and 2'-deoxyadenosine respectively. N.m.r.
and
laser Raman spectroscopy have
structure of a RNA-DNA hybrid r(A),*d(T),.240
been used
to determine the
Nucleotide residues in the
riboadenylate strand exhibit a C-3' & sugar pucker and a phosphodiester
0rgamphosphoru.s Chemistry
HN
(1 52) x =~~S-NHCO-(CH,)+ONH (153) X = H, H
as+
243
6: Nucleotides and Nucleic Acids conformation that is characteristic of an A-form helix. strand exhibits a C-2'
endo
The deoxythymidylate
sugar pucker similar to that of B-form DNA.
solution structure is very similar to that proposed for poly(rA)*poly(dT) basis of X-ray fibre diffraction studies.
The
on the
The C-8-H proton and the phospho-
diester 0-5' atom in each adenylate are sufficiently close for a C8-H 0-5' hydrogen bond and may explain the previously reported resistance of adenine C-8-H protons in poly(rA)-poly(dT)
to deuterium isotope exchange.
Positive ion fast atom bombardment mass spectrometry has been used to develop
a
procedure
for
Computational studies have --conformation,
whilst
the
identification
shown
that
cGMP
of is
cyclic expected
nucleotides.'"' to
CAMP prefers the anti-conformation.24Z
prefer An
the
intra-
molecular hydrogen bond between the C-2 amine function of guanine and the axial oxygen atom of the cyclic phosphate is implicated in increasing the relative stability of the =-conformation
of cGMP.
These conformational profiles may
help to explain selectivity of binding and activation of proteins by cyclic nucleotides. Previous studies have reported that the rate of hydrolysis of ATP to ADP and subsequently AMP was 25-fold greater during microwave heating than during conventional heating at comparable temperature. 2 4 3
This increase in rate was
attributed as evidence for a non-thermal microwave effect, possibly by direct absorption of microwave energy.
More detailed studies have since shown that no
special microwave heating effects on the hydrolysis of ATP are observed and the microwave heating results can be accounted for by conventional reaction kinetics when accurate temperature data are used.2""
344 REFERENCES 1
2
3 4
5
6
7
8 9
10
11 12
13
1* 15 16
17
18 19
20
2 1
22
23
24 25 26 27 28
29
30
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J. Haralambidis, K. Angus, S. Pownall, L. Duncan, M. Chai and G.W. Tregear, Nucleic Acids Res., 1990, Is, 493. J.-P.Leonetti, G. Degols, P. Milhaud, C. Gaynor, M. Lemaitre and B. Lebleu, Nucleosides Nucleotides, 1990, g, 825. Y. Ji, W. Bannwarth and B. Luu, Tetrahedron, 1990, 46, 487. D.R. Corey, D. Pei and P.G. Schultz, J.Am.Chem.Soc., 1989, 111, 8523. D. Pei and P.G. Schultz, J.Am.Chem.Soc., 1990, 112, 4579. L.E. Rabow, J. Stubbe and J.W. Kozarich, J.Am.Chem.Soc, 1990, 112, 3196.
L.E. Rabow, G.H. McGall, J. Stubbe and J.W. Kozarich, J.Am.Chem.Soc., 1990,
112,
3203.
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I. Saito, H. Kawabata, T. Fujiwara, H. Sugiyama and T. Matsuura, J.Am.Chem.Soc., 1989, 111, 8302. D.P. Mack and P.B. Dervan, J.Am.Chem.Soc., 1990, 112, 4604. D.W. Celander and T.R. Cech, Biochemistry, 1990, 29, 1355. R.J. Fiel, J.Biomol.Struct.Dyn., 1989, 6, 1259. H.I. Elsner and E.B. Lindblad, DNA, 1989, 8, 697. M.F. Weidner, J.T. Millard and P.B. Hopkins, J.Am.Chem.Soc., 1989,
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J.T. Millard, S . Raucher and P.B. Hopkins, J.Am.Chem.Soc.,
215 216 217 21a
111,
9270. 1990,
112,
2459.
221 222
22’
224
A. Schwartz, M. Sip and M. Leng, J.Am.Chem.Soc., 1990, 112, 3673. C.A. Lepre, L. Chassot, C.E. Costello and S.J. Lippard, Biochemistry, 1990, 29, 811. B.C.F. Chu and L.E. Orgel, DNA Cell Biol., 1990, 2, 71. J.D. Roberts, B.V. Houten, Y. Qu and N.P. Farrell, Nucleic Acids Res., 1989,
225
226
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A.E. Friedman, J.-C. Chambron, J.-P. Sauvage, N.J. Turro and J.K. Barton, J.Am.Chem.Soc., 1990, 112, 4960. T. Wolf, R. Kaseman and H. Ottenwaelder, Carcinonenesis, 1989, lo, 655.
227 220 229
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F.P. Schmidtchen, Tetrahedron Lett., 1989, 30, 4493. M.A. Mitchell, P.D. Johnson, M.G. Williams and P.A. Aristoff, J.Am. Chem.Soc., 1989, 111,6428. C.H. Hurley, M.A. Warpehoski, C.-S. Lee, J.P. McGovren, T.A. Scahill, R.C. Kelly, M.A. Mitchell, N.A. Wicnienski, I. Gebhard, P.D. Johnson and V.S. Bradford, J.Am.Chem.Soc., 1990, 112, 4633. A. Chadha, J.M. Sayer, H.J.C. Yeh, H. Yagi, A.M. Cheh, L.K. Pannell and D.M. Jerina, J.Am.Chem.Soc., 1989, 111, 5456. G. Gopalkrishnan, M.P. Stone and T.M. Harris, J.Am.Chem.Soc., 1989,
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7 YIides and Related Compounds BY B. J. WALKER
1 Introduction Reports of the use of the Wittig and related methods in synthesis have, if anything, increased and many of these include useful innovations. New results and speculation on the mechanism of the Wittig reaction continue to be published by groups with well established reputations in the area. There has been a substantial increase in the number of reports of the use of iminophosphoranes in synthesis, especially those of heterocycles.
2 Methylenephosphoranes Preparation and Structure.- Molecular orbital calculations at the MNDO, PM3 and 3-21G* ab initio SF3-MO levels have been used to compare
2.1
the reactions of formaldehyde with ylides and with phosphaalkenes.1 While the Wittig reaction is predicted to occur via a planar, symmetrical and relatively low energy transition state, that of the phosphaalkene reaction is non-planar, unsymmetrical and higher energy. The pKa values of a number of phosphonium salts have been measured for the first time (with surprising results in some cases) via the kinetics of proton transfer and comparisons with carbon acids of known acidity.* 13C, 15N, and 31P n.m.r. spectroscopic studies of a range of N-aroyl triphenylphosphine imines (1) have been reported.3 In an attempt to generate and study an allylic radical of the type (2) involving participation of a phosphoranyl function, a single crystal of the aldehydo-stabilized phosphonium ylide (3) has been studied by e.s.r. after Xray irradiation.4 A number of X-ray-based structural studies of ylides have been reported including one of methylenetriphenylphosphorane using advanced X-X techniques.5 This study shows significant differences from previous results. The ylide-salt (4) has been prepared and shown by X-ray studies to contain a planar allylic system.6 The chemistry of di- and triphosphabenzenes has been little studied. Both the lk5,3k5-diphosphabenzene ( 5 ) 7 and the lX5,3k5,5k5-triphosphabenzene (6)* have now been prepared by relatively simple routes, albeit in low yield in the latter case, and their structures determined by X-ray crystallography. I n contrast to earlier reports9 the product of the reaction of bromoacetone with diphenyltrimethylsilylphosphine is now shown to be the salt (7).10 This salt is readily converted (Scheme 1) into the corresponding ylide (8) which on treatment with butyllithium gives an ylide-anion shown to 252
7: YIides and Related Compounds
253
Ph,P=CHCHO
(3)
+
H
PPh2Me
MePh2P
H (4)
2BrCH2COCH3
i
+ Ph2P(CH2COCH3)2 Br-
(7)
/ iii
Ph, ,Ph HC=P-CH
Reagents: i, Ph2PSiMe2,- 60 "C, Et20; ii, NaOH, H20; iii, BuLi, THF
Scheme 1
+
CF3,
CHBr + Ph3P /
Me
=-
CF3CH2CH2PPh3Br(10)
COR RCONHCHMeCH=PPh3 (1 1)
have a lithium enolate structure ( 9 ) by X-ray crystallography. I , 1 , I Trifluoroisopropyl bromide reacts with triphenylphosphine to give the 3,3,3trifluoropropyl salt ( 1 0).1 1 This unexpected result provides a convenient route to the corresponding ylide and hence to 4,4,4-trifluorobut-l -enes via the Wittig reaction. The ylides (11) have been generated by the reaction of N-acylaziridines with phosphine and allowed to react with aldehydes to provide a non-stereoselective route to a-substituted primary allylic amines.12 w- A z i d o a l k y l i d e n e t r i p h e n y l p h o s p h o r a n e s ( 1 2 ) have been prepared and shown to be stable at -8OOC for several hours (Scheme 2).13 The synthesis of the ylide ( 13 ) . which contains three phosphorus functions, has been r e p o r t e d l 4 ; however (13) does not react with aldehydes. Convenient syntheses of 1-iodoalkyl ylides, e.g. (14) and ( 1 5 ) , have been reported and, through Wittig reactions, provide routes to ( Z ) - 1 -iodoalkenes. 15 2.2
Reactions
of
Methylenephosphoranes
2.2.1 Aldehydes.- A recent review of the Wittig and related reactions includes information on the development and use of new Wittig reagents and cyclizations using intramolecular Wittig reactions.16 The first positive evidence against betaines being intermediates in the Wittig reaction has been reported.17 N.m.r. studies show that the ratio of the two diastereomeric pseudorotamers (17) and (18), generated from Wittig reaction of the ylide (16) with dihydrocinnamaldehyde at temperatures where pseudorotation is slow, is in the range 2.7-6.5:l.This is quite different from the ratio (1:l.l-4.2) of the same pseudorotamers generated via the betaine (20) by base treatment of the hydroxyphosphonium salt (19). Both of these ratios are different from the value (1.8:l) at equilibrium. Vedejs points out that his results do not distinguish between the other hypothetical intermediates which have been suggested for the Wittig reaction. Vedejs and his group have also carried o u t a definitive study of the importance of reversibility in the Wittig reactions of ester-, vinyl-, and benzyl-stabilized y l i d e s . 1 8 From these studies i t is clear that for o x a p h o s p h e t a n e s reversibility is not important. When oxaphosphetanes are generated by base treatment of 2-hydroxyalkyl phosphonium salts, betaines are the initially formed intermediates and betaine-reversal can be observed. However betaines are probably not involved in the analogous Wittig reactions between ylides and carbonyl compounds and reversal is not then important. It is also concluded that Wittig reactions of conjugated ylides are under kinetic control. McEwen and Ward have investigated the effects of the presence of different metal cations, both from the generating base and added salts, on alkene stereochemistry in Wittig reactions of benzylidenediphenylmethylphosphonium ylides ( 2 l ) . 1 9 What are now well established methods have
7: Ylides and Related Compounds
+
i
Ph3PCH2(CH2),,CHZN3
Ph3P=CH(CH2),,C H2N3
Br-
(1 2)
1
ii
H
Ph3PO t Reagents: i, (Me3Si)2NK,THF, - 80 "C; ii, RCHO, - 80 "C, 1h Scheme 2
0
II
R
0
II
Ph,P=CH-PCH,P(OPh),
I
OPh
+
(13) NaN(SiMe3)2
Ph3PCH2I
Ph,P=CHI
x-
(14)
H
+ H
250
Organophosphorus Chrrnisrr?:
also been used to monitor the reactions and it is concluded that under the conditions used there is little or no reversibility or equilibration of diastereomeric oxaphosphetanes. It is suggested that while the generally accepted ionic mechanism operates in the presence of lithium ions, when sodium or potassium ions are present the reactions take place via an unstable The results of spin-paired diradical intermediate (22) (Scheme 3). measurements of the 14C kinetic isotope effect in the reaction of isopropylidenetriphenylphosphonium ylide (23) with benzaldehyde-7-14C and the Hammett plot obtained from a similar reaction with substituted benzaldehydes have been interpreted in terms of a rate-determining single electron transfer (SET) mechanism.20 An estimate of the electron-donor ability of ylide (23) was obtained by observing the isomerization of cis2,2,6,6-tetramethylhept-4-en-3-onein the presence of (23). These results suggest that the oxidation potential of (23) is of a magnitude sufficient to allow SET to benzaldehyde. Similar experiments with semi-stabilized ylides suggest that SET is less likely with these ylides. These experiments have substantial implications for the way in which oxaphosphetane (and hence alkene) stereochemistry is controlled in Wittig reactions involving reactive ylides. Extremely high cis-selectivity has been observed in Wittig reactions of ylide (24) with saturated the tri(o-substitutedpheny1)alkylphosphonium straight-chain aldehydes.2 1 Methylenation of aldehydes in good yield under neutral conditions has been achieved by the reaction of iodomethyltriphenylphosphonium iodide in the presence of dibutyltelluride.22 A one-pot synthesis of silylated 1,3-dienes (25) in good to excellent yields has been achieved by a silylation, Wittig reaction sequence (Scheme 4).23 2-Vinyl-1 -azadienes (27), and hence divinylketones, have been prepared by a Wittig reaction of the phosphonium salt (26) (Scheme 5).24 The reaction occurs in good to excellent yield even without isolation and purification of the salt (26). In contrast to some earlier reports, reactions of 1-alkoxy-2-alkenylene ylides (28) with aldehydes are reported to give normal Wittig reactions (rather than y-attack) and hence provide a route to the unsaturated ketones (29).25 However exclusive yattack to give (30)was observed when the reactions were carried out in the presence of trimethylsilyltriflate (TMSOTf). Wittig reactions of unstabilized and stabilized ylides have been studied using three different barium hydroxide catalysts, each with different surface-area values and amounts of basic and reducing sites.26 A number of conclusions are drawn concerning the mechanism of ylide generation through solid base-salt interactions. Ylide-anions continue to be used in synthesis. Treatment of the trifluoromethylketo-stabilized ylide (31) with butyllithium leads to formation of the ylide-anion (32) via nucleophilic addition of the alkyllithium to the carbonyl group.27 The ylide-anion (32) reacts readily with aldehydes
7:
Ylidrs and Related Compounds
257
Li+ 0-
6Ph2Me
I
Ph,MeP=CHPh
I
LY \
(211
\
RCH-cHP
+ RCHO
O-PPhZMe
I
,CH-CH
0-PPh2Me
I
I
/ R
Ph
I
RCH *CHPh
(22) Scheme 3
<"""
[ do]
Ph3P=CMe2
P=CH(CH2),CH3
(23)
3
(24)
+
Ph,PCH&H=CH,
-
i, ii
+
Ph3P-CH=CHCH2SiMe3 CI -
Bri, iii
t H
RCH=CH,
SiMe3
H (25)
Reagents: i, BuLi; ii, Me3SiCI; iii, RCHO
Scheme 4
+ PPh3 Br-
(26) i-iii
li
*
R'
d+ PPh3 Br-
R' Reagents: i, BuLi, - 70 "C, THF; ii, R2CH0, - 70 "C to 25 "C; iii, H20 Scheme 5
(27)
Organophosphorus Chrmistn,
(28)
J
R’CHO, TMSOTf
H30+
R
Ph
-
6H Ph2X,TC-H
C5Hi 1CHO HMPA/THF
ph-C5H11
I
Ph (34) x = P (35) X = A S
Ph3As=CHSP h
R& ’ R‘ A
P
SPh
h
(37) Reagents: i, R’CHO, THF; ii, RCHO, THF/HMPA
Scheme 6
7:
Ylidcs and Related Compounds
259
to give moderate yields of alkenes (33). This is a useful synthetic procedure since the ylide (31), and the analogous arsorane, are unreactive towards aldehydes. The first report of the use of ylide-anions of arsenic has appeared.** The presence of HMPA in reactions of ylide-anions ( 3 4 ) derived from semi-stabilized phosphonium ylides leads to increased E -selectivity i n certain cases. The effect of HMPA on reactions of analogous arsenic ylideanions (35) is much more dramatic. Wittig reactions of ( 3 5 ) in THF give complex mixtures, while similar reactions in HMPA/THF give excellent yields of almost exclusively E-alkene. A source of complications in the absence of HMPA may be competing Stevens rearrangement of either the arsenic ylide or ylide-anion.29 The HMPA/THF solvent mixture has also been used to achieve almost exclusive formation of the alkene product (37) in reactions of phenylthiomethylenetriphenylarsorane ( 3 6 ) with aldehydes.30 I n THF this reaction gives exclusively epoxide (Scheme 6 ) . I t has also been reported that reactions of semi-stabilized arsonium ylides with carbonyl compounds can be directed towards either epoxide or alkene product by the choice of the base used to generate the ylide.3 1 The use of potassium hexamethyldisilazide leads to alkenes, while the use of lithium hexarnethyldisilazide leads to epoxides. These results are explained on the basis of the lithium counterion coordinating with the oxyanion i n the betaine/oxaphosphetane intermediate and hence hindering collapse to alkene. T h e ( 5 , 5 - d i e t h o x y - 2 - ( E ) penteny1)triphenylarsonium ylide (38) can be considered as a new 5-formyl butadienyl anion (39) equivalent and as such provides a five carbon homologation of aldehydes (Scheme 7 ) . 3 2
Ketones.- A new synthesis of cyclopentadienes by t h e reactions of allylidenetriphenylphosphonium ylides (40) with a - h a l o g e n o c a r b o n y l
2.2.2
compounds has been reported.33 Wittig reactions of the ylide derived from the phosphonium salt ( 4 1 ) provide the hydrazones ( 4 2 ) . 3 4 This reaction combined with hydrolysis of ( 4 2 ) constitutes a method for the n+2 homologation of ketones and aldehydes (Scheme 8). a-Oxygenated ketones generally react with stabilized ylides to give mainly (E)-alkenes and with non-stabilized ylides to give mainly ( Z ) - a l k e n e s. It is now reported that 1 -acetyl-2-methoxy-(4 3 ) and 1 -acetyl-2-hydroxy(44)-indol-3(2H)-one react with stabilized and semi-stabilized ylides to give predominantly ( 2 ) - a l k e n e s ( 4 5 ) . ( 4 6 ) and ( 4 7 ) . 3 5 Th e reaction of phenanthrene-9,lO-quinone with keto-stabilized phosphonium ylides gives a variety of products. The expected initial intermediate ( 4 8 ) has now been trapped by reaction with ethyl vinyl ether.36 D i f l u o r o m e t h y l e n e p h o s p h o n i u m ylides ( 4 9 ) are reported to be intermediates in the reaction! of phosphines with difluorohalomethanes i n the presence of metals and carbonyl compounds; these reactions give 1 , I -difluoroalkenes.37
0rgutwphosphonr.s Chrmistp
i
*
R
I +
;pHO
RL
OEt ii,iii
C
H
O
-
(39) Reagents: i, RCHO; ii, TFA, CHC13; iii, Et3N, Et20
Scheme 7
+?+ ,i$ CO2Et
R2
R3
R1
___.)
X
(40)
+
Ph3PCH=CHNHNMe2 Br-
i, ii
R1\ C=CH CHzNNMe2 R2/
(42)
1 R\
iii
C=CHCHO
R2/
Reagents: i, BU'OK, THF; ii, R1R2CO;iii, &O+ Scheme 8
dXO N
Ac (43) R = Me (44) R = H
Ac (45) R = Me, X 5 COR (46) R = H, X = COR (47) R = Me, X = Ar
7: Ylides and Related Compounds
26 I
Q Me
OH
I
i-iii
R’$bCH2Ph Br -
c
R3R4CHCH2Ph
(52) Reagents: i, R2Li;ii, R3R4CO;iii, b0
Scheme 9
,Me
MeO,
-
(WSW.
$
,N+, Ph Ph
A
or hv
OMe
+
PhN=C, OMe
[PhN=W(CO),] (55)
(54) 1Ph.P
+
Ph (OC),W-
N:
+ PPh3 (56)
307
Wittig reactions i n the solid state of the inclusion compound of 4methyl- or 3,5-dimethyl-cyclohexanone and an optically active host with carbethoxymethylenetriphenylphosphorane gave optically active alkenes (50) and (51) with optical purities i n the range 5-6096.38 The reactions of carbonyl compounds with benzyltrialkylstibonium ylides have been investigated (Scheme 9).39 The products are either benzyl alcohols ( 5 2 ) or mixtures of alkenes and epoxides depending on the base used to generate the ylide. A mechanism is suggested for the formation of (52). 2.2.3 Ylides Coordinated to Metals.- The crystal structure of the osmium-ylide complex (53) has been reported.40 The thermal decomposition of the tungsten zwitterion complex (54) in the presence of triphenylphosphine results i n the trapping of the nitrene complex ( 5 5 ) as its phosphine-stabilized adduct ( 5 6 ) .4 1 The two enantiomeric iron-complexed phosphonium salts ( 5 7 ) and ( 5 8 ) have been prepared and their ylides reacted with the chiral oxirane aldehyde ( 5 9 ) to give one geometrical isomer i n each case although there is a substantial difference in reactivity between the two ylides.42 This is perhaps not as surprising as the authors suggest since diastereomeric transition states which are likely to be of quite different energy are involved. Similar reactions of ( 5 7 ) and ( 5 8 ) with the chiral aldehyde ( 6 0 ) have been used to synthesize chiral iron-complexed analogues of leukotriene A4 and 5,6-DIHETE.43 The bis(methy1enephosphonium ylide) platinum complex ( 6 1) reacts with 3-butyn-1-01 to give the vinylphosphonium salt ( 6 2 ) and evidence is presented for intermediate formation of the carbene complex ( 6 3 ) . 4 4 Phosphoranylidenephosphine complexes ( 6 4 ) have been synthesized and shown to undergo "phospha-Wittig" reactions with aldehydes to give the phosphaalkene complexes (65) which can be isolated or t r a ~ p e d5. ~ 2.2.4 Miscellaneous Reactions.- Thermolysis of 6 - h y d r o x y p h o s p h o n i um ylides ( 6 7 ) provides a useful route to a,P-unsaturated ketones. The ylides (67) have been prepared by the reaction of an appropriate ylide ( 6 6 ) with propriolactones, although the success of this method depends on the cation of the base used in the generation of (66).46 An alternative and more generally useful method of generating ( 6 7 ) from acylated ylides ( 6 8 ) has now been reported .47 Wittig reactions of diethyl oxalate with a variety of arylmethylenetriphenylphosphonium ylides under mild conditions provide a highly (2) stereoselective synthesis of ethyl 3-aryl-2-ethoxyacrylates ( 6 9 ) . 4 8 Wittig reactions of the a-keto amino acid derivative ( 7 0 ) with stabilized, semi-
stabilized and reactive ylides have been used to prepare the synthetically
7: Ylides and Related Compounds
263
BFq(57) OHC,
0
H
CH2),C02Me HA(
Po+ 0
R’
0
R‘
Ph3P=CHR2 - - + p h 3 p e 0 %ph,po ~
Ph,P=CHR1
R2COX
+
R
2
0 A
R2
-
R2 Ph3P& R’
(68)
Bu”Li
-
R3COR4
p h 3 p G ; 3 R’
R2
R
l
264
0rgatioyhosyhoru.s C'hcmistry
ArCH=PPh3
THF
+ (C02Et)2
c
OEt
R.T.
-
CO~BU'+ Ph,P=CHX
ph2C=NK 0
(711
(70)
0
0
-
PhMe
150 "C, 110 bar
0
(73)
(72)
"2w 0
PhsPIEt3N m
cc14
R'
(75)
(74)
aco2H
0
Ph3P
COPh
cc14
Ph
(77)
i-iii
Ph3P=CR1R2
h
/cF3 R1R2C=C\ H ,
c=c
H'
Reagents: i, ( C F S C O ) ~THF; ~ , ii, Ph3As= CH2; iii, BrCH2CQMe, 20 "C
Scheme 10
\C02Me
7:
Ylides and Related Compounds
265
useful dehydroamino acid derivatives (71) predominantly as the ( Z ) isomer.49 Wittig reactions of stabilized ylides are known to take place more readily with increasing pressure and this fact has now been applied to the synthesis of (73) from (72) which occurs with epimerization at C-5 as s h o w n . 5 0 A mechanism involving intramolecular Wittig reactions of intermediate ylides has been proposed for the cyclization of appropriaiely substituted benzoic acids, e.g (74) and (76) to give (75) and (77), respectively, in one step on treatment with triphenylphosphine and carbon tetrachloride.5 The reactions of ylides have been extensively used in the synthesis of fluorinated compounds, including a one-pot synthesis of 4-trifluoromethyl2,4 -d ien y 1 car box y 1ate s ( Scheme lo) .52 ( E ) - y ,6- U n sat u ra t ed t r i f 1u or o me t h y I ketones (80) have been prepared i n excellent yield by exclusive y trifluoroacetylation of allylidenetriphenylphosphorane to give (78), followed by generation of the ylide-anion (79) and Wittig reaction (Scheme 11).53 Depending on the alkyl substituents R1 and R2 a-fluoroalkylvinyl-(82)-or a fluoroepoxyalky1-(83)-phosphonates are the products of the reaction of diethyl lithium phosphite with fluorinated P-oxoalkylphosphonium salts (8 1) (Scheme 12) .54 (FI uoroc ar boe t h ox y - met h y 1e ne )trip hen y I p h osp h or ane ( 8 4 ) has been used to prepare, through acylation, a-fluoro-P-ketoesters (85) (Scheme 13)55 and, through alkylation, a-fluoroalkanoates (86) (Scheme
*
1 4). 5 6 N-Sulphonyloxaziridines (87) have joined the reagents which have been used to oxidize phosphonium ylides to alkenes or ketones; claimed advantages for (87) over other reagents are convenience and higher yields.57 The o x a p h o s p h o l a n e (88) has been prepared by the reaction of methylenetriphenylphosphorane w i t h butadiene monoepoxide followed by treatment with sodium hydride (Scheme 15).58 Treatment of (88) with base followed by reaction with aldehydes gave the dienes (89) generally with poor stereoselectivi ty. The reactions of ethynylphosphonium salts (90) with phosphonium ylides have been investigated.59 Treatment of ( 9 0 ) with methylene ylide gives the ylide-salt ( 9 1 ) , whereas a similar reaction with benzylidene ylide or isopropylidene ylide gives the 1,1 -diphosphaallyl ylide salts (92). Isopropylidenetriphenylphosphorane reacts with the chiral oxazolidine substituted alkene (93) with excellent n-face selectivity to give only one detectable isomer (94) which is converted into hemicaronic aldehyde with high optical purity.60 A number of phosphaalkenes (96) have been prepared by the reaction of phosphonium ylides with chloro(2,4,6-tritert-buty1phenyl)phosphine ( 9 5 ) . 6 1 The reactions of hs-phosphazenes have been used to provide a variety of synthetic methods. A one-pot, high yield synthesis of 3-alkoxycarbonyl-2aza-l,3-butadienes (98) from N-vinylic h5-phosphazenes (97) has been
Orgunophosphorus Chemistrv
260
1
iii-iv
R 1 w C O C F 3 R2 R Reagents: i, CF3C02Et;ii, RLi; iii, R1R2CO;iv, H30+ Scheme 11
i
Ph3P=CR'R2
+
Ph3P-CR1R2 (!'ORf
hC02-
f:
ii
? + R1AP(OEt)2
RlMP(OEt)2 Rf
R2
(811
h
R2
(83)
(82)
0
II
Reagents: i, (RfC0)20;ii, (EtO)2PLi
Scheme 12 BU3p=CFCo2Et
i
(84)
Bu$CF(COR)C02Et X-
ii
RCOCHFC02Et
Reagents: i, RCOX; ii, X -, HC03-, R.T. Scheme 13
i, ii
Bu~P=CFCO~E~ (84)
Reagents: i, RX, THF, - 70 "C; ii, NaHCO3, H20
Scheme 14
0
/ \
PhSO2NVLPh
"MR2 ~ 2 '
H '
, 7 R'
R'=H
Ph,P=C, R2
R'COR~
7: Ylides and Related Compounds
267
Ph,P. Ph3P Ph3P=CH2
+
0
i, ii
Br-
I1
Ho? iv. ii
iii
Reagents: i, THF, 0 "C; ii, H20; iii, NaH, THF, 50 OC, 5 h; iv, LiBr, THF; v, Bu'Li, THF, - 23 "C; vi, RCHO
Scheme 15
Ph36&HH
+
Ph3P-CEC-R'
X-
(90)
?
PPh3
X-
(91)
1
Ph,P=CR2R3
R'
R 2 y L y Fph3 R3
PPh3 (92)
Ph,P=CMe, D
Ph (93) 2 Ph3P=CHR
(94)
+ ArPHCl (95)
Ar=
ArP=CHR
(96)
+ + Ph3P + Ph3PCH2R CI-
268
(97) Reagents: i, R3COCI; ii, Et3N, HY
Scheme 16
0 H i (R’ = C
O
)
= H, C0,Et)
R21
R3
Reagents: i, Me02CC,CC02Me;
ii, Heat Scheme 17
CH2N=PPh3 (1 011
Reagents: i, RMgBr; ii, NH3, H20
Scheme 18
x;cp02M h2 e
C02Me
7:
Ylides and Related Compounds
269
reported (Scheme 16).6* The reactions of (2)-p-enamino k 5 - p h o s p h a z e n e s (99) with dimethyl acetylenedicarboxylate have been investigated and shown to involve initial attack of electrophilic acetylene at either ylide carbon or nitrogen depending on the N-substituent (Scheme 17).63 Different cyclization reactions of (100) can be achieved o n base-treatment. A new synthesis of primary amines is available from the reaction of phosphine imines (101) with Grignard reagents or lithium alkyls followed by hydrolysis with aqueous ammonia (Scheme 18).64 New heterocycles, e.g. (105), containing P-P bonds have been prepared by the reaction of arsinyl-( 1 0 2 ) and phosphinyl-[( 103) and (104)] substituted cyanomethylene ylides.65
3 Reactions of Phosphonate Anions The structure of lithium coordinated P-carbonyl-phosphonate and -phosphine oxide carbanions has been reviewed.66 Lithiated anions ( 1 0 6 ) of secondary a-amidophosphonates and ( 1 07) of tertiary a-amidophosphonates have been prepared both by reaction of the appropriate a -phosphonyl carbanion with an isocyanate or carbamate (Scheme 19) and by reaction of an amide enolate with diethyl chlorophosphate (Scheme 2O).67 The anions (106) and (107) have potential use in synthesis since they undergo olefination reactions and can be hydrolysed to give a-amidophosphonates (108). Synthetic routes to, and the conformation o f , 2-alkyl-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one carbanions (109) have been investigated (Schemes 21 and 22).68 The method shown in Scheme 21 always produced a mixture of (109), (110) and (111). It is possible to prepare (109) by direct deprotonation at low temperature (Scheme 22); at temperatures above -35OC self-condensation to give (111) occurs although (109) can be stabilized by the presence of an equivalent of lithium salt. The structures of 2-benzyl-2-0x0- 1,3,2-dioxaphosphorinane ( 1 12), 2-benzyl-2-0x0- 1,3,2-diazaphosphorinane (113) and their carbanions have been studied in solution by IH, 13C and 31P n.m.r. and, in the case of the lithium carbanion of (113), i n the solid phase by X-ray crystallography.69 As might be expected there is a dramatic upfield shift of all aromatic and benzylic proton absorptions and those of the 0 - and p-carbons compared to the neutral molecules. The p-zinc and copper metallated phosphonates ( 114) have been prepared from 0-bromoalkylphosphonates and reacted with a variety of electrophiles to provide routes to p - s u b s t i t u t e d alkylphosphonates.7o Olefinations involving phosphonate anions continue to be used and developed. The effect of the cation, temperature and THF or DME as solvent on the stereoselectivity of aliphatic aldehyde olefination with trimethyl phosphonoacetate carbanion has been investigated.71 Low ( E I Z ) ratios are favoured by potassium cations, low temperature and THF as solvent. The
270
Orgunophosphorns Cherni s q
NPri, CN
/
Ph3 P=C,
CN
Ph3P =C,
As( NPri2)2 (102)
CN
/
P(NPri2)2
Ph3PA
(103)
CN
P+PPh3 NPr2 (104)
Reagents: i, 2xLDA; ii, R2N=C=O; iii, R2R3NC02Et;iv, H30+
Scheme 19
0
I1
Reagents; i, 3xLDA; ii, (Et0)2PCI
Scheme 20
BPh4P-P-CI Pr',N/
A
(105)
7: Hides and Related Compounds
27 1
R'
R'
Reagents: i, 2xR'CH&, THF, - 70 OC to 0 OC
Scheme 21
(109)
Reagents: i, BuLi, THF, - 70 O
C
Scheme 22
0 R1CH2P(OEt)2 II
i-iii
-
R3
0
R 2 S w R 4 R' (115)
Reagents: i, BuLi, C6HI2; ii, 0.5xR2SCOCI; iii, R3R4C0,- 70 "C to 20 "C
Scheme 23
phosphonate-based olefination of furfural i n dioxan has been studied using solid hydrated barium hydroxide, potassium carbonate and cesium carbonate as the basic catalysts.72 The yield and rate of reaction depend on the quantity of water present. a,P-Unsaturated thiocarboxylic acid S-esters (11 5 ) have been prepared from simple alkylphosphonates in a one-pot reaction (Scheme 23)73 and a new, (E)-selective synthesis of a,P-unsaturated acylsilanes is available from aldehydes by olefination reactions of (a-phosphonoacy1)silanes ( 1 16).74 Two carbon homologation of carbonyl compounds to a,P-unsaturated aldehydes has been achieved by the Wittig-Horner reaction with the phosphonoacetamide ( 1 1 7 ) followed by reduction (Scheme 24).75 T h e synthesis of (1,3-butadienyI)phosphines ( 1 2 1) by olefination with the phosphonate carbanions ( 1 1 8 ) is hindered by the reluctance of the adducts (119) to undergo elimination to alkene. This problem has been solved by the use of the cyclic phosphonate carbanions ( 1 2 O ) 3 Esters react with the carbanion (122) of phosphonofluoroacetate in the presence of diisobutyl aluminium hydride (DIBAL) to give good yields of a fluoro-a,p-unsaturated esters in a one-pot reaction (Scheme 25).77 Alkylation of the carbanion of diethyl difluoromethylphosphonate (123) followed by the standard acetoamidomalonate procedure has been used to synthesize 2amino-7,7-difluoro-7-phosphonoheptanoic acid ( 1 2 4 ) ; the alkylation step gives less than 50% yield.78 Olefination with the phosphonate (125) has been used to synthesize a , P-dehydro homoserine ethers ( 1 2 6 ) which undergo base-induced regio- and stereo-selective isomerisation to provide the P,ydehydro analogues (127) (Scheme 26).79 The use of the 2-phosphono-1,3-dithioles ( 1 2 8 ) in the synthesis of analogues of tetrathiofulvene has been extended to a variety of p quinodimethane analogues (e.g. 129).80 A somewhat different method using the 1,3-dithiole ( 1 3 0 ) and 1-selena-3-thiole ( 1 3 1 ) phosphonates has been used to provide a range of new, unsymmetrical tetrathiafulvalene and selenatrithiafulvalene derivatives, respectively (Scheme 27).81 Reaction of organolithium or Grignard reagents with phosphonodithioformates (132) and the corresponding sulphines ( 1 3 3 ) provides anions ( 1 3 4 ) and ( 1 3 3 , respectively.82 Protonation, alkylation or olefination of ( 1 3 4 ) and ( 1 3 5 ) provide routes to a variety of intermediates. The stabilized ylides (137) have been prepared by the reaction of phosphonodithioformates ( 1 3 6 ) with trialkyl phosphite.83 The ylides do not undergo Wittig reactions but do undergo alkylation at sulphur to give ( 1 3 8 ) which, in appropriate cases, undergo electrocyclic rearrangement to give the C-alkylated products (139). A new route to P-keto phosphonates (141) and ( 1 4 2 ) from diethyl 1(trimethylsilyl)vinylphosphonate ( 1 4 0 ) has been reported.84 Reaction of (140) with lithium alkyls followed by addition of acid chloride or alkyl isocyanates provides (141) or ( 1 4 2 ) , respectively (Scheme 28). a,P-
7:
Y1ide.s und Related Compounds
273
0 SiButMe2
R'CHO, LicI,
(Me0)2PCH2CSiButMe2
DBU, CH3CN
Reagents: i, BuLi, R'R2CO; ii, LiAIH4
Scheme 24
It
RCOR'
i, ii
0-11+
/
- RCH=CFC02Et 0
Reagents: i, DIBAL, THF, - 78 "C; ii, (Et0)/kFC02EtLi+ (1 22) Scheme 25
0
II
(Et0)2PCHF2 (123)
LDA, THF; Br(CH2)4Br
-
0
It
Br(CH2)4CF2P(0et)2
1
274
ii, iii
RO+02Me NHX (127) Reagents: i, BU'OK, CH2CI2,- 70 "C then 25 "C; ii, LDA, THF, - 70 "C;iii, NH4CI Scheme 26 R
HR
sXs H P(OMe)2
8
(128) R = H; RR = benzo
" l S f R2
X
F(OMe)2 H BF4-
(130) X = S (131) X = S e
Reagents: i, Bu"Li, THF, - 78 "C; ii, Si02 Scheme 27
R4
R3
7:
Ylidcis urid Related Cornpourids
? 5
(R10)2P-CSR2
27 5
R3Li
E YR3
(R10)2P-q-Li
5r2 (134) X = S (135) X = S O
(132) X = S (133) X = SO
1.
I,
iv, iii
(142) Reagents: i, RLi, THF; ii, R'COCI; iii, HCI, H20; iv, RNCO
Scheme 28
276
Organophosphorus Chrmistty
Unsaturated tert-butyl esters undergo stereoselective anti-Michael addition of a -1ithiated phosphonates to give a range of substituted 4phosphorylbutanoates (143). 8 5 The tetra(isopropy1) ester of 1.1cyclopropanediylbis(phosphonate) (145) has been synthesized by intramolecular alkylation of (144)via its thallium(1) salt.86 Treatment of nitrobenzophenones with phosphonate anions containing leaving groups (Cl, SR) at the carbanionic centre leads to a variety of different reactions including oIefinatioa.87
4 Selected Applications in Synthesis 4.1 Carotenoids, Retenoids and Pheromones.- Classical Wittig methods involving the ylide (146) an'd the dialdehyde (147) have been used to synthesize (148). a diastereoisomer of decaprenoxanthin.88 The retinonitrile (150) has been prepared as a mixture of four geometric isomers by phosphonate-based olefination of the 7-cis, 9-cis-C 15-aldehyde (149).89 It was possible to separate the four isomers of (150) and reduce each of them to the corresponding retinal. Lignarenone A (152), a possible alarm pheromone of the sea mollusc Navanax inermis, has been synthesized by highly stereoselective phosphonate-based (E)-olefination of the aldehyde (151).go Lignarenone B, the 2E, 4E-isomer of (152). can be obtained from (152) by isomerisation induced by sunlight. Eight geometric isomers of 3,6,8-dodecatrien-l-01 (153), the trail-following pheromone of subterranean termites, have been synthesized by Wittig reactions of ylides (154) and (155) with enones (156) and (157), respectively, followed by separation of t h e resulting mixtures of isomers by h.p.l.c.91
4.2 Leukotrienes, Prostaglandins and Related Compounds.-
Ex a m p l e s of the use of Wittig methods in the synthesis of leukotrienes and their analogues include those of a 7.6-dihydrofuran analogue of leukotriene A4,92 the nor-leukotriene D4 analogue (158)93 and the use of the ylide ( 1 5 9 ) i n the preparation of cyclohexane analogues (e.g. 160).94 Both Wittig and phosphonate-based methods, involving the salts (161) and (162) and the phosphonate (163), respectively, have been used in the synthesis of various metabolites of leukotriene E4 including tritium-labelled derivatives.9 5 Phosphonate-based alkene synthesis, for example from (164), has been used to synthesize various geometrical isomers, for example (165) and (166), of lipoxin A4 and B4 methyl esters.96 A synthetic approach to a bioactive dihydroxyeicosanoid from the deoxypyranose (167) using an ylide-induced elimination of benzoate to give the unsaturated aldehyde ( 1 68) has been reported, although it is not clear how the elimination step is carried out.97 Reaction of (168), without isolation, with 7-carbomethoxyhepta-3(Z)-en-1 -
7: Ylides and Related Compounds
0
0 Li II
I
(R10)2P-CHR2
277
+
R 3 v C 0 2 R 4
II
* (R'0)2PCHR2CHR3CHCO2R4
77s HO(CH2),[CH=CH]3(CH2)20H (153)
CH=PPh3
6
(CH2)&02H Cys-Gly
I
C5Hll
(1 59)
+
C5H1 1
7:
279
Ylides arid Related Cornpoumis
(168)
1
(CH2)3C02Me
Ph3P-
OR2
(CH2)3C02Me OR' (169) R' = PhCO, R2 = H (170) R' = H, R2 = PhCO
0
0 (MeO),I&
;;;I
HO(CH2),,CH=CHCCH2CSBut (1 77)
0
0 SBu'
ylidenetriphenylphosphorane gave a mixture of esters ( 1 6 9 ) and ( 1 7 0 ) and showed that the original stereochemical assignment was i n error. Phosphonate methods continue to be used i n the synthesis of prostaglandins and their analogues, for example ( 1 7 1 ) 9 * and the biologically potent PGD2-analogue (172).99 In the latter case the double bond i n the a side chain could be introduced with high ( 2 ) - or (E)-selectivity and i n excellent yield by appropriate choice of alkyl groups in the phosphonate ester used. The complex phosphonate ( 1 7 3 ) has been used in a new synthesis of levuglandin E2 (174).100 A stable derivative, suitable for characterization of ( 1 7 4 ) . was prepared by olefination with fluorenylidenetriphenylphosphorane. Macrolides and Related Compounds.- Phosphonates have been used prepare a variety of precursors for the synthesis of macrocycles. Olefination with (175) has been used to introduce a P-keto acid function in two highly convergent syntheses of the macrocyclic lactam, tetramic acid antibiotic (+)-ikarugamycinlol and in developing a methodology for synthesis of the medium-ring lactone (-)-kromycin.’o2 Olefination reactions of the anion 4-diethylphosphono-3-oxobutanethioate ( 1 7 6 ) with of S - t e r t - b u t y l aldehydes have been used to prepare products (e.g. 1 7 7 ) which can be cyclized by treatment with copper ( I ) trifluoroacetate to give p ketomacrolides or P-ketomacrodiolides ranging in ring size from 13 to 32.103 The complex phosphonate ( 1 7 9 ) , synthesized from the lactone ( 1 7 8 ) , has been used in the synthesis of the macrolide mycinolide-V.104 Complex ylides and phosphonates continue to be used to construct macrocyclic molecules. For example, a Wittig reaction of the ylide (180) has been used to synthesize the C1g-C35 segment,lOs and coupling of the ylide ( 1 8 1 ) with the acid chloride ( 1 8 2 ) has been used to synthesise the C I - C I 5 segment,l06 of the immunosuppressant FK-506. The Wittig reaction of a range of ylides with a complex aldehyde obtained from the selective cleavage of the 22-23 bond of avermectin B2a has been used to prepare avermectins with novel C-24 and C-25 substituents.107 Cyclization via intramolecular olefination of complex phosphonates remains the most important method of synthesis for complex natural macrocycles. Examples include syntheses of 20-membered macrolide antibiotic, aglycones of venturicidins A and B,lo8 oleandomycin (a 14membered macrolide antibiotic),lo9 the 19-membered macrocyclic antibiotic, anti-tumour agent (+)-hitachimycin,l10 and the macrocyclic lactones (183).1 1 1 Cyclization of the phosphonate (184) under Masamune-Roush conditions has been used to synthesize the 28-membered macrolactam myxovirescin B.l 1 2 Intramolecular Wittig reactions of a - a l d e h y d o p h o s p h o n i u m ylides (185) under conditions of high dilution provide monomeric ( 1 8 6 ) , dimeric
4.3 to
28 1
7: Ylides and Reluted Compounds
R'O
CI
(183) R = H, Me
OR
( 1 8 7 ) , trimeric (188) and polymeric species.l The proportion of each product depends on the chain length of (185). This method is complemented by a new synthesis of macrodiolides ( 1 8 9 ) from diols involving the use of a Wittig reaction for chain construction and an intramolecular Wittig reaction for cyclization (Scheme 29).1 l 4 A number of the cytotoxic, macrocyclic riccardins (e.g. 1 9 0 ) have been prepared using the Wittig reaction to link rings A and B.115 4.4 Nitrogen Heterocycles.- Reactions of iminophosphoranes have been used to prepare a wide range of heterocycles. Examples of compounds prepared by intramolecular aza-Wittig reactions include 3,4dihydroquinazolines ( 1 9 1 ) and quinazolines ( 1 9 2 ) , 1 1 6 quinazoline derivatives (e.g. 193),117 pyrrolo[ 1,2-a]quinoxalines ( 1 9 4 ) , indolo[3,2c]quinolines ( 1 9 5 ) , and indolo[ 1,2-c]quinazolines (196),118 i m i d a z o l i n o n e s (197),119 quinazolinones (198).119$ 120 pyrido[2,3-d]pyrimidine derivatives (199),121 and 4,5-dihydropyrazolo[3,4-d]pyrimidine derivatives (200).1*2 Tr i b u t y I ( c y c 1o h e p ta - 1 ,3,5 - tri e n y 1 i m i n o)ph o s p h o r a n e ( 2 0 1) , prepared by thermal isomerization of the 2,4,6-derivative, reacts with a , P - u n s a t u r a t e d ketones to give 9H-cyclohepta[blpyridine derivatives (202) . I 2 3 A synthesis of (2,4)pyridinophanes ( 2 0 4 ) by the reaction of N-vinyliminophosphoranes (203) with a,P-unsaturated ketones has been reported.124 Various hetero-, for example ( 2 0 5 ) 2 5 and (206),126 and carbo( 2 0 7 ) 1 2 5 cycles have been prepared by aza-Wittig reactions of iminophosphoranes with isocyanates and diphenylketene, respectively, followed by cyclization. The reaction of triphenylphosphine with o azidobenzaldimines ( 2 0 8 ) followed by hydrolysis has been used to prepare 2,3-diamino-2H-indazole derivatives (209) (Scheme 30).127
*
4.5 Miscellaneous Reactions.- The phosphonate isostere ( 2 1 2 ) of (*)myo-inositol-1 -phosphate has been prepared by olefination of the ketone ( 2 1 0 ) with the methylene bisphosphonate anion ( 2 1 1) followed by reduction and deprotection.128 Further studies of the use of the phosphonatebased olefination of pyranoses in the synthesis of C-glycosides (e.g. 2 1 3 ) have been reported.129 In order to study possible side reactions which may reduce the yield in the Woodward method of annulation of azetidin-2-ones (Scheme 3 1 ) similar reactions of ylides ( 2 1 4 ) , which do not contain groups capable of conversion to carbonyl by DMSO-acetic anhydride treatment, have been investigated.130 A range of products, e.g. ( 2 1 5 ) and ( 2 1 6 ) , were obtained. A mild, fourcarbon homologation of the 4-formyl-substituted azetidinone ( 2 17) involving reaction with the phosphonium ylide ( 2 1 8 ) has been used to synthesize ( 2 1 9 ) , a useful intermediate in the synthesis of carbacephem antibiotics.’ 3 1
(189) m = n = l ; m = 1 , n = 2 ; m =n =2 Reagents: i, CH2CI2;ii, PCC, AcONa; iii, Ph3P, CH3CN; iv, Et3N, CH3CN, high dilution
Scheme 29
284
Organophosphorus Chrmisrty
H (193) X = 0, S, NR
&
(194)
Ph
H
Nk X
0
Me
NH
Ph H (200) x = 0,s
I
N=PBu~
I
0
+ A3
A3
7 Hides and Related Compounds
285
(203)
(204)
n =6-9 Ph
Ph
fJ--rJNo2
CH2Ph
A , / N K0N M e s
NHR
ArNH&
Ph
\
(205) NHR~
NHR~
(208)
Reagents: i, Ph3P, CH2C12; ii, HCI, H20, Dioxan, R.T., 5 h Scheme 30
+
[
(MBO)~!]?H
TBSO"'
HOQof
(OH),
HO'.'
OBn (213) Bn = PhCH2
OH
i
Reagents: i, DMSO, (CH3C0)20
Scheme 31
0~ y ~ 0 2 P N B
0g Y : 0 2 P N B
Ph3P
X
(214) R = C02Me, CN
(215) X = CH2 (216) X = H, OAC
0 x 0
0
" 0"
P
O
0
R
2
R2
i,ii
(221) n = 0, 1 Reagents: i, R3R4C0,BU'OK; ii, H30'
Scheme 32
R
4
W
c
H
0
7:
Ylida und Reluted C'otnpountls
287
Attempted similar reactions with the unprotected 0-ketoester phosphonateand ylide-analogues of (.218) were unsuccessful. Phosphorus-based olefination has been used to prepare a variety of natural-occurring and purely synthetic dienes and polyenes, for example the polyene system required for the synthesis of the tricyclic fungal metabolite cytochalasin D has been prepared from ( 2 2 0 ) 1 3 2 and a variety of polyethylenic aldehydes ( 2 2 2 ) have been obtained in one-pot reactions of the anions of phosphonates ( 2 2 1 ) with carbonyl compounds (Scheme 32).133 A (2)-stereoselective Wittig reaction between 3 - ( Z ) - h e p t a - 3 , 6 - d i e n -1 y 1 id e n e t r i p h e n y 1 p h o s p h o r a n e and 8 - ( 2 , 3 , 6 - tri ac e tox y -5 (223) methoxypheny1)octanol ( 2 2 4 ) is the key step in the first reported synthesis of ( 2 2 5 ) , a germination stimulant for Strigo asiatica ( w i t c h w e e d ) . l 3 4 Olefination reactions with various allylphosphonates have been used to prepare a range of 1,3-butadiene-2-carboxylates ( 2 2 6 ) , 2-alkenyi-2(5H)furanones ( 2 2 7 ) , and 3-alkenylcoumarins ( 2 2 8 ) . I 3 5 The unique C2o amino acid (Adda) ( 2 2 9 ) , a structural fragment of the hepatotoxins nodularin and microcystin-LR, has been synthesized by a convergent route involving the ylide (230).136 The Staudinger equivalent of the Wittig reaction has been used to introduce the appropriate amino side chain in a synthesis of a number of mycosporins (e.g. 2 3 1 ) (Scheme 33).137 Sphingosines (e.g. 232) have been prepared by a strategy involving Wittig reactions of long chainalkylphosphonium salts (e.g. 233).138 The Wittig reaction and its variants have been used extensively in a total synthesis of palytoxin carboxylic acid and amide; the naturally occurring toxin is one of t h e most poisonous compounds known.139 A double Wittig reaction of the ferrocenyl bisylide (234) has been used to synthesize the potassium-selective ionophore ( 2 3 5 ) .I40 The use of phosphonate-based olefination in the preparation of terpenes containing gem-dimethylcyclopropyl rings has been investigated .I4' The keto aldehyde (236) is both easily oxidised and base sensitive, leading to aldol products, and thus unsuitable for reaction with phosphonate carbanions. The ketal of ( 2 3 6 ) is not sensitive to base but olefination gives poor stereoselectivity. However, the aldehyde ( 2 3 6 ) can be converted into the alkene (238) quantitatively with good (E)-selectivity by reaction with the phosphonate ( 2 3 7 ) using LiN(TMS)2 in DME as the base system at low temperature. The acetal function in ( 2 3 7 ) is suggested to moderate the basicity of the phosphonate carbanion and hence preclude aldol condensation of (236) while allowing olefination. (Z)-Selectivity was obtained through the use of the fluoroalkyl phosphonate ( 2 3 9 ) with a DBU/LiCI base system (Scheme 34). The reaction of phosphonate carbanions (e.g. 2 4 0 ) with ethylene oxide has been used as the cyclopropanation step in the synthesis of
288
Organophosphorus Chcmistty
OR
\
(224) R = A c OR
OR (225) R = H
#0. O
I chr
PhSPe N
HOOCCH2N
OMe
OMe
(2311 Reagents: i, excess PhCH202CCH0, THF, 25 "C; ii, NaBHaCN, MeOH; iii, TFA/CHCIdH20,0 OC, 20 min; iv, H2, 10% Pd/C Scheme 33 NH2 OH HO+
C14H28
OH (232)
+
n-C13H2,PPh3 Br(233)
7: Ylidrs and Related Compounds
289
‘0
+ 2 \
(234)
Fe
(235)
Mw
OHC+ i
H”
Me Me
(236)
~
Me Me
e o
\
(€1
%c
Me Me
Me02C
(2) (238)
‘42,
LiN(TMS)2, DME, - 50 “C;
Reagents: i, (MQO)~P
C02Me
(237) ii, ( C F 3 C H 2 0 ) 2 ! d 7 ,
DBU, LiCI, CH3CN
C02Me
(239)
Scheme 34
(238)
0 II
E
A
(
*
PhH
Et0
CO2Et (240)
H2Nd:
Me3N 0
Ar =
Ar A N \H 1 / ( :
0 (242) X = P(O)(OMe)2,Y = H (243) X, Y = CHAr
(244) Reagents: i,
P(OR1)2,MeOH;
-
ii, CICOC02R2,2xPri2NEt, CH2CI2, 78 “C to R.T.
Scheme 35
-Ro*p
+
RO
CH,P(OEt)2 (246)
1
ii, iii
0
Me (248) Reagents: i, Base; ii, NaH, THF, CH3CHO; iii, Et3&I, KF, CH3CN
Scheme 36
(247)
7:
Ylides and Related Compounds
%
O I C
29 1
i
0
H
(251)
(249)
0
II
Reagents: i, (Me0)2PCHN2,BU'OK, THF, - 78 "C
(250) Scheme 37
a number of y-butyrobetaine hydroxylase inhibitors (e.g. 241).142 Olefination with the complex phosphonate ( 2 4 2 ) has been used to synthesize the oxygen-sensitive tunicate blood pigment (&)-tunichrome A n - 1 (243). 1 4 3 Intramolecular phosphonate-based olefination has been used to construct five-membered rings in a number of syntheses; for example in a novel approach to [3.3.0] fused pyrazolidinones (244) (Scheme 35), a totally synthetic class of antibacterial agents.144 A new, convergent synthesis of the fungal metabolite and useful synthetic intermediate (+)-terrein ( 2 4 8 ) has been reported.145 The method is based on two phosphonate olefination steps. The diphosphonate (245), obtained from L-tartaric acid, gives, on treatment with base, a mixture of the required phosphonate ( 2 4 6 ) and the diphosphonate ( 2 4 7 ) . However, under appropriate conditions ( 2 4 6 ) is the major product and can be converted into (+)-terrein by reaction with acetaldehyde (Scheme 36). Olefination of the ketone ( 2 4 9 ) with dimethyl diazomethylphosphonate ( 2 5 0 ) provides, via carbene insertion, the cyclopentene ( 2 5 1 ) and hence a new route to (-)-frontalin ( 2 5 2 ) (Scheme 37).146
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8 Phosphazenes BY C.W. ALLEN Iatroduct i o a This chapter covers the literature of phosph(v)azenes with occasion reference to lower valent species where appropriate. The challenges of basic research and numerous practical applications insure a steady flow of papers and patents in this area. While there have not been any general reviews, some highly focused reviews are available and will be cited in the appropriate sections below. 2 . ACYCliC PhosDhazenea Interest continues in the area of acyclic phosphazenes which are variously referred to as phosphazo derivatives, The phosphine imines or more correctly phosphoranimines. only review published during this period discusses acyclic intermediates in the synthesis of cyclic metallaphosphazenes from bifunctional acyclic phosphazenes.' Ab initio MO calculations on the electronic structure of O P ( F , ) N P ( F , ) N P F , show many similarities to the cyclic species, ( N P F ) 3 , 4 , but differences such as phosphorus-nitrogen bond length alteration occur. The opening up of the P N P bond angles results in reduced overlap along the chain and leaves in and out of plane 7r interactions with P N P "islands".' The hypothetical 1,2 hydride shift between H,PN and HNPH was investigated by ab initio MO methods. The migrating H follows out of plane path and behaves as a hydride., Ab initio calculations at the SCF and MCSCF level on H 2 N P N H i show a 4 R planar (C,,) allylic system. This is in contrast to H2PNPH,+ where the C,, structure undergoes a Jahn-Teller distortion by rotation about the P N bond via mixing of highest energy R , orbital with a low lying u* orbital.4 Ab initio MO calculations show that on going from HN=PH to HN=PNH, the P=N bond shortened and was independent of NH, group rotation indicating a lack of conjugation.' Similarly x-ray crystallography of (Me$) &H2N=PP (CMe,) shows The dimerization reactions of no N = P , P-P conjugation.' R , P ( X ) = N Y species have been discussed with special emphasis on the role of the electrophilicity of the P X u bond.6 MO calculations on matrix isolated P N allow for an estimate of 1.
,
8: Phosphuzenrs
299
the dissociation energy.7 A comparison of structural data for PhNP (NEt) AlC1,' with other four coordinate phosphorus compounds suggests a zwitterionic structure IR intensity and ESCA data have been used to determine the charge distribution
.'
in Ph,PNPh; (N=-0.5, P=+0.9)'. The 13C, 15N and 31P NMR spectra for the series Ph,P=NC(O)C,H,-p-R have been correlated with Hammett substituent constants. The one bond J,, coupling is controlled by pn-dn interactions while J,, is controlled by pxu * effects. The Ph3PN unit was shown to be a stronger electron donor the NH, group and the Ph,PNSO, and Ph,PNC(O) moieties are moderately electron withdrawing. lo The ,'P NMR parameters for the 1inear ol igomers C13P=N( PC12=N)"- P (0)C12) (n=0-2) have been obtained. The effects of the OP(=NPh)Ph, substituent on the adamatane 'H NMR parameters has been determined. l 2 The Staudinger reaction continues to be the most popular method of synthesis of acyclic phosphazenes. In addition to the reactions reported below, many of the phosphazenes prepared for further synthetic elaboration (see below) are prepared using the Staudinger reaction. The intermediate phosphazides, R,PN,R', can occasionally be isolated. The x-ray data on (morpholino)pN-N=N-R (R=2,4,6-(02N)3C6H2,2 , 6 , 4 Br,C,H,) l2 and Ph3P=N-N=N-C,H,C02H'3 show the zwitterion character of the PN3 unit. Alkylation of the negatively charged nitrogen The Staudinger reaction atom can be achieved using Et,OBF,." was used to prepare the following series of acyclic phosphazenes : RC,H,C (0) N=PPh, (R=NMe,, O-n-C,%, Et ) lo ; Me,SiN=P(Ph) (R)CH2CHMe, (R=alkyl, cycloalkyl) 15; (RO),PNP(O) (OR') (Rzsubstituted phenyl, R'=alkyl) l6 R,R'P=NSiMe3 (R=Pr, Bu; R'=alkyl,cycloalkyl) .17 The secondary phosphines, PhPH(R) (R=alkyl, cycloalkyl) react with two moles of Me3SiN3 to give Me,SiN=P (R)(Ph)NHSiMe,. The Staudinger reaction of the cyclic phosphite 1 (X=lone pair, Y=OEt) gives an intermediate phosphazene (X=NHCH,Ph) which rearranges to the phosphoramidate (X-0, Y=PhCH,NEt) l9 The diphosphazenes, CH2(PR2=NC,H,~,-R*) (R8=N02,Me), are available via reaction of the diphosphine with R'C6H,N3. The diphosphazenes undergo aza-
,
Wittig reactions with CO,, protonation of the imide nitrogen The atom and deprotonation of the methylene fragment.,' germanium substituted phosphoranimine Me,GeNPPh,CH,PPh, has a complex series of conformations as shown by NMR spectroscopy.2' A novel reaction shows the formation of [MO(NPMe,)C12(PMe,),]C1 The phosphazo molybdenum species from MO(N)Cl, and PMe,.
300
Organophosphorus Chemistry
2+
(4)
(7)
8: Phosphazenes
30 1
,
rearranges to ( Me,P) ,C13MoNnoC13( PM~,) J Me,PNPMe,. " In a somewhat related process the unstable nitrene complex (CO),W-NPh can be trapped by reaction with PPhs to give (CO)5W(PhN=PPhs) which can be directly obtained from the reaction of W(CO)5(THP) with PhsP=NPh.B The reaction of PhNHC ( N3)-C (CN)C o p e with Ph,P gives Ph,PN,C (NHPh)=C (CN)C o p e A four component which upon heating gives the phosphazene." Ph,PCl and Me,SiN, reaction system comprising PhCN,LiN (SiMe,) leads to (Me3S1)$JC(Ph)=NPPh,-NSiMe, which has been used for metallocycle synthesis (section 5) 25 A variety of other methodologies have been employed to prepare acyclic phosphazenes. The recently developed redox condensation method which employs diethylazodicarboxylate (DAD) was used to form N-CN phosphazenes, Ph,P (=NCN)( CH,) ,P (-NCN)Ph, (n=2,3) and Ph,Ph,P (-NCN) (CH,) ,PPh (-NCN) ( CH,) ,P (=NCN)Ph, from the appropriate phosphine and cyanamide. The corresponding -Ph,P==NSO,NH, derivatives are obtained if sulfamide is used in place of cyanamide. The corresponding reaction with Ph,PCH,PPh, gives a small yield of a cyclic compound (see section 4) and Ph, as the major product. Ph,P (-NS0pH2)CH,P (0) Arene fused 15Crown-5 derivatives with an -SO$J==PR, functionality on the arene can be produced from the - S O P , derivatives. Direct reaction with PC1, gives R=Cl while for R=Ph,OPh a multistep sequence involving addition of Cl,, NaOH and PRs sequentially is required.,' The reaction of PC1, with NH,C(O)NHAc gives [Cl,P=NCCl==N=CHPCl,]+ which upon treatment with formic acid NHCCl=NCCl=CHP(0)Cl,. 28 The condensation of yields C1,P (0) (RO),PNHPh with 1-nitro-1-alkanes gives (RO),P(=NPh)CHRwCH2N0, (R,R'-C,-C, alkyl) Oxidative hination of RP=C(SiMe,) , (R=Ph, amino) with CINRwSiMes (Rv=Me3C,SiMes) gives RP(=NR@)=C(SiMe3)2.M The reaction of PRs with R'R2C=NC1 gives R'R2CC1N=PC1, when R=C1 and [ R'R2C=NPPh,]+C1- with Ph3P.31 The Treatment reaction of Ph,C=NPPh, with diazocyanides gives 2 of Me3CC(C1)=NCH,Ph with (EtO),PNHPh gives Me,CC(-NCH,Ph)P(=NPh) (OEt), which upon heating rearranges to The acid catalyzed cyclization Me,CCH(N=CHPh) P(=NPh)(OEt)2.33 of Me2C=C==CRP(0)HNHC6H,Br(R=H, Me) with acetone gives 3.% The trimethylsilylation of [ ( PhO)2P(0) NCN) ] - with Me,SiCl gives,a mixture of cyanamidophosphates and ( PhO),P (=NCN)OSiMe,. " Another pseudohalide reaction involves the reaction of (Et2N)3P with RSCN (R=alkyl) to give (Et2N),P(S) and a mixture of
,,
.
."
(Et,N),P=NC(CN),C(CN),N=P(NEt,), and (Et2N),P=NC(CN)=(C(CN)2R.35 Bromination of (RR'N),PNEtPh gives [ (RR'N) ,P(Br) NEtPh]+Br- which on heating gives (RR'N),PBr=NPh3' which undergo unusual dimerization reactions. Addition of aziridine gives (RR'N),P(NC,H,)NHPh* which can be reduced with sodium to give (RR'N),P(=NPh)NC,H,. Upon warming the cation gives (RR N) ,hN (H)CH2CH,kPh* which in turn can be reduced with sodium to give (RR1N)2h=N(CH,),flPh.37 Similar reactions occur with ethylene oxide. Treatment of (MeN),P with CC1, and MeSiNCS gives [ (Me2N)3PNCS]*C1-which upon addition of RRINH [R=R1=H,alkyl;RR' =(CH2)*J =P(NMe,), provides (Me,N),P=NCSNRR' .38 The addition of PBr, to Me,CNBr, gives Me,CN=PBr, which after dimethylaminolysis and dehydrobromination yields Me3CN=P(NMe,) 39 Addition of alkyl halides to ( R2N),P=NSiMe, which can be reduced with sodium to gives [ (R,N),PN(R')SiMe,]' give (R2N)3P=NR'.40 The amino group in 3 , 3 bis(dimethylaminophenyl)-6-aminophthalide can be converted to the phosphazo derivative . 4 1 Reactions of acyclic phosphazenes continue to prove of value in the synthesis of new materials especially in the area o f organic chemistry. Reactions in which the phosphazene unit is transformed will be considered first followed by reactions in which the phosphazene unit stays intact. The phosphazenes are usually prepared by the Staudinger reaction. The diversity of reactivity of phosphazenes such as PhN=PPh,CH=C(NH,)C,H,-p-Me in interactions with electrophiles is shown by reactions with protons or alkyl halides which give phosphonium salts (N-alkylation or protonation). In the presence of bases, alkylation of the enamine occurs.42 Phosphazene substituents can serve as precursors to amines. The hydrolysis of RP(NPh) (OCH,CH,Cl), gives RP(0) (OCH,CH,Cl)NHPh while rearrangement of the phosphazene gives RP (0) (OCH,CH,Cl) N (Ph)CH2CH2C1. Kinetic parameters for the rearrangement were measured.43 Az idopyridazines yield the aminopyridazine upon hydrolysis4'. Reactions of electrophiles such as alkylhalides with Ph,PNLi gives Ph,PNR(R=alkyl) which upon further reaction give Ph,PNHR* or Ph,PNR,*. Hydrolysis of
,.
the phosphonium salts gives the primary and secondary amines .45 Alkyl and ally1 RN=P(OEt), species upon hydrolysis yield RNHP(0) (OEt),.', The benzotriazol 4 is a synthon for the *CH2NH, group. Reactions of organolithium or Grignard reagents with 4 The Utility of yield RCH2NH, following hydrolytic work up."
8: Phosphuzmes
303
the aza-Wittig reaction in organic synthesis continues to be exploited. Diastereofacial selectivity was observed in formation of erythro-PhN=PPh2R ( R=CH,CHR1CHR2NPh) from the c-1 metallated phenylphosphine imide and aldimines. Reaction of the product with CO, and LiAlH, gives erythro-Ph,P(O)R and Ph,PR respectively.c8 The reaction of Ph3P=NPh with [CH-CCH,PPh, ]+Br-
.
followed by PhCHO gives [ PhCH=CHC (NHPh)=CHPPh3]+Br 49 The reaction of the isocyanate ROCS,CRR’NCO with Ph3P-NC6H#¶e3 gives the carbodimide”. The aza-Wittig reaction is increasingly being used for heterocyclic synthesis. The general strategy is to form a phosphazene unit as a side chain on a ring followed by internal cyclization via reactions with another functional group on the ring. The following citations will be limited to identification of species undergoing reactions and products formed. For details of the process, the reader is directed to the original paper. The addition of PhNHN-C(CO#¶e)N=PPh, with cyclic anhydrides gives cyclic triazoles The aza-Wittig reaction of iminophosphorane sites on pyrroles with heterocumules gives functionalized pyrroloquinoxalines. 52 Fused five and six membered triazo heterocycles can be prepared by reactions of triazanes with an -N-PPh, unit on one nitrogen center with thi~ureas.’~ The azaWittig reaction of iminophosphoranes derived from Nsubstituted o-azidobenzamides and related ring system with heterocumulenes leads to functionalized quinazolines. ” Condensation of 2-(iminophosphorane)cyclopent-1-ene-1carbaldehyde with ethyl acetate is followed by cyclization to The aza-Wittig reaction of 0- (1a ~yclopenta[b]pyridine.~~ pyrroly1)phenyl iminophosphoranes with isocyanates, isothiocyanates, C02 or CS, can lead to pyrrolo[l,2alquinoxalines. Similar processes starting with indoles lead to indoloquinolines 56 The thermal rearrangement of N(cycloheptadieny1)iminophosphoranes gives, via a 1,5 hydrogen migration, 5 (R=Ph, Bu). The reaction of 5 with a-
.”
.
bromoacetophenone derivatives leads to the 1-azaazulene ring system” and with PhSP=NCPh=CH, plus 2,4,6-cyclooctatrieone to give a azabicycloundeca-tetraene which undergoes an internal Diels-Alder reaction to give a tetracycl ic ring.58 Sevenmembered ring chemistry is also found in the reaction of 2 chlorotropone with a N-(3 indeny1)imino-phosphorane to give a cycloheptandenopyrrole 59 The react ion of an o-iminophorane-
.
azaindole with isocyanates give aminophenylpyridoindoles.
The isocyanate reaction with imidazoles having -N=CRN=PPh3 as a substituent on a ring nitrogen center gives imidazotriazines.61 The internal cyclization of o-(iminophosphorane)-benzaldimines gives 2,3-diamin-2H-indazoles Reactions of iminophosphoranes with o-phthalaldehyde gives, depending on conditions, N-substituted isoindoline-1-ones or 3acylisoquinolines The insertion of an acetylene into the phosphazene bond has been observed and utilized. The reaction of acetylene dicarboxylates with R'CH2PPh2=NC(0)OR gives R' CH,PPh,=C (C0,R) C (C0,R)=N-C (0) OR which undergoes base catalyzed internal cyclization.& Similar insertions occur with H,NCR=CR'P (=NPh)Ph, and acetylenedicarboxylates The enamine phosphazene derivatives undergo a diverse array of cyclizations to give phospha-aza-heterocycles .65 Phosphalkenes, RR'PPR"CR"'=CH,, are formed, along with phosphamides RR'PNHR"', by the thermal decomposition of diphosphineimines RR'PR(=NR")R". In some cases the reaction The reaction of the aziridine derivatives is reversible.& (R,N),P(=NR)NC,H, with MeJSiX or RC(0)Cl gives the cyclic phosphonium ion [ ( R2N),$NRR' CH,CH,hR] * (R'=S iMe, , C (0) R) 67 The dimerization of halophosphazo derivatives (R,N),P(Br)=NR gives the cyclic diphosphonium ion 6 . * @ This is in contrast to the behavior of R3P=NR species which form neutral, five coordinate phosphorus, dimers. An unusual disruption of the phosphazene bond occurs when Fe,(pCH2) (CO)* reacts with R3P=NR' (R,R' alkyl,
.
.
aryl) to give 7. The strong base property of (Me,N),PNMe has been employed in condensation of silanes with trimethylsilyltriflates.M The coupling of podophyllotoxin to glycosfdes was accomplished via a (NMe,),P(=NMe) derivative of the latter. Reactions also occur in which the phosphazene unit is unchanged during reactions at other sites in the molecule thus allowing for substituent elaboration. Certain of the studies indicated below also show reactions of the phosphazene unit but are arbitrarily included in this section. The reactions
''
of the low valent phosphorus derivatives X=PCl (X
=
C(SiMe3)z,
NC,H,(CMe,),) with Me3SiNPR3 gives X=PN=PR, which can go on to The add Me3SiC1 to either the P=C or P=N bonds.n phosphazosilane Me,SiN=PPh, reacts with aryltetraiodophosphoranes to give [ ArP ( I,) N=PPh, J *I- which undergo base hydrolysis ( H,O/Na,SO,) to give ArP (0)(OH)N=PPh, while in water alone the PN bond also undergoes reaction.n
8: Phosphazenrs
305
Treatment of C1,P (0) N=PC13 with HN ( CH2CH2C1),HC1 gives C1,P (0) N=PC12N( CH2CH2C1) which shows anti-tumor activity. 74 The Peterson olefination of C-silylated phosphoranimines has been 76 explored. The reaction of Me,S iN=P (Me)(X)CH,S iMe, (X=OCH2C1,, OPh) with butyl lithium followed by addition to aldehydes or ketones and quenching with Me,SiCl gives Me3SiN=P(Me) (X)CH=CRR‘ (R’=H,R)7 5 . Olefins containing heterocyclic substituents (furan, thiofuran, pyridines) were also prepared by this route.76 The addition of H C W C N to five membered rings with a NPPh, moiety as a substituent on an endocyclic double bond gives benzannelated heterocycles with the NPPh, unit intact.n This is in contrast to the insertion of acetylene dicarboxylates into the PN The reaction
,.
of C3F7P(0) C1, with Ph3PNSiMe, gives C3F7P(0)(N=PPh,) 78 The attack of Me3ENPPh2CH2PPh, (E=Si, Ge) on pentaf luorobenzonitrile occurs exclusively at the para position to give NCC6F,NPPh,CH2PPh2. 21 The phosphoryl unit can be replaced by a chlorine atom in the reaction of ( PhO).Cl,-,P=NP (0)(OPh)$12-,,, with PC1, to give [ (PhO)nC1,~nPNP(OPh)mC1,~,]+PC1~ (n=0-3,m=0-2) The interaction of Me3SiNPRR’R” with MePF,, Me,PF,, PhPF, gives phosphonium ions such as F (Ph)P[N=P (NMe,)3]*PhPF5-80. Tetraphenylimido diphosphate forms chelated complexes with
.*
MF, (M=Nb, Ta, Sb)
Other imidodiphosphates, (RO),P(O)NP(O)(OR’), can be used as additives to give fireresistant polycarbonates .w Other examples of acyclic phosphazenes or reactions of acyclic phosphazenes can be found in sections 4-5. 3.
CYolODhOSDhaSOlleg
Very little in the way of review material has appeared in the time frame under consideration; the only exceptions being a detailed discussion of the reactions of (NPCl,),,, with polyfunctional nucleophilesm and a brief survey in Japanese of the flame retardant effects of cyclophosphazenes Ab initio MO calculations on (NPF2)3,4 show highly polarized R (in plane) and R’ (out of plane) systems.,
.@
Semiempirical MNDO and CNDO/2 have been used to explore steps in the hydrolysis reaction. The parent, (NPCl,),, molecular structure was reproduced by the calculations and the crossring phosphorus-phosphorus interactions were shown to be repulsive. The trans non-geminal species was slightly favored for N,P3C1,(OH), while the chair form for (NP(OH),), was predicted. All rings were conformationally labile and the
path of the phosphazene-phosphazane rearrangement was explored A novel synthesis of PN (9) involving passing
.”
(NPC12), over silver was reported. The matrix isolated diatomic undergoes trimerization to (PN), which, based on SCF calculations, was predicted to be a ring.7 Auger and x-ray photoelectron data for several reference compounds were compared to the equivalent transitions in (NPCl,), and show a highly polarized PN bond. Eximer fluorescence in aryloxy , (NP(OAr)2)S,derivatives occurs between the two aryloxy groups bonded to the same phosphorus atom.87 The photochemistry of poly[bis(4-isopropylphenoxy)phosphazene is sensitized by N,P, [ OC6H,0C (0) CH,Ph] in solution. No photochemistry was observed in the solid state.88 The Raman and IR spectra of (NPX,), (X=Cl, F) have been obtained as a function of temperature. The normal vibrations for the low temperature (skew-tub) and high-temperature (skew-chair) forms of (NPCl,), have been assigned. Preliminary assignments for (NPF,), were also presented. 89 The perturbation of vibrational frequencies of cyclophosphazenes by pressure and solvent effects has been discussed in terms of the highly polarized x bond model for these systems. A new synthesis of (NPBr,), (n=3-5) using NaN, and PBr, has A direct synthesis of P,N,(NH,)6* 1/2NH, from been developed.” white phosphorus and ammonia at pressures 2 5 kbar is of interest .92 Since the amidophosphazenes have proven to be effective textile flame retardants, patents have appeared concerning their ~ r e p a r a t i o nand ~ ~ purification .% The aqueous ammonlysis of (NPCl,), has been reexamined and found to give 2,2- and 2, 6-N,P,Cl6(NH2) and a trace of the monosubstituted The reaction of (NPCl,), with cyanamide and derivative.% dicyanamide gives N,P,C~~-,(NHCN), (n=2,4)% and NSPSC1,[N(CN) respectively. Derivatization of N,P,(OPh) ,C1 with aminosiloxanes provides N,P, (OPh),NH (CH,),R (R=SiMe,OSiMe,, Si (OSiMe,),) .98 A cyclophosphazene with cycloborazines as substituents , 2, 2-N3P3(“Me2) (NH%N,Me,) 2 , has been prepared by An the reaction of 2,2-N3P,(NMe,),(NH,), with N,l3$~fe~Cl.~
,
2~r97
extensive series of studies involving diamine phosphazene reactions demonstrates the continued interest in the complexities of these reactions and structures of the products. A series of spirocyclic derivatives of 2 , 2 N,P, (NHCMe,) zC1, have been prepared and have the fol lowing
formulation 2,2,4, 4-N3P3(NHCMe3) ,[X(CH2)Y]C1, (X=Y=O,NH; n=2-4 ; x=O, Y=NH, n-2-4; X=Y=NMe, M=2,3; X=NH, Y=NMe, n=2,3; x=o, Y=NMe, n-2). Extensive N M R studies were reported on these systems including the use of solvent effects and lanthanide shift reagents for clarification of the 31P spectra.”’ The spirocycle derived from 1,2-diaminopropaneI N,P3X, [ NHCH,CHMeNH] (X=Cl) and its permethoxy derivative (X=OMe) have been prepared. lo’ The biologically active geminal aziridine derivatives, N,P3(NC2H,),[NH(CH,)nNH] (n=l-4) have been reported.lo2 The reaction of (NPCl,), with (H,NNH),P(S)OPh gives the hydrazino spirocycle 8.’03 Of particular interest in this area is the wide array of structures formed from the reactions of long chain oxodiamines with (NPCl,),. Solvent effects appear to be particularly important in these processes. The 16-membered spirocycle (9, boxomethylene, X=C1) N,P,C14 [ NH ( CH,) 30( CH2),O ( CH,) ,O (CH,),NH] occurs in two allotropic forms which differ in the conformations of the macrocycle.104 Change of solvent to an interfacial system produces major structural changes in the products of the reactions of (NPCl,), with NH, (CH,),O (CH,),O ( CH,) ,NH, (x=2, y=2 ; x=3, y=2 ,4) and NH, ( CH,) ,O ( CH,O (CH,),O ( CH,) 3NHZ. In THF the ansa ( 10) structure is formed while in the toluene/water system the spirocycle (9, X=C1) is formed and in the ether/water the bino, N3P3C15NHLNHN,P3C1, (L=oxymethylene fragment) , derivative is obtained. The dispiro derivatives, N,P,Cl, [ NHLNH] (9, L=(CH2)30(CH2)40(CH,)3, (CH,),0(CH,),0(CH,),0CCH2)3; X,=NHLNH) lo* as well as the mixed dispirocyclic derivatives
“H(cH~)~o(cH,),o(cH,)~NH1and N,P,C12 [ NH (CH,),O (CH,) ,O (CH,),NH] [ NH (CH,),O ( CH,) ,O (CH,),NH] lo7 have been prepared and characterized. Finally, the 1:2 N,P,Cl,[NH(CH2)30(CH,),O(CH,),NHI
(NPCl,),: diamine reaction in the ether/water or n-propanol solvent systems gives rise to dibino derivatives N,P,Cl,NH (CH,) ,O (CH,),O ( CH,) ,NHN,P,Cl, (X=2, Y=2 ; X=3, Y=2,4) in which the amines are in a trans non-geminal array relative to each phosphazene ring (11).‘08 Two examples of heavier congers in the nitrogen group as exocyclic substituents have been prepared by the reaction of Li [N,P,Cl,PhBEt,] with EPh,C1 to give 2,2 -N,P,Cl, (Ph)EPh, (E=P, As) The arsenic derivative is the first example of a phosphazene with a P-As bond.‘(@
.
The synthesis of cyclophosphazenes bridged to exocyclic groups via oxygen atoms also continue to attract attention. The isoxazoyl derivative 12 has been prepared. Reactions of
Organophosphorus Chemistry
308
isoxazoyl oxyanions with shorter methylene chains lead to incomplete substitution presumably by steric hindrance to the incoming groups. 'lo The hexakis (octadecyloxy)cyclotriphosphazene has been prepared. '11 Cyclotriphosphazenes with poly ether substituents, N3P3(OR)6
[R=(C2H40)3C4Hp8 (CzH4O)Zc1$Z# (Cp40)sC6H4-,-C~l,l, have been prepared and found to be effective as phase transfer agents.'" Hexa (2-chloro ethoxy)cyclotriphosphazene, N3P3(OCH,CH,Cl) 6, can be obtained from the parent alcohol and (NPCl,), in the presence of pyridine. Previous studies have indicated the unique gerninsl to non-geminal rearrangement of the NH, group in the reactions of 2,2-N3P,C1,(NH,), with the methoxide ion. It now appears that this process also occurs in the tetrameric series as shown by the reaction of 2,2-N4P4c16(NHz)2 with the methoxide ion which yields, in addition to the expected 2,2(OMe)6 (m2) 2 I 2 ,6-N4P, (OMe) (NH,) 2 and N4P4( OMe)F Z .In a related experiment 2 , 6-N4P4C1,(NHz) is converted to two isomeric N,P, (OMe)6 (NH,) derivatives and NIP4(OMe)pH,. 9s A s in the case of amino derivatives, the reactions of polyfunctional alcohols with cyclophosphazenes are of recent interest. Alkanedioxy and mixed aminoalkaneoxy spirocycles have previously been discussed. loo In addition to these materials, a monodentate ,OH and the bis spiro derivative NsP3(NHCMe,) C1,O (a,) derivatives N3P3(NHCMe,) [ 0(CH,)3,40]are available. loo Alkane diols react with (NPCl,), to give the spiro derivatives (X-1-3; n=2-4), ansa (i.e. 2,4) N,P,[O(CH,),O]C~,~,~ NsP3[ 0(CH,) ,O] C1, , spiro-ansa N3P3[ 0(CH,) ,O] zC1z ( 13) , N,P,C1,0 (CH,) ,ON3P,ClS (n=3;4 ) and monodentate N3P3[ 0 (CH,) ,OH] Cl, (n-3,4) all of which have been characterized by 'H and "P NMR In the corresponding reactions of the spectroscopy. '14 tetramer, (NPCl,),, ethandiol doesn't give any characterizable product. Longer chain diols give rise to the spirocyclic 0 (CH,) ,O] [ X=l, n=3,4 t X=2, n=3,4 ; X=3, derivatives, N,P,Cl,~,,[ n=3,4; X-4, n=4]. The bis derivatives (X=2) occur as both the The reactions of 2,2,4,4- and 2,2,6,6- structures.'" glycerol, a triol, with (NPCl2),,, give the spiro bridged derivatives 14 or the analogous tetramer and the spiro cyclic The only with one free hydroxyl N,P,Cl, [ OCH,CHO (CH,OH) ].'16 phosphorus-carbon linked derivatives reported in this period are the malonodinitriles , N3P3C16-,[CH (CN),In (n=2,4) which are available from (NPCl,), and NaCH(CN),. Possible phosphazene/phosphazene equilibria in these and the related
"'
,
,
,
309
8: Phosphazenes
R X
1
R (1 9)
3 10
Organophosphorus Chemist0
cyanamides have been considered.96 The synthesis of new cyclophosphazene derivatives by reactions of the exocyclic groups now represents a major route to these materials. The donor properties of the exocyclic phosphine are shown by the formation of the metal carbonyl derivatives, 2,2'N,P,Cl,(Ph)PPh,*R (R=Cr(CO),, Fe(CO),, RU,(CO),~. The exocyclic phosphorus-phosphorus and phosphorus-arsenic bonds in 2,2'N3P3C1,(Ph)EPh, (E=P,As) under go nucleophilic cleavage with NaOCH,CF, leading to replacement of the -EPh, fragment with the trifluoroethoxy group.lo9 The reactions of the p-lithiophenoxy derivative, N3P3(OPh)50C,H4Li, with chlorosilanes or hexamethylcyclotrisiloxane represents a viable route to the organosilylphosphazene derivatives N3P3(OPh) ( OC6H4-p-R) (R=SiMe,, SiME,, Ph , SiMePh,, SiMe,CH=CH, , SiMe,( 0s iMe,) ,OS iMezBu The rates and activation energy of and SiMe,(OSiMe,) ,0SiMe3).l17 the reaction of N,P3 (NH,) with formaldehyde to yield N,P, (NHCH,OH) have been measured.'18 The thermal decomposition products of 2,2-N3P3C14 (NH,) have been identified using IR spectroscopy and thin-layer chromatography.'19 Reduction of the nitroaryloxy derivative N3P3(OC6H3(Me)NO,) (15) gives the amine which reacts with a wide variety of aldehydes to give The reactions of metal the Schiff base, N,P,(OC,H,(CH,)N=CHAr),. salts, MX, (X=C1, M=Zn, Pt; X=Acetate, M=Zn, Pd), with the Schiff bases gives metal complexes of these 1igands.120 The hexakis (p-alkoxypoly(ethoxy)-p-benzyloxy)cyclophosphazenes are available from the reaction of N3P3(OC,H4CH20H) with polyethylene glycol monoalkylether tosylates. These materials show effective phase transfer catalyst properties in a number The reaction of N,P,(OCH,CH,Cl), with of reactions. CH,=C (Me)CO,K gives the methylacryloxyethoxyphosphazene. '13 Similar materials are prepared from N,P, (OCH,CH,OH) and CH,=C (Me)C (0) C1. lZ2 The incorporation of cyclophosphazenes into polymers by exocyclic group reactions has been approached a variety of reactions. The copolymerization of the p-vinyl biphenyloxy derivative, N,P,c~,OC,H,C,H,CH=CH, with styrene or methylmethacrylate has been studied. Alfrey Price parameters show the phosphazene as a sigma electron withdrawing substituent. The copolymers have increased thermal stability induced by the pho~phazenes."~ Homopolymerization of the pvinylbiphenyloxy species shown above and numerous derivatives arising from replacement of the halogen atoms gives heat and
,
,
,
8: Phosphuzenes
31 1
fire resistant polymers.124 If the substituents are oligo(oxylethy1ene) units, the corresponding carbon chain polymers with cyclophosphazene substituents can bind various substrates. The binding constants of a dye, the 6anilinonaphthalene-1-sulfonate anion, to this polymer have been determined.12' The use of Friedel-Crafts catalysts allow for polymerization of N3P3(OPh), through the phenoxy groups without disruption of the cyclophosphazene. The aminophosphazenes, 2 , 2-N3P3(NH,) ( OPh) and N3P3C13( me,) 3 have been used to cure epoxy polymers.'21 A particularly large number of applications of cyclophosphazene derivatives has been noted. Of particular interest is the large number of reports focusing on methacryloyloxyethoxy derivatives, typically Uses claimed for derivatives N3P3 ( OCH2CH20C(0) C (Me)=CH2)6 . center on the easy cure which can be accomplished due to the reactivity of the appended methacrylate. Several reports focus solely on the preparation of the hexasubstituted derivative either from 2-hydroxyethylmethacrylate and 128-131 or by two step indirect routes which have been (NPC12)3 noted above.113'122 The range of applications cover lenses, The most common coating magnetic recording materials, etc. cure is to prepare a mixture of the phosphazene and giving a system photoinitiator and subject to W ~-adiation'~~-'~~ which can be used as 1ens132'133'135 abrasion-resistant film coatings,134s138 high refractive index glass s~bstitutes'~''~~, optical decorations (such chandelier)139, transparent polymers with hardness and chemical resistance'40, composites for coating printed circuit boards'&' and adhesives.142 Composites can also be prepared by thermal cure of the methacryloyl phosphazene. The intense interest shown in the methacrylates has not been at the expense of other derivatives. As always a significant number of claims focus on the well established flame retardant characteristics of the cyclophosphazenes. Woods treated with varying amounts of chloro, methoxy and phenoxy phosphazenes have been studied by IR spectroscopy and other techniques after pyrolysis all of which confirm phosphazene fireproofing ability.lL4 The thermal and rheological effects of adding p-bromophenoxyphosphazenes to poly (ethylene terephthalate) have been studied.145 Specific fire proofing applications include various phosphazenes with phenolic resins146,aminophosphazenes for treatment of fibers
''
'**
.
(cotton, etc ) 147g148 amidophosphazenes for wood and timber
,
products'49, propoxyl derivatives for Rayon urethane foams from polyisocyanates and 2 , 2 -
and
,
or 2 , 2-N3P, (OPh) (NH,) and poly (oxypropyrene)trio115,. Fluoroalkoxy aryloxyphosphazenes N,P, (OPh) ( NHCH20H) ,15,
make excellent self-extinguishing hydraulic fl ~ i d s ' ~ ~ 'and '~~ magnetic recording media. lM Thermosetting phosphazene systems (see above also) giving heat and flame resistant matrices are prepared from bismaleimides and phosphazenes with ally1 or vinyl containing aryloxy groups'57 or maleimidophenoxyphosphazenes 15' High phosphazene content is obtained in the combina'tion maleimidophenoxyphosphazenes and aminophenoxyphosphazenes. 159 Acrylates bound to phosphazenes such as N,P,(OCH,CF,),(OC(0)CR=CH2),, can be UV cured to heat resistant resins. '60 Various aminophosphazenes have been used to cure expoxy resins and thus provide improved thermal stability. 1270161'16t In addition to flame proofing textiles,
.
phosphazene derivatives have been used for crease proof ing163*164 and waterproofing. 165 Aminophosphazenes have been used for the preparation of nitrogen-phosphorus fertilizers. 166g167 Amidophosphazenes have been used as deodorants to remove NH,, H2S or mercaptans. Addition of phosphazenes improves the process for sodium polyphosphate manufacture 169 4. CvalODho 8Dha(thia)zenes and Re 1ated CornDoun da The majority of the publications in this area have been concerned with low valent (two-and three-coordinate) sulfur species. Semiempirical (PM3) S C F MO calculations on a series of hypothetical molecules derived from insertion of a nonmetal fragment into one of the sulfur-sulfur bonds of S,N, have been carried out. The species with a phosphorus bridging atom ( 1 6 ) has been determined to have two possible forms, with and without a sulfur-sulfur bonding between the remaining twocoordinate sulfur atoms. lrn Details of the Lewis acid/base behavior of 17 (E=S, X=Y=Ph) resulting in the formation of 1 7 H + B F , - , 17Me* CF,SO,- , 17 BX, ( X = F , C1) have been reported. The site of adduct formation varies from the unique nitrogen atom located between the two phosphorus centers ( 1 7 H*) to the
.
nitrogen atom between sulfur and phosphorus ( 1 7 Me+) or mixtures of the two ( 1 7 - B X 3 ) . The lack of regiospecificity in adduct formation has been attributed to charge equalization possibly due to the S-phenyl group."' The Lewis base behavior of 1 8 ( E = S ) has also been examined with the following adducts
313
being obtained: 18H+ BF,-, 18Me+ CF,SO,-, 18-BC13, 18HF(CF,S03-)2, (18),(SnCl,),. The monoadducts are all similar and the structural effects on the heterocyclic ring has been rationalized using MO arguments. The disubstituted material contain mixtures of symmetrical and unsymmetrical isomers which interconvert in solution. The Mossbauer spectrum of the tin complex can be interpreted as showing a polymeric structureSelenium containing by an octahedral trans-SnC1,(18) unit .ln heterocycles have been attracting recent attention. The reaction of Ph,P(=NSiMe,)N(SiMe,), with RSeC1, gives rise to 18 (E=S, Se when R=Et, Me) and 19 (E=Se, R=Ph, Me, Et R' =Ph) . The reaction of [ClPh,PNPPh,Cl]+ with (Me3SiN),E (E=S, Se) gives 17 (E=S, Se; X=Cl; Y=Ph) while the condensation of (Me3Si),NP( Ph,) NC (Ph)NSiMe, with SC1, or SeC1, gives 20 ( E = S , Se : R=R'=Ph; X=C1). Reduction of the chloro derivatives with triphenylantimony gives the two coordinate S(se) free radicals 17 (X=electron; E=S, S e ) and 20 (X=electron; E=S,Se). The electron spin resonance spectra of these radicals show that conjugation is restricted to the CNS unit with very little evidence coupling to phosphorus. The model compounds with R=H have been investigated by MNDO calculations in order to aid i n the esr assignments. The results suggest that 17 and 2 0 can be viewed as inner salts of a phosphonium ion fragment (Ph,PN,* in 2 0 and Ph,PNPPh,* in 17) with an anionic (SN,' or NSNC-) fragment. The radicals dimerize in different ways. The sulfur containing system gives a symmetrical ( S , S ) dimer while in the selenium system the rings are joined by a Se-N bond.'74 The reaction of triphenylphosphine with 21 leads to a eightmembered phospha(thia)zene with an exocyclic triphenylphosphazo unit. The product exists in two conformations, the exo form (22) and the endo form in which the exocyclic nitrogen is up and the exocyclic phosphorus atom is down with respect to the triphenylphosphazo substituted sulfur atom. N M R studies show a rapid interconversion of the two conformations with the exo form favored. Since MNDO calculations show the two to be close in energy, it is assumed that the difference is steric in nature. The phosphazo derivatives undergo a slow decomposition in solution to give the six membered phospha (thia)zene, P h , m N . 175 ,The reaction of S4N4 with the symmetrical tertiary phosphines R,P (R=Me,C, C,H,,, CH2C6H5,C,H,-p-OMe) give 23. The corresponding reaction with P(C,H,-p-C1) gives a low yield of 1,s- [ (C,H,-p-C1) 3PN]2S,N,
,
,S =N, ,N , ,?-NPR3 S-N
(23)
Ph2P-N
I
SiMe,
-Ti-
c12
NSiMe3
I1 I -I -11
Me3SiN-Ti
N
CI2
PPh2
315
which undergoes ring contraction in solution to give ~3.l’~. The analogous reactions of aminophosphines (R2N),P with S,N, also leads to structures of the 2 3 type. The reaction of one of these derivatives, (C,H,$) ,PNS,N, with norbornene gives a cycloadduct in which norbornene adds to the two coordinate sulfur atoms. A few reports on higher valent (four coordinate sulfur) species have appeared. The reactions of trans-NPCl,(NSOPh), with Grignard reagents have been carefully studied. With methylmagnesium chloride evidence for both metal-halogen exchange and substitution pathways was presented. The mono and dimethyl derivatives as well as the phosphorus-phosphorus bridged dimer [NPMe(NSOPh),], were obtained. With bulky Grignards (Me,CMgCl , Me$ iCHpgC1 and (Me,Si ) ,CHMqCl) good yields of the substitution products were obtained. The copper (CUIP(C&H~)~) catalyzed reaction of MeMgCl in the presence alkyl, ally1 halides or 2-propanol give the methyl/alkyl, methyl/allyl or methyl/hydrido derivatives respectively.
Heating of the tetrahydrate of the sodium [(H,N),PN],SO,NH salt leads to replacement of one amide by a hydroxide.ln The oxidation-reduction condensation of sulfamide with Ph,PCH,PPh, in the presence of diethyl azodicarboxylate gives the phosphorus-sulfur-carbon nitrogen heterocycle, k=PCH2P”NbOZ.26 5.
Wi8o.llaa.OU8
PBpppharaao Coatainina Riaa
8 -
ZncludLUJ M.tall.Dho8Dhat.a.8* The reaction of a phosphatriazene 24 (E=PC12) with SbF, gives 24 (EXn=PFC1). The reaction of 24 (EXn=PF2)with KCN gives the anionic cyanide 24 (EXn=P(CN)F2).The SPFC1 center in 24 can be displaced by BF3*OEt, to give a boron-nitrogen heterocycle.lm The 1,3- addition of PhNO to the phosphorus and carbon atoms in the PPh,NCPh, fragment in 2 gives a five member heterocycle with an internal phosphazene unit which adds activated ketones.,* The interaction of amidines with dihalophosphines leads to phosphazene containing heterocycles the identity of which are very dependent on the nature of the organic substituent on the phosphine and amidine. The reaction or RPC1, (R=(Me,Si),CH) with PhC(=NSiMe,)N(SiMe3), is complex leading to a five-membered ring with a phosphorusphosphorus bond which upon hydrolytic disilylation gives 25 (R as above) A similar reaction employing RC (=NSiMe,)N (SiMe,)
.
(R=perfluoroalkyl, CF,C,H,) and R’ PC1, (R’=alkyl, Ph) gives a bicyclic species (26). The phosphine transannular bridge can
be disrupted with using SO,Cl, to give 19 (E=C, R',=R' , Cl) The remarkable reaction of (Ph,P),NLi with P, gives 27 which degrades to a linear species upon nucleophilic attack. The two coordinate phosphorus atoms can be electrophilically methylated to give cationic forms of 27 or can act as Lewis bases to give trans four coordinate PflCl, complexes (M-Pd, Pt) with MC1, unit acting as a transannular bridge in 27 .la Metallacyclophosphazenes have attracted increased attention in this time period. Reactions leading to many of these materials start with a linear species and as such could be also considered as an extension to section 2. The pathways of six membered rings with a MNPNPN core have been reviewed.' The reaction of PhpNSiMe, with MC1, (M=In, n=3; M=Sn, n=2; M=Fe, n=3) gives the four membered rings, 27 (M=In, x=y=2;M=Snlx=3, y=2) , M=Fe, x=2) '84 A volatile six-membered ring with a core is formed from (CF,),P(Cl)=NSiMe, and Me,SiN-VCl,. '8s The reaction of Ph,P(=NSiMe,) N(SiMe,), with TiC1, gives 28 (X=Cl, Me,CN adduct) or 28 with X=NPPh,N(SiMe,),. The former dimerizes slowly in solution to give 29. Bis(iminophosphoranes) are obvious ligand choices for the construction of rnetallaphosphazenes. The reaction of RN=PPh,CH,CH,PPh,=NR (R=SiMe,) with NbC1, gives the linear species where R=NbCl,. This material undergoes a complex reaction with THF to give the oxygen containing heterocycle, Cl,hN=PPh,CH,CH2PPh2=NNbCl,d. The react ion of (RN=PPh,) $H, (IPCO, $=l ,5-cyclooctadiene (COD)) (R=pMeC6H,) with (RhI+l) gives two different products 30,31 (R'=Ph,PNHR). The lithiated form of the ligand, (RN=PPh2)2CHLi, gives 31 (R'=Ph,P=NR) .lM The linear unit, (Me,Si),NC(Ph)=NPPh,=NSiMe, is another building block for cyclic heterophosphazenes as shown by the reaction with SeC1, which yields ClSe=NPPh,=NCPh=N. The reactions with ,Pt give rise to ( Ph3P),Pt ( C2H4) and ( Ph3'P) ( Ph,P) 2f;tN=C(Ph)NIP ( Ph2)-kS iMe, and [ (Ph,P),#tN(H) C(Ph)=NP(Ph,)=$H]+ re~pectively.,~ Alternatively, the reaction with MoC1, gives 32 which shows another coordination mode for this ligand. '89 Linear monophosphazenes with another donor atom in the chain can also be used to construct metallacyclophosphazenes. The reaction of Me,ENPPh,CH,PPh2 (E=Si, Ge) or Me,SiNPPh, (CH,) $sPh, with PdCl,(PhCN), leads to formation of the metallacycles 33 (E=Si, Ge, n=l, L=P; E=Si, n=2, Q=As, kC1,). The hydrolysis of one of these, (Me,SiNPPh,CH,PPh,) PdC1, gives the free imine complex
.
,
"'
8: Phosphazeites
317
CI R
R
I
I
Ph2
/"=') \ N=P
1
'\
Me3SiN
L2Rh
R
,CI
0- Mo
L2Rh?pph2 R'
Ph2
(31)
(30)
Me0
(35)
(37)
(HNPPh,CH,PPh,) PdC1,. 21 The reaction of Me,SiNPPh,CH,PPh, and Me,SiNPPh2CH2CH$isPh, with (Me,SiO)Re0, give the metallacycles kPPh,CH,PPh,R& (0)(0siMe,) and kPPh,CH,CH+sPh2&e (0)( 0 s iMe,) respectively. In each migration of an SiMe, group from the ligand to a terminal oxygen on Re occurs.1w Coordination of the same ligands to low valent (0,I) metals has also been explored. Both retention and cleavage of the trimethylsilyl group upon coordination has been noted. 19' Thus reactions with M(CO),$ (M=W, G C O ; M=Mo, kpiperidine) give 33 (E=Si, n=l, Q=P, L= (CO),, M=Mo, W) while the corresponding reaction with.[Ir(COD)Cl], (COD=cyclooctadiene) proceeds with Me,Si group cleavage to give 33 (no Me,Si, n=1, Q=P, k C O D , M=Ir). Trimethylsilylfluoride elimination occurs in the addition of pentafluoropyridine or pentafluorobenzonitrile to Me,SiNPPh,CH,PPh, resulting in the formation of Ar,NPPh,CH,PPh, (Ar,=para substituted C,F,N or C,F,CN) which combine with [Rh(CO),Cl], to give 33 (Me,E replaced by Arf, n=1, Q=P, MLFRh(C0)Cl). The reactions of
,
,
,
,,
,
,
[ Rh (COD)C1 ] and Me,SiNPPh, (CH,) +sPh, with [ Ir (COD)C1 ] [Rh(CO)Cl], yield 33 (Me,E absent, n=2, Q=As, M=Ir, Rh, L=COD) and 33 (E=Si, n=2, Q=As, M L F R ~ ( C O ) C ~ ) . ~ ~ '
6.
Polv-es)
This section is devoted to polymers containing open-chain phosphazenes. Cyclolinear and cyclomatrix phosphazenes are covered in section 3. Brief reviews of the following topics have appeared: Materials science aspects of solid poly (phosphazenes)' 9 2 , synthesis by the DeJaeger route (see below) and applications of poly (phosphazenes),'9~ the relationships between morphology and phosphazene pr~perties'~' and two less accessible reviews covering recent applications to a broad spectrum of problems.lPSO'% The synthesis of poly(phosphazene) from small molecular precursors is a continuing and important subject of interest. Alternatives to the bulk polymerization of (NPCl,),, such as catalyzed solution polymerization, have been a continuing focus of attention. One such system uses BC1, as the catalyst in solvents such as 1,2,~-c,H,c~, .197*19% The rate (as measured by Raman spectroscopy and molecular weight) depends both on (NPCl,), and BCl, concentration. Small amounts of chain branching were detected. The Mark-Houwink constants for (NPC1,) were determined in this solvent system. 197 Repeated addition of fresh oligomer allows molecular weights in the
8: Phosphazenes
3 19
5,000,000-6,000,000 range to be attained.l9' polymerization of (NPC1,) using sulfamic
,
Solution or
toluenesulfonic and sulfobenzoic acidsZoogives high molecular weight materials. The active catalyst is a decomposition product involving the acid group hence an induction period exists. Water, available from CaS0,-2H20, does not act as a catalyst (as it does in bulk polymerization) but as a promoter to achieve high molecular weight with narrow distribution. Molecular weights are high at the start of the reaction indicating a chain propagation mechanism. 1w'200 Onium salts such as Ph21+AsF6-have also been used as polymerization catalysts."' A brief report on some details of the plasma polymerization of (NPC1,) indicates higher oligomers, (NPC1,)&. 6 , form first followed by chains.202 A detailed study of the radiation induced polymerization of ultrapure (NPCl,), shows that under melt conditions molecular weights are low and results lack producibility. The solution (in decalin) polymerization is 3/2 order in (NPC12), with low molecular weights however the addition of a bulky electron acceptor such as pyromellitic dianhydride results in higher rates and molecular weights.203 An alternative route to
,
poly(dich1orophosphazene) involves the polycondensation of C1,PNP (0) Cl, which eliminates P (0) C1, and yields The mechanism of this process has been C13PN(PC1,N) .P (0) Cl,. examined by 3'PNMR and the rate determined by rate of release of P(0)Cl3. The catalytic effects of NH,C1 and HN[P(0)C12] Effective catalysis by 2,4,6have been noted." trimethylpyridine also occurs. The cyclic oligomer component of the polymer mixture can be controlled by controlling the Cl,PNP(X) C1, (X=O, S) concentration.205 The molecular weights obtained in the condensation reaction can be controlled by addition of C1,(0R),~,P(0) NPC1,(OR)3-v (R=fluoroalkyl, aryl; x=1-2; y=O-2) .2w A particularly noteworthy trend during this time period is the synthesis of polymers which in addition to a phosphazene component in the backbone, have other organic or inorganic moieties. The Staudinger reaction of Ph,PRPPh,(R=p-C6H, or (CH,) n=2-5) with 1,4-diazidobenzene gives [NPPh2RPPh2NC6H4],. The new, thermally stable, polymers are insoluble in common solvents so w$re characterized (including CPMAS NMR) as solids. End group analysis gave molecular weights in the range of 1800-2600. Bulk thermal polymerization of 17 (X=Y=Cl; E=C, S) yields the
new heterophosphazene polymers [ (NPCl,NPCl,NCCl J O;P
and
[ NPClzNPClzNSC1],201respectively.
Both can be derivatized in a manner analogous to that used on (NPCl,),; thus the carbophosphazene can undergo partial or complete halogen replacement by phenoxide'" while in the poly (thiophosphazene) the halogens can be replaced by phenoxide or aniline.'1° A new phosphorus oxynitride, Mg3PN30, is formed by the reaction of PNO and P,O, with Mg3Nz.z11 The synthesis of poly(phosphazene) derivatives by single or multistep reactions of preformed poly(phosphazenes) continues to represent a major pathway to new members of this class of materials. Certain details of the nucleophilic substitution reactions of poly(dichlorophosphazene), (NPCl,),, with oxyanions have been elucidated. The effect of reaction time and temperature in the preparation of phenoxy, 8naphthyloxy and trifluoroxy derivatives and how these variables effect polymer properties has been studied. The time required for complete substitution depends on the strength of the nucleophile. Excess heating during reaction leads to chain branching in the product .lw'zoo The rate of substitution depends also on the nature of neighboring substituents on the phosphazene chain with the following order of substituent effects being noted: OCH,(CF,),H > OCHZCF3 > OMe > OEt > OPh.'" Patents describing efficient methods of preparation of sodium alcoholates 213 and purification of the polymer obtained from substitution reactionsz1' are available. A series of aryloxy derivatives, [NP(0Ar),(OAr1),l,, where the aryloxides are phenoxy, 2 or 4-methylphenoxy, 2,3 or 4-phenylphenoxy, 4-benzylphenoxy, 4-cumylphenoxy and 4-tertbutylphenoxy have been reported. Complete substitution was achieved by carrying out the reaction of the sodium aryloxides with (NPCl,), in dioxane at 150' in an autoclave. The effect of substituent structure on thermal transition behavior and optical properties was explored. The synthesis of poly(dibenzy1oxyphosphazene) from the sodium alcoholate has been described. The value for square radius of gyration and second virial coefficients were lower than those for [ NP (OPh) The Mark-Houwink coefficients in chloroform were
,I,;,.
obtained. Poly (octadecyloxyphosphazene)has been prepared. 11' A series of patents are available describing the syntheses of poly(phosphazenes) with cure sites in the side chains (see also section 3). Substituents used for these purposes may be
8: Phosphuzenes
32 I
the only side chain groups or a component of a mixed substituent polymer where the remaining substituents are alkyl- or aryloxides. Reactive groups used for these purposes include malimides (34),17, acrylates available from the reaction of alkoxy groups having a terminal hydroxide with isocyanatomethacrylates 218'2'9 Other substituents include eugenoxides (35)2208221, and alkenyl or alkynyl alcohol derivatives.222 Hydrophobic groups such as N-vinyl-2pyrrolidone and be grafted onto bis(trif1uoroethoxyphen0xy)phosphazenes by direct exposure to radiation. The kinetics of the grafting reaction have been followed.2a The partial lithiation of [NP(CO,H,Br),], followed by coupling with chlorosilanes on ring-opening addition to (Me,SiO), gives the series [NP(OC,H,Br),-, (oc,H,R),],, (R=SiMe,, SiMe2Ph, SiMePh,, SiMe,(OSiMe,),0SiMe3). A significant variation of Tg (-68 to 45') with the identity of the siloxane was noted.''? The (X=O, 0 . 5 , 1.5; R=OCH,CF,, reactions of [NP(OR)2-xClx]n OCH2CH,0CH,CH20Me, OPh) with aminosiloxanes gives [NP (OR) (NH(CH2)3R1)x]n (R'=SiMe,0SiMe3; Si (OSiMe),) Contact angle measurements show hydrophilic or hydrophobic surfaces which depend on the nature of the group (amine or siloxane) oriented towards the surface. Poly (phosphazenes) having directly bound -PPh, side groups have been synthesized in solution but are hydrolytically unstable and decompose on attempted isolation.'09 Side chain elaboration of the methyl group in [NP(Me)PhJ, by deprotonation with n-butyl lithium and the substitution reactions of the organolithium center, [NP(CH,Li)Ph],, gives rise to a wide variety of new organophosphazenes 224 Reactions with aldehydes and ketones give the poly(phosphazenes) with alcohol substituents, [ NP ( CH,CRR' OH) Ph] (R:R' =H ; Me, Ph, C5H,FeCp, thiophene : Me : Me, Ph, C5H,FeCp) .225 A series of fluorinated alcohol The addition of (Me,Sio) derivatives were also prepared.,,, followed by Me3SiC1 or further addition of cyclosiloxane gives siloxane or poly (siloxane) substituents.227'228 The addition of CO, to the lithiated intermediate gives a carboxylate function which can be converted to the free acid or esterified with pnitrobenzylbromide .226'229 The addition of styrene to [NP(CH2Li)Ph], causes anonic polymerization of styrene and thus the formation of poly(methylpheny1phosphazene)-graftpolystyrene copolymers.230 Physicdchernical studies of poly(phosphazenes) have been
.
.
.
,-
attracting an increasingly larger share of the research in this area. Extended Huckel MO calculations on [NP(OCH,CF,)Cl], with trans dispositions of substituents show that the observed increased rate of substitution of the phosphorus-chlorine unit is due to a polar effect of the trifluoroethoxy group."' An energy-decomposition technique for the analysis of band structures in (NPX,), (X=H, F, Cl) has been developed. The band gap is too large to allow for semiconducting behavior. The substituents play an important role in the occupied ( n HOMO) band and d orbitals may be involved. The unoccupied ( K * LUMO) depends only the backbone. 231 X-ray photoelectron and Auger data for (NPCl,), and (NPCl,), indicate that the bonding in the polymer is more polarizable than in the trimer." Both direct and sensitized photochemistry of poly(bis[4isopropylphenoxy ] phosphazene) has been investigated. 88'232 When benzophenone was employed as a sensitizer, solution photochemistry gave degradation or cross-linking depending on the avaxlability of 0,. Photocross-linking is the major process in films with hyperperoxides and carboxylic acid groups also being formed in air.',' Sensitization can also be effected by the phosphazene trimer or polymer with 4-benzoylphenoxy groups as substituents. Photolysis of air-equilibrated CH,C1, solutions of the isopropylphenoxy polymer with the phosphazene sensitizers results in significant viscosity decrease indicating chain scission. Interestingly no photochemical change was induced in the solid state. X-ray diffraction and DSC investigations indicate this is due to phase segregation Excimer of the two different types of phosphazenes.M fluorescence in poly[bis(phenoxy and p-cresoxy)phosphazenes)] occurs by three routes: between geminal aryloxy groups, adjacent groups and intermolecular transfer. Intermolecular excimer forming sites appear to be pervasive in solution. The binding energies for excimer formation have been obtained8'. Structure and phase changes in the solid state continues to be an area of considerable interest and complexity for poly(pho8phazenes). Measurement of depolarized light intensity changes has been found to be a useful new technique for the following phase changes of poly(phosphazenes). The first-order changes T ( l ) and Tm are easily detected with the changes from 3D to 2D phases being noted. Crystalization rates could be measured isothermally at temperatures below T(1).
Examples of all of these effects have been given.233 A
study of the relation of side group size on phase transitions shows that both T(l) and Tg show a rough linear correlation to size. X-ray diffraction data show that interplanar distances also relates to size. Most poly(phosphazenes) that exhibit
.
the T ( 1) transition exhibit polymorphic forms 234 Mesophases have been obtained by solvent evaporation of proproxy, butoxy and pentoxy poly(phosphazenes). The existence of a significant number of defects results in the absence of the me~ophase.~ A ~number ~ of studies of the protypical species, poly[bis(trifluoroethoxy)phosphazene] (PTFE), have appeared. The rheological properties of PTFE have been related to the variety of phase structures which occur over the range of -150' to 250'. These properties where characterized by the existance of a yield (inelastic deformation) point, low melt viscosity, jet contraction on exit from a capillary, etc. The PTFE mesophase system was compared to isotropic polymers and liquid crystalline rigid chain polymers.236 The transformations of two crystalline modifications of PTFE to the mesophase has been modeled as 1-dimensional long range order between layers but only short range order within the Evidence for this **condis'*mesophase structure was obtained from x-ray diffraction, SEM and DSC.238 Structural changes in PTFE fibers were studied by x-ray diffraction as a function of temperature. The structure depends on stretching and thermal treatment with the number of defects determined by the annealing temperature. 239 Treatment of PTFE with alkali metal salts or hydroxy compounds following wet spinning and heating at 300' gives fibers which 100% stretch recovery after being stretched to 300%.2c0 Extruded PTFE was examined in the 453493 O K range by x-ray diffraction and DSC. Significant rheological and some structural changes occur. The conformation transition observed was related to formation of a structure intermediate between the unidimensional layer and a 2-dimensional pseudohexagonal structure. 241 The kinetics of isothermal crystallization of PTFE in the sub Tm region and sub T(l) region have been examined by DSC and depolarized light intensity techniques. The former region involves change from an isotropic phase to the 2-D pseudohexagonal mesophase while the latter is the mesophase to a 3-D orthorhombic phase. Classical nucleation theory was applied to estimation of the interfacial surface free energy which was shown to be more than an order of magnitude lower than observed in the
324
Orgatwphosphorus Chemistn;
crystallization of regular homopolymers.242 Another system which has been the focus of serious study is PolYEbis(phenoxy)phosphazene], PBP. As in the FTFE system, several polymorphic forms of PBP are detected and by
combination of electronmicroscopy, x-ray diffraction and DSC, enthalpy changes associated with phase changes have been recorded.243 Solution grown crystals of PBP are a 3-D (a) form which transformed in a 2-D pseudohexagonal (6) form upon passing through T(1). The 6 form can be trapped by quenching at liquid nitrogen temperature. Heating close to T(l) yields a hexagonal ordering .2c4 The isothermal crystallization kinetics of PBP have been examined by DSC and depolarized light intensity measurements. Kinetics of transformations in the sub Tm and sub T ( 1 ) regions depend on an isotropic mesophase going to a 2-D mesophase in the former and formation of a 3-D orthorhombic phase in the later region.245 The transformation kinetics are similar to those of PTFE discussed above. 242'245 The phase transition behavior of PBP with halogens ( F , C1, Br) in the para position is strongly influenced by halogen size. Intermolecular distances, polymorphic crystallization and morphology all depend on halogen size.246 Liquid crystalline poly(phosphazenes) with 6-[4-(4-methoxy-pmethy1stryl)phenoxylhexyl substituents have increased rates of side-chain crystallization due to decoupling of side-chain motion from the flexible ba~kbone.~" Poly(phosphazenes) with 2-[(4-(4-butylphenyl)azo)phenoxy]ethoxy substituents show formation of a smectic (liquid crystalline) mesophase. In mixed substituent polymers which additionally have a trifluoroethoxy group a mesophase was also detected but with weaker stacking of side groups than in the former polymer.248 The reversible phase changes obtained on heating/cooling of crystalline [NP(OR)2]npolymers show promise for using these Another side group materials as recording materials. orientation effect was realized in [NP(OCH2CF3),,{ (O(CH2CH20)3where 2nd-order non-1 inear optical p-C,H,CH=CH-p-C,H,NOz}m]
"'
properties were detected.250 Solution characterization of poly(ph0sphazenes) is an important area of concern. Some of these studies were mentioned above in conjunction with the polymer synthesis. Electrooptical properties (Kerr effect) of PTFE have been examined. The Kerr constant was significantly higher than those of flexible chain polymers which was suggested to result
8: Phosphazen es
325
from large-scale motion of the polymer.25' A comparison of the sedimentation constants, intrinsic viscosity and Mark-Houwink coefficients for PTFE and the corresponding -OCH,(CF,),H (n=2,4) derivatives in THF suggest that only PTFE can be considered a flexible-chain polymer .252 The viscosity and viscoelasticity of nearly monodisperse PTFE as a function of concentration and temperature indicates that PTFE is a less compact coil than other flexible-chain polymers. As concentration increases, a conformational change resulting in an increase in coil size occurs. In all cases limited intercoil interactions occur. 257 Detailed size-exclusion chromatography studies have also been reported. Optimization of conditions for chromatography of PTFE has been examined as a function of solvent. Cyclohexanone is the solvent of choice for use in conjunction with viscometric determination. These studies show that PTFE has a bimodal distribution with different Mark-Houwink coefficients for each component. 254'255 The effect of concentration induced chain compression on calculation of the molecular weight distribution was examined.255 Various poly (aryloxyphosphazenes) in THF have been examined using light scattering detection. These measurements gave accurate correlations between molecular weight, hydrodynamic volume and viscometric measurements. 256 Other physical characterization studies are often directly related to a specific application. One such application is the use as polymer electrolytes in batteries. Salts of poly(2[(2-methoxyethoxy)ethoxy]phosphazene), KEEP, are the most common materials for this application. ESCA and solvatochromic modeling data for MEEP-Li+ salts have been obtained. Complex impedance, ionic conductivity and battery cycling data have been related to variables such as polymer synthesis methods, substituents, polymer film stability and anode reactive species.257 Detailed impedence measurements on KEEP-LiC10, can be understood using a model with two conduction paths, one along the chain and other between chains. Neither path is continuous across the electrolyte.258 The reaction of (MEEP)flI salts (M=Li; Na) with I, leadsto aseriesof polyiodide complexes, (MEEP),MI, (n=1-9) which have been characterized by Raman spectroscopy, DSC and electrical measurements. Triiodide and polyiodide species are observed when n>l. High polyiodide concentrations give high conductivity by a process involving iodide transfer between polyanions 259-260 Radiation
.
crosslinking of MEEP-LiCF,SO, does not lower the conductivity. 261 Mixed polymer electrolytes consisting of Li+ salts of MEEP and poly(ethy1ene oxide) have higher conductivities than those involving only poly(ethy1ene oxide) salts.
Systems containing mixed LiBF,, and LiC10, salts give the best conductivity. 262 Sodium ion complexes of phosphazenes with covalently bound sulfonates have been examined.253 Aminophosphazene polymers such as [NP(NHPh),In become electrically conductive when treated with C1S0,H.264 The use of poly(ph0sphazenes) as membranes for separations has recently attracted interest. The gas transport parameters for 14 gases across PTFE films have been measured with a high selectivity towards CO, being noted.265 The oxygen gas permeability of 15 different poly(phosphazenes), including phenoxide, alkoxide and amino derivatives, in water has been measured with [ NP (NEt,) (NHCMe,) 3 having the highest value. 256 The 0, permeability and O,/N, selectivity of multilayer membranes consisting of porous substrates which enclose a poly (phosphazene) middle layer have been measured. 267 Diffusion of solutions of Cr3+, Co2+ and Mn2+ ions through a PTFE membrane allows for separation of Cr3+ from the remaining ions.268 Thermal stability of polymeric materials is a significant consideration in many poly(ph0sphazene) applications. The kinetics of the thermal degradation of PTFE are best fit with a model requiring a two step initiation for depolymerization. These steps involve formation of defect units, such as =P(O)NH- and =P(0)N(CH2CF3)-, which become active centers for d e p o l y m e r i ~ a t i o n . ~Mixed ~~ fluoroalkoxyphosphazene rubber materials are more resistant to abrasion and tearing than fluorosilicone but have poor long term properties in air at elevated temperature^.^^' The isothermal weight loss has been used to evaluate the thermal A stability of an elastomeric poly (phosphazene)
.,”
comparative study of fireproofing effectiveness in epoxy resins of cyclic, linear polymeric and cyclolinear polymeric phosphazenes with alkoxy, phenoxy and fluoroalkoxy substituents has been examined with linear fluoroalkoxy species being found to be most effective.2n Patents describing specific applications or formulations are available. Specific items which appeared include: aryloxyphosphazenes for flame-retardant panels2n and fibers MEEP-LiCF,SO, based thermally actuated secondary hydrogen
, 274
8: Phospha w n es
327
battery275, PTFE films for insulation of printed circuits226and lift-off mask for A1 film patterns2n, [NP(OPh),], resist layers,2T8additives for epoxy resins used for potting semiconductors,279 MEEP-KCF3S03 to effect antistatic properties in photographic film2B0,crosslinked mouldings based on fluoroalkoxyphosphazenes, rigid poly (phosphazene) foams282, bioerodible phosphazenes for sustained-release of pharmaceuticals2= and activated fluoroalkoxyphosphazenes as carriers for enzyme immobilization.m 7. Holooular Structures of Phoppharones. The following structures have been determined, except where noted, by x-ray diffraction. All distances are in picometers and angles in degrees.
ComBound PhN=PCl (NEt,),*AlCl,
Comments PN bonds equal, mean 160 one N pyramidal, others planar
(morph),PNl=N N+, (Et) c6H2 (NO,) morph=morpho fino
PN, 168.4(1) : N,+ 127.2(2) N2N3, 131.2(2) PN, 165.1(1) N,N,127. 9 (1) LPNlN2 109.5 (1) H-bonding to N,.
2
No data given
CH, ( PPh2=NC6H,-p-Me)
PN 156.8(2), 156.6(2)
CH, ( PMe,=NC,H,-p-NO,)
,
[ Mo ( NFWe,) C1, ( PMe,) 3]C1
[ ( P M 8 3 ) 2C1,MoN140C13( PMe,) ,] [ Me,PNPMe,
OEt N,P3C1,NHC (0)
I
Ree. 8
13
13,14
32 20
PN 158.0(4)
20
PN 163.6(4) LMoNP 167.6 (3)
22
PN156.4(6), 156.0(6) LPNP 141.7(5)
22
Chair PNd 160.2 PNcxo164.1-166.0 LPNP 122O, LNPN 115 H-bonding gives dimers of cofacial rings.
92
slightly pucked mean PN 157.0(5) PNexo166.2 (6) LNPN 117.6 (6)i LPNP 121.4 (3) H-bridged dimer
285
Ref.
Comments twist boat P3N3 mean PN,,, 166 PN&,
99
160.1(4), 161.8(7)
P3N3 planar 286 , N P at sub. P 158-162 others 155.1 (6)-157.1 (6) PN,,, 162.4 (5) , 162.3 (6) 287 P3N3 Planar , N P 153.1 (13)-163.5 (11) PN,,, 160.4 ( 11) 165.6 ( 12 )
-
P3N3 Non-planar
, N P PN,,, 36
37
287
156.1 (9)=160.9 159.6 (9)-161.2 (9)
P3N3 non-planar 288 , N P 156.0(8)-160.5(8) ; 160.1(7)-160.9 (7) PN,,, 162.7(8), 162.6(7) 160.7(5) P3N3 planar 288 153.4 (10)-162.3 (8) PN,,, 166 (2), 162 (2)
,N P 9
allotrope of structure in ref. 286 differ in spiro loop conf.; P3N3 planar
104
, N P 158-162; 155.7-158.9 LPNP (endo) 112.7 at sub. P; PN,,, 160-164 , N P 154.2 (9)-163 (1) PNqxo163 (1)-167 (1)
106
spiro rings highly unsymmetrical , N P 155.815)162.5 (6) PNvo 16 3.7 ( 4 ) 165.0 ( 6)
106
-
spiro rings unsymmetrical trans 2,4 sub. on P,N, Macrocycle chair ,N P PN,,, 2,2’ -N3P3C1,(Ph)PPh2
289
156.0 (5)-159.5 (4) 161.1(5), 161.5(4)
angles at sub. P: LCPP=106.7 (1),
109
LNPN 114.5(2) PN=161.1(5), 161.9(5) at
sub. P, 151.1(3), 156.1(3),
157.0
8: Phospharettts
3 29 PP=2 19.9 ( 2 )
ComDound
Comments
,
2,2' -N,P,Cl, (Ph)[ PPh,. Cr (CO) ]
angles at sub. PLCPPE107.0(2), LNPN=114.8 PN=160.7 (5), 160.2 (2) at sub. P, 155.3(0)158.7 (7) Pw223.4 (2)
2,2 -N3P,C1, (Ph)[ PPh,*Ru, (CO)11 3
Two forms diff. with
Ref. 109
109 orient. of PPh,; angles at sub. P LCPP 102.3(7), 104.3(7), LNPN 116.7(9), 115.1(8) PN 157-162; 157-159; 153-157 N3P3 slight crown conf. PN 160-6 (5), 154.0 (5) 158 (1)
290
highly distorted boat 171 PN 157.7(3), 159.7(3), 163.3(4), 168.8(3) ; LNPN 108.5(2), 113.6(2) ( 18 CH,) *CF,SO,-
E=S
Methyl on N; PN 159.1(6), 166.6(5); 163.0(5), 162.8 (6)
172
17 E=Se, X=C1, Y=Ph
Se out of P,N, plane; 291 PN 163.7(5), 158.4(4) LNPN 117.8(2)
19 R1=Ph, R=Me, E=Se
chair, Se above N, plane; PN 162.3(3), 159.2 (3)
39 (R=tolyl)
rings nearly parallel, LNSS=102.5, 96.7; PN 160.4 (6)-163.3 (6) S-S 248.9(9)
40
3 coord. N down from 174 plane, 3 coord. Se up from plane of its ring, LSeNSe 118.7 (8) PN 156.5( 15)-165.4 (14)
41 ( R=C,H,,N)
P=N 159.5(3) ; PNC,H,, 161.9 (3)-163.9 (3)
25
PN,,, 159.9 (5), , N P 161.1(5), 162.4(5) exo LPNS 118.7(3)
173
174
177 175
330
Organophosphorus Chemis[?
t
8: Phosp ha m w s
33 1 Comments
COrnDOUM [NPMe (NSOPh ) 2]
C6H,
24 E=P, X=F
25
Ref.
P-P 221.6(9);
one enantioneric form; Me trans; PN 161.4(2)
178
Electron diffraction PN 157.9(10) LNPN 109-2 (7)
180
ring nearly planar: 181 , , N P 163.0(3) I 163.4(3) PN,,, 169.3 (3)
19 E=C, R=Ph, R,'=Ph,
C1
trans Ph(C1) configuration mean PN 156.9
182
42 CH,Cl,
boat like; 2 coord. P 183 out of N plane PN 159.9(1) I 159.2(1) LPPN 120.78(4) , 120.29(4)
42 PdC1,
PdC1, forms transannular 183 bridge between 2 coord. P; PN 160.2(7) , 160.3(7) LPPN 120.1
27 M=In, X=Y=2
DMF bound to each In: PN 157.0(3)
184
27 M=Sn, X=3, Y=l
PN=161.1(11) I 161.0 (11)
184
27 M=Fe X=Y=2
PN=160.6 (5), 160.9 (5)
184
24 E=V, X=C1, n=2
nearly planar 18 5 PN 159.3(3) I 161.2(4) LVNP 129.0(3) LPNP 121.3 (4)
28 X=C1
186 MeCN adduct at Ti PN 162.2(2) , 161.6(3) LNPN 98.0(1)
,
28 X=NPPh,N ( SiMe3)
186 , N P 160.4(9) I 161.3 (8): P=NCXO156.1 (9) PN (SiMe,) 164.9 (3) LNPN,, 101.6(4)
29
PN 160.4(4), 161.7(3) LNPN 101.6 (2)
186
PN=160-8 [3)
187
31 R=tolyl ; R' =PPh,NH (tolyl) $=COD
PN,,, , N P
188
32
distorted OH at Mo PN 165.3(6) I 162.1(6)
Cl$bONbCl,N=PPh,
( CH),PPh,=h
165.8 (10) 161.3(8)
189
332 ComDountJ
!3m!wJb
33 n=1, Q=P, M=Pd, L=C12
ESiMe, replaced by H
PN 159.9(6) LPNPd 115.4(3)
17 Y-Ph, E=Se, X=C1
PN 161.3(2),
(43)C1-
PN=160.3(11), 162.0(9)
1.
2. 3. 4. 5.
6. 7. 8.
9. 10.
11. 12. 13.
15. 16. 17. 18. 19. 20. 21. 22. 23.
164.2(2)
21 25 25
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69.
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70 71. 72. 73. 74. 75. 76. 77. 78.
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m,
m,
91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104.
105. 106.
u,
. .
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273. W. 8. Mueller, US 4818603 (Chem. Abst - , 1989, 111, 59228u). 274. S. Taguchi and M. Fujimoto, Jpn. Kokai Tokkyo Koho, JP 01132810 ( a e m . m,1990, U , 38098g). 275. D.N. Palmer, J.S. Cartwright and J.K. O’Neill, US 4808494 ( m m . Abst., 1989, 10300~). 276. Y. Yamashita, T. Ito and N. Kajiwara, Jpn. Kokai Tokkyo , 1989, U 215665s). Koho, JP 01045149 -( 277. Y. Yamashita, T. Ito and N. Kajiwara, Jpn. Kokai Tokkyo 48165~). Koho, JP01044935 (Chem. Abst;., 1989, 278. V. Yamashita, T. Ito and N. Kajiwara, Jpn. Kokai Tokkyo A b s t . , 1989, 48164~). Koho, JP01044927 279. A. Matsura, K. Nishii, Y. Yakigawa and Y. Nakada, Jpn. Kokai Tokkyo Koho, JP 63/349 (Chem. Abst., 1988, m, 7711k). 280. J. Chen, W.T. Ferrar, J. E. Kelly and A.S. Marshall, Ep 304296 &g& ., 480024). 281. N. Saiki, JPn. Kokai Tokkyo Koho (Chem. Abst., 1989, 111, 176063v\. 282. W.B. Mueller and S . D . Landry, US4870113 (Chem. A&&., 1990, U , 2365042). 283. C.T. Laurencin, R.S. Langer, H.R. Allcock and T.X. 120908j). Neenan, W08809664 (Chenf. Ab&. , 1989, 284. T. Matsuki and N. Saiki, Jpn. Kokai Tokkyo Koho, JP 32652m). 01030650 ( a m . Abst,, 1990, 285. A. Meetsma, P.L. Buwalda and J.C. van de Grampel, &&a Crvstalloar.. Sect. C: Crvst. Struct. Commun., 1990, m, 886. 286. T.S. Cameron, A. Linden, F. Sournies, A. El Bakili and 41. J.F. Labarre, J. Mol. Struct., 1989, gJ7, 287. T.S. Cameron, A. Linden, A. El Bakili, P.Castera, J.P. Faucher, M. Graffeuil, F. Sournies and J.F. Labarre, J. Bola Struct., 1989, 212, 281. 288. T.S. Cameron, A. Linden, G. Guerch, J.P. Bonnet and J.F. Labarre, J. Mol. Struct., 1989, U , 295. 289. R. Enjalbert, J. Galy, F. Sournies and J.F. Labarre, J. ml. Struct., 1990, m, 253. 290. A. Meetsam, A. van der Lee, A.P. Jekel, J.C. van de Grampel and K. Brant, Bcta Crvstalloara.. Sect. C: Crvst. 909. , Struct. Commun.. 1990, Ql§ 291. A.W. Cordes, K. Bestari and R. T. Oakley, Bcta -oar.. Sect. C: Struct. Commun,, 1990, m, 504.
u,
.
(m.
(m.
u, u,
m,
u,
u,
Author Index
I n this index the number g i v e n in parenthesis is the Chapter number of the citation and this is f o l l o w e d b y the reference number or numbers of t h e r e l e v a n t citations within that Chapter
Aagard, O . M . (5) 82 Abaev, V.T. (1) 263, 264 Abdel-Rahman, N . M . (1) 138 Abdou, W.M. (1) 138, 139; (4) 14 Abdullina, N.A. (1) 105 Abe, J. (1) 193 Abe, K . (1) 303 Abe, N . (1) 149 Aberkane, 0 . (1) 297 About-Jaudet, E. (5) 101; (7) 67 Abraham, K . M . (8) 262 Abramov, V.Yu. (8) 31 Abramyan, T.D. (5) 110 Absalon, M . J . (6) 148 Abushanab, E. (6) 19 Achiwa, K . (1) 29, 30 Ackermann, E. (8) 24 Ackermann, M. (1) 246; (5) 93 Adamov, A.V. ( 5 ) 193 Adler, M.E. (7) 98 Affandi, S. (1) 72 Agarwal, K. (6) 237 Agrafiotis, D . K . (2) 10 Agrawal, S. (6) 120, 189, 190 Ahlert, K . (4) 63 Ahlrichs, R. (8) 7 Ahmad, A. (1) 283 Ahmad, W.-Y. (5) 126 Ahmed, S. ( 8 ) 96, 97 Ahn, K.4. (1) 39 Aitchison, K.A. (1) 59 Aitken, R.A. (7) 48 Akacha, A.B. (1) 83; (3) 8 Akai, H. (7) 38 Akega, M. (8) 82 Akekseiko, L . N . (8) 85
Akelah, A. (1) 301 Akita, H. (7) 108 Akiyama, T. (5) 15 Aksinenko, A.Yu. (1) 244 Aksnes, G. (3) 25 Aladzheva, I.M. (1) 291-294 Alajarin, M. (7) 117, 118; (8) 52-54, 56 Alamgir, M. (8) 262 Alario, F. (1) 297 Alberti, M. (8) 91, 119, 202 Alcaraz, J.M. (1) 79 Alcock, N.W. (1) 134, 419, 420 Aldenhoven, H. (1) 318; (4) 88 Aleinikov, S.F. (5) 133 Alewood, P.F. (5) 29 Al'fonsov, V.A. (8) 29 Ali, R. (2) 13 Alkubaisi, A.H. (8) 114, 115 Allcock, H.R. (8) 98, 99, 109, 117, 192, 209, 210, 215, 250, 261, 283 Allen, C.A. (8) 268 Allen, D.W. (1) 275 Aller, E. (8) 61 Al-Madfa, H.A. (8) 116 Alonso, E.O. (1) 295 Alovitdinov, A.B. (5) 165 Altenbach, H.-J. (7) 145 Altier, D . J . (8) 90 Alyea, E.C. (1) 179, 180 Amasaka, T. (8) 155 Amaudrut, J. (5) 195 Amri, K. (5) 108 Anderson, D.R. (5) 61 Anderson, C. (8) 9
343
Andrianarison, M. (1) 66, 67 Andrus, A. (6) 101 Angelov, C.M. (5) 194, 203, 216 Angelova, 0 . 1) 96; (7) 10 Angst, C. (5) 175 Angus, K . (6) 206, 207 Annen, U . (1) 448 Anthony-Cahil , S.J. (6) 92 Antipin, M.Yu. (1) 167, 292, 293, 336, 390; (5) 96; (8) 5, 13, 14, 68 Antipov, E.M. (8) 236-239, 241 Aoki, S. (5) 142 Aoki, Y. (8) 231 Appel, R. (1) 305 Arasappan, A. (7) 49 Aravamudan, G. (1) 250; ( 4 ) 27
Arbogast, B. (6) 133 Arbuzov, B.A. (1) 111-113, 115, 116, 157, 364, 365; (5) 97, 219 Archibald, R.S. (8) 117 Arendt, A. (5) 28 Arif, A.M. (1) 58, 375 Aristoff, P.A. (6) 231 Ariyoshi, S. (8) 123 Armstrong, R.W. (7) 139 Arques, A. (1) 166; (7) 122, 127; (8) 62 Arzumanyants, E . A . (1) 264 Asakura, T. (1) 358 Aseeva, R!M. (8) 164 Asseline, U. (6) 182
Atezhanova, G.O. (1) 75 Atkins, E.D.T. (8) 248 Atokhina, L.A. (5) 13 Atreyi, M. (6) 47 Atwood, J.L. (1) 55 Aubert, T. (8) 55, 63 Auer, M. (6) 34 Avasthi, K. (7) 100 Avens, L.R. (1) 118 Avery, T.L. (1) 444 Ayed, N. (1) 83; (3) 8 Ayrey, P.M. (3) 28 Baader, E. (3) 31 Baba, M. (6) 141 Babbit, P.C. (6) 38 Baccar, B. (1) 83; (3) 8 Baccolini, G. (1) 117, 446; (3) 13
Baceiredo, A. (1) 360, 366; (3) 46; (4) 34, 93, 94 Bachmeier , N. (6) 4 Backer-Dirks, J.D.J. (1) 59 Badri, M. (5) 56 Baechler, R.D. (1) 181 Baer, D.R. (8) 86 Bar, M. (8) 7 Baggiolini, E.G. (3) 35 Bagoutdinova, D.A. (5) 219 Bailar, J . C . (1) 12 Bailey, J.M. (6) 201 Baker, R. (5) 16, 17, 26 Bakker, C.G. (6) 72 Bakuradze, R.Sh. (8) 212
Balasubramanian, K.K. (1) 169, 170
Balegroune, F. (1) 213 Balgoblin, N. (6) 84 Balogh-Hergovich, E. (1) 160; (2) 33
Balueva, A.S. (1) 112, 115, 265
Balzarini, J. (6) 10, 141 Banbery, H.J. (1) 107 Banerjee, S. (7) 142 Bankmann, M. (1) 331, 410; (3) 27
Bankovskii, Yu.A. (1) 194 Banks, M.A. (1) 199 Banks, M . R . (5) 41 Bannwarth, W. (4) 40; (6) 62, 63, 209 Bansal, R.K. (4) 13 Bao, R. (5) 186 Baran, J. (7) 87 Barancheeva, V.V. (8) 236, 241 Baranov, A.P. (3) 15
Baranov, Yu.1. (1) 234 Barbato, S. (6) 66 Barcel6, D. (3) 5; (5) 72 Barluenga, J. (1) 284, 455, 456; (7) 24, 62, 63; (8) 42, 48, 49, 64, 65 Barnfield, E.A. (2) 8 Barrans, J. (4) 35 Barsegova, M.N. (1) 219 Barthelat, M. (2) 11 Bartmann, W. (3) 31 Barton, D.H.R. (5) 191; (6) 14 Barton, J.K. (6) 225 Bartsch, R. (1) 432-435; (8) 80 Basait, S . A . (6) 241 Batchelor, R.J. (1) 165; (8) 21 Bats, J . W . (8) 32 Battioni, J.P. (6) 139 Batyeva, E.S. (1) 189; (2) 2; (8) 29 Baudler, M. (1) 120-127 Bauer, S. (1) 340 Bauer, W. (1) 353; (7) 61 Baxter, S.G. (1) 414 Bazile, D. (6) 8 1 Bazin, H. (4) 64; (6) 183 Beachley, O.T. (1) 199 Beal, P. (6) 131 Beasley, V.R. (7) 136 Beau, J.-M. (7) 139 Beaucage, S.L. (4) 20; (6) 100 Beaucourt, J.-P. (1) 262; (7) 42, 43 Beck, G. (3) 31 Becker, G. (1) 65 Beer, P.D. (7) 140 Behl, H. (1) 290 Beijer, B. (6) 142 Beiter, A.H. (6) 53 Belakhov, V.V. (8) 34 Bell, A. (1) 39 Bellamy, F. (7) 28 Belletti, D. (1) 427 Below, P. (3) 31 Bel'skii, V.E. (5) 69 Belt, H.-J. (1) 184 Bel'tsova, T.G. (8) 144 Benac, B.L. (1) 58 Benevides, J.M. (6) 240 Bengstrom, M. (6) 192 Ben Jaafar, B. (2) 31 Benner, S.A. (4) 66; (6) 135, 154, 168, 169 Bennett, J.L. (8) 261 Bennett, M.A. (1) 132 Bentrude, W.G. (4) 17, 51; ( 6 ) 20
Berg, H. (6) 174 Bergamini, P. (1) 134, 202
Bergmann, A. (3) 31 Bergstrasser, U. (1) 413; (2) 34
Bergstrom, D. (6) 130, 131
Bernadou, J. (6) 7 Bernard, P.S. (5) 175 Bernardi, A. (7) 60 Bernardinelli, G. ( 7 ) 4 Bern&, J. (5) 89 Bertani, R. (8) 120 Bertrand, G. (1) 360, 366; (3) 46; (4) 93, 94
Besancon, J. (1) 40 Bespal'ko, G.K. (2) 49 Bestari, K. (8) 174, 291 Bestmann, H.J. (1) 289, 290; (7) 15, 50, 59
Bethel, D. (1) 162 Bhat, S.P. (6) 195 Bhattacharjya, A. (1) 147 Bhaumik, M. (1) 147 Biddle, J.A. (5) 142 Biedenbach, B. (1) 382 Bigge, C.F. (5) 173, 174, 176; (7) 78
Bihatsi-Karsai, E. (7) 115
Bildstein, B. (1) 63 Billington, D.C. (5) 16, 17
Bindig, U. (6) 175 Binger, P. (1) 377, 382 Birkel, M. (1) 377 Bittner, S . ( 8 ) 26 Bjergarde, K. (4) 68; (6) 127
Bjoerk, F. (8) 270 Blackburn, C. (7) 140 Blackburn, G.M. (6) 1 Blacker, J. (6) 229 Blanchard, L. (5) 175 Blank, I.B. (1) 263 Blanquet, S. (6) 31 Blaszczyk, J. (3) 32 Bleasdale, C. (6) 44 b a l , J.H. (5) 78; (6) 108
Bobde, V. (6) 47 Bobovski, T.P. (5) 176 Bock, H. (1) 331, 399, 410; (3) 27
Bode, U.K. (1) 220 Bodurow, C. (7) 131 Boeckman, R.K., jun. (5) 144; (7) 101, 102
Boese, R. (1) 319-321, 323, 324, 373, 374
Boganova, N.V. (1) 94;
345
Author Index
(2) 26; (4) 3, 4; (5) 139 Bohlen, R . (2) 51 Bohn, B.D. (1) 148; (7) 51 Boileau, S. (1) 297 Boisdon, M.T. (4) 35 Boizau, C. (6) 109 Boldaski, R. (7) 135 Bollen, A. (4) 60; (6) 191 Bologensi, A. (8) 232 Bolton, P.H. (6) 148 Bongartz, J.-P. ( 5 ) 126 Bonnet, J . P . (8) 288 Bonora, G.M. (6) 51, 68 Bookham, J . L . (1) 48 Books, J.T. (8) 220 Booth, P.M. (7) 103 Borai, V . N . (6) 5 Borch, R . F . ( 5 ) 77 Borden, W.T. (1) 385 Bordere, S. (8) 205, 214 Borer, B.C. ( 7 ) 90 Borer, P.N. (6) 77 Borisenko, A . A . (1) 6, 349, 350; (8) 66 Borisenkova, E.K. (8) 236, 237, 241 Born, M. (1) 297 Bornancini, E . R . N . (3) 26 Boros, P . (5) 113 Borowiecka, J . ( 5 ) 39 Borrmann, H. (1) 452; (7) 8 Bortolus, P. (8) 88, 232 Bosio, L. (8) 248 Bosyakov, Yu.G. (1) 75 Bott, S.G. (1) 55 Bottka, S. (6) 21, 22 Bou, A . (5) 124 Boubia, B. (7) 28, 30 Boucho, D. (5) 51 Bould, J . (1) 206 Boumendjel, A. (7) 75 Boutorine, A . S . (6) 139 Bowman, E. (5) 149 Bowyer, M. (1) 38 Boyd, E . A . (1) 4; (4) 10; (5) 105 Boyd, V.L. (5) 78 Bradford, V.S. (6) 232 Bradley, D.C. (1) 57, 59 Braga, D. (1) 428 Brahce, L . J . (5) 174 Brakel, C.L. (6) 118 Brandi, A. (3) 43, 44 Brandt, K. (8) 102, 290 Braun, M. (5) 120 Braunstein, P . (1) 213 Bremer, M. (1) 290 Brennan, D.J. (8) 117
Brenton, A.G. (6) 241 Breque, A . (1) 79 Bretsko, M.M. (8) 50 Breuer, E. (5) 201 Brevet, A. (6) 31 Brill, W.K.-D. (4) 70; (6) 125 Brint, P. (1) 206 Britten, J . F . (1) 269 Broder, S. (6) 108, 109 Brodesser, B. (5) 120 Broeders, N . L . H . L . (6) 238 Bronson, J . J . (5) 189, 190 Brooks, P.J. (1) 38 Broughton, H.B. (7) 103 Brovarets, V.S. (1) 285, 286 Brown, D.M. (6) 170, 171 Brown, D.W. (1) 198 Brown, J . M . (5) 226; (6) 86, 87 Brown, R . S . (1) 14 Brown, T. (6) 45 Briick, T. (1) 436 Brunden, M.J. (6) 74 Bruneau, C. (1) 192 Brunner, H. (1) 27, 95, 178; (3) 1; (7) 9 Brusilovskii, P . I . (1) 194 Bruvere, A. (1) 194 Bryce, M.R. (7) 81 Buchan, N . I . (1) 195-198 Buchanan, R.A. (3) 38 Buche, L. (8) 51 Buchko, G.W. (6) 167 Buchmann, B. (7) 99 Buchta, B. (5) 225 Buck, H.M. (5) 82, 214; (6) 238 Budzelaar, P.H.M. (1) 18, 42 Buisch, T . (1) 310 Bulpin, A. (4) 23; (5) 140, 141; (7) 82, 83 Bumber, A.A. (1) 263, 264 Bundel, Yu.G. (1) 152 Bungardt, D. (1) 319 Bunlov, A.R. (4) 91 Buono, G . (3) 42 Burangulova, R . N . (2) 37 Burgada, R . (2) 31, 42; (5) 138 Burilov, A . R . (1) 254; (4) 30, 31 Burn, A . J . (5) 70 Burnaeva, L . A . (2) 35-37 Burton, D.J. (7) 55, 56, 77 Burton, S.D. (2) 40
Busalev, Yu.A. (8) 81 Busch, R . D . (5) 170 Busch, T . (1) 337, 442; (4) 86; (8) 4 Busia, K. (5) 18, 25 Buwalda, P.L. (8) 285 Buzykin, V . I . (5) 197 Bykhovskaya? O.V. (1) 291, 292 Cabioch, J.-L. (1) 89, 90; (5) 122 Cadogan, J . I . G . (5) 41 Caesar, J . C . (2) 30; (4) 11 Caffyn, A . J . M . (1) 428 Cai, L. (1) 211 Cairns, S.M. (1) 255 Calderon, C.E. (5) 57 Caliceti, P. (8) 223 Callahan, L. (6) 237 Calogeropoulou, T. (5) 146 Cambell, T. (5) 175 Cameron, T.S. (8) 286-288 Caminade, A.-M. (1) 356, 362, 363; (4) 81; (5) 56; (8) 72 Carrmack, J.H. ( 7 ) 137 Camp, D. ( 1 ) 176 Cannavo, P. (3) 44 Cano, F.H. (7) 117; (8) 42 Capobianco, M.L. (6) 68 Caprioli, R.M. (5) 28 Carcuro, A. (6) 68 Carenza, M. (8) 223 Carey, J.V. (5) 226 Carless, H . A . J . (5) 18, 25 Carless, M. (5) 105 Carmichael, D. (1) 214 Carmichael, W.W. (7) 136 Carneiro, T.M.G. (1) 213 Carr, M.A. (7) 131 Carrera, P. (6) 65 Carrie, R . (1) 361, 367; (7) 13 Cartwright, J . S . (8) 275 Caruthers, M.H. (4) 54, 70; (6) 39, 115, 122, 125 Casey, C.P. (1) 26 Casida, J.E. (5) 74 Castera, P. (8) 105, 108, 287 Cavell, R.G. (1) 164, 165; (2) 50; (8) 21, 190, 191 Cazenave, C. (6) 109 Cech, D. (4) 63; (6) 160
346
Cech, T.R. (6) 94, 216 Cedergren, R.J. (6) 83, 93
Celander, D.W. (6) 216 Celentano, G. (7) 116 Celeries, J.P. (1) 287 Cen, W. (5) 132 Chabardes, P. (7) 133 Chabert, P. (7) 32 Chaddha, M. (6) 40 Chadha, A. (6) 233 Chadnaya, I.A. (1) 5, 6 Chai, M. (6) 207 Chaix, C. (6) 90 Chakrovarty, P.K. (5) 170 Chambers, R.D. (5) 127, 128
Chambrette, J.P. (8) 204, 205
Chambron, J.-C. (6) 225 Chamizo, J.A. (1) 437 Chandrasekhar, V. (8) 101 Chang, K. (5) 98, 106, 143; (7) 84
Chang, S.C. (8) 218, 219 Charandabi, M.R.M.D. (5) 163
Charrier, C. (1) 83, 355, 431; (3) 8
Charubala, R. (6) 107, 150, 151, 199
Chassot, L. (6) 222 Chattopadhyay, P. (1) 147 Chattopadhyaya, J . (6) 84, 132, 157
Chauzov, V.A. (1) 236, 237; (4) 36 Chavis, C. (6) 35 Cheh, A.M. (6) 233 Chehab, F.F. (6) 194 Chen, A. (7) 13 Chen, B.-C. (7) 57 Chen, C. (7) 39 Chen, J. (6) 31; (8) 280 Chen, J.-H. (6) 69 Chen, K. (8) 263 Chen, M. (5) 50 Chen, R. (5) 53, 185, 186, 221
Chen, S. (5) 156 Chen, S.J. (1) 215 Cheng, L. (5) 185 Cheng, M.-C. (1) 34 Cheon, S.H. (7) 139 Cherches, G.Kh. (8) 166, 167, 169
Cherkasov, R.A. (5) 136 Chernega, A.N. (1) 167, 325, 336, 390, 392, 397; (5) 96; (8) 5, 13, 14, 68 Chernov, A.N. (1) 189;
(5) 1 2 1
Chernova, A.V, ( 5 ) 183 Chest, V.P. ( 6 ) 181 Chi, D.Y. (6) 204 Chiba, M. (1) 29 Chiba, T. (1) 8 1 Chiche, L. (1) 277; (8) 45
Chida, N. ( 7 ) Chiesi-Villa, Chirkova, L.P. Chistokletov,
110 A. (1) 249 (1) 235
V.M. (2)
36, 37
Chivers, T. (1) 460; (8) 171-173
Chizhikova, 0.1. (8) 166 ChlGdek, S. (6) 91 Cho, B.S. (8) 118 Cho, S.K. (5) 160 Chojnowski, J. ( 5 ) 2, 223 Chopra, A.K. (7) 88 Chou, T.4. (7) 70 Chou, W.-N. ( 7 ) 3; (8) 10 Choukroun, R. (1) 363 Christ, W.J. (7) 139 Christau, H.-J. (1) 136, 276, 277; (7) 34; (8) 45 Christodoulou, C. (6) 86, 87 Christol, H. (1) 136 Chrnov, P.P. (2) 38 Chu, B.C.F. (6) 223 Chu, P.J. (1) 177 Chugunov, Yu.V. (4) 15, 24 Chung, Y.-C. (5) 66, 67 Church, K.M. (6) 235 Churusova, S.G. ( 5 ) 75 Cichy, A.F. (6) 19 Ciesla, J.M. (6) 23 Ciora, R.J., jun. (8) 242, 245 Cirule, M. (1) 194 Ciuffreda, P. (7) 129 Claesson, A . (5) 119 Clegg, W. (8) 22 Climent, M.S. (7) 26 Clyne, J. (6) 188 Coates, R.M. (5) 62 Coclizza, A.J. (4) 61 Coggio, W.D. (8) 98, 117 Cohen, J.S. (4) 62; (6) 102, 104, 105, 109 Colin, B. (6) 12 Collignon, N. (5) 101; (7) 67 Colman, R.W. (6) 201 Colombo, D. (1) 356; (4) 81; (7) 129; (8) 72 Colonna, F.P. (6) 51 Colston, J.E. (6) 196
Combs, P. (5) 170 Conda, L. (8) 112 Connolly, B.A. (6) 173 Conrad, P.C. (3) 38 Contreras, R. ( 2 ) 45 Coolidge, M.B. (1) 385 Cooper, M.K. (1) 92 Corbel, B. (5) 117, 145 Cordes, A.W. (8) 174, 175, 291
Corey, D.R. (6) 210 Corey, E.J. (7) 92, 105 Corless, M. (4) 10 Cory, M. (6) 236 Cosstick, R. (4) 72, 73; (6) 155, 156
Costello, C.E. (6) 222 Coughenour, L.L. ( 5 ) 174 Couret, C. (1) 389 Coutrot, P. (5) 158 Cowley, A.H. (1) 58, 317, 342, 375; (4) 89
Cox, M.B. ( 7 ) 141 Cramer, F. (6) 202 Cravador, A. (4) 60; (6) 191
Cregge, R.J. (7) 93 Cropper, P.E. (1) 275 Cruickshank, K.A. (6) 184 Csonka, G. (1) 439, 440 Cummings, D.G. (8) 268 Curtis, N.J. (I) 14 Cypryk, M. (5) 223 Czira, G. (5) 113 Dabkowski, W. (4) 76; (6) 114
Dahl, B.H. (4) 68; (6) 127
Dahl, 0. (4) 55, 68; (6) 127
Dahlem, A.M. (7) 136 Dahlhoff, W.V. (4) 39 Dake, L.S. (8) 86 Dakternieks, D. (1) 61 Dalpozzo, R. (1) 446 Damha, M.J. (4) 57, 65 Danheiser, R.L. ( 7 ) 74 Daniels, L.M. (5) 55 Danilov, S.D. (1) 234 Dare, H.F. (1) 381, 383 Dargatz, M. (3) 21 Darmuth, M. (1) 326 Dartiguenave, M. (1) 269; (4) 94
Dartiguenave, Y. ( 1) 269; (4) 94
Dartmann, M. (1) 313, 442 Darvich, M.R. (1) 136 Daumas, M. (7) 79 Davelaar, E. (5) 30
Author
Index
Davies, F.A. (7) 57 Davies, L.C. (6) 37 Davies, R.J.H. (6) 239 Davis, G. (8) 197 Davis, M.E. (1) 41 Davisson, V.J. (4) 48; ( 5 ) 34
Davtyan, A.G. (8) 216 Dawes, H.M. (1) 57 Dawson, M.I. (6) 176 Day, R.O. (2) 40; (5) 180, 181
Debart, F. (6) 137 de Boer, J.L. (8) 178 de Bont, H.B.A. (4) 44, 45
DeBruin, K.E. (5) 220 Debyser, 2. (6) 141 Decamp, D.L. (6) 201 De Clercq, E. (6) 10, 33, 141, 151
Declereq, J.P. (5) 57 Dedek, V. (1) 259 Deeming, A.J. ( 7 ) 40 Degols, G. (6) 208 Deinzer, M.L. (6) 133 DeJaeger, R. (8) 11, 74, 193, 204, 256
de Jesus, R. (5) 175 Dellaria, J.F., jun. (1) 135; (7) 12
Delmas, M. (5) 56; (7) 26, 72
Delorme, D. (7) 95 Dembek, A.A. (8) 215, 250, 261
Demuth, R. (1) 253 De Napoli, L. (6) 66 Dgn'e, G.Y. (8) 172 Deng, H.-B. (1) 252 Denis, J.M. (1) 90, 329, 330; (5) 122
Denmark, S.E. (7) 69 Denny, D.B. (1) 271 Dents, J.-M. (1) 89 DePoortere, M. (8) 219 Dervan, P.B. (6) 70, 71, 215
Deschamps, B. (1) 231, 412
Deschamps, E. (1) 418; (3) 10
Deschamps, R. (1) 409 Desmond, R. (3) 34 Desmyter, J. (6) 141 de Solms, S.J. (5) 16, 17 Despax, C. (4) 9 Desrosiers, P.J. (1) 2 1 1 Detsch, R. (1) 395 Deus, N. (1) 8 Deutsch, W.F. (8) 100 Devillers, J. (2) 11
347 Devine, R.L.S. (8) 250 Devon, T.J. (1) 10, 36 De Vos, M.-J. ( 4 ) 60; (6) 191
De Waal, B.M.F. (5) 82 Dewan, S.K. (5) 70 D'Halluin, G. ( 8 ) 11 Dhawan, B. (3) 7; (5) 116, 204
Dhindsa, A.S. (7) 8 1 Diefenback, U. (8) 103 Diel, P.J. (5) 169 Diemert, K. (1) 230 Dikshit, A. (6) 40 Dillon, K.B. (1) 279; (2) 13
Ding, M. (1) 21 Ding, X. (1) 300 Discher, S. (1) 155 Dissinger, S. (6) 196 Ditrich, K. (7) 104 Dixneuf, P.H. (1) 192 Dmitrichenko, M.Yu. (2) 23; (8) 28
Dmitriev, V.I. (1) 108 Doan, K.E. (8) 263 Dodge, J.A. (8) 210 Dobler, C. (1) 110 Dokuchaeva, I.S. (2) 36 Dolgushin, G.V. (8) 28 Dolinnaya, N.G. (6) 98 Dominski, Z. (6) 119 Domkowski, L. (5) 167 Dondoni, A. ( 7 ) 138 Donskikh, V.I. (1) 228, 245; (2) 23; (8) 28
Dorfman, Ya.A. (1) 103; (5) 8
Dormond, A. (1) 40 Dorokhov, V.I. (8) 50 Dorow, R.L. ( 7 ) 69 Dose, K. (6) 197 Dostalek, R. (7) 15 Douglas, T. (1) 423, 426 Downes, J.M. (1) 92 Downing, K. (6) 188 Downs, A.J. (2) 8 Doxsee, D.D. (8) 173 Doxsee, K.M. (3) 9 Doyle, T.W. (1) 171 Drach, B.S. (1) 285, 286 Draeger, M. (1) 389 Draheim, S.E. (7) 144 Drapailo, A.B. (1) 391 Dreef, C.E. (5) 168 Dreef-Tromp, C.M. (6) 46 Dreval, V.E. (8) 236 Dreyer, R. (1) 155 Driess, M. (1) 130 Drozdova, T.D. (5) 60 Drozdova, Ya.A. (1) 254; (4) 91
Drummond, J.T. (5) 173, 174, 176; (7) 78
Dubovik, 1.1. (8) 235 Duchamp, D.J. (6) 237 Duchenko, I.N. (2) 32 Duckworth, P.A. (1) 92 Dufour, N. (1) 356, 362, 363; (4) 81; (8) 72
Duhamel, L. (7) 133 Duhei, I.Ya. (6) 59 Duke, C.B. (8) 2 Du Mont, W.-W. (1) 182 Dunaway-Mariano, D. (5) 149
Dunbar, K.R. (1) 215 Duncan, L. (6) 206, 207 Dunn, S.F.C. (1) 162 Duplan, A.M. (6) 90 Dupre, D. (6) 139 Durand, G. (3) 5; (5) 72 Durst, H.D. (5) 66 Dutasta, J.P. (5) 57 Dvorakova, H. (6) 17 Dvornikov, A.S. (1) 159 Dybowski, P. (5) 35 Dylla, M. (1) 95; (7) 9 Dziewonska-Baran, D. (7) 87
Dziwok, K. (1) 82; (3) 4 Ebisuya, K. (4) 42; (5) 19
Edelmann, F.T. (4) 87 Edmundson, R.S. (8) 19 Edwards, M.L. (1) 173 Effinger, G. (1) 131 Efimov, V.A. (6) 59 Efremov, Yu.Ya. (1) 235, 364; (4) 16
Egan, W. (4) 20; (5) 78, 142; (6) 100, 108, 113
Egawa, T. (4) 80 Egorov, M.P. (1) 159 Eguchi, S. (7) 119, 120 Ehle, M. (1) 413; (2) 34 Eifert, G. (5) 113 Einstein, F.W.B. (1) 165; (8) 21
Eisenberg, R. (1) 209 Ejike, E.N. (1) 73 El Bakili, A. (8) 105, 106, 286, 287
El-Din, G.N. (1) 416, 417 Elekes, I. (5) 27 Eley, C.N. (5) 61 Elgadi, A. (5) 158 El Gaied, M.M. (5) 108 Elhaddadi, M. (5) 153 El Hamshary, H. (1) 301 Elias, A.J. (1) 167; (8) 176, 177
348
Orgunophosphorus Chemistry
Eliseenkova, R.M. (4) 32 Elkik, E. (5) 125 Ellermann, J . (1) 35; (5) 52
Elliot, D.J. (1) 207 Ellwood, S.B. (6) 44 El-Manouni, D. (2) 31, 42; (5) 138
El-Rahman, N.M.A. (4) 14 Elsevier, C.J. (8) 20, 188
Elmer, H.I.. (6) 218 Emanuilidi, S.E. (1) 263 Engel, R. (5) 91 Engelhardt, U. (5) 54; (8) 103
Engela, J . (1) 251; (4) 74, 75;
(6) 110,
158
Englard, S. (7) 142 Enholm, E.J. (7) 58 Enjalbert, R. (8) 289 Epiehina, T.A. (1) 241; (5) 5
Erabl, T. (3) 22 Erastov, O.A. (1) 111-116, 157, 265, 364, 365 Eritfa, R . (4) 54, 59; (6) 115 Erkelens, C. (4) 46 Ernst, L. (1) 261, 274 bcalc, R. (7) 94 Escudie, J. (1) 389 Eskew, N.A. (2) 17, 29 Eetrada-Yanez, H.R. (8) 182 Et-d-Hoghadh, G. (1) 351, 352 Eto, H. (5) 47, 48 Ettel, M.L. (5) 163 Evans, S . A . , jun. (2) 5, 17, 29 Exarhoa, G.J. (8) 90 Eya, B.K. (7) 91
Faaabender, F.J. (8) 77 Faucher, J.P. (8) 107, 108, 287
Federov, S.G. (8) 272 Fedorenko, T.V. (1) 1 Fedorov, S.B. (5) 69 Feher, M. (1) 120 Feng, H. (5) 112 Fenake, D. (1) 25 Ferguson, G. (1) 141, 142 Fernandes, J.R. (8) 89 Ferrar, W.T. (8) 254, 255, 280
Ferrero, M. (7) 62 Ferris, I.F. (8) 2, 90 Feshchenko, N.G. (1) 239 Featiaov, V.I. (5) 37 Fetter, J. (7) 130 Fidanza, J.A. (6) 103 Fiel, R.J. (6) 217 Field, L. (5) 73 Fife, T.H. (5) 65 Fild, H. (1) 227 Filonenko, L.P. (8) 67 Finch, R.A. (1) 444 Fincham, J.K. (8) 95 Fiacher, J . (1) 72, 420 Fischer, H. (2) 41 Fisher, K.J. (1) 179 Fisher, H. (8) 24 Fisher, H.H. (7) 107 Fittkau, S. (7) 73 Fleck, T.J. (2) 19; (7) 18
Flbrke, U. (1) 17 Flora-Vela, A. (3) 16 Floriani, C. (1) 249 Fluck, E. (1) 452; (7) 8 Focee-Focee, H.de la C. (7) 117; (8) 42, 54 Fbldesi, A. (6) 84 Fogagnolo, H. (7) 138 Foken, H. (4) 79 Fokin, A.V. (1) 236, 237; (4) 36
Facchin, G. (8) 120 Facklam, T. (1) 457 Fairley, T.A. (6) 236 Fait, J . (8) 171, 173 Faktor, M.M. (1) 59 Falck, J.R. (5) 20; (7) 30, 97
Fallouh, F. (1) 136 Fang, Y. (8) 111 Fanta, A.D. (1) 130 Fantin, G. (7) 138 Farina, V. (1) 172 Farnier, M. (8) 55, 63 Farooq, 0. (1) 240 Farrell, N.P. (6) 224 Farrow, S.N. (6) 10
Folkeason, B. (8) 9 Folkman, W. (6) 28 Fomina, E.A. (8) 169 Fontaine, X.L.R. (1) 206 Ford, M.J. (7) 103 Ford, R.R. (8) 225, 229 Forth, I. (8) 19 FOBS, V.L. (1) 349, 350; (8) 66
Foucard, A. (1) 402 Fournier, C. (8) 74 Fournier, J. (1) 192 Fox, C.M.J. (7) 103 Fraenkel, G. (1) 68 Frank, C.W. (8) 87 Franke, R . (2) 39; (5) 137
Franz, J.E. (5) 171 Frebel, H. (1) 320, 321, 323, 324
Frehel, D. (5) 124 Frejd, T..(l) 11 Freaneda, P.M. (7) 126; (8) 60
Frick, J.A. (5) 49 Friedman, A.E. (6) 225 Friedrich, C. (8) 248 Friedrich, D.M. (8) 86,
90 Friedricksen, B.P. (3) 14 Frigo, D.H. (1) 59 Frijns, J.H.G. (1) 18, 77 Fritz, G. (1) 128, 129 Froehlich, R. (1) 371 Fuchs, E.P.O. (1) 337 Fujii, H. (4) 56; (6) 60, 79 Fujikawa, K. (8) 154 Fujimoto, M. (8) 274 Fujimoto, T. (4) 42 Fujioka, H. (7) 139 Fujiwara, T. (4) 56; (6) 60, 214 Fukuyaoa, Y. (8) 264 Fulde, H. (8) 32 Furdon, P.J. (6) 119 Furmanova, H.V. (1) 200, 201
Furukawa, Furukawa, Furusawa, Furuyama,
1. (1) 149
M. (8) 217 0. (1) 298
E. (6) 76
Glirtner-Winkhaus , C. ( 1) 394
Gafarova, A.F. (1) 105 Gaffney, B.L. (6) 163 Gait, H.J. (6) 1 Gajda, T. (4) 17 Galakhov, M.V. (5) 130 Gallagher, M.J. (1) 38 Galluzzi, H.C. (5) 114 Galy, J . (8) 289 Gemper, H. (6) 205 Gamper, S. (1) 70 Ganapathiappan, S. (8) 229, 263
Ganem, B. (5) 14 Ganesh, G.N. (6) 186 Gao, L. (1) 21 Garanti, L. (8) 51 Garbed. A. (6) 51, 68 Garcia, C. (1) 276 Gareev, R.D. (8) 29 Gasc, M.B. (7) 34 Gaset, A. (5) 56; (7) 26, 72
Gaami, V. (2) 11
349
Author Index
Gaur, R.K. (6) 47 Gautel, M. (6) 34 Gautier, C. (6) 81 Gaynor, C. (6) 208 Gazizov, I.G. (5) 198 Gazizov, M.B. (5) 121 Gazizov, T.Kh. (1) 254; (4) 15, 24, 91
Gebel, W. (5) 43, 45 Gebhard, I. (6) 232 Geiser, T. (6) 101 Genet, J.P. (5) 159 Geoffroy, G.L. (8) 69 Geoffroy, M. (7) 4 Gerlt, J.A. (6) 148, 149 Gero, S.D. (5) 191; (6) 14
Gervais, D. (1) 363 Getman, T.D. (1) 252 Geue, R.J. (1) 104 Geyer, E. (1) 400; (5) 215
Ghazzouli, I. (5) 189, 190
Ghosh, D. (6) 241 Gibson, D. (5) 201 Gibson, V.C. (8) 22 Gierstae, R. (3) 25 Gildea, B. (6) 146 Gilham, P.T. (6) 74, 75 Gillam, I.C. (6) 179 Gillier, H. (2) 42 Gilyarov, V.A. (8) 16 Girard, J.P. (7) 94 Girard, Y. (7) 95 Glanz, D. (5) 44, 81; (8) 35
Glemarec, C. (6) 132 Gleria, M. (8) 88, 120, 232
Glidewell, C. (1) 141, 142
Gloer, K.B. (5) 146 Glowacka, D. (6) 198 Godovikov, N.N. (5) 96 Gold, B. (6) 235 Goldblum, A. (5) 201 Gol'dfarb, E.I. ( 8 ) 36 Gol'din, G.S. (8) 272 Golding, B.T. (6) 44 Golinski, J. (7) 87 Golokhov, D.B. (2) 22; (4) 25
Golova, L.K. (8) 239, 253 Golovan, E.B. (1) 6 Golovanov, A.V. (5) 133 Gomelya, N.D. (1) 239 Gonce, F. (1) 356; (4) 81; (8) 72
Goodchild, J. (6) 177 Goody, R.S. (6) 34 Gopalkrishnan, G. (6) 234
Gor, M. (1) 146 Gorchakov, V.V. (8) 85 Gorgues, A. (5) 56 Gorn, V.V. (6) 82 Gorshunov, I.Yu. (1) 189 Goryunov, E.I. (5) 11, 12 Gosney, I. (5) 41, 70 Gottsegen, A. (7) 115 Gough, G.R. (6) 74, 75 Gouygou, M. (1) 351, 352 Grabowski, S. (6) 29 Grachev, M.K. (4) 19 Graczyk, P. (3) 15 Graf, W. (7) 5 Graffeuil, M. (8) 108, 287
Grajkowski, A. (4) 67; (6) 153
Grandi, G. (6) 65 Grandjean, D. (1) 213 Granier, M. (3) 46 Grant, P.G. (6) 201 Grapov, A.F. (5) 75 Grassi, M. (5) 114 Gray, G.A. (1) 419 Gray, G.M. (1) 37 Gree, R. (1) 262; (7) 42, 43, 113, 114
Green, D.L.C. (5) 49 Green, L.M. (1) 31 Greenlee, W.J. (5) 170 Gregg, M.R. (1) 247; (4) 77
Grekov, L.I. (1) 103 Grelet, D. (1) 136 Griffith, M.C. (6) 92 Griffiths, D.V. (2) 30; (4) 11
Griffiths, P.A. (2) 30; (4) 11
Grigoryan, N.Yu. (1) 78 Grimaldo Moron, J.T. (1) 87
Grison, C. (5)'158 Grobe, J. (1) 253, 312, 313, 332-335,
371
Grobelny, D. (4) 6 Groebke, K. (6) 145 Grohmann, A. (1) 156 Grossmann, G. (5) 225 Grosspietsch, T. (1) 313 Gruber, M. (1) 119, 246; (4) 96, 97; (5) 93
Grueger, C. (7) 5 Grutzmacher, H. (1) 272, 273, 344, 345, 360; (3) 46; (4) 33, 93; (7) 65 Gryaznov, S.M. (6) 159 Gryaznova, 0.1. (6) 98 Gu, R.-L. (3) 33 Guastini, C. (1) 249
Gubnitskaya, E.S. (5) 166 Gudat, D. (1) 372 Guerch, G. (8) 288 Guesnet, J.-L. (6) 140 Gueth, W. (1) 442 Guida, W. (5) 175 Guilard, R. (8) 55, 63 Guillemin, J.C. (1) 329, 330
Guillemont, J. ( 7 ) 133 Gullidge, P.M.N. (6) 227 Gunji, H. (7) 109 Guo, C.Y. ( 5 ) 129 Gupta, K.C. (6) 47, 181 Gusar', N.I. (5) 79, 80 Gusarova, N.K. (1) 108, 109
Guy, P.M. (6) 243 Guybitg, K. (8) 20 Ha, H.-J. (4) 7; (5) 152 Ha, T.K. (8) 3 Habadie, N. (1) 269 Habicher, W.D. (4) 18 Habus, I. (1) 22, 23 Haegele, G. (1) 246; (5) 93
Haelters, J.P. (5) 117, 145
Hagan, M.D. (6) 91 Haggerty, B.S. (1) 426 Hagiwara, S. (7) 119 Hagnauer, G.L. (8) 197 Hahn, J. (1) 121, 123 Haikal, H.F. (6) 35 Hala, T. (6) 32 Halford, M.H. (6) 96 Hall, C.D. (1) 271 Halpern, J. (1) 211 Halterman, R.L. (1) 24 Ham, W.-H. (7) 139 Hambley, T.W. (3) 37 Hametin, J. (1) 354 Hammond, G.B. ( 5 ) 147; (7) 141
Hamor, T.A. (1) 107 Han, F. (6) 237 Hanack, M. (1) 257; (7) 11
Hanafusa, T. ( 7 ) 20 Hanaya, T. (5) 118 Handa, Y. (1) 91 Hanna, M.M. (6) 196 Hanson, B.E. (1) 41 Hanssgen, D. (1) 318; (4) 88 Hara, E. (8) 57 Haralimbidis, J. (6) 206, 207
Hargeave, P.A. (5) 28 Harger, M!J.P. (5) 206,
3io 207
Harlow, R.L. (1) 20 Harmat, N.J.S. (3) 29 Harris, F.M. (6) 241 Harris, R . K . (8) 80 Harris, R.L.N. (4) 8 Harris, T.M. (6) 234 Harrison, K . N . (1) 212 Harrison, P.J. (3) 30 Hartmann, H.-M. (1) 65, 441
Hartung, H. (3) 21 Harusawa, S. (5) 85-87 Hasegawa, Y. (6) 52 Hasenbach, J . (1) 121 Hashimoto, S. (1) 149; (8) 71
Hashizume, N. (3) 22 Hassanein, M. (1) 301 Hassler, K . (1) 60, 387 Hata, T. (4) 56; (6) 60 Hatakeyama, S. (3) 36 Hatanaka, M. ( 7 ) 33 Haupt, H.-J. (1) 17 Hawkins, L . D . (7) 139 Hayakawa, S. (6) 41 Hayakawa, Y. (4) 41; (6) 42, 43, 50, 85
Hayashi, A . (5) 99; (7) 85
Hayashi, T. (1) 9 Hayashi, Y. (8) 149 Hayes, J.A. (6) 74, 75 Haynes, R.K. (3) 37 Hays, S . J . (5) 176 Hearst, J.E. (6) 204 Heathcock, C.H. (7) 71 Hecht, G. (1) 95; (7) 9 Heckmann, G. (1) 452; (7) 8
Hecquet, B . (8) 74 Hegemann, M. (1) 332 Heimer, N.E. (5) 73 Heine, J . (1) 396; (2) 39; (5) 131, 135
Heinicke, J. (1) 102, 439, 440; (5) 115
Heintz, R . A . (1) 133 Heitz, M.-P. (1) 151, 153 Helbing, R . ( 4 ) 26 Helene, C. (6) 139 HeliGski, J . (5) 71 Helmut, S. (6) 228 Henkel, T. (8) 185, 186 Hensel, R . (1) 182 Herbst, H. (6) 64 Hercouet, A . (1) 256 Herdewijn, P . (6) 150, 151
Hermann, E. (8) 79 Hermesdorf, M . (1) 377 Hernandez Cano, F. (8) 54
Herne, J . (5) 58 Herrema, J.K. (8) 178 Herrmann, E. (8) 202 Herrmann, R. (1) 8; (6) 4 Hess, N.J. (8) 90 Hessell, E.T. (1) 16 Heuer, L. (1) 220, 221, 232, 274
Heung-Cho, P. (5) 83 Hey, E. (1) 62, 64 Heydt, H. (1) 337, 377, 457
Heyen, B.J. (8) 261 Hida, M. (4) 80 Hidaka, T. (5) 148 Hietkamp, S. (1) 226 Higgins, S . J . (1) 183 Hilali, S. (8) 74 Himdi-Kabbab, S. (1) 354 Himeda, Y. (7) 33 Hinman, L.M. (1) 74 Hirao, I. (6) 52, 80 Hiraoka, K . (8) 150, 151 Hirashima, A . (5) 47, 48 Hirata, K. (3) 22 Hiroi, K . (1) 193 Hirose, M. (6) 85 Hirose, T. (8) 265 Hitchcock, M.J.M. (5) 189, 190
Hitchcock, P.B. (1) 214, 433-435
Hobbs, P.D. (6) 176 Hodge, P. (1) 2 Hodgson, P.K.G. (5) 41 Hohn, A . (1) 104 Hoffmann, H. (3) 19 Hoffmann, R.W. (7) 104 Hogarth, G. (1) 205 Hojo, M. (1) 9 Holah, D.G. (1) 207 Holl, M.M. (1) 39 Holmes, J.M. ( 2 ) 40 Holmes, M . A . (7) 107 Holmes, R . R . (2) 40 Holt, M.S. (1) 419 Holy, A . (5) 192; (6) 17, 18
Holzappel, W . (7) 145 Holzl, W. (1) 368 Honda, K. (4) 53 Honda, T. (8) 71 Hong, S. (5) 143; (7) 84 Hoogerhout, P. (6) 46 Hoover, J . F . (1) 270; (7) 44
Hopkins, P.B. (6) 185, 219, 220
Horenstein, B . A . (7) 143 Horn, H.G. (1) 187 Horn, T. (6) 187, 188 Hornback, W.J. (7) 49
Horne, D . A . (6) 70 Horner, L. (1) 400; (4) 38; (5) 215
Hosoya, I. (8) 139 Hosseini, M.W. (6) 229 Houard, S. (6) 191 Houten, B.V. (6) 224 Hovanec, J.W. (5) 66 Hovard, S. (4) 60 Howard, J.A.K. (1) 381, 383
Howard-Lock, H.E. (1) 15 Hoye, P.A.T. (1) 212 Hrncir, D.C. (1) 56 Hruska, F.E. (6) 167 Hsi, J.D. (7) 31 HSU, L.-Y. (1) 252 Hu, D. (1) 380 Hu, S. (5) 53 Huang, H.-C. (7) 105 Huang, Y.-Z. (7) 22, 39 Huff, J.R. ( 5 ) 16, 17 Huffman, J.C. (7) 49 Huffman, J.H. (5) 163 Hughes, A.N. (1) 207, 222; (3) 17; (5) 180, 181 Hummel, M. (6) 64 Hurley, C.H. (6) 232 Hurst, G.D. (6) 205 Hursthouse, M.B. (1) 57, 59 Hussain, B. (1) 59 Hussain, W. (1) 107 Hustedt, E.J. (6) 185 Huszthy, P. (1) 146 Hutchings, D.S. (1) 19 Hutchinson, A.J. (5) 175 Hutchinson, D.W. (5) 102; (7) 86 Huy, N.H.T. (1) 415
Ibraimova, Zh.U. (5) 8 Ichida, H. (1) 13 Igau, A . (1) 360, 366; (4) 93
Ignat'ev, Yu.A. (1) 296 Ignat'eva, S.N. (1) 112, 364
Ignatov, M.G. (8) 81 Iida, A. (3) 11; (5) 107 Iino, Y. (7) 123 Iizawa, T. (1) 304 Iizuka, K. (5) 83 Ikai, K. (3) 11 Ikeda, M. (8) 155 Ikeda, S. (4) 80 Ikegami, S. (8) 71 Ikeuchi, T. (6) 120 Il'in, E.G. (8) 81 Il'ina, M.N. (8) 269
Author Index I l n o , Y. (8) 57, 59 I l ' y a s o v , A.V. ( 1 ) 189; ( 5 ) 121, 183 Imagawa, T. (8) 82 Imai, S. (5) 148 Imaki, N. (1) 93 Imamoto, T. (1) 88 Imamura, A. ( 8 ) 231 Imbach, J.-L. (6) 35, 81, 137, 138, 141 Imbeaux, M. (5) 125 Imhoff, P. (8) 20, 188 Inamoto, N. (1) 311, 314, 357; (3) 6; ( 5 ) 178 Inanaga, J. (1) 91 Indzhikyan, M.G. (1) 78; (5) 110 Inoguchi, K. (1) 30 Inomata, K. (1) 302 Inoue, K. (8) 123-125 Iocono, J.A. (6) 146 I o n i n , B.I. (5) 123, 205; (8) 34 Ionkin, A.S. (1) 364, 365 I r i b a r r e n , A. (6) 142 I s a a c s , N.S. (1) 416, 417 Ise, T. ( 1 ) 28 Ishchara, T. (5) 59 I s h i , S. (7) 146 I s h i d o , Y. (6) 52 Ishiyama, T. ( 7 ) 109 Ishmuratov, A.S. ( 5 ) 37 Islam, M.S. (8) 224, 226229 I s s l e i b , K. (1) 429, 430 I t o , T. (8) 276-278 I t o , Y. (1) 9 Ivanov, A.N. (1) 241 Ivanov, B.E. (5) 69 Ivanov, S.A. (4) 28 Ivanov, Yu.V. (8) 8 5 Ivanova, V.N. (5) 197, 198 Iverson, P.L. ( 6 ) 102 Ivonin, S.P. (1) 223 Iwai, S. (6) 240 Iwase, R . (6) 32 Iyer, R.P. (4) 20; (5) 142; (6) 100, 108 I z s o , G. (1) 146 Jachow, H. (1) 120, 125 J a c k , A.G.C. ( 5 ) 41 Jackson, J . A . (5) 146, 147 Jackson, R.H. (5) 175 Jackson, S.A. (7) 14 Jackson, W.R. (1) 216 Jacob, P. (6) 4 Jacobs, €I. (8) 92
35 1 Jacobs, P.W.M. (8) 258 Jacobson, R.A. (5) 55 Jacoby, D. (1) 249, 287 J a c q u i e r , R. (5) 153 J a g e r , L. (5) 43-45, 81; (8) 35, 96, 97 Jahngen, E.G.E. (6) 243, 244 Jahngen, J . H . (6) 243 J a i n , J.K. (4) 13 James, K. (4) 10; ( 5 ) 105 Janca, J. (8) 202 Jand, J. (8) 8, 104, 106, 181 J a n e c k i , T. (7) 135 Janoschek, R. (1) 309 Janssen, R.A.J. (5) 82 J a o u h a r i , R. ( 5 ) 127, 128 Jaud, J. (1) 447; ( 4 ) 82; ( 5 ) 56 Jaworska, M.M. (6) 106, 111 J e d l i n s k i , Z. (8) 102 Jeganathan, S. (1) 3; (7) 21 Jegorov, A. ( 1 ) 217 J e k e l , A.P. (8) 178, 290 J e n d r a l l a , H. (3) 31 J e n k i n s , A.M. (6) 241 J e n k i n s , C.L.D. ( 4 ) 8 J e n k i n s , I.D. (1) 176 Jennings, M.C. ( 1 ) 428 Jeong, B.D. ( 8 ) 161 Jeong, J. (7) 5 J e r i n a , D.M. ( 6 ) 233 J e u l a d e , M.-P. ( 7 ) 76 J i , Y. (6) 209 J i a n g , J. (7) 64; (8) 47 J i a n g , M.Y. (6) 93 J i a n g , X. (5) 164 Jideonwo, A. (1) 7 3 J i n , H. ( 7 ) 139 J i n a , A.N. (6) 176 J i r i k o w s k i , G.F. (6) 180 Johns, R.B. (4) 43; ( 5 ) 29 Johnson, D. (4) 59 Johnson, D.M. (5) 220 Johnson, D.R. (6) 198 Johnson, G. (5) 173, 174, 176; (7) 78 Johnson, P.D. ( 6 ) 231, 232 Johnston, L.J. (1) 295 Jones, A.S. (6) 10, 96 Jones, C.J. (1) 107 Jones, N.M. (6) 12 Jones, P.G. (1) 119, 220, 261; (4) 96 Jones, R.A. (1) 55, 58; (6) 163 Jones, S.S. (6) 8 6 , 88
Jones, T.K. ( 3 ) 34 Jordan, M. (4) 38 Joseph-Nathan, P. ( 2 ) 45 J u a r i s t i , E. ( 3 ) 16 Juge, S. ( 5 ) 159 Jungell-Nortamo, A. ( 6 ) 192 Junk, P.C. ( 1 ) 19 J u t z i , P. (1) 315 Kabachnik, M.I. (1) 238, 291-294; ( 3 ) 15; (5) 10-12, 60, 96, 177; (8) 4 3 Kabachnik, M.M. ( 1 ) 5 , 6; (5) 184 Kachkovskaya , L. S ( 1) 401; (8) 30 Kadel, J. ( 8 ) 180 Kadoura, J. (1) 277; (8) 45 Kadow, J.F. (1) 171 Kadyrov, A.A. (5) 130 Kadyrov, R. ( 1 ) 102; ( 5 ) 115 Kadyrova, V.Kh. (1) 105 Kaiser, K. (6) 175 Kajiwara, M. (8) 126, 196, 266 Kajiwara, N. (8) 146, 152, 165, 264, 276-278 Kajtar, M. ( 5 ) 100 Kajtar-Peredy, M. (1) 146; (7) 115, 130 Kalabina, A.V. (1) 245 Kal'chenko, V . I . (8) 27 Kallenbach, N.R. (6) 69 Kallmiinzer, A. (1) 449 Kalnik, M.W. (6) 164, 165 Kamaike, K. (6) 52 Kamaletdinova, R.N. (2) 35 Kamalov, R.M. (8) 36 Kamata, K. (8) 59 Kamer, P.C.J. (4) 2 I (6) 99 Kamiya, Y. (8) 265 Kamiyama, S. (8) 93 154, 217 Kan, Y.W. (6) 194 Kaneti, J. (1) 96; 7) 10 Kang, S.H. (7) 139 Kanoh. S. (1) 260 K a n o i t a , N.-(7) 124; (8) 58 Kant, M. (4) 26 Kanzaki, M. (3) 22 Kaplan, B.E. (4) 59 Kappe, T. (8) 44 Kaptein, R. (6) 239 Karaman, R. (5) 201
.
3s: Karasik, A . A . (1) 111, 113, 114, 116, 157 Karataeva, F.ICh. (5) 136 Kardanov, N.A. (5) 96 Kargin, Yu.M. (1) 296 Kariko, K . (6) 107 Karimov, K.R. (5) 165 Karino, H . (1) 81 Karl, R. (5) 90; (6) 3, 4 Karsch, H.H. (1) 69, 70 Kaseman, R. (6) 226 Kasukhin, L.F. (1) 167; (8) 13, 14 Katahira, M. (6) 240 Kato, H. (4) 41; (6) 41, 50 Kato, M. (6) 42 Kato, N . (5) 84 Kato, T. (1) 304 Katritzky, A.R. (7) 64; (8) 47 Katsuta, M. (8) 201 Katsutoshi, K . (8) 71 Katti, K.V. (1) 164, 165; (8) 21, 190, 191 Kaushik, M.P. (5) 163, 202 Kawabata, H. (6) 214 Kawasaki, T. (7) 35 Kawashima, T . (3) 6; (5) 178 Kazakov, P.V. (5) 103 Kazakov, V.P. (2) 18 Kazantseva, M.V. (1) 228, 245 Kazmierczak, K. (1) 124 K e l l , B. (6) 121 K eller, K. (4) 87; (8) 185 Keller, T.H. (7) 111 K eller, U . ( 1 ) 70 Kellner, K . ( 5 ) 115 Kellner, R . (1) 102; (3) 19 Kelly , J.E. (8) 280 K elly , R.C. (6) 232 Kemp, B.E. (5) 29 Kemp, T . J . (1) 202 Kennedy, J . D . ( 1 ) 206 Kennepohl, D.K. (2) 50 Kenyon, G.L. (6) 36, 38 Kesseler, K . (3) 31 Kettani, A.E.-C. (6) 7 Kezdy, F. (6) 237 Khabbass, N.D.A. (1) 279 Khachatryan, R . A . (1) 78 Khairullin, R.A. (5) 121 Khamatova, Z.M. (5) 183 Khambay, B . P . S . (7) 88 Khan, M.R. (4) 51; (6) 20 Khandker, M . N . I . (1) 283 Kharchenko, A . V . (1)
223; (8) 38 Khaskin, B.Q. (5) 37 Khasnis, D.V. (2) 48 Khawli, L.A. (5) 126 Khidre, M.D. (1) 139 Khizbullin, F.F. (5) 162 Khodaei, M.M. (1) 162 Khodah, A . A . (8) 16 Khotinen, A . V . (5) 97 Khristov, V . (5) 203 Khustnutdinova, E.K. (2) 35 Kibardin, A.M. (1) 453, 454 Kibler-Herzog, L. ( 6 ) 121 Kidd, K.B. (1) 58 Ki el basi n sk i , P. (3) 32 Kim, C. (8) 250 Kim, C.U. (5) 188, 190; (6) 15, 16 Kim, D.H. (8) 118 Kim, S. (1) 266, 288; (5) 55; ( 7 ) 25 K i m , S.S. (1) 266 Kim, T.C. (1) 403; (4) 85; (8) 8 K i m , T.V. (5) 208-210; (8) 33 K i m , Y.C. (1) 288; (7) 25 Kim, Y.J. (5) 160 Kimura, I. (8) 150, 151 Kimura, Y. (1) 298, 299 King, T . J . (8) 19 Kinoshita, K . (8) 125 Kinting, A . (1) 49, 110 Kirchgiisaner, R. (8) 92 Kirchmeier, R.L. (5) 129, 132 Kirchner, J . J . (6) 185 Kireev, V.V. (8) 2 6 Ki ri l ov, E.M.G. (1 96; (5) 76; (7) 10 Ki ri l ov, M. (1) 96 (7) 10 Kirpichnikov, P.A. 105 Kisarova, L.I. (1) 263, 264 Kiseleva, E.I. (5) 208-210; (8) 33 Kishi, K . (1) 9 Ki sh i , Y . (7) 139 Ki si el owski , L. (1) 289; (7) 59 Ki tas, E.A. (4) 43 Kitayama, M. (8) 122, 128-136, 138, 140, 160 Kliimer, F.-G. (1) 422 Klein, E. (1) 388 Klein, M. (6) 4 Kleinpeter, E. (3) 21 Klepa, T.I. (8) 12
Klinge bie l, U . (1) 66, 67; (8) 180 Klings te dt, T. (1) 11 Klobucar, W.D. (8) 220, 221 Klos ins ki, P. (5) 92 Kluge, H . (1) 448 Klumpp, E. (5) 113 Kniezo, L. ( 5 ) 89 Knight, G.J. (8) 271 Knoch, F. (1) 35; (5) 52 Knochel, P. ( 7 ) 70 Knoll, F. (1) 305 Knox, S.A.R. (1) 205 Knuppel, P.C. (1) 317; (4) 89 Kobayashi, E. (8) 84, 93, 94 Kobayashi, K . (8) 127 Kobayashi, Y . (6) 240; (7) 80 Koch, P . (1) 121, 122; (5) 200 Kohler , H . (5) 43-45, 81; (8) 35, 96, 97 Koenig, M. (1) 351, 352 Konig, T. (4) 18 Konig, W.A. (1) 178; (3) 1 Koguchi, Y . (7) 109 Koidan, G.N. (1) 242, 243, 346-348; (8) 38-40, 67 Koike, T . (1) 267 Kojima, M. (8) 234, 243, 244, 246, 249 Kojima, S. (3) 6; (5) 178 Kolbe, A . (8) 96 Kole, R. (6) 119 Kolesnik, N.P. (1) 101 Kolesnikov, S.P. (1) 159 Kolich, C.H. (8) 220 Koll, B. (2) 41 Kolleck, V . (1) 145; (7) 37 Kolodyazhnyi, 0.1. (1) 98, 200, 201; (2) 22; (4) 25 Kolova, E.V. (8) 272 Komarova, N.I. ( 6 ) 82 Komissarov, V . D . (2) 18 Komissarova, N.G. (7) 98 Komiyama, M. ( 5 ) 68; (6) 24-27 Komoda, Y . (4) 42 Kon, Y . (8) 127 Kondo, T. (1) 302 Kong Tho0 Lin, P.V.S. (6) 170, 1 7 1 Konieczko, W.T. (5) 4 Koning, T.M.G. (6) 239 Kononova, O.A. (5) 75
A ut hor I n d6lc.x Konopka,' A . (6) 120 Konovalova, I . V . (2) 35-38; (5) 6, 7 Konstantinov, 1.1. (8) 236 Koole, L.H. (5) 214; (6) 238 Koreeda, M. (7) 31 Korenchenko, O . V . (1) 244 Korkin, A . A . (1) 390; (2) 24; (8) 5, 6 Kormachev, V . V . (1) 234 Korolev, A.V. (1) 103 Korotaeva, N.M. (2) 18 Korshak, V . V . (8) 164 Korshin, E.E. (4) 16, 32 Kosar, W.B. (1) 198 Koschmieder, S.U. (1) 55 Koser, G.F. (4) 12; (5) 111 Koshushko, B . N . (5) 94 Kosolova, T . N . (8) 164 Kostyuk, A . N . (1) 100, 224 Kotek, R. (8) 145 K o u r i l , M. (8) 91, 119, 202 Kovalenko, L.V. (5) 103 Kovaleva, T . V . ( 2 ) 16; (8) 73, 78 Kovenya, V . A . (8) 68 Koyano, H. (5) 144 Kozarich, J . W . (6) 212, 213 Kozawa, H. (1) 281; (3) 24 Kozhushko, B . N . (5) 1 Koziara, A. (1) 150; (8) 46 Koziolkiewicz, M. (4) 67; (6) 108, 153 Kozlov, E.S. (1) 100, 223, 224 Kozlov, V . A . (5) 75 Kozmik, V . (1) 259 Kramer, B. (1) 394 Krauch, T. (6) 168 Krause, H.-W. (4) 79 Kravtsova, S.F. (8) 272 Krawiecka, B. (5) 224 Krebber, R. (1) 178; (3) 1
Krebs, B . (1) 313, 371, 442 Kreiter, C.G. (1) 379 Kreitmeier, P. (1) 359 Kremer, M. (1) 399 Krepyshevh, N.E. (2) 15 Kretschmann, M. (5) 44 K r i e g e r , C . (6) 34 Krishan, K.S. (8) 229 K r o l e v e t s , A.A. (5) 193
353 K r o l i k i e w i c z , K. (1) 148; (7) 51 Kron, V . A . (1) 228 Kropf, H. (3) 47 Kruchinin, N.P. (8) 239 Krug, A. (6) 160 Krutikov, V . I . ( 5 ) 133 Krzyzanowska, B. (5) 155 Ku, B. (5) 98, 106, 143; (7) 84 Kubelka, V. (1) 259 Kubo, I. (7) 9 1 Kubota, S. (8) 147, 148 Kuchen, W. (1) 230 Kudryavtsev, A.A. (8) 37, 40 Kudryavtseva, I.Yu. (5) 10, 11
Kudryavtseva, L.A. (5) 69 Kudzin, Z.H. (5) 151, 157 Kuehnel-Lysek, K. (1) 366 Kung, E. (4) 40; (6) 63 Kukhar, V . P . (1) 98, 167, 200, 201; (8) 13, 14 Kuksis, A. (1) 247, 248; (4) 77, 78 Kulagowski, J.J. (5) 16, 17, 26, 187; (7) 128 Kulak, T.I. (6) 9 Kulesha, I. (3) 35 K u l i c h i k h i n , V . G . (8) 236-239, 241, 251, 253 Kumar, A. (6) 10 Kumar, V. (6) 186 Kupchik, I.P. (1) 143 Kuptsov, S . A . (8) 238 Kurachi, I. (8) 264 Kurachi, Y . (8) 153 Kurahashi, A. (8) 113, 140, 143, 160 Kurihara, T . (5) 85-87 Kuroboshi, M. (5) 59 Kuroiwa, T . (5) 196 K u r t s , A.L. (1) 152 Kurukawa, M. (8) 201 Kusmierek, J.T. (6) 28 Kusumoto, T . (1) 88 Kuzmin, V.A. (1) 159 Kuznetsov, O.M. (7) 98 Kvasyuk, E.I. (6) 9 Kwon, C.-H. (5) 77 Kyogoku, Y . (6) 240 L a a l i , K. (1) 240 L a b a r r e , J.F. (8) 104-108, 286-289 L a b a u d i n i e r e , L. (2) 42 L a b e i t , S. (6) 34 Lachmann, J. (1) 69, 82; (3) 4
Lacombe, S. (1) 330 L a i , J.S. (1) 203 L a k h l i f i , T. (5) 195 Lakoba, I . S . (1) 219 L a l , K. (7) 100 Lalo, J. (5) 124 Lamande, L. (2) 43, 44 Lamberson, C.L. (6) 236 Lampeka, R.D. (1) 100 L a n c e l o t , G. (6) 140 Landgraf , B. (6) 4 L a n d i n i , D. (8) 112 Landry, S.D. (8) 282 h g , H. (1) 405-407 Lange, G. (1) 334 Langer, R.S. (8) 283 Langhans, P.K. (1) 51-54 Lanneau, G. (5) 223 Lao, Y . ( 7 ) 39 Laramee, J . A . (6) 133 Larsen, C . A . (1) 195-198 Larsen, S.B. (1) 444 L a s b a s t i d a , V. (3) 16 Laszkiewicz, B. (8) 145 h t i p o v , Sh.H. (1) 454 Lattman, M. (2) 48 Latypov, Z.Ya. (5) 13 Laude, B. (5) 195 Laurencin, C . T . (8) 283 L a u t e n s c h l a g e r , H.-J. (1) 27, 178; (3) 1 L a v r e n t ' e v , A.N. (5) 133 Lavrova, E.E. (8) 12 Lebedev, A . V . (4) 37; (6) 112, 116, 117 Lebedev, V . B . (5) 133 Le B i g o t , Y. (7) 26 Lebleu, B. (6) 107, 208 Lecacheux, D. (8) 256 Le C o r r e , M. (1) 256; (7) 46, 47 Le Doan, T. (6) 139 Lee, C . - S . (6) 232 Lee, P.H. (1) 266 Lee, S. (5) 149 Lee, S.J. (6) 240 Lee, S.W. (1) 137 Lee, V.M.-Y. (5) 27 Leeson, P.D. (5) 26 L e f k a d i t i s , D.A. (7) 36 Le Floch, P. (1) 338, 450; (7) 45 Le Floch, Y . (7) 113, 114 Le Gallic, Y. (7) 133 Le G o f f , P. (1) 421; (3) 12 Le G o f f i c , F. (7) 79 Le Guennec, M. (1) 329 Legusch, E.W. (5) 171 Lehn, J.-M. (6) 229 L e i s e , M. (1) 406, 407 h i s s r i n g , E. (1) 429,
353 430, 438
Lellouche, J.-P. (1) 262; (7) 42, 43
Lemaitre, M. (6) 208 Lemmen, P. (6) 4 Lempert, K. (1) 146; (7) 130
Lenders, J.-P. (4) 60; (6) 191
Leng, M. (6) 221 Lensink, C. (2) 46, 47; ( 5 ) 55
Lentz, R.R. (6) 244 Lenz, R.W. (8) 248 Leon, R. (4) 58; (6) 193 Leonetti, J.-P. (6) 208 Leont'eva, I . V . (1) 292-294
Leopold, D. (2) 7 Lepre, C . A . (6) 222 Lerner, M.M. (8) 259, 260 Le ROUX, J. (7) 46, 47 Leroux, Y. (2) 31, 42; (5) 138
Lesiak, K. (6) 33, 152 Lesnikowski, Z.J. (6) 106, 111
Leumann, C. (6) 145 Le Van, D. (1) 253, 312, 313, 332-335,
371 Levan'kov, S.V. (1) 97 Leveque, F. (6) 31 Levina, E.Ya. (1) 453, 454 Levina, L.V. (1) 103; (5) 8 Levison, B. (7) 100 Ley, S.V. (5) 24; (7) 103 Lhomet, G. (1) 287 Li, B.F.L. (6) 162, 164, 165 Li, S. (2) 12; (5) 50, 63, 211-213 Li, S.H. (1) 195-198 Li, S.W. (6) 107, 199; (7) 22 Lianis, P.S. (7) 36 Liao, Q. (5) 134; (7) 54 Liao, X. (2) 12; ( 5 ) 63, 211-213 Libermann, J. (8) 187 Liblong, S.W. (8) 171, 172, 175 Libonas, J. (8) 164 Lieser, B. (1) 120 Lilo, B. (5) 51 Lim-Chung, S. (1) 280 Lin, H.Q. (8) 203 Lin, I.J.B. (1) 203 Lind, R. (6) 131 Lindblad, E.B. (6) 218 Linden, A. (8) 286-288
Lindner, E. (1) 326 Lindner, H.J. (1) 187 Linehan, K. (3) 18 Ling-Chung, S. (7) 2 Liorber, B.G. (5) 183 Lipka, P. (5) 39 Lippard, S.J. (1) 39; (6) 222
Lipsom, S.E. (6) 204 Liskmp, R.M.J. (4) 44-46 Litinas, K.E. (7) 36 Liu, C.W. (1) 203 Liu, G. (1) 300 Liu, H.-J. (5) 88 Liu, L.K. (5) 50 Liu, M.-G. (1) 2 Liu, *R.S.H. (7) 89 Liu, S.-T. (1) 33, 34 Liu, X.P. (5) 42 Liuzzi, M. (6) 147 Livantsov, M.V. (1) 94; (2) 26; (4) 3, 4; ( 5 ) 139
Liverton, N . J . (5) 26 Lock, C.J.L. (1) 15 Lodaya, J.S. (4) 12; (5) 111
Lumin, S. (7) 97 Lumma, W.C., jun. (6) 242 Lunsford, J.H. (1) 177 Lutsenko, I.F. (1) 5, 6, 94, 349, 350; (2) 26, 28; (4) 3, 4; (5) 139, 184; (8) 66 Luu, B. (6; 209 Lyons, L.J. (8) 259, 260 Lyttle, M.H. (6) 77
Ma, Q.-F. (6) 36, 38 Ma, X. (5) 46
Ma, Y.-X.
(6) 122
McAleer, J.F. (7) 140 Macaudiere, P. (1) 79 McCaffrey, R.R. (8) 268 Maccarone, E. (1) 185 McCarthy, J.R. (1) 173 Maccioni, A. (8) 112 McClard, R.W. (7) 14 McCleverty, J.A. (1) 107 McDonald, J.F. (5) 171 McDowell, J.H. (5) 28 McElwee-White, L. (1) 161; (7) 41; (8) 23
Loecher, S.P. (8) 90 Lijschner, T. (1) 251;
McEwen, W.E. (1) 255;
(4) 74; (6) 110 Logunov, A . P . (1) 75 him, N.M. (1) 219 Loke, S.L. (6) 105 Lomakina, A.V. (5) 1 Lomonosov, A.V. (8) 272 Look-Herber, P. (1) 261 Lopez, A. (8) 53 Lopez, F. (1) 455, 456; (7) 63; (8) 42, 48, 64, 65 topusiihki, A. (5) 3, 4, 179 Lora, S. (8) 223 Lorcy, D. (7) 8 1 Lorenz, I.-P. (1) 131 Lorenzen, D. (1) 230 Lorenzo, A. (8) 6 1 Lorimer, J.W. (8) 258 Lough, A.J. (1) 142 Lu, H.-J. (1) 33 Lu, K.-L. (8) 69 Lu, X. (5) 109 Lu, Y. (3) 3 Lucas, A , , I11 (8) 157 Luczak, (5) 179 Ludeman, S.-M. (5) 78 Ludman, C.J. (1) 279 Ludwig, R. (1) 155 Luebke, K.J. (6) 71 Lucke, E. (1) 373 Luh, B.Y. (5) 188, 190; (6) 15, 16
McFadden, H.G. ( 4 ) 8 McFarlane, W. (1) 48 McGall, G.H. (6) 213 McGill, J.M. (7) 112 McGovern, J.P. (6) 232 McGrady, G.S. (2) 8 McGuigan, C . (4) 47; (6)
(2) 21; (7) 19
11-13
Macicek, J. (1) 96; (7) 10
Mack, D.P. (6) 215 McKenna, C.E. (5) 126
McKenna, E.G. (7) 29 Mchughlin, L.W. (6) 103, 146
Macomber, R.S. (5) 217, 218
McQueney, M.S. (5) 149 McWhorter, W.W., jun. (7) 139
Madak, A.S. (6) 86 Madden, H. (7) 88 Maeding, P. (3) 2 Miirkl, G. (1) 353, 359, 368, 449; (7) 61
Maffei, M. (3) 42 Maffrand, J.P. ( 5 ) 124 Mag, M. (4) 75; (6) 158 Magill, J.H. (8) 194, 199, 200, 233, 234, 242-246 Mahran, M.R. (1) 138, 139; (4) 14
Author
Index
355
Maia, A. ( 8 ) 112 Maier, L. ( 5 ) 169 Maigrot, N. ( 1 ) 355, 431 Maikuma, S. ( 4 ) 53 Maisano, F. ( 6 ) 65 Maizel, J. ( 6 ) 120 Majchrzak, M.W. ( 5 ) 157 Majewski, P. ( 1 ) 188; ( 5 ) 9 , 104
Majoral, J.-P.
( 1 ) 356, 362, 363, 402, 404, 447; ( 4 ) 81-84; ( 5 ) 56; ( 8 ) 7 2 , 181 Makhaeva, G.F. ( 5 ) 37 Makosza, M. ( 7 ) 87 Malavaud, C. ( 4 ) 35 Malito, J. ( 1 ) 180 Malone, T. ( 5 ) 174 Maloney, J.D. ( 1 ) 199 Malygin, V . V . ( 5 ) 37 Malysheva, S.F. ( 1 ) 108, 109 Mamedov, V . A . ( 1 ) 144 Mang, M.N. ( 8 ) 109, 215 Manitto, P. ( 7 ) 129 Manna, S . ( 7 ) 30 Manners, I. ( 8 ) 9 9 , 109, 209, 210 Manoharan, M. ( 6 ) 149 Manojlovic-Muir, L. ( 1 ) 428 Mansay, D. ( 6 ) 139 Marchenko, A.P. ( 1 ) 242, 243, 346-348; ( 2 ) 4 9 ; ( 8 ) 37-40, 67, 68 Marcoux, F.W. ( 5 ) 174 Marecek, J.F. ( 5 ) 22 Mariano, P.S. ( 5 ) 149 Marinas, J.M. ( 7 ) 26 Marinetti, A. ( 1 ) 338-341, 376; ( 7 ) 45 Markovskii, L.N. ( 1 ) 101, 306, 307, 325, 336, 391-393, 397, 401; ( 8 ) 27, 30, 31 Marron, B.E. ( 7 ) 96 Marsden, C.J. ( 2 ) 9 Marshall, A.S. ( 8 ) 280 Marth, C.F. ( 2 ) 20; ( 7 ) 17
Martin, J.C. (5) 188-190;
( 6 ) 1 5 , 16
Martin, S. ( 1 ) 312 Martinelli, M.J. ( 7 ) 139 Martynchik, S.P. ( 8 ) 169 Martynov, I.V. ( 1 ) 241, 244; ( 5 ) 5 , 37
Martynyuk, E.G. ( 8 ) 78 Maruyama, I. ( 8 ) 201 Maryanoff, B.E. ( 2 ) 4 Mashchenko, N.V. ( 1 ) 238; ( 8 ) 43
Massiot, G. ( 7 ) 75 Masson, S . ( 4 ) 23; ( 5 ) 140, 141; ( 7 ) 8 2 , 83
Mastryukova, T.A. ( 1 ) 238, 291-294; ( 5 ) 103; ( 8 ) 43 Masuda, I. ( 6 ) 52 Masuko, T. ( 8 ) 233 Mathey, F. ( 1 ) 7 9 , 214, 231, 338-341, 343, 355, 376, 408, 409, 412, 415, 418, 421, 424, 425, 431, 450; ( 3 ) 1 0 , 12; ( 7 ) 45 Matsuki, T. ( 8 ) 284 Matsukura, H. ( 7 ) 108 Matsukura, M. ( 6 ) 108, 109 Matsumoto, K. ( 8 ) 82 Matsumoto, Y. ( 6 ) 27 Matsuoka, Y. ( 5 ) 196 Matsura, A . ( 8 ) 279 Matsuura, T. ( 6 ) 214 Matsuura, Y. ( 1 ) 13 Matt, D. ( 1 ) 213 Matteucci, M. ( 6 ) 136 Matveev, E.D. ( 1 ) 152 Matzke, T. ( 1 ) 374 Mautz, D.S. ( 4 ) 4 8 ; ( 5 ) 34 Mavrin, G . V . ( 5 ) 198 Mawer, I.M. ( 5 ) 1 6 , 17 May, C.J. ( 1 ) 247, 248; ( 4 ) 7 7 , 78 Mayer, F. ( 1 ) 363 Mayer, R.B., jun. ( 6 ) 205 Mayer, U. ( 3 ) 19 Mayol, L. ( 6 ) 66 Mays, M.J. ( 1 ) 428 Mazidres, M.-R. ( 1 ) 402-404, 447; ( 4 ) 82-85; ( 8 ) 8 , 181 Mazumder, A . ( 6 ) 148, 149 Medvedeva, L.Ya. ( 8 ) 179 Meek, D.W. (1) 31 Meetsma, A . ( 8 ) 178, 285, 290 Meidine, M.F. (1) 372 Meier, G.P. ( 3 ) 38 Meijboom, N. ( 1 ) 42, 7 7 , 191 Meille, S.V. ( 8 ) 88 Meindl, P.E. ( 1 ) 248; ( 4 ) 78 Meinhold, H. (5) 36 Meisel, M. ( 1 ) 399 Mellin, T.N. ( 5 ) 170 Mel'nikov, N.N. ( 5 ) 75 Menu, M.-J. ( 4 ) 94 Mercer, S . ( 1 ) 161; ( 7 ) 41; ( 8 ) 23 Mercier, F. ( 1 ) 343,
408, 409
Mergardt, B. ( 7 ) 73 Merifield, E. ( 7 ) 132 Merino, I . ( 1 ) 284; ( 7 ) 24; ( 8 ) 49
Merker, R.L. ( 8 ) 200 Mertsulova, F.F. ( 5 ) 13 Merzweiller, K. ( 1 ) 25 Messeguer, A . ( 3 ) 5 ; ( 5 ) 72
Metternich, H.J. ( 1 ) 370 Meunier, B. ( 6 ) 7 Meyer, M. ( 8 ) 180 Meyer, U. ( 1 ) 315 Mezzina, E. ( 1 ) 117, 446; ( 3 ) 13
Michalska, M. (5) 39, 40 Michalski, J. ( 4 ) 7 6 ; ( 5 ) 4 , 40, 7 1 , 179; ( 6 ) 114 Midura, W. ( 5 ) 100 Mieloszynski, J.L. ( 1 ) 297 Miezere, R. (1) 194 Miftakhov, M.S. ( 7 ) 98
Mikhailopulo , I.A. (6) 5, 9
Mikhailov, I . E . ( 1 ) 263 Mikhailov, V.B. ( 1 ) 453 Mikhailov, Yu.B. ( 1 ) 453 Mikolajczyk, M. ( 1 ) 391; ( 3 ) 1 5 , 32; ( 5 ) 100
Mikulcik, P. ( 1 ) 69 Milhaud, P. ( 6 ) 208 Millard, J.T. ( 6 ) 219, 220
Miller, D.B. ( 7 ) 100 Miller, L.S. ( 1 ) 74 Miller, S.M. ( 8 ) 254, 255 Mills, J.L. ( 1 ) 118 Mills, S.G. ( 3 ) 34 Milosavljevic, E.B. ( 1 ) 420
Minami, T. ( 1 ) 80, 268; ( 5 ) 9 9 ; ( 7 ) 16, 85
Mindin, Ya.1. ( 8 ) 164 Minto, F. ( 8 ) 8 8 , 232 Mioskowski, C. ( 1 ) 151, 153; ( 7 ) 28, 30, 32
Mirkin, C.A. ( 8 ) 69 Mironov, V.F. ( 2 ) 3 8 ; (5) 6, 7
Miroshnichenko, V . V . ( 8 ) 37, 39, 68
Mirza, H.A. ( 1 ) 207 Mirzadegan, T. ( 7 ) 89 Misco, P.F. ( 5 ) 188, 190; ( 6 ) 16
Misra, K. ( 6 ) 40, 48 Mitchell, M.A. ( 6 ) 231, '232
Mitchell, T.N. ( 1 ) 184
3 56 Mitchell, W.M. (6) 107 Mitsuya, H. (5) 142 Mitter, F. (1) 387 Miura, H. (1) 9 Miura, K. (6) 52, 80 Miyemoto, T.K. (1) 13 Miyano, S. (5) 83 Miyaahi, T. (7) 80 Miyashita, A. (1) 81 Miyazaki, T. (7) 125 Miyoahi, K. (5) 196 Mizan, S. (6) 121 Mizoguchi, K. (8) 265 Mizrakh, L . I . (1) 282 Mizuno, M. (7) 139 Mlotkowska, B. (1) 175 Modak, A.S. (6) 87 Modro, T.A. (5) 64 Mohan, T. (1) 250; (4) 27 Moise, C. (1) 40 Mokrzan, J. (5) 151 Molaire, T.R. (8) 254, 255 Molchanova, G.N. (5) 60 Molin, H. (5) 119 Molina, P. (1) 166; (7) 117, 118, 121, 122, 126, 127; (8) 52-54, 56, 60-62 Molko, D. (6) 90 Moll, M. (1) 35; (5) 52 Moll, R. (5) 36 Mondeehka, D.M. (5) 194, 216 Monforte, J.A. (6) 204 Monoda, Y. (5) 19 Monteflorl, D.C. (6) 107 Montl, D. (7) 129 Montoneri, E. (5) 114 Moore, A.J. (7) 81 Moore, M. (6) 176 Moore, W.T. (5) 28 Moorhoff, C.M. (5) 64 Moreau, M. (5) 51 Morgan, T.K., jun. (6) 242 Mori, K. (4) 62; (6) 104, 105, 109 Mori, S. (8) 128-136, 138, 140, 141, 143, 156, 160 Morimoto, A. (8) 151 Morimoto, S. (8) 150 Morimoto, T. (1) 29, 30 Moroney, S.E. (6) 168, 169 Moro-oh, Y. (1) 208 MOrozova, L.N. (1) 100 Morris, R.E. (1) 204 Morse, K.W. (5) 163 Morvan, F. (6) 141 Moakva, V.V. (1) 233, 234
Orgon op hosp horus c'h em istn, Moss, G.P. MOSS, R.A.
(;{
z;,
67 Mostecky, J. (1) 259 Motoi, M. (1) 260 Motoki, S. (7) 125 Mouloungui, Z. (7) 26, 72 Mourey, T.H. (8) 254, 255 Mrozlk, H. (7) 107 Mualla, M. (5) 218 Miiller, C.E. (4) 22; (5) 38 Miiller, G. (1) 32, 69, 70, 82, 156, 158, 258, 451; (3) 4; (7) 5-7 Mueller, W.B. (8) 273, 282 Muhamnad, A. (1) 154 Mujumdar, A.N. (8) 199, 200 Mukhemetov, F.S. (4) 16, 32 Mukmeneva, N.A. (1) 105 Muller, E.P. (2) 41 Mullins, M.J. (3) 38 Munke, S. (3) 47 Munoz, A. (2) 43, 44 Munsey, M.S. (8) 110 Murehashi, E. (3) 41 Murashov, D.A. (8) 85 Muratom, S. (1) 260 Murillo, A. (2) 45 Murphy, D.E. (5) 175 Murray, W.T. (2) 29 Musin, R.G. (4) 30 Musin, R.Z. (1) 235, 454; (5) 121, 183 Mustaphin, A.H. (5) 97 Nabekawa, S. (1) 229 Nagai, H. (4) 56; (6) 60 Nagal, W. (1) 367 Nagalch, A.K. (6) 48 Nagano, K. (1) 81 Nagareda, K. (7) 20 Nagase, S. (7) 20 Nagata, R. (3) 40, 41 Nakada, Y. (8) 279 Nakahara, H. (8) 125 Nakamoto, A. (6) 78 Nakamura, H. (8) 123, 267 Nakamura, T. (1) 268 Nakane, M. (7) 125 Nakaniahi, K. (7) 143 Nakaniahi, T. (6) 144 Nakano, H. (4) 52; (6) 54 Nakata, M. (7) 139 Nakata, T. (7) 108 Nakayama, M. (1) 268 Nakazawa, H. (5) 196 N a , G.4. (4) 7; (5) 152 N m e , A. (6) 178
Namikoshi M 7) 136 Napier, J:J..($) 101 Narahara, T. (8) 158, 159 Natale, N.R. (8) 110 Navech, J. (4) 9 Nazmutdinova, V.N. (1) 235 Neckers, L. (6) 105 Neenan, T.X. (8) 283 Nefedov, O.M. (1) 159 Neganova, E.G. (1) 349, 350; (8) 66 Negrebetskii, V.V. (1) 293; (5) 75 Neijedly, Z. (6) 6 Neilaon, G.W. (6) 227 Neilson, R.H. (1) 4; (8) 75, 76 Nekhoroshkov, V.M. (1) 364; (4) 16 Nelson, J.H. (1) 72, 419, 420 Nelson, P.S. (4) 58; (6) 193 Nerker, R.L. (8) 199 Nesterov, L.V. (2) 15 Netzel, T.L. (6) 184 Neuman, A. (2) 42 Neuner, P. (6) 202 Newall, A.R. (1) 162 Newman, P.C. (6) 173 Newton, R.P. (6) 241 Nguyen, T.M. (8) 3 Nicolaides, D.N. (7) 36 Nicolaou, K.C. (7) 96 Niecke, E. (1) 310, 366, 369, 370, 372, 378, 388, 394-396, 442; (4) 86, 95 Nlef, F. (1) 424, 425 Nleger, M. (1) 310, 318, 378, 388, 394-396; (4) 86, 88, 95 Niel, G. (7) 94 Nlelsen, J. (4) 69; (6) 127, 128 Nlentledt, J. (1) 335 Nletzechmnn, E. (1) 102; (5) 115 Nlfant'ev, E.E. (4) 19 Nlitsu, T. (1) 311 Nlkltln, E.V. (1) 296 Nikltina, G.S. (8) 272 Nlkogosyan, L.L. (8) 166 Nlkolaeva, I . L . (4) 30, 31 Nikolaides, N. (5) 14 Nikonoror, K.V. (5) 13 Nikonov, G.N. (1) 112, 114-116 Nlnmons, H.L. (1) 24 Nlshiguchl, T. (1) 210
Author Index Nishii, K . (8) 279 Nishijlma, Y. (4) 52; (6) 54 Nishikawa, T. (8) 154, 217 Nishikova, N.G. (1) 152 Nishikubo, T. (1) 302-304 Nishioka, E. (1) 9 Nitta, M. (7) 123, 124; (8) 57-59 Nixon, J.F. (1) 214, 372, 432-435 Noble, N.J. (5) 33 Noel, C. (8) 248 Nogradi, M. (7) 115 Noguchi, T. (8) 201 Noh, S . K . (1) 133 Nohira, H. (1) 81 Noltemeyer, M. (1) 458; (8) 25, 182, 184, 187, 189 Nonaka, Y. (7) 35 Noren, C.J. (6) 92 Noren, J.O. (5) 119 Norman, N.C. (1) 375 Norval, E.M. (8) 80 Novak, P.M. (5) 176 Novikova, Z.S. (1) 5, 6; (2) 28; (5) 184 Nowick, J.S. (7) 74 Noyori, R. (4) 41; (6) 39, 41-43, 50, 85 Nozaki, H. (7) 146 Nuel, D. (7) 40 Numata, H. (3) 36 Nun, C.M. (1) 58, 317, 342, 375; (4) 89 Nuretdinov, I.A. (1) 144 Nuyken, 0. (8) 209, 210 Nuzillard, J.M. (7) 75 Nyangulu, J.M. (5) 88 Nyilas, A. (6) 84, 132 Nyulaszi, L. (1) 439, 440 Oae, S. (1) 281 Oakley, R.T. (8) 174, 175, 291 Oberhamner, H. (8) 180 Odaka, F. (8) 264 Odinets, I.L. (1) 238; (2) 28; (5) 103 O'Donnell, M.J. (7) 49 Oebels, D. (1) 422 Oehme, G. (1) 49 Ofitserov, E.N. (2) 38; (5) 6, 7 Ogilvie, K . K . (4) 65; (6) 83, 93 Oh, D.Y. (5) 98, 106, 143; (7) 84 O'Hagan, D. (5) 127, 128
357 Ohira, S. (7) 146 Ohira, Y. (8) 82 Ohms, G. (5) 225; (8) 79 Ohshima, Y. (6) 32 Ohta, H. (1) 267; (3) 22 Ohtsuka, H. (7) 35 Ohtsuki, M. (6) 56 Oishi, T. (7) 108 Oka, A. (4) 52; (6) 54 Okada, Y. (1) 80, 268; (5) 59 Okamoto, K . (8) 146, 152 Okamoto, T. (8) 93, 94, 154, 222 Okamoto, Y. (1) 358 Okamura, A. (5) 83 Okazaki, E. (3) 40 Okhlobystin, 0.Yu. (1) 263 Okude, K . (1) 13 Okuizumi, R. (8) 233 Okuma, K. (1) 267 Okuyama, T. (8) 153 Olah, G.A. (1) 240 Olders, E.A.T.A. (5) 214 Oleinik, V.A. (1) 242, 243, 346-348; (8) 39 O l m s , P. (8) 185 Olmstead, M.M. (1) 315 Omieljanczuk, J. (1) 391 Omori, H. (1) 208 O'Neill, J.K. (8) 275 Ono, M. (8) 158, 159 Onozawa, T. (1) 88 Ontsuka, E. (6) 240 Onys'ko, P.P. (5) 208-210; (8) 33 Oohasi, T. (8) 153 Opiela, S. (1) 123, 315 Opresnik, M. (5) 214 Or-, 0. (1) 405 Oretskaya, T.S. (6) 160 Orgel, L.E. (6) 95, 223 Ornstein, P.L. (5) 172 Orpen, A.G. (1) 18, 212, 375 Ortiago, J.F. (6) 180 Osaki, T. (5) 86 Osanai, K. (3) 36 Oshikawa, T. (5) 107 Oshiki, T. (1) 88 O m a n , F.H. (5) 180, 181 Ossig, E. (1) 326 Ostakhov, S.S. (2) 18 Otsuka, S. (1) 28 Otsuka, T. (7) 91 Ottenwaelder, H. (6) 226 Otvoe, L. (5) 27; (6) 161 Ovakimyan, M.Zh. (5) 110 Ovchinnikov, V.V. (5) 136 Ozaki, H. (4) 52, 53; (6) 54, 78, 129
Ozaki, S. (4) 42; (5) 15, 19, 23 Paetzold, E. (1) 49 Pagniez; G. (8) 205, 206, 213, 214 Pakrashi, S.C. (1) 147 Pakulski, M. (1) 342 Palacek, J. (1) 259 Palacios, F. (1) 284, 455, 456; (7) 24, 62, 63; (8) 42, 48, 49, 64, 65 Palazewski, K . (5) 28 Paliichuk, Yu.A. (5) 94 Palma, G. (8) 223 Palmer, D.N. (8) 257, 275 Palui, G.A. (1) 264 Palyutin, F.M. (1) 296 Pannell, L.K. (6) 233 Panosyan, G.A. (5) 110 Paoletti, C. (6) 81 Papkov, V.S. (8) 235, 253, 269 Paquer, D. (1) 297 Parc, G. (1) 297 Parente, D. (6) 65 Parish, R.V. (1) 73 Park, K.P. (4) 7; (5) 152 Parkes, H.G. (8) 114 Parra, M. (5) 24 Parsons, W.H. (5) 170 Parvez, M. (8) 99, 109 Paschalidis, C. (1) 32, 158, 258, 451; (7) 6, 7 Pasimourt, N. (8) 206 Paskevicius, R. (8) 164 Passerini, A. (1) 185 Pastor, S . D . (1) 16 Patalinghug, W.C. (1) 19 Patchett, A.A. (5) 170 Patel, D . J . (6) 164, 165 Paterson, M.C. (6) 147 Patois, C. (7) 68 Pauer, F. (8) 186 Pauli, J. (8) 81 Pautard-Cooper, A. (2) 5, 29 Pauwels, R. (6) 141 Pavlenko, N.V. (2) 14 Pavlov, V.A. (5) 183 Pechkovskii, V.V. (8) 166, 167, 169 Pedrini, P. (7) 138 Pei, D. (6) 210, 211 Pellerin, B. (1) 89, 330; (5) 122 Pellon, P. (1) 354 Peng, S.44. (1) 34 Pennington, W.T. (1) 56 Penny, S. (1) 15
35X
Percec, V. ( 8 ) 247 Peresypkina, L.P. (5) 166 Perez de Vega, M.J. ( 8 ) 53
Perich, J.W. ( 4 ) 43 Peringer, P. ( 2 ) 41 Perlikowska, W. ( 1 ) 391 Perlmutter, P. ( 1 ) 216 Perni, R.B. ( 7 ) 101 Perreault, J.-P. ( 6 ) 8 3 , 93
Pesheck, P.S. ( 6 ) 244 Pestana, D.C. ( 1 ) 386 Petersen, K.H. ( 4 ) 6 9 ; ( 6 ) 128
Petit, H. ( 1 ) 287 Petrov, A.A. ( 5 ) 123, 205 Petrov, G. ( 1 ) 96; ( 7 ) 10 Petrova, T.V. ( 5 ) 8 Petrovskii, I.L. ( 8 ) 43 Petrovskii, P.V. ( 1 ) 291-294;
( 5 ) 1 2 , 60 Petrus, C. ( 5 ) 153 Petrus, F. ( 5 ) 153 Petter, R.C. ( 7 ) 142 Petter, W. ( 2 ) 41 Peyman, A. ( 6 ) 97 Pfaffenschlager, A . ( 8 ) 44
Pfister-Guillouzo, G. ( 1 ) 330
Pfleiderer, W. ( 6 ) 4 9 , 53, 107, 150, 151, 199 Phillips, G.W. ( 1 ) 1 0 , 36 Phillips, L.R. ( 4 ) 20; ( 5 ) 142 Phillips, S.G. ( 8 ) 175 Phuong, P. ( 5 ) 126 Piccailli, G. ( 6 ) 66 Piccirilli, J.A. ( 6 ) 168 Pieles, U. ( 6 ) 202 Pieronczyk, W. ( 1 ) 9 5 ; (7) 9 Pietrusiewicz, K.M. ( 3 ) 20, 43-45 Pika, J. ( 6 ) 93 Pilichowska, S . ( 5 ) 155 Pilotti, M.U. ( 1 ) 381 Pinchuk, A.M. ( 1 ) 100, 242, 243, 346-348; ( 2 ) 49; ( 8 ) 37-40, 6 7 , 68 Pinsard, P. ( 1 ) 262; ( 7 ) 42, 43 Pirozhenko , V V. ( 1 ) 285, 286 Piteau, M. ( 1 ) 240 Pitt, H.S. ( 8 ) 7 Piven, V.A. ( 1 ) 219 Pla, F.P. ( 1 ) 271 Plass, W. ( 1 ) 452; ( 7 ) 8 Plate, N.A. ( 8 ) 236-239, 24 1
.
Plateau, P. ( 6 ) 31 Ple, G. ( 7 ) 133 Plgnat, F. ( 1 ) 136 Plyshevskii, S.V. ( 8 ) 166, 167
Podda, G. ( 8 ) 112, 121 Podsiadlo, S . ( 8 ) 211 Poirier, J.-M. ( 7 ) 133 Pokrovskaya, E.N. ( 8 ) 144 Polezhaeva, N.A. (5) 219 Polikarpov, Yu.M. (5) 177 Polonskaya, L.Yu. ( 1 ) 282 Polozhaeva, N.A. ( 5 ) 97 Polozov, A.M. (5) 97 Polushina, V.L. ( 1 ) 144 Pomerantz, M. ( 7 ) 3 ; ( 8 ) 1 0 , 26, 207, 208
Pompon, A . ( 6 ) 35 Pon, R.T. ( 6 ) 93 Ponomarchuk, M.P. ( 1 ) 167; ( 8 ) 1 3 , 14
Popov, A.G. (5) 193 Porizo, W. ( 8 ) 88 Porritt, G.M. ( 4 ) 7 1 ; ( 6 ) 123, 124
Porzio, W. ( 8 ) 232 Potapov, V.K. ( 6 ) 61 Potin, P. ( 8 ) 1 1 , 193, 204-206, 213, 214, 256 Potter, B.V.L. ( 5 ) 33 Potts, M.L. ( 8 ) 197 Poulter, C.D. ( 4 ) 4 8 ; ( 5 ) 34 Povolotskii, M.I. ( 1 ) 336, 392, 393, 401; ( 5 ) 210; ( 8 ) 30 Powell, D. ( 1 ) 130 Powell, J. ( 1 ) 247, 248; ( 4 ) 7 7 , 78 Powell, N.I. ( 7 ) 40 Power, P.P. ( 1 ) 315, 384, 386 Pownall, S . ( 6 ) 207 Pracejus, H. ( 4 ) 79 Prasad, G. ( 7 ) 58 Prestwich, G.D. (5) 22 Prihoda, J. ( 8 ) 79 Prikhod'ko, Yu.V. ( 1 ) 97 Prikota, T.I. ( 6 ) 5 Pringle, P.G. ( 1 ) 134, 202, 212 Prishchenko, A.A. ( 1 ) 9 4 ; ( 2 ) 26; ( 4 ) 3 , 4 ; ( 5 ) 139 Pritchard, C.E. ( 6 ) 45 Pritzkow, H . ( 1 ) 272, 273, 344, 345, 360, 380; ( 3 ) 4 6 ; ( 4 ) 33, 93; ( 7 ) 65 Probert, A.W. ( 5 ) 174 Prognayova, N. ( 8 ) 91 Provotorova, N.P. ( 8 )
212, 235
Pruitt, J.R. ( 7 ) 102 Puckette, T.A. ( 1 ) 10, 36 Pudovik, A.N. ( 1 ) 8 4 , 189, 235, 254, 453, 454; ( 2 ) 2, 35-38; ( 4 ) 30, 31, 9 1 ; ( 5 ) 6 , 7, 136; ( 8 ) 29 36 Pudovik, M.A. ( 1 ) 254; ( 4 ) 30, 91; ( 8 ) 36 Pujari, M.P. 5 ) 65 Pupeiko, N.E. ( 6 ) 5 Pykko, P. ( 2 ) 6
Qabar, M. ( 3 ) 39 Qing, W. ( 4 ) 7 6 ; ( 6 ) 114 Qiu, W. ( 5 ) 134; ( 7 ) 54 Qu, Y. ( 6 ) 224 Quaedflieg, P.J.L.M. ( 6 ) 238
Quartin, R.S. ( 6 ) 118 Quashie, S . ( 1 ) 375 Quassini, A. ( 8 ) 74 Quiclet-Sire, B. ( 5 ) 191; ( 6 ) 14
Quin, L.D. ( 1 ) 222; ( 3 ) 1 7 , 1 8 ; ( 5 ) 42, 180, 181
Rabow, L.E. ( 6 ) 148, 212, 213
Rademacher , P. ( 1 ) 442 Radics, L. ( 6 ) 21, 22 Ragulin, L.I. ( 4 ) 36 Rahmoune, M. ( 1 ) 361 Rahn, J.A. ( 1 ) 419 Raithby, P.R. ( 1 ) 428 Rakhmatulina, T.N. ( 1 ) 108, 109
Ramondenic, Y. ( 7 ) 133 Ranaivonjatovo, H . ( 1 ) 389
Randina, L.V. ( 5 ) 7 9 , 80 Rankin, D.W.H. ( 2 ) 8 Rano, T.A. ( 7 ) 110 Ransom, S.C. ( 6 ) 149 Rao, C.B. ( 1 ) 240 Rao, C.N.R. ( 8 ) 89 Rao, G. ( 7 ) 4 Rao, M.N.S. ( 1 ) 168, 250, 460; ( 4 ) 27
Rao, M.V. ( 6 ) 67 Rardon, D. ( 5 ) 217 Raston, C.L. ( 1 ) 19 Rathgeber, G. ( 6 ) 197 Ratner, M.A. ( 8 ) 263 Ratovskii, V.G. ( 8 ) 28 Raucher, S . ( 6 ) 220 Rault, I. ( 1 ) 354 Raundhill, D.M. ( 5 ) 76
Rausch, M.D. ( 1 ) 218 Raychaudhuri, S.R. ( 7 ) 100
Rayner, B. ( 6 ) 8 1 , 8 8 , 137, 138, 141
Raza, Z. ( 1 ) 22 Reamer, R.A. ( 3 ) 34 Rechencq, E. ( 7 ) 94 Reddy, N.S. ( 8 ) 101 Reddy, V.V.S. ( 1 ) 37 Redgrave, A.J. ( 5 ) 24 Rcdmill, K.A. ( 1 ) 37 Redmore, D. ( 3 ) 7 ; ( 5 ) 116, 204
( 6 ) 99
Roeschenthaler, G.V. ( 2 )
Reed, A.E. ( 2 ) 3 Reese, C.B. ( 4 ) 7 1 ; ( 6 ) 56, 67, 86-88,
Rippel, H.C. ( 7 ) 15 Robert, A. ( 7 ) 81 Roberts, J.D. ( 6 ) 224 Robertson, S.A. ( 6 ) 92 Robinet, G. ( 2 ) 11 Robins, R.K. ( 1 ) 444 Robinson, B.H. ( 6 ) 185 Robinson, G.H. ( 1 ) 56 Robles, D. ( 1 ) 8 Rockenbauer, A. ( 1 ) 146 Rodger, D.R. ( 5 ) 41 Roelen, H.C.P.F. ( 4 ) 2 1 ;
123, 124
Reffy, J. ( 1 ) 439, 440 Regan, A.C. ( 4 ) 1 0 ; ( 5 ) 105
Regan, J.B. ( 4 ) 20; ( 6 ) 100
Regitz, M. ( 1 ) 308, 337, 377, 379, 382, 398, 411, 413, 443, 448, 457; ( 2 ) 34 Reichenbach, N.L. ( 6 ) 107 Reitel, G.V. ( 1 ) 392, 393 Reiter, B. ( 1 ) 387 Reitz, A.B. ( 2 ) 4 Renner, G. ( 8 ) 209, 210 Rensch, 8. ( 3 ) 21 Repkova, M.N. ( 6 ) 8 2 , 143 Retherford, C. ( 7 ) 70 Reuter, J. ( 1 ) 128, 129 Revenko, G.P. ( 1 ) 75 Reynolds, M.A. ( 6 ) 36 Reynolds, R.K. ( 8 ) 262 Rhee, S. ( 6 ) 176 Rheingold, A.L. ( 1 ) 426; ( 8 ) 69 Rhodes, C.J. ( 1 ) 190, 316 Ribot, S.A. ( 5 ) 30 Ricard, L. ( 1 ) 7 9 , 214, 231, 338, 340, 341, 355, 421, 424, 425, 431, 450; ( 3 ) 1 2 ; ( 7 ) 45, 68 Richardson, J.F. ( 8 ) 172 Richter, W. ( 5 ) 9 0 ; ( 6 ) 3, 4 Rico, I. ( 5 ) 124 Ried, W. ( 8 ) 32 Rienhart, K.L. ( 7 ) 136 Riesel, L. ( 1 ) 145; ( 4 ) 26; ( 7 ) 37; ( 8 ) 81 Rife, J.P. ( 6 ) 112, 117 Rigby, J.H. ( 3 ) 39 Rihs, G. ( 1 ) 140 Riker, A.I. ( 6 ) 112 Riley, P.A. ( 6 ) 11-13 Riley, T.A. ( 1 ) 444
39, 51; ( 5 ) 58, 131, 135, 137 Roesky, H.W. ( 1 ) 458; ( 4 ) 87; ( 8 ) 1 , 25, 182, 184-187, 189 Rogers, R.D. ( 1 ) 199 Roget, A . ( 4 ) 6 4 ; ( 6 ) 183 Rokach, J. ( 7 ) 95 Rokhlin, E.M. ( 5 ) 130
Rokita-Trygubowicz, T. ( 5 ) 39
Rollin, P. ( 1 ) 174 Rolls, C.L. ( 1 ) 61 Romakhin, A.S. ( 1 ) 296 Romanenko, V.D. ( 1 ) 306, 307, 325, 336, 391, 393, 397, 401; ( 8 ) 5 , 30 Romanov, G.V. ( 1 ) 84 Roques, C. ( 1 ) 356, 402, 404, 447; ( 4 ) 81-84; ( 8 ) 7 2 , 181 Rosenberg, I. ( 5 ) 192; ( 6 ) 1 7 , 18 Rosenmeyer, H. ( 6 ) 174 Rosenthal, A. ( 4 ) 6 3 ; ( 6 ) 160 Rossi, E. ( 7 ) 116 Rossi, J.C. ( 7 ) 94 Rossi, R.A. ( 1 ) 50; ( 3 ) 26 Rossornondo, E.F. ( 6 ) 243 Rotello, V.M. ( 7 ) 106 Roth, A. ( 5 ) 170 Roth, D. ( 7 ) 50 Roth, H.J. ( 4 ) 22; ( 5 ) 38 Rott, N.T. ( 5 ) 62 Rozanov, I.A. ( 8 ) 8 5 , 179 Rozinov, V.G. ( 2 ) 23; ( 8 ) 28 Ruban, A.V. ( 1 ) 325, 336, 391-393, 397, 401; ( 8 ) 5 , 30 Rudkevich, D.M. (8) 27 Rudnitskaya, L.S. ( 1 ) 236, 237 Ruiz-Mazon, M. ( 1 ) 437 Rumpel, H. ( 5 ) 200
Running, J.A. ( 6 ) 188 Runova, O.B. ( 5 ) 21 Rusakov, V.A. ( 8 ) 272 Rusanov, V.M. ( 1 ) 234 Russell, M.J.H. ( 5 ) 226 Russer, A. ( 8 ) 258 Ryabov, B.V. ( 5 ) 123, 205 Rybkina, V.V. ( 8 ) 28 Rymar, V.T. ( 8 ) 166 Rymtsev, E.I. ( 8 ) 251 Ryzhikov, D.V. ( 8 ) 36 Ryzhikova, T.Ya. ( 1 ) 84 Rzepa, H.S. ( 7 ) 1 ; ( 8 ) 170
Saadein, M.R. ( 4 ) 5 1 ; ( 6 ) 20 Saalfrank, R.W. ( 8 ) 24 Sabatino, P. ( 1 ) 428 Sabio, M. ( 6 ) 242 Sabol, J.S. ( 7 ) 93 Sackett, P.H. ( 6 ) 244 Sadana, R. ( 6 ) 167 Sadanani, N.D. ( 5 ) 4 2 , 181
Safina, Yu.G. ( 5 ) 136 Safsaf, A. ( 2 ) 42 Sagandykova, R.R. ( 5 ) 8 Sagi, J. ( 6 ) 161 Sahi, T.A. ( 8 ) 124 Saiki, N. ( 8 ) 240, 284 Saito, I. ( 3 ) 40, 41; ( 6 ) 200, 214
Saito, T. ( 7 ) 125 Sakai, N. ( 8 ) 281 Sakama, T. ( 8 ) 165 Sakamoto, M. ( 7 ) 35 Sakamoto, N. ( 8 ) 146, 152 Sakatsume, 0. ( 4 ) 49, 50; ( 6 ) 55-57, 76
Sakhibullina, V .G. ( 5 ) 219
Sakulin, G.S. ( 5 ) 69 Sakuma, K. ( 7 ) 137 Salcedo, R. ( 1 ) 437 Sales, K.D. ( 1 ) 280; ( 7 ) 2
Salisbury, S.A. ( 6 ) 45 Sal'keeva, L.K. ( 4 ) 24 Sallin, K.J. ( 1 ) 135; ( 7 ) 12
Salornon, R.G. ( 7 ) 100 Samadi, M. ( 5 ) 191; ( 6 ) 14
Samuels, W.D. ( 8 ) 90 Sanchez, M. ( 1 ) 403, 404, 447; ( 4 ) 82-85; ( 8 ) 8 , 181 San'chez-Baeza, F. ( 3 ) 5 ; ( 5 ) 72 Sangen, 0. ( 4 ) 52; ( 6 ) 54
Organophosphorus C'hc.mi.siry
Sangokoya, S.A. (1) 56 Santacroce, C. (6) 56 Santiago, A.N. (1) 50 Sappa, E. (1) 427 Sarfati, S.R. (6) 178 Sargent, M.V. (7) 134 Sargeson, A.M. (1) 104 Sarin, P.S. (6) 120 Sarroff, A. (1) 38 Sasaki, S. (1) 357 Sasaki, Y. (1) 13, 80 Sasakura, T. (8) 149, 163, 168 Satge, J. (1) 389 Sathyanarayana, S. (6) 181 Satici, H. (7) 58 Sato, H. (7) 35 Sato, K. (1) 88 Sato, T. (1) 314 Sauer, H.E. (6) 197 Sauvage, J.-P. (6) 225 Savignac, P. (1) 99; (5) 101; (7) 67, 68, 76 Sawada, S. (6) 25 Sawai, H. (6) 30 Sawyer, J.F. (1) 204 Sayadyan, S.V. (1) 78 Sayer, J.M. (6) 233 Scahill, T.A. (6) 232 Scaiano, J.C. (1) 295 Schiifer, H.-J. (6) 197 Schaefer, M.A. (8) 224, 228, 230 Schiiufele, H. (1) 380 Schaffhaueen, J.G. (3) 38 Schanze, K.S. (6) 184 Schaumann, E. (7) 73 Scheide, G.M. (8) 75, 76 Scheldrick, W.S. (8) 183 Schelkun, R.M. (7) 70 Scheller, D. (3) 2 Scherer, O.J. (1) 327, 328, 436 Schiemann, A. (1) 371 Schier, A. (7) 5 Schirmer, W. (1) 17 Schlewer, G. (5) 21 Schleyer, P.von R. (2) 3, 10 Schlosser, M. (1) 3; (7) 21
Schloz, U. (8) 25 Schmaltz, T. (6) 130 Schmidbaur, H. (1) 32, 82, 156, 158, 258, 451; (3) 4; (7) 5-7 Schmidpeter, A. (1) 459; (8) 183 Schmidt, H. (1) 429, 430, 438; (2) 46, 47; (5) 55
Schmidt, H.-G. (8) 187 Schmidtchen, F.P. (6) 230 Schmuck, A . (2) 6, 7 Schmutzler, R. (1) 86, 119, 220, 221, 232, 246, 261, 274; (2) 27; (4) 29, 96, 97; (5) 93; (8) 80 Schnalke, M. (1) 123 Schneider, J. (1) 379 Schneider, K.C. (4) 66; (6) 135, 154 Schneider, L. (5) 175 Schneider, R. (1) 382 Schnochel, H. (8) 7 Schnurr, W. (1) 411, 443 Schoeller, W.W. (1) 310, 337, 442; (4) 86; (8) 4 Schollmeyer, D. (3) 21 Scholz, G. (1) 126, 127 Scholz, M. (4) 87 Scholz, U. (1) 457; (8) 182, 189 Schomburg, D. (1) 221, 232, 274 Schubert, F. (4) 63 Schultz, P.G. (6) 92, 210, 211 Schulze, J. (1) 313 Schwartz, A.W. (6) 72, 221 Schwartz, C.E. (3) 38 Schwarz, W. (1) 65 Schweitzer, C.T. (1) 204 Schwetlick, K. (4) 18 Scolaatico, C. (7) 60 Scott, B. (5) 129 Scott, D.L. (8) 229 Scremin, C.L. (6) 51 Sczakiel, G. (6) 34 Sedqui, A. (5) 195 Seega, J. (1) 246; (5) 93 Seela, F. (6) 174, 175 Seeman, N.C. (6) 69 Segall, Y. (5) 74 Seger, J. (8) 91 Seidl, S. (1) 60 Sekine, M. (4) 56; (6) 60, 73, 144 Sekini, M. (6) 32 Seliger, H. (6) 180 Seligsohn, H.W. (6) 117 Selim, A. (1) 301 Sella, A. (1) 204 Semenii, V.Ya. (8) 78 Semkina, E.P. (1) 84 Sene, A. (4) 23; (5) 140, 141; (7) 82, 83 Sennett, M.S. (8) 197, 198 Seppelt, K. (2) 6, 7 Serafinowska, H.T. (6) 87
Serhan, C.N. (7) 96 Seeeke, U. (8) 184 Seto, H. (5) 148 Seyden-Penne, J. (5) 199; (7) 65 Shaborova, Z.A. (6) 160 Shackleton, J.M. (6) 13 Shadid, B. (5) 30-32 Shagvaleev, F. Sh (1 ) 233, 234 Shahnazarian, N. (1) 179 Shaikhudinova, S.I. (1) 108 Shakhidoyatov, Kh.M. (5) 165 Shapoahnlkov, S.I. (8) 38 Sharifuuln, A.Sh. (1) 105 Sharipov, G.L. (2) 18 Sharma, D. (4) 13 Sharma, P. (6) 181 Shaw, B.L. (1) 183 Shaw, R.A. (8) 83, 95, 100, 114-116 Shcherbina, T.M. (5) 10, 12 Sheldrick, G.M. (1) 66; (8) 184-186 Shen, G.S. (3) 9 Shen, Y. (5) 134; (7) 23, 27, 52-54 Shereshovete, V.V. (2) 18 Sherman-Gold, R. (4) 58; (6) 193 Shermergonn, I.M. (8) 29 Shermolovlch, Yu.G. (1) 101, 143; (8) 31 Shevchenko, I.V. (1) 200, 201 Shi, L.-L. (7) 22 Shi, Y.B. (6) 204 Shibazaki, H. (8) 93, 94 Shigeo, M. ( 8 ) 113 Shih, T.L. (7) 107 Shih, Y.E. (5) 50 Shiina, A. (1) 304 Shima, K. (4) 92 Shimamura, C. (1) 260 Shimamura, J. (1) 81 Shimamura, K. (1) 260 Shimazu, M. (6) 30 Shimidzu, T. (4) 52, 53; (6) 54, 78, 129 Shimojo, M. (1) 304 Shinohara, K. (7) 146 Shinohara, T. (4) 42 Shinozaka, K. (6) 30, 105, 121 Shiomi, D. (1) 311 Shiozawa, N (1) 278 Shiuey, S.-J. (3) 35 Shlyapintokh, L.P. (8)
.
.
Author Index 169 Shokol, V.A. (5) 1, 94, 95 Shore, S.G. (1) 252 Short, R.L. (1) 59 Shreeve, J.M. (5) 129, 132 Shriver, D.F. (8) 259-261, 263 Shtennikova, I.N. (8) 251 Shugar, D. (6) 23 Shurubara, A.K. (5) 79 Shvets, V.I. (5) 21 Sibanda, S. (6) 86, 88 Siddique, R.M. (1) 186 Sidky, M.M. (4) 14 Sidorov, V.I. (8) 144 Sih, C . J . (3) 33 Sikanyika, H. (7) 140 Silina, E.B. (5) 95 Sills, M.A. ( 5 ) 175 Simon, E.S. (6) 29 Singer, B. (6) 28 Singh, D. (6) 186 Singh, R.K. (6) 40 Singler, R.E. (8) 87, 248 Sinisterra, J.V. (7) 26 Sinitsa, A.D. (2) 32; (5) 209, 210; (8) 33 Sin'ko, N.L. (8) 272 Sinyashin, O.G. (1) 189; (2) 2 Sinyashlna, T.N. (2) 38; (5) 6, 7 Sip, M. (6) 221 Slriwardane, U. (2) 48 Sitdikova, T.Sh. (1) 233, 234 Slvets, G.G. (6) 5 Skirl, R. (5) 44 Skoda, J. (6) 6 Skolirnowaki, J.J. (1) 222; (3) 17 Skowroiiska, A. (5) 35 Skowroiiska, R. (5) 151 Skrypczybski, 2. (5) 71, 222 Skuballa, W. (7) 99 Skuratovich, L.G. (8) 166, 167 Sladky, F. (1) 63 Slawin, A.M.Z. (7) 103 Sleiman, H.F. (1) 161; (7) 41; (8) 23 Slonimskii, G.L. (8) 235, 269 Smirnov, V. (4) 54; (6) 115 Smith, A. (5) 206 Smith, A.B., I11 (7) 110 Smith, L.M. (1) 57 Smith, M.B. (1) 212
36 1 Smith, S.J. (1) 247, 248; (4) 77, 78 Smith, T.D. (6) 205 Smolii, O.B. (1) 285, 286 Snatzke, G. (1) 23 Sobol, R.W. (6) 107, 199 Sokolov, M.P. (5) 197,
198 Sokolov, V.B. (1) 241, 244; (5) 5 Sokolova, M.E. (8) 169 Sokolova, N.I. (6) 159 Solouki, B. (1) 399 Solov'ev, A.V. (1) 101 Solujic, L. (1) 420 Sommer, H. (1) 226 Sonmer, V.B. (4) 68 Son, T. (8) 249 Sonnenberg, U. (1) 322 Sopchik, A.E. (4) 17, 51; (6) 20 Soroka, M. (5) 154 Sostero, S. (1) 134, 202 Sournles, F. (8) 104-106, 108, 286, 287, 289 Spahn, M. (1) 452; (7) 8 Spangler, C.W. (8) 250 Spaniol, T.P. (1) 383 Spasov, S.L. (5) 216 Speers, P. (1) 271 Speier, G. (1) 160; (2) 33 Spek, A.L. (8) 178 Speranza, G. (7) 129 Spiegel, G.U. (1) 85 Spielmann, H.P. (6) 204 Spless, B. (5) 21 Splnk, C.W. (1) 218 Sproat, B.S. (6) 142, 202 Stack, M. (1) 181 Stadelmann, W. (8) 80 Stadlbauer, W. (8) 44 Staley, D.L. (8) 69 Stalke, D. (1) 66, 67, 378; (4) 87, 95; (8) 185, 186 Stam, C.H. (8) 20 Stamatov, S.D. (4) 28 Staninets, V.I. (1) 143; (8) 31 Stankevich, I.V. (8) 212 Stannett, V.T. (8) 203 Stavinoha, J.L. (1) 10, 36 Stawinski, J . (4) 90; (6) 58, 126 Stec, W.J. (4) 67; (6) 102, 108, 111, 113, 153 Steglich, W . (5) 161 Steier, W.H. (8) 250 Stelgelmann, 0. (1) 32,
156, 158, 258, 451; (7) 6, 7 Stein, C.A. (6) 102, 104, 105, 109 Stein, H. (6) 64 Steinmiiller, F. (8) 183 Stelzer, 0. (1) 51-54, 85, 226; (8) 80 Stemerick, D.M. (1) 173 Stenberg, B. (8) 270 Stengele, K.-P. (6) 49 Stepanov, A.E. (5) 21 Stepanov, G.S. (8) 36 Stepanova, E.V. (1) 219 Stephm, H. (1) 345 Sternfield, F. (5) 24 Stevenson, K. (1) 181 Sting, P. (5) 161 Stirchak, E.P. (6) 133, 134 Stolarski, R . (6) 23 Stone, F.G.A. (1) 381, 383 Stone, M.P. (5) 73; (6) 234 Storm, C. (6) 108 Strada, A. (7) 116 Stradi, R. (7) 116 Stranln, B.P. (5) 162 Strazewski, P. (6) 172 Streitwleser, A. (2) 10 Streubel, R. (1) 369, 370, 378; (4) 95 Stringfellow, G.B. (1)
195-198 Stromberg, B. (5) 54 Struchkov, Yu.T. (1) 167, 263, 292, 293, 336, 390; (5) 96; (8) 5, 13, 14, 68 Stryker, J.M. (1) 270; (7) 44 Stubbe, J. (6) 148, 212, 213 Studnev, Yu.N. (1) 236, 237; (4) 36 Sturis, A. (1) 194 Sturtz, G. ( 5 ) 117, 145 Stutz, A.E. (7) 139 Su, D. (5) 129, 132 Su, W . 4 . (7) 92 Subasinghe, C. (4) 62; (6) 102, 104, 105 Subheendra Rao, M.N. ( 8 ) 176, 177 Subramanian, R.S. (1) 169, 170 Suda, H. (1) 260 Sugawara, T. (8) 158, 159 Sugeta, H. (6) 240 Sugiyama, H. (6) 200, 214 Suhadolnik, R.J. (6)
362 107, 199
Sulikowski, G.A. (7) 110 Sulkowski, W . (8) 216 Sumitomo, T. (8) 165 Summerton, J.E. (6) 134 Sun, D. (6) 120 Sun, D.C. (8) 243 Sun, W.-C. (6) 243 Sun, X. (3) 3; (5) 109 Sund, C. (6) 157 Sunjic, V. (1) 22, 23 Suriano, J.A. (1) 20 Sutter, P. (5) 200; (8) 41
Suwa, K . (1) 28 Suzuki, H. (1) 208, 298 Svara, J . (1) 51-53 Swamy, K.C.K. (2) 40 Swann, P.F. (6) 162, 164, 165
Swinson, J. (5) 73 Switzer, C. (6) 169 Swords, B. (4) 47 Symons, M.C.R. (1) 190 Syvanen, A.-C. (6) 192 Szameitat, J . (1) 381, 383
Szecsi, J . (6) 161 Szemo, A. (6) 161 Szewczyk, J. (3) 18 Szulagyi, J. (5) 113 Szymoniak, J. (1) 40 Taba, K.M. (4) 39 Tabone, J.C. (6) 205 Tabyaoui, B. ( 8 ) 55 Tachon, C. (1) 351, 352 Taguchi, S. (8) 274 Tajima, S. (7) 109 Takada, M. (1) 229 Takagi, M. (8) 123 Takahashi, A. (8) 158, 159
Takahashi, K. (8) 127, 162, 267
Takaku, H. (4) 49, 50; (6) 55-57, 76, 79 Takano, S. (3) 36 Takaya, H. (1) 81 Take, Y. (1) 208 Takechi, N. (5) 15 Takeishi, M. (1) 278 Takeshige, Y. (6) 24, 25 Takeuchi, H. (7) 119, 120 Takeuchi, K . ( 6 ) 27 Takeya, R . ( 5 ) 47 Takuma, Y. (1) 93’ Talamas, F.X. (7) 139 Talanov, V.S. (8) 31 Tamada, Y. (5) 107 Tamai, Y. (5) 83
Tamas, J . (1) 146; (7) 130
Tambute, A. (1) 79 T m , C. (6) 172 Tamura, Y. (8) 162 Tan, P.S.G. (5) 70 Tancheva, C.N. (5) 194, 216
Tancic, Z. (7) 4 Tand, C.W. (5) 220 Tand, Y. (5) 221 Tang, C. (5) 221 Tang, Y.-Y. (6) 189 Tangour, B. ( 4 ) 35 Tani, K. (1) 28 Tanigaki, T. (8) 123-125 Tanigawa, E. (1) 28 Taniguchi, M. (7) 139 Tao, X. (3) 3; ( 5 ) 109 Tarasova, R.I. (1) 233, 2 34
Tasdelen, E.E. (1) 216 Tassone, G. (1) 185 Tatsuno, Y. (1) 28 Tatsuta, K . (7) 109 Tay, M . K . (5) 101; ( 7 ) 67 Taylor, R.J.K. (7) 90 Teare, J . (6) 203 Tebbe, K.-F. (1) 120, 126 Tebby, J.C. ( 2 ) 30; (4) 11
Telser, J . (6) 184 Tenner, G.M. (6) 179 Te‘oule, R. (4) 64; (6) 90, 183 Ternansky, R.J. (7) 144 Teterevkov, A.I. (8) 169 Teulade, M.-P. (1) 99 Thakker, D.R. (5) 142 Thelin, M. (4) 90; (6) 58, 126
Thenappan, A . (7) 55, 56, 77
Theopold, K.H.
(1) 133, 423, 426 Thorn, G . L . (7) 48 Thomas, E.J. (7) 132 Thomas, G . J . , jun. (6) 240 Thompson, C.M. (5) 49 Thompson, S.K. (7) 7 1 Thoraval, J.Y. (1) 367 Thornton, D.M. (5) 102; (7) 86 Thornton-Pett, M. (1) 57, 206 Thorpe, F.G. (1) 2 Thuong, N.T. (6) 182 Tikhonenkova , N. E. (8) 272 Tikhonina, N . A . (8) 16 Tikhonov, V.P. (8) 12
Timofeeva, G.I. (8) 252 Timokhin, B.V. (1) 228, 245
Tinant, B. (5) 57 Tino, J.A. (7) 139 Tinofeev, A . M . (5) 96 Tiriicchhio, A . (1) 427 Tiripicchio Camellini, M. (1) 427
Titova, M . I . (1) 1 Tkachenko, O.V. (6) 9 Tmaas, J . (5) 113 Toda, F. ( 7 ) 38 Toia, R.F. (5) 74 Tokmoto, Y. (6) 32 Tollerfield, S.M. (6) 11, 13
Tolmachev, A . A . (1) 100, 223, 224
Tolstikov, G . A . (2) 18, (7) 98
Tomasz, J . (6) 21, 22 Tomazos, D. (8) 247 Tondelli, L. (6) 68 Tonge, J . S . (8) 259, 260 Tonnard, F. (1) 354, 361 Topal, M.D. (6) 166 Topiol, S. (6) 242 Topolski, M. (5) 167 Torgasheva, N . A . (5) 37 Torgomyan, A.M. (5) 110 Torkelson, S. (6) 176 Torreilles, E. (1) 277; (8) 45
Torrence, P.F. (6) 33, 152
Toscano, R . A . (1) 437 Toscano, V . G . (1) 295 Toth, I. (1) 41 Totschnig, K . ( 2 ) 41 Toulme, J . J . (6) 109 Toupet, L. ( 7 ) 113 Touzin, A.M. (5) 159 Toyota, K. (1) 358 Traverso, 0. (1) 134, 2U2 Tregear, G.W. (4) 43; (6) 206, 207
Trehan, A. (7) 89 Treichler, A. (5) 225 Tristin, Yu.G. (2) 36, 37 Troev, K . (5) 76 Trofimov, B.A. (1) 108, 109
Trogler, W.C. (1) 137 Trommer, W.E. (6) 197 Tsubokawa, M. (8) 122, 156
Tsuchiya, H. (1) 229 Tsukamoto, M . (1) 3; (7) 21
Tsukamoto, Y. (5) 99; (7) 85
363
Tsutsumi, H. (8) 155 Tsvankin, D.Ya. (8) 235 Tsvetkov, E.M. (2) 24; (8) 6 Tumas, W. (1) 20 Tupchienko, S.K. (2) 32 Tur, D.R. (8) 212, 235-39, 241, 251-53, 269 Turecek, F. (1) 217 Turner, G. (6) 45 Turner, M.A. (1) 15 Turner, M.L. (1) 205 Turro, N.J. (6) 225 Tutunjian, P.N. (1) 177 Tuzar, Z. (8) 252 Tzschach, A. (1) 102, 106; (5) 115; (8) 70 Ubasawa, A. (6) 86, 88 Ubasawa, M. (6) 88 Uchida, J. (1) 303 Uchida, Y. (1) 281; (3) 24 Uchiyama, M. (6) 41 Ueda, I. ( 7 ) 33 Ueda, K. (7) 139 Uehara, A. (1) 12 Uemura, M. (6) 79 Uenishi, J.-I. (7) 139 Ueyama, S. (8) 222 Ugi, I. (5) 90; (6) 3, 4 Uhlig, W. (1) 106; (8) 70 Uhlmann, E. (6) 97 Ullmann, J. (1) 257; (7) 11 Umezu, Y. (1) 80 Urdea, M.S. (6) 187, 188 Urogdi, L. (7) 64; (8) 47 Uskokvic, M.R. (3) 35 Usman, N. (4) 65; (6) 93 Usmanova, L.N. (1) 254; (4) 15, 91 Utley, J.H.P. (1) 280; (7) 2 Uziel, J. (5) 159 Uznanskl, B. (4) 67; (6) 108, 152, 153 Vacca, J.P. (5) 16, 17 Vahldiek, M. (1) 227 Vaidyanathaswamy, R. (5) 202 Valeeva, F.G. (5) 69 Valerio, R.M. (5) 29 Valero, R. (1) 271 van Asselt, R. (8) 20 van Boom, J.H. (4) 21, 44-46; (5) 168; (6) 46, 99
van de Grampel, J.C. (8) 178, 285, 290 van den Elst, H. (4) 21; (6) 99 van der Klein, P.A.M. (5) 168 van der Lee, A. (8) 290 van der Marel, G.A. (4) 21; (5) 168; (6) 46, 99 van der Plas, H.C. (5) 30, 31, 32 Van de Woerd, R. (6) 72 van Doorn, J.A. (1) 42, 76, 77, 191 van Genderen, M.H.P. (6) 238 van Malssen, K.F. (8) 20 van Oijen, A.H. (4) 46 Vanvalkenburgh, V. (1) 181 Van Wazer, J.R. (5) 73 Varghese, B. (8) 177 Varma, V. (8) 89 Varshney, A. (1) 37 Vasil'eva, N.V. (8) 253 Vaultier, M. (7) 13 Veale, C.A. (7) 96 Vedejs, E. (2) 19, 20; (3) 38; (7) 17, 18 Veits, Yu.A. (1) 349, 350; (8) 66 Velat-Bellini, A. (6) 65 Vemlshetti, P. (6) 19 Ven'yaminova, A.G. (6) 82, 143 Verfuerth, U. (6) 4 Verkade, J.G. (2) 46, 47; ( 5 ) 55 Vermes, B. (7) 115 Vesely, I. (1) 259 Veszpremi, T. (1) 439, 440
Vial, J.-M. (6) 84 Viaud, M.C. (1) 174 Victor, M.W. (8) 207, 208 Vidal, A. (5) 24; (7) 117, 118; (8) 52, 54, 56 Vidal, J.P. (1) 87; (7) 94 Vilaplana, M.J. (7) 121 Villa, R. (7) 60 VilliGras, J. (5) 108 Vinader, M.V. (1) 166; (7) 122, 127; (8) 62 Vincens, M. (1) 87 Vinogradova, S.V. (8) 212, 235, 252, 253 Visscher, J. (6) 72 Vogel, J. (2) 41 Vogt, H. (1) 145; (7) 37 Voigt, J.M. (6) 166
Voitsekhovskaya, O.M. (1) 1 Volkov, E.M. (6) 160 Volozhin, L.M. (1) 105 Vondung, J. (1) 327, 328 Vonk, C.R. (5) 30 Vonwiller, S.C. (3) 37 vo Quang, L. (7) 79 Vo Quang, Y. (7) 79 Vorbriiggen, H. (1) 148; ( 7 ) 51, 99 Vork, M.V. (8) 50 Voronkov, M.G. (1) 109 Vostrikov, N.S. (7) 98 Votava, V. (1) 259 Votruba, I. (6) 6 Vovelle, F. (6) 140 Vrieze, K. (8) 20 Vyas, D.M. (1) 171 Vyle, J.S. (4) 72, 73; (6) 155, 156 Vysotskii, V.I. (1) 97 Wada, H. (8) 264 Wada, M. (3) 22 Wagner, A. (1) 151, 153 Wagner, 0. (1) 379, 413, 457; (2) 34 Wakabayashi, H. (6) 50 Wakabayashl, S . (4) 41; (6) 39, 41, 42 Walker, B.J. (3) 23; ( 7 ) 29 Walker, D.M. ( 5 ) 171 Walker, P.A. (4) 59 Walker, R.T. ( 6 ) 10 Wallenhauer, S . (2) 7 Waltere, M.A. (5) 144 Walton, T.J. (6) 241 Wamhoff, H. (8) 77 Wang, D. (6) 89 Wang, G. (5) 156 Wmg, H.-E. (1) 34 Wang, J.S. (5) 50 Wang, L.Q. (5) 180 Wang, P. (2) 10 Wang, T. (7) 23, 27, 53; ( 8 ) 226 Wang, W.-D. (1) 209 Wang, Y. ( 6 ) 89 Wang, Y.Y. (6) 77 Wang, Z. (8) 111 Wangchareontrakul, S. (7) 134 Ward, W.J., jun. (2) 21; (7) 19 Warner, B.D. (6) 188 Warner, S . (1) 39 Warpehoski, M.A. (6) 232 Warren, S. (3) 28, 29 Wasiak, J. (5) 71
364
Wasielewski, C. (5) 167 Wasiucionek, M. (8) 258 Wasserman, H.H. (7) 106 Watabe, H. (8) 264 Watal, G. (6) 40 Watanabe, E. (8) 231 Watanabe, K. (6) 52 Watanabe, Y. (3) 38; (4) 42; (5) 19, 23 Watt, W. (6) 237 Watts, J . P . (7) 132 Webb, R.R. (5) 189 Webber, S.E. (7) 96 Weber, L. (1) 319-324, 373, 374 Weber, M. (1) 441 Weedon, B.C.L. (7) 88 Weferling, N. (1) 51-54, 86; (2) 27; (4) 29 Wei, L. (1) 39 Weichmann, H. (3) 21 Weidert, P . J . (1) 400; (5) 215 Weidner, C.H. (7) 101 Weidner, M.F. (6) 219 Weiler, L. (7) 111 Weinfield, M. (6) 147 Weiss, C.D. (1) 140; (5) 200; (8) 41 Weies, S. (6) 34 Weissman, S.A. (1) 414 Weker, M.F. (8) 99 Weller, D.D. (6) 133, 134 Weller, F . (1) 64 Welling, L.L. (1) 132 Wenzinger, G.R. (4) 37; (6) 116, 117 Wess, G . (3) 31 West, R. (1) 130 Westermann, H. (1) 310; (4) 86 Westman, E. (6) 126 Wetmur, J.G. (6) 118 Wettling, T. (1) 379 White, A.H. (1) 19 White, J . B . (7) 139 White, J.D. (7) 137 Whiteker, G.T. (1) 26 Whitesides, G.M. (6) 29 Whitlock, H.W. (3) 14 Whittaker, C. (7) 40 Whitten, J.E. (1) 37 Wiaterek, C. (1) 123, 124 Wicienski, N.A. (6) 232 Wickstrom, E. (4) 37; (6) 112, 116, 117 Widelav, A. (8) 9 Wieczorek, M.W. (3) 32, 44 Wieland, P. (1) 140 Wiemer, D.F. (5) 146, 147; (7) 141
Orgunophosphorus C 'hPmi s i n , Wierzorek, W. (3) 20 Wife, R.L. (1) 76 Wilde, R.L. (5) 220 Wilk, A. (4) 67; (6) 108, 153 Wilkinson, D.L. (1) 82, 158; (3) 4; (7) 5 Will, N. (1) 35; (5) 52 Willett, R.D. (5) 129 Williams, B.D. (6) 196 Williams, D . J . (7) 103 Williams, D.N. (8) 22 Williams, D.R. (7) 112 Williams, I . D . (1) 39 Williams, M. (5) 175 Williams, M.G. (6) 231 Williamson, M. (5) 78 Williard, P.G. (1) 68 Willingham, R.A. (8) 247, 248 Willis, A.C. (1) 104 Wilson, D.W. (6) 121 Wilusz, E . J . (5) 175 Wimmer, T. (1) 156 Winchester, W.R. (1) 68 Winfield, J.M. (1) 186 Winter, H. (8) 178 Wintergrass, D. (5) 55 Wippler, J . (6) 62 Wirkner, C. (1) 438 Wirth, U. (8) 24 Wisian-Neilson, P. (8) 224-230 Witt, M. (8) 1, 185, 186 Witzcak, M.K. (7) 3; (8) 10 Wojna-Tadeusiak, E. (5) 224 Wolf, R . (1) 403; (4) 85; (8) 8 Wolf, T. (6) 226 Wolfsberger, W. (1) 46, 47, 71, 163, 225; (8) 15, 17, 18 Wollenzien, P. (6) 203 Wolmershliuser, G. (1) 327, 328, 436 Won, Y.M. (8) 118, 161, 195 Wong, S.S. (6) 198 Wood, D.L. (7) 91 Woodward, P . R . (7) 103 Woolins, J.D. (8) 170 Woulfe, K.W. (1) 428 Wozniak, L. (5) 2, 223 Wright, M.E. (1) 7 Wright, W.W. (8) 271 wu, s.-Y. (5) 74 Wu, S.Y. (5) 47, 48 Wu, T. (6) 83 wu, X.P. (5) 180 Wulvik, E.A. (3) 25
Wurdeman, R.L. (6) 235 Wynne, K.J. (8) 215 Xi, S.K. .(2) 46, 47; (5) 55; (8) 26 Xiang, Y. (7) 52 Xie, X. (5) 150 Xu, J. (3) 3; (5) 109 xu, w. (1) 445 Xu, Y. (5) 164 Yadagiri, P. (5) 20 Yadau, V.K. (4) 5 Yagi, H. (6) 233 Yaguchi, A. (8) 122, 128, 134, 137, 138, 141, 142 Yagupol'skii, L.M. (2) 14 Yakigawa, Y. (8) 279 Yalovskaya, A.I. (1) 152 Yamada, €I. (7) 108 Yamagata, T. (1) 28 Yamagishi, T. (4) 80 Yamaguchi, H. (5) 196 Yamaguchi, K. (5) 59 Yamaguchi, M. (1) 80, 91; (4) 80; (5) 99; (7) 85 Yamekage, S. (6) 76, 79 Yamamoto, A. (1) 9 Yamamoto, H. (5) 118; (8) 267 Yamamoto, K. (8) 93, 94 Yamamoto, N. (4) 49, 50; (6) 55, 57 Yamamoto, S. (1) 267 Yamamoto, T. (8) 127, 162 Yamana, K. (4) 52, 53; (6) 54, 129 Yamanaka, H. (3) 40, 41 Yamane, H. (4) 49, 50; (6) 55, 57 Yamaahita, M. (3) 11; (5) 107 Yamaahita, T. (4) 92 Yamashita, Y. (7) 80; (8) 276278 Yamataka, H. (7) 20 Yamazoes, 0. (8) 168 Yamoto, s. (4) 53 Yanagi, K. (1) 9 Yankovskapa, V.L. (5) 37 Yanovekii, A.I. (1) 263 Yasnikova, N.A. (1) 143 Yasuda, M. (4) 92 Yasuhiro, Y. (8) 162 Yau, E.K. (4) 70; (6) 122, 125 Yazawa, N. (1) 298 Yeh, H.J.C. (6) 233
Author Index Yeh, J.T. (1) 118 Yeung, A.S. (8) 87 Yeung Lam KO, Y.Y.C.
365 Yurchenko, A.G. (1)
361, 367
Yieh, C.-H. (1) 33 Yonaga, M. (7) 139 Yoneda, A. (5) 196 Yoneda, R. (5) 85-87 Yonekura, K. (1) .267 Yonetake, K. (8) 233 Yoon, H.S. (8) 161 Yoehlda, Y. (1) 298, 299 Yoshlfujl, M. (1) 311, 314, 357, 358 Yoehlkawa, Y. (8) 154, 222 Yoehlnari, It. (5) 68 Young, K.H. (8) 174 Young, S.G. (8) 199, 200, 246 Youelf, N.M. (2) 25; (5) 182 Yozhuehko, B.N. (5) 95 Yuan, C. (2) 12; (5) 63, 112, 150, 156, 164, 211-213 Yuan, Q. (5) 150
(1) 1;
(8) 12
Yurchenko, R . I .
(1) 1;
(8) 12
Yvergnaux, F. (7) 113, 114
Zabarylo, S. (4) 57 Zablocka, M. (3) 20, 44, 45
Zaikov, G.E. (8) 164 Zaln, R. (6) 126 Zaltaeva, G.V. (6) 9 Zak, B. (1) 259 zakharov, L.S. (5) 10-12, 60 Zalaehko, L.M. (6) 5 Z a l w e k l , D.J. (1) 177 Zal'taPan, I.S. (2) 49; (8) 40, 67 Zamal,
H. (6) 65
Zamecnik, P.C. (6) 120 Zanin, B. (8) 106, 107 Z a r l l n g , D.A. (6) 176 Z a r m , D. (1) 194 Zawada, E. (1) 207
Zecchi, G. (8) 51 Z e l l n e r , K. (1) 69 Zemlyanoi, V.N. (1) 98 Z e n j i , N. (8) 201 Zenkova, M.A. (6) 82 Zenneck, V. (1) 380 Zhang, J.-L. (1) 445 Zhao, Y. (5) 46 Zhou, X.-X. (6) 84 Zhu, J. (3) 3; (5) 109 Zhut-skli, P.V. (4) 4 Ziehlermartln, J.P. (4) 59
Zielonacka-Lie, Zlmnerman, S.C. Zimmcfaann, fi. Zlnchenko, A.I. Zlnovich, Z.Z.
E. (6) 8
(6) 236 (8) 24 (6) 5 (8) 216 Zon, G. (6) 101, 102, 108, 113, 121 Zorln, B.Ya. (5) 133 Zoeolapova, Z.A. (6) 143 Zsolnal, L. (1) 406, 407 Zurmeuhlen, F. (1) 398 Zyablikova, T.A. (1) 265; (5) 121, 183, 198 Zykova, T.V. (1) 233, 234
