Organophosphorus Chemistry: (Volume 24) A Review of the Recent Literature Published Between July 1991 and June 1992

Organophosphorus Chemistry Volume 24

A Specialist Periodical Report

Organophosphorus

Chemistry Volume 24 A Review of t h e Recent Literature Published between July 1991 and J u n e 1992

Senior Reporters

D. W. Allen, Sheffield Hallam University B. J. Walker, 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

SOCIETY OF CH EMISTRY

ISBN 0-85186-320-5 ISSN 0306-0713

Copyright

0The Royal Society of Chemistry 1993

All Rights Reserved N o part of this book may be reproduced or trammitted in any form or by any means-graphic, electronic, including photocopying, recording, taping, or information storage and retrieval system-without written permission from The Royal Society of Chemistry Published by The Royal Society of Chemistry, Thomas Graham House, The Science Park, Cambridge CB4 4WF

Printed in Great Britain by Athenaeum Press Ltd., Newcastle upon Tyne

Introduction The highlight of the year for many of us was the Xllth International Conference on Phosphorus Chemistry held in Toulouse, France during July 1992 Toulouse is a beautiful city and holds special attractions for the gourmet. The conference organisation was excellent and smoothly coped with a transport drivers' blockade. The enormous range of interesting phosphorus chemistry available in 180 lectures and almost 200 posters for the 600 persons attending demonstrated both the magnitude of the organisers' task and the continuing and growing importance of the subject throughout the world. We look forward to the Xlllth International Conference in Jerusalem, Israel in 1995. Sadly we must report the death of Dr D W Hutchinson. David contributed to this publication from its inception in 1970, was a Senior Reporter from volume 10 until volume 17 and made many other contributions to organophosphorus chemistry. He will be missed by all who knew him. The increased length of the introduction to this volume compared to earlier ones reflects the authors' assessment of increased activity in many areas, particularly those associated with biological and medicinal chemistry. Activity in phosphine and phosphonium salt chemistry remains at a high level, although exceptional contributions have been rare. A convenient synthesis of 5-phenyldibenzophosphole by treatment of triphenylphosphine oxide with phenyllithium and the facile route to triphenylphosphine sulphides offered by the reaction of the corresponding phosphines with sodium polysulfides in aqueous acetone are worthy of mention. Interest in the chemistry of p,-bonded phosphorus shows no sign of decline and steady progress continues. Interest in hypervalent phosphorus chemistry has been maintained, especially with regard to structural studies and the synthetic utility of pentaco-ordinate phosphorus compounds. Conformational effects of ring fusion and heteroatom substitution in six-membered rings of spirocyclic oxyphosphoranes have received further attention and have added fuel to the debate over the occurrence of diequatorial six-membered ring orientations as tbp models for enzymatic action on c-AMP. A novel departure has occurred in the area of hexaco-ordinate phosphorus chemistry with the

preparation of further derivatives of the porphyrin ring system containing hypervalent phosphorus coordinated by the tetrapyrrole unit. Phosphine oxide-based olefination reactions continue to be widely used in synthesis, for example, in those leading to vitamin 0 3 and its derivatives. An alternative method for the conversion of diastereomerically pure menthyl phosphinates to optically active phosphine oxides has been reported. Structural studies on a variety of phosphine oxide binary and ternary co-crystallization compounds have been carried out and the first complex involving the binary PO ligand has been prepared. In the area of trivalent phosphorus acid chemistry some very unusual reactions have been reported from combinations of 4-dimethylaminopyridine (DMAP) with phosphorus trichloride. In one case a phosphide and free chlorine are claimed to be formed! The extreme nucleofugicity of a tervalent phosphorus atom bearing two DMAP groups also stimulates an unprecedented Arbusov reaction of a tervalent derivative. Another surprise is that, although the reaction is certainly acid-catalysed, the mechanism of substitution at phosphoramidites does not involve either P- or N-protonated species. A final surprise in this area is the preparation, by Russian chemists, of some tervalent phosphorus compounds which apparently contain P-OH groups. On the pentavalent phosphorus acid front interest in fundamental phosphate ester chemistry is still in decline. However, activity in a wide range of phosphonic and phosphinic acid chemistry continues at a high level. Reports on phosphates of biological interest continue to increase and there has been a surge of interest in biological phosphonic analogues and "medicinal" phosphonates. Interest in myo-inositol phosphate and phosphonate chemistry continues. Also worthy of mention are the isolation of mercaptoalkyl products from rearrangements of sugar thiophosphates, the use of chiral templates based on amino sugars for the synthesis of aminophosphonic acids and the results and mechanistic conclusions stemming from further studies of the hydrolysis of cyclic phosphonic esters. The area of nucleotide and nucleic acid chemistry continues to be dominated by studies which are relevant to the use of nucleic acids as therapeutic agents. The chemical synthesis of DNA is now highly developed and very few papers are appearing on the synthesis of unmodified DNA. There is increasing interest in the synthesis and evaluation of phosphonate and phosphotriester analogues of mononucleotides as potential anti-viral drugs and some important developments have now been made in this field. It appears increasingly likely that triple helix formation, between a single strand which is complementary through Hoogsteen base pairing to an existing DNA duplex, will be exploited in the therapeutic development of

Intrndirction

vii

oligonucleotides. Triple helical structures of RNA homopolymers first appeared in the literature twenty-five years ago, yet the number of papers devoted to this subject has grown dramatically during the last two years, with many elegant studies being reported, particularly from Dervan's group. Interest in the structure of DNA and its interaction with other molecules has been spurred by world-wide initiatives in the study of recognition processes. Undoubtedly investigations in this area have been aided by developments in NMR spectroscopy, such as multidimensional experiments and the use of isotopically labelled substrates. It can now be forcefully argued that NMR-based techniques are the singularly most important method for the elucidation of DNA structure. In the chemistry of phosphorus-stabilized carbanions the number of publications reporting theoretical studies and those reporting mechanistic studies have increased following the reduction in these numbers last year. One of these reports includes the isolation and separate decomposition of certain oxaphosphetanes and this has allowed the first kinetic study of the second step of the Wittig reaction, albeit for a rather special system. Complex phosphonate carbanions and ylides continue to be widely used in synthesis. The number of reports of the use of the aza-Wittig and related reactions in heterocyclic synthesis remains at a high level, although many of these involve relatively minor modifications of earlier work. Academic and commercial exploitations of phosphazene chemistry by organic, inorganic, organometallic, physical and polymer chemists continue unabated. Recent work has brought order and clarity to the binary PN anions and there has been increased interest in metal complexes containing phosporanimine ligands with a view to providing routes to compounds with high metal-nitrogen bond orders. The role of ring strain in ring-opening polymerization of cyclophosphazenes has been examined in detail. Notable firsts include the polymerization of a cyclophosphazene without halogen substituents and the synthesis of a poly(phosphazene) with a transition metal bonded to each substituent. A greater connection to material science has also been noted. Unfortunately our promise of a return of a "Physical Methods" chapter in this volume has not been fulfilled. We apologise for this and hope that such a chapter will appear from volume 25. D W Allen and 6 J Walker

Contents CHAPTER

1

Phosphines and Phosphonium S a l t s B y D . W . Allen

Phosphines

1

1.1 Preparation 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5

From Halogenophosphines and Organometallic Reagents Preparation of Phosphines from Metallated Phosphines Preparation of Phosphines by Addition of P-H to Unsaturated Compounds Preparation of Phosphines by Reduction Miscellaneous Methods of Preparing Phosphines

1.2 Reactions of Phosphines 1.2.1 1.2.2 1.2.3 1.2.4

1 1

5 7

9 11 11 11 13 14

Halogenophosphines

16

2.1 Preparation 2.2 React ions

16 16

Phosphonium Salts

18

3.1 Preparation 3.2 Reactions

18 22

4

pl-Bonded Phosphorus Compounds

24

5

Phosphirenes, Phospholes and Phosphinines

31

References

35

2

3

CHAPTER

Nucleophilic Attack at Carbon Nucleophilic Attack at Halogen Nucleophilic Attack at Other Atoms Miscellaneous Reactions of Phosphines

1

2

Pentaco-ordinated and Hexaco-ordinated Compounds By C.D. Hall

Introduction

49

Structure, Bonding and Ligand Reorganization

49

Acyclic Phosphoranes

51

X

C 'onten ts 4

5

CHAPTER

3

Ring Containing Phosphoranes

51

4.1 Monocyclic Phosphoranes 4.2 Bicyclic and Tricyclic Phosphoranes

51 54

Hexaco-ordinated Phosphorus Compounds

63

References

68

Phosphine Oxide and Related Compounds By B.J.

CHAPTER

4

Walker

Preparation of Phosphine Oxides

70

Structure and Physical Aspects

73

Reactions at Phosphorus

75

Reactions at the Side-Chain

75

Phosphine Oxide Complexes

81

References

81

Tervalent Phosphorus Acid Derivatives B y 0. D a h l

1

Introduction

84

2

Nucleophilic Reactions

a4

2.1 Attack on Saturated Carbon 2.2 Attack on Unsaturated Carbon 2.3 Attack on Nitrogen, Chalcogen, or Halogen

84 a4 87

Electrophilic Reactions

87

3.1 Preparation 3.2 Mechanistic Studies 3.3 Use for Nucleotide, Sugar Phosphate,

87 90

3

Phospholipid or Phosphoprotein Synthesis 4 5

CHAPTER

3.4 Miscellaneous

93 98

Reactions involving Two-co-ordinate Phosphorus

9a

Miscellaneous Reactions

103

References

103

5

Quinquevalent Phosphorus Acids B y R . S . Edmundson

1

Phosphoric Acids and their Derivatives

106

1.1 Synthesis of Phosphoric Acids and their 106 Derivatives 1.2 Reactions of Derivatives of Phosphoric Acids 121 2

Phosphonic and Phosphinic Acids and their Derivatives

136

xi 2.1 Synthesis of Phosphonic and Phosphinic

Acids and their Derivatives 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.6 2.1.7 2.1.8 2.1.9

Alkyl Phosphonic Acids Alkene-, Alkyne-, Aryl-phosphonic and -phosphinic Acids (Halogenoalky1)-phosphonic and -phosphinic Acids Hydroxy- and Epoxyalkyl-phosphonic and -phosphinic Acids, and Related Sulfur or Selenium Compounds (Oxoalky1)-phosphonic Acids (Aminoalky1)-phosphonic Acids and -phosphinic Acids Sulfur and selenium-containing Compounds Compounds with Phosphorus-Nitrogen Bonds Compounds of Biological Interest

136 136 143 149 149 156 156 161 163 165

2.2 Reactions and Properties of Phosphonic

and Phosphinic Acids and their Derivatives

CHAPTER

6

179

Uses of Derivatives of Quinquevalent Phosphorus Acids in Synthesis

194

The Structures of Quinquevalent Phosphorus Acid Derivatives

196

References

198

Nucleotides and Nucleic Acids B y R. cosstick

1

Introduction

2 08

L

Mononucleotides

2 08

2.1 Nucleoside Acyclic Phosphates 2.2 Nucleoside Cyclic Phosphates

2 08 221

3

Nucleoside Polyphosphates

224

4

Oligo- and Poly-nucleotides

234

4.1 DNA Synthesis

234

4.2 RNA Synthesis

235

4.3 Modified Oligonucleotides

24 1

Oligonucleotides Containing Modified Phosphodiester Linkages 4.3.2 oligonucleotides Containing Modified Sugars 4.3.3 Oligonucleotides Containing Modified Bases 4.3.1

5 6

24 1 254 2 58

Oligonucleotide Labelling, Conjugation and Affinity Studies

268

Nucleic Acid Triple-Helices and Other Unusual Structures

279

xii

C ‘ontents 7

8 9 10

CHAPTER

7

Cleavage of Nucleic Acids Including SelfCleaving RNA

285

Interaction of Nucleic Acids with Small Molecules

291

Interaction of Nucleic Acids with Metals

3 04

Analytical and Physical Studies

307

References

310

Ylides and Related Compounds B y B.J.

Walker

1

Introduction

320

2

Methylenephosphoranes

320

2.1 Preparation and Structure 2.2 Reactions of Methylenephosphoranes

320 325

2.2.1 2.2.2 2.2.3 2.2.4

Aldehydes Ketones Ylides Co-ordinated to Metals Miscellaneous Reactions

The Structure and Reactions of Phosphonate Anions

332

Selected Applications in Synthesis

339

4.1 Carbohydrates 4.2 Carotenoids, Retenoids and Pheromones 4.3 Leukotrienes, Prostaglandins and Related

339 339

Compounds

CHAPTER

8

325 327 327 329

4.4 Macrolides and Related Compounds 4.5 Nitrogen Heterocycles 4.6 Miscellaneous Reactions

342 342 342 345

References

3 54

Phosphazenes B y C.W. Allen

1

Introduction

3 59

2

Acyclic Phosphazenes

359

3

Cyclophosphazenes

368

4

Cyclophospha(thia)zenes

378

5

Miscellaneous Phosphazene Containing Ring Systems Including Metallophosphazenes

379

6

Poly(phosphazenes)

380

7

Crystal Structures of Phosphazenes

390

References AUTHOR INDEX

395 408

Abbreviations AIBN CIDNP CNDO CP DAD DBN DBU DCC DIOP DMF DMSO DMTr EDTA E.H.T. ENU FID g.1.c.-m.s. 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 0 THF Th f %S

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 trifluoromethanesulphonic 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-sulphonic acid ultraviolet

Abbreviations used in Chapter 6 are detailed in Biochem. J., 1970,120, 4 4 9 and 1978,171,l

1

Phosphines and Phosphonium Salts BY D. W. ALLEN 1 Phosphines

1.1

Preparation

I.I.I

From Hulogenophosphines and Orgunometullic Reagents. - Organolithium procedures

have been employed in the synthesis of a range of new tertiary phosphines and chelating diphosphines. Direct metallation of tetrathiafulvalenes with lithium diisopropylamide followed by treatment with halogenophosphines has given a series of electron-rich phosphines ( I ) and the related chelating diphosphine (2).',* Double metallation of dibenzofuran and dibenzothiophen is the key step in the synthesis of the diphosphines (3).' Metallation of indene using butyllithium, followed by treatment with chlorodiphenylphosphine,initially yields the chiral phosphine (4). However, in solution, this compound undergoes isomerisation to the thermodynamically more stable form (5).4 Sequential metallation of substituted 2,2'-dibromobiphenyls and introduction of phosphino groups has been employed in the synthesis of the chiral unsymmetrical diphosphine (6)."* Direct metallation routes have also featured in the preparation of new types of phosphine

ligand bearing reactive functional groups, e.g., (7)' and (8).' Both Grignard and organolithium procedures have been utilised in the synthesis of a series of hydrophilic carboxylated arylphosphines, e.g., (9), starting from dibromobenzenes or bromobenzonitriles. In this work, it was noted that attempted acid hydrolysis of the o-cyanophenylphosphine (10) resulted in the unprecedented formation of the phosphine oxide ( I 1) bearing an aldehyde function, trichlorosilane reduction of which provided the related ph~sphine.~,"' Grignard procedures have also been used in the preparation of the chiral phosphine (12)" and the eight-membered heterocyclic compound ( 13).12 Routes to new chiral phosphine ligands based on metallocene systems, e.g., (14),13 (15),14 and ( I6),l5 all involve regiospecific metallation of the parent metallocene as the initial step, followed by a reaction with the appropriate halogenophosphine.

I . 1.2

Prepururion of Phosphines from Metallared Phosphirws. -

The generation of

arylphosphide reagents by the reductive cleavage of carbon-phosphorus bonds using alkali metals has received detailed study for a wide range of functionalised triarylphosphines and related

Organophosphorus Chemistry

2

(3) X = O o r S

H PPh2

@

MeMwe

H H

fYJq

\IM

\ / PPh2

Ph2P

PPh, (6)

(4)

COOH (9)

(7)

M PBu' W

MeN

co

I:

Phosphines and Phosphonium Salts

3

H P R1R2Si )SiR1 R2 P H

<

ep;; ke @P{h Pr'

Me2 (Et2P-SiMe20Li),

Ph2PCH2

0 0

C l P R Me2 (20) R = Ph or Me3Si

(21)

(22)

Ph2PfCH2k6Me3 X -

(24) n = 2,3,6, or 10

Cr(CQ3 (25) R = Ph or Cy

(23) R = Cy or Ph X=OorS

MeSCH2CH2 PhPCH2CH2PPh I CH2CH2SMe I

(29) R = Me or OMe

RP -ph2

P h 2 P e P P h 2

(30) R = Me, Et, or Pr'

4

Organophosphorus Chemistry

arylalkylphosphines. The course of cleavage is very much dependent on the nature of the aryl substituent and on the conditions. However, the reaction can be controlled in many cases to give preparatively interesting secondary or primary phosphines. The reducing agents Li/THF and NdNH, often give complementary results; however, with the latter, products derived from the Birch reduction of the arene are also possible in the protic solvent. A significant finding is that secondary qlphosphide reagents bearing strongly electron-withdrawing substituents such as F or CF, cannot be prepared by the reductive cleavage of triarylphosphines.'b'8 With iodomethane, the phosphide reagent (1 7) derived from P-phenyl cleavage of the related rruns-diphenylphosphete (18; R=Ph) yields the rrum-diphosphete (18; R=Me). However, if (17) is complexed at the phosphido-phosphorus with a tungsten carbony1 acceptor, and then treated with iodomethane, the related complex of the cis-phosphete (18; R=Me) can be isolated, and the free cis-diphosphete obtained subsequently by decomplexation using diphos. A structural comparison of the isomeric cis- and trans-diphosphetes has revealed that no cyclic delocalisation occurs in the cis-isomer, which undergoes thermal isomerisation to the related rram- form at temperatures above 130°C.'9 Silylphosphide reagents have generated considerable interest over the past year. Alkali metal bis(trimethylsily1)phosphides isotetraphosphines

P(PR,),

diorganochlorophosphines.'('~*'

are useful

(R = Ph

or

building blocks

cyclohexyl)

via,

for the synthesis of their

reactions

with

An X-ray structural study has revealed that lithium

bis(tnmethylsily1)phosphide has a hexameric ladder-like structure involving six lithiumphosphorus interactions.22 Several reports have appeared of the involvement of silylphosphide reagents in the development of the chemistry of the 1,3-diphospha-2,4-disilabicyclo[ 1,l ,O]butane system ( 19).2'-2s The reaction of a bis(chlorosily1)alkane with dilithium phenylphosphide has given the 1,3,2-disiIaphosphorinanesystem (20).26 Lithium diethylphosphide has been shown to undergo insertion into the silicon-oxygen bond of polydimethylsiloxane to form the phosphinosilanoxide (2 l).*' The reactions of lithiophosphide reagents with alkyl halides or sulphonate esters have continued to find wide application in the synthesis of new phosphines. A series of phosphinoethers, e.g., (22), has been prepared from the reactions of chloromethyl-substituted ethers with lithium diphenylph~sphide.~"-*~ A one-step synthesis of macrocyclic phosphino-ethers and -thioethers (23) is afforded by the reactions of dilithio-organophosphideswith bis(@-chloroethyl)ethers and -thioethers derived from ethane-l,2-diol and ethane- 1,2-dithiol, respectively.30 A new family of water soluble phosphonio-phosphine ligands (24) has been prepared by the reaction of a,w-dihaloalkanes with one mole of lithium diphenylphosphide, followed by quaternisation of the intermediate o-haloalkylphosphine with trimethylph~sphine.~'The new ligand system (25) has been prepared by the reaction of chloromethylbenzene-chromium tricarbonyl with

1:

Phosphines and Phosphonium Salts

5

monolithiophosphide reagents derived from diphosphin~propanes.~'The tetradentate P,S, ligand

(26) is afforded by the reaction of the dilithiophosphide reagent derived from 1,2bis(pheny1phosphino)ethane with j3-~hloroethyl(methyl)thioether.~~ Both isomers of the phosphinocyclohexane system (27) have been obtained from the reactions of related isomeric mesylate esters with lithium diphenylphosphide.' Sulphonate ester-phosphide combinations have also been used in the synthesis of interesting c h i d diphosphines, e.g., (28),35 (29),36and (30)." Full details of the synthesis of other ligands beanng chiral phospholane units have now appeared.37-38The development of modified c h i d dioxolane bis(phosphine) ligands of the DIOP series has also been reviewed.39 As usual, although much less popular than lithiophosphide reagents, examples of the

use of sodio- and potassio-phosphide reagents have continued to appear. Sodium amalgam has been found to promote aromatic radical nucleophilic substitution reactions of phosphide reagents with haloarenes in liquid ammonia.40 An improved route to the tetraphosphine (31) has been developed which

involves the reaction of sodium diphenylphosphide with tetrakis-

(bromomethyl)methane."

Similarly, the reaction of 1 , I-bis(chloromethy1)ethene with sodium

diphenylphosphide affords the diphosphine (32). In contrast to the behaviour of other closely related unsaturated phosphines, treatment of the latter with diphenylphosphine in the presence of a base does not result in addition to the double bond, but instead leads to the formation of a mixture of isomers of the diphosphine (33), via an allylic rearrar~gement.~'Potassio-phosphide reagents have found use in the synthesis of a range of new chiral chelating diphosphines, e.g., (34)43 and (35).44 A route to I-phenylphosphetane (36) is afforded by the reaction of phenylphosphine, coordinated to an iron acceptor, with 1,3-dibromopropane in the presence of base.45

Metallophosphide reagents have also found further application in the development of

the chemistry of polyphosphorus compounds.

and, once again, we have seen notable

contributions from the groups led by Ba~dler'~-~' and F r i t ~ . ~ "Interest ~' has also continued in the use of metallophosphide reagents for the synthesis of phosphino-zirconium?* -indium63systems.

gallium

and

Further structural studies on lithium phosphinomethanide reagents have

appeared,Mand new applications of such reagents in synthesis have been reported, particularly for the preparation of compounds involving phosphorus and other p-block elements, e.g., aluminium,65 indium,66 and germanium,67 bridged by a methylene group. Evidence has been presented for the formation of carbon-phosphorus bonds from organophosphides coordinated to iridium bearing a hydrocarbyl substituent.68

1.1.3

Preparation of Phosphines by Addition of P-H to Urnamrated Compounds.- A series

of zirconium phosphido complexes, e.g., (37), has been shown to promote the formation of

Organophosphorus Chemistry

6

[Ph2PCH214C

Ph2PCH2 F Ph2PCH

(31)

C

b

/CH2PPh2

phcH2(ph)p*G

Me

PhCH,(Ph)P

Ph2PCH=C,

NH

(33)

(32)

(34)

H (35) Ar = Ph or 2-thienyl

(36)

(37)

(38)

PH2

I

C H2=CH(CH2)2CHC H2CH=CH2

(39)

F3C*CF3

8:: \

PPh2 PPh2

I Fe

I Fe

(42) (43) R = Ph or Cy

H

(44)

COOH (45) (46)

Ph

(47) n = 2 o r 3

I:

Phosphines and Phosphonium Salts

7

primary alkylphosphines from the reaction of alkenes with phosphine under the mildest

conditions reported to date. These complexes do not appear to be true catalysts, since they are converted during the process to related hydride complexes.69 Chiral phospholanes, e.g., tarpholan (38), undergo base-catalysed addition to alkenes already bearing phosphino- or phosphinyl-substituentsat the double bond to form new chiral phosphorus ligand systems, e.g., (39).70 Radical-initiated intramolecular cyclisation of 4-phosphino-octa-1,7-diene (40) occurs with formation of the cis-1-phosphabicyclo[4,3,O]nonane system (4 1):'

1. I . 4

Preparation cf Phosphines by Reduction. - Trichlorosilane has been widely employed

for the reduction of the oxides of a range of chiral phosphines and chelating diphosphines. Among these are the 2,2'-bis(diphosphino)biphenyl systems (42)n and (43),'3 and related biferrocenyl system^,^^." e.g., (44),75the chiral bis(phosphino)cyclopropane system (45),76and the chiral phosphinoisoquinoline (46).77 The latter was found to undergo rapid racemisation in solution at room temperature. Trichlorosilane has also been used in the final stage of the synthesis of a range of chiral phosphino-carboxylic acids (47), full details of which have now appeared,78and for the reduction of the oxide of the first I-benzophosphepine (48).79 The latter is stable in the solid state for several weeks, but on heating to 60-80°C in solution eliminates phenylphosphinidenewith the formation of naphthalene. The stereochemical course of reduction of the bicyclic phosphine oxide (49) (the main product from the reaction of norbornadiene and

dichloro(methy1)phosphine) has been shown to depend on the nature of the silane reagent used. With phenylsilane, reduction occurs with retention of configuration at phosphorus, whereas, surprisingly, inversion is observed with trichlorosilane.80 Hexachlorodisilane has been used for the reduction of the disulphides of the vinylidenediphosphines(50)." Reduction of the oxides of chiral phospholanes, e.g., (51), has been achieved using eirher phenylsilane or lithium aluminium hydride.82 The latter reagent, in combination with chlorotrimethylsilane, has been employed in the reduction of the phosphonate ester (52) to give the primary arylphosphine (53), a key precursor for the synthesis of a 14-membered P2S,-macrocyclicsystem.83 In combination with aluminium chloride, lithium aluminium hydride has also been used for the reduction of the oxides of a series of chiral ferrocenylphosphines. Di-isobutylaluminiumhydride has been used for the reduction of the oxide of the chiral phosphine (54)." Reduction of the phosphinate (55) using sodium dihydrobis(2-methoxyethoxy)aluminate provides the secondary phosphine (56) which, on treatment with acid, rearranges to form (57), the first example of a hexopyranose analogue having trivalent phosphorus in place of the hemiacetal oxygen.86 Reduction of arylphosphonium salts e.g., (58), using eirher electrochemical techniques or sodium naphthalenide at low temperatures, provides a route to new hybrid ligand systems, e.g., (59),

x

Organophosphorus Chemistry

PPt ph2x2 -- - QPh

Ph

Me

Ph

(50) R = H, Me, or Ph

(49)

(51)

y(Ph)CH2CH(OH)Ph CH20Me

(55)

Ph (58) R’ = H or Me R2 = Ph or PhCH2

R

I-

(OC)SW-P-P(OEt)2

II

0

(59) R’ = H or Me

(60)

1:

Phosphines and Phosphoniuni Salts

9

the precursor phosphonium salts being readily available vio the reaction of o-haloanilines with tertiary phosphines in the presence of a nickel(I1) halide.87

A high yield route to

cyclohexylphosphines is afforded by the reduction of related phenylphosphines with hydrogen under pressure in the presence of niobium aryloxide complexes.88

I . I .5

Miscellaneous Methods of Preparing Phosphines. - Perhaps the year's most surprising

reaction is the formation of 5-phenyldibenzophosphole (60) in 65% yield on treatment of triphenylphosphine oxide with two equivalents of phenyllithium under reflux in THF.89 The reactions of "phospha-Wittig" reagents, e.g. (61), with epoxides have given the first examples of optically active phosphiranes, e.g., (62)' isolated as tungsten carbony1 complexes.w Various routes to o-cyanoalkylphosphines have been d e ~ e l o p e d . ~ 'The ~ ~ *chiral phosphine-borane (63) has been metallated at the carbon of the methyl group and the resulting reagent treated with methyltrichlorosilane to form (after deprotection at phosphorus) the C,-symmetric, optically pure tripodal ligand (64)' each phosphorus centre having the same ~ h i r a l i t y . ~Metallation ~ of

o-bromophenyldiphenylphosphine with butyllithium gives the o-lithiophenyl derivative (65), an X-ray structural study revealing little interaction between phosphorus and the metal.94Treatment of (65) with dibutylchloroborane has given the o-borylphosphine (66),in which there is similarly little interaction between phosphorus and boron.95

Heating various 1,3-substituted

haloadamantaneswith the phosphine-aluminiumchloride complex provides a high yield route to the functionally substituted adamantylphosphines (67).% Routes to the aminomethylphosphines

(68) and the related amides (69) are provided by the reactions of tris(trimethylsily1)phosphine with chloromethyl-amines and -amides, re~pectively.~~ Cycloaddition of nitrones to vinyl-

phosphines provides a route to isoxazolidinylphosphines,e.g., (70), the regioselectivity of the reaction being controlled largely by the substituents on the nitr~ne.~* The C-phosphanylimines (71) have been obtained from a one-pot reaction between cyanobis(di-isopropylamino)phosphine,

chloro(hydrido)dicyclopentadienylzirconium, and diorganochIorophosphines.* Various routes to chlorostannylphosphines, e.g., (72),'O0and new chelating ligands, e.g., (73), involving a silicon-phosphorus link, have been developed."' development of

routes to

the

diorganoborylvinyl-substituents.'02~'03

Interest has also been shown in the

phosphines bearing 8-organo-stannylethyl- and

8-

Unexpected epimerization at the 2-carbon of the

thiomethylphosphonium salts (74) occurs on treatment with tris(dimethylamino)phosphine, to form the phosphinodithianes (75).'"' Work on the formation of phosphines from the reactions of elemental phosphorus with electrophiles in superbase media has c o n t i n ~ e d , ' ~ and ~ ~this ' ~ area

has now been reviewed.""

Interest has also continued in the preparation of water-soluble

sulphonated arylphosphines.'08-''o The reactivity of the carboxyl group of the functionalid

10

Organophosphorus Chemistry

Me I

aPP aPPh2 BBu~

Li

(64)

PH2

I

R ( Me3Si),PCH2N:

COR

(67)R = CI, Br, or Me

But2CISn

R P

’

-.

SnCIBut2

(71)R = Ph or Pri2N

(73)

(76)

(77)

(78)

I:

Phosphines and Phosphonium Salts

11

phosphine (76) has been utilised in the synthesis of new asymmetric ligands, e.g., (77)."' In a similar vein, a range of new c h i d ferrocenyldiphosphines, e.g., (78),'" has been prepared by side-chain elaboration of substituted ferrocenyldiphosphines.112-115 1.2

Reactions of Phosphines

I . 2. I

Nucleophilic Attack at Carbon.- A good correlation exists between the rate constants

for the reactions of triarylphosphines with iodomethane in ethanol at 25°C and the 'Hchemical shift of the methyl protons of the related methylphosphonium salts.'I6 The reactions of secondary phosphines with the triphenylmethyl carbonium ion have been shown to result in the formation of the phosphonium salts (79),rather than the phosphenium ion R,P+: and triphenylmethane.'17 The allenic phosphonium salts (80) are formed in the reactions of tertiary phosphines with tris-

(alky1thio)cyclopropenyl cations.''8 The c h i d salt (81) is accessible from the reaction of (S)3,3,3-trifluoropropene oxide with triphenylphosphine and trifluoroacetic acid.'I9

A

reinvestigation of the reaction between triphenylphosphineand tetracyanoethylene has shown, by

X-ray techniques, that the colourless product first reported in 1963IZ0is the phosphoranimine

"'

(82).

Whereas conventional Lewis acids, e.g., the boron trifluoride-diethyl ether complex,

promote the formation of a-hydroxyalkylphosphinesfrom the reactions of secondary phosphines with carbonyl compounds, the presence of catalytic quantities of niobium(V) chloride promotes

further transformations which result in oxygen transfer from the a-carbon to phosphorus, with the formation of the phosphine oxides R2P(0)CH2R in excellent yield.'"

Migration of a

trimethylsilyl group from phosphorus to carbon occurs in the reactions of silylphosphines with acrylonitrilein the absence of solvents, which give rise to the phosphines (83)."' The betaines (84) are formed in the reactions of triphenylphosphinewith azo-alkenes, and undergo conversion

to pyrazoles on heating under reflux in acetonitrile.''

The zwitterionic adduct (85) has been

isolated, along with other products from the reaction of the phosphine (86) with phenylisocyanate.'*'

Similar

compounds

arise

in

the

related

reactions

with

''*

phenylisothiocyanate.

I . 2.2

Nucleophilic Attack at Halogen. - A kinetic study has revealed that the reactions of

triphenylphosphine with tetrahalomethanes under various conditions exhibit a second order rate law and proceed significantly faster that the corresponding reactions of p a r t d l y halogenated alkanes, suggesting a charge-transfer process for the tetrahalomethanes compared with a simple nucleophilic substitution process of the S,2 type for other haloalkanes.'n Nucleophilic attack at halogen of 2-halo-thiazoles and -benzothiazoles occurs on treatment with tertiary phosphines

in ethanol, with the formation of the phosphine oxide, bromoethane, and the dehalogenated

12

Organophosphorus Chemistry

R’S

+

Ar2PHCPh3 Clod-

OH CF3COO-

R’S

(80) R’ =Pr‘or But R2 = Bu or Ph

(79)

NC CN ,CN ’PCH H Ph’ 2C\SiMe3 R

P h S P = N q CN

Me R02C-CH-C:

I

+PPh3

-

N-NR

(83)

y

Ph2P

lBu

6-BU Ph

0 (87)

0

II

But PC32OEt

Ph3P=NCON=CRCI

II

NPh (89)

NHR CI2C=CC + PPh3 CI (92) R=COCl

(90)

0

II

Ph2PCHR1CHR2CHR3COR4 (93)

I:

Phosphines and Phosphonium Salts

1.3

heterocycle. Evidence for the involvement of intermediatealkoxyphosphonium ions was obtained from "P n.m.r. studies."'

Attack at halogen also takes place in the reactions of

triphenylphosphine with N-alkylsulphinimidic chlorides, ArSC 1 =mu', with the formation of

dichlorotriphenylphosphorane and aminyl radicals, [ArSNBu). ITJ

The reactions of

triphenylmethylhalides with phosphines have received further attention, a single electron transfer pathway being indicated. I 3 O X-ray studies have shown that adducts of triphenylphosphine with bromine and iodine, respectively, formed in non-ionising solvents, have the four coordinate transition state-like structure (87), with a linear phosphorus-halogen s k e l e t ~ n . ' ~Further '~~~~ applications of phosphine-positive halogen reagent systems have appeared. A combination of triphenylphosphine with trichloroacetonitrile has been used to convert a series of alcohols into the respective chl~roalkanes.'~~ The triphenylphosphine-hexachloroethanereagent has been used in a triethylamine-acetonitrilesolvent system for the intramolecular cyclocondensationof @-amino acids to form @-1actams.lM The triphenylphosphine-tetrachloromethane system in refluxing THF smoothly converts a-lactones and acetates into the corresponding dichloromethylene

derivative^.'^' In contrast, some unusual results have emerged from a study of the attempted dichloromethyleneation of y- and 6-lactones, using the tris(dimethy1amino)phosphinetetrachloromethane system.'% An unprecedented migration of an acyl group from nitrogen to oxygen

occurs

on

treatment

of

2-acylaminoalcohols with

the

triphenylphosphine-

tetrabromomethane reagent.137

1.2.3

Nucleophilic Attack at Other Atoms.- A detailed "P n.m.r. study of the Mitsunobu

esterification reaction involving tributylphosphine and diethyl azodicarboxylate has shown that such reactions are more complex than hitherto supposed. The order of mixing of the reagents can dramatically change the mechanism and stereochemistry of the esterification reaction. 13* Applications of the triphenylphosphine-diethyl azodicarboxylate reagent system have been described for aryl ether ~ynthesis,'~~ in morphine chemistry

in glycoside,14' nucleo~ide,"**'~'

and peptide chemistry,Ik4and for the synthesis of 1-azidoalkylphosphonateeaster

A reaction

involving an abnormal stereochemical outcome, i.e. retention of configuration at the key carbon atom, has been attributed to a neighbouring group participation.'46This reagent system has also been applied in a new synthesis of silyl ethers from the reactions of alcohols and phenols with ~ilanols.'~~ A method of carbon-carbon bond formation involving the use of o-nitroarylacetonitriles as carbon acids has provided a rare example of the participation of such compounds

in the Mitsunobu procedure. 148

Also reported is a palladium-modified allylic Mitsunobu

displacement process, in which the initially formed allyloxyphosphonium salt interacts with the metal to form an-ally1 complex, which then undergoes attack by the carboxylate anion in a

14

Organophospho r w (’hemistry

regiospecific and stereospecific manner.

Recent advances in the Staudinger reaction of tertiary phosphines with azido compounds have been reviewed.lm The reaction of the alkynylphosphine (88) with phenylazide yields the unstable intermediate (89), which in the presence of protic substances undergoes nucleophilic addition to the triple bond.”’ The reactivity of the nitrogen-silicon bond of the phosphinimine derived from triphenylphosphine and trimethylsilylazide has been exploited in reactions with chloroformyl reagents to generate new functionalid phosphinimines, e.g., (90).’52 Potassium permanganate in acetone has proved to be the most effective reagent for the oxidation of both E- and 2-(P-stanny1vinyl)phosphines. The less reactive oxidising agents M n 0 2 and 0,react selectively with only the E-isomers, possibly due to interactions between the phosphorus lone pair and the triorganostannyl moiety in the Z-isomer, making the latter more resistant to o~idation.”~ The kinetics of a ruthenium(II1)-catalysed oxidation of triphenylphosphine with iodosylbenzene have been studied.IM A mass spectrometric study has lent support to a previously proposed mechanism for the reaction of triphenylphosphine with elemental sulphur.’5SA very convenient and rapid route to triarylphosphine sulphides is provided by the reaction of the phosphine in aqueous acetone solution with sodium polysulphide at room temperature, the phosphine sulphide crystallising from the reaction mixture.’s6 The results of a kinetic study of the reaction between tertiary phosphines and diaryltrisulphides are consistent with a biphilic mechanism analogous to that proposed for the related reactions with elemental sulphur.

The reagent system arising from tributylphosphine and diphenyldisulphide has been

used in a high pressure transformation of sterically hindered primary and secondary alcohols into the related thiophenyl ethers.15* The triphenylphosphine-di(2-pyridyl)disulphide system has been used to promote the macrolactamisation of w@-aminopheny1)carboxylic acid^."^ Treatment of solutions of lithium aluminium hydride in ether with the hydrochloride salts of bulky trialkylphosphines provides a route to stable tertiary phosphine adducts of alans AIH,.Iw

1.2.4

Miscellarwous Reactions of Phosphines.- The basicities of a series of bidentate

phosphines have been determined by a study of their enthalpies of protonation with

trifluoromethanesulphonic acid in lY2-dichloroethane. I*’

Ring-opening of sultones via

nucleophilic attack by nitrogen occurs on treatment with tri-(2-pyridyl)phosphine, with the formation of the water-soluble phosphine systems (91)

A novel aldehyde-olefination

procedure is afforded by the reactions of aldehydes, diazomethanes, and tertiary phosphines in the presence of a catalytic amount of the powerful Lewis acid methyltrio~orheniurn.’~~ Attempts to prepare carboxyphenylphosphinesby the ring metallation of triphenylphosphine followed by

I:

1s

Phosphines and Phosphonium Salts

introduction of carbon dioxide have been frustrated by the aselective nature of the metallation process, mixtures of o-, m-, and p-isomers being isolated.lM The reaction of triphenylphosphine with 1,2,2,2-tetrachloroethylisocyanate has given the salt (92)."j5 A route to tetrathiafulvalenes is afforded by the reactions of dithiolselenones with triphenylphosphine.'66 Phosphine oxides (93) have been isolated from the reactions of secondary phosphines with 1,4-

dike tone^.'^^ The reactions of o-hydroxyphenylphosphines with boron reagents have been studied, borylation occurring at oxygen.'m Some novel approaches have been developed for the optical resolution of chiral phosphines.

A part~al enrichment of one enantiomer of 2-

hydroxyalkyldiphenylphosphineshas been achieved by acylation with isopropenyl acetate under enzymatic catalysis.'@ Examples of the resolution of chiral phosphines using chiral metal complexes have also been rep~rted.'~~.'~' "Good to excellent" regiocontrol has been reported for the rhodium-catalysed hydroformylation of a range of alkenylphosphines.ln

Prototropic

rearrangement of the alkenyldiphosphine (32), in the form of its metal carbonyl complexes, has been e~tablished.'~' Alkynes undergo insertion into the phosphorus-phosphorus bond of diphosphines coordinated to a molybdenum acceptor to generate novel phosphorus ligand systems.'" Further examples have appeared of the cleavage of phosphorus-carbon bonds of phosphines coordinated to transition metals in homogeneous catalyst ~ystems,'~'-'~~ and also of the advantages of using tri-(2-furyl)phosphine instead of triphenylphosphine as a ligand in phosphine-metal complexes active as homogeneouscatalysts. '79~180 The extent to which the nature of phosphine ligands induces selectivity in metal complex-catalysed carbon-carbon bond formation reactions has been reviewed.'"

Tris(alkyny1)phosphines are useful sources of

functionalised phosphido and phosphinidene ligand systems.'" The coordination chemistry of the 1,2-dihydrophosphete system (94) has also attracted some attenti~n.'~' Treatment of diphenylacetylphosphine with butyllithium gives rise to the enolate (95) from which a number of transition metal derivatives have been prepared.'" The electrochemical behaviour of 1,3,2,5dioxaboraphosphorinanes (96) and their copper(1) complexes has been studied.

'"

Electrolysis

of triphenylphosphine and L-a-aminoacids under nitrogen in a one compartment cell results in the formation of L-a-aminoaldehydes and the phosphine oxide. The reaction is believed to involve the initial formation of the triphenylphosphine radical cation, and subsequently an acylphosphonium ion which is reduced at the cathode.'86The triphenylphosphine radical cation is also implicated in the dediazoniation of arenediazonium in alcoholic solvents at ambient

temperature and in the dark.'" Two reports have appeared of the formation of transient threeelectron bonding interactions between a phosphine radical cation and an appropriately situated donor phosphorus'" or sulphur'" atom, respectively.

16

Organophosphorus Chemistry

2 2.1

Halogenophosphines

Preparation.- The reaction of red phosphorus with chlorobenzene in phosphonts

trichloride containing one of a number of catalytically-active substances, e.g., copper(1) chloride

or

sulphur,

gives a

reasonable conversion

to

phenyldichlorophosphine.I9O

The

halophosphinonaphthalenes (97) have been prepared by direct reaction of the substituted naphthalene with the appropriate phosphorus trihalide.19' Similarly, direct reaction of 2methylfuran with phosphorus tribromide in pyridine provides a route to the substituted furylbromophosphines (98).

Analogous reactions of furan and thiophen require harsher

conditions.Iw The aryldifluorophosphine (99) has been prepared by the reaction of l-lithio-2-

methoxybenzyldimethylaminewith chlorodifluorophosphine. An X-ray study of this compound reveals a significantdonor-acceptor interaction between the amino nitrogen and phosphorus.'91 Photochemically-induced dibromophosphinylation of 2-methylbut-2-ene with phosphorus tribromide has given a mixture of the dibromophosphines (100) and (101). Similarly, 2,3dimethylbut-2-ene gave (102) as the sole product.'w In a similar vein, the photochemicallyinduced reaction of butadienes with phosphorus trichloride resulted in dichlorophosphines (103), which on treatment with

butadienyldichlorophosphines ( 104).'95

the allylic

triethylamine gave rise to the

The adamantylhalogenophosphines (105) have been

prepared from the reactions of 1,3dehydroadamantanewith organodichlorophosphines.'% Other routes to adamantylhalogenophosphines have also been developed. The dihalogenophosphines

(106; X=Br or I) have been obtained by the reactions of I-adamantylphosphine with bromine or iodine, respectively. The related difluorophosphine (106; X=F) is accessible from the reaction of the related dichlorophosphine with sodium fluoride in the presence of 15crown-5 in acetonitrile.'w Chlorophosphines have also been converted into fluorophosphines by treatment with the triethylamine-hydrogenfluorideadduct in the presence of free triethylamine. This route

permits the synthesis of fluorophosphinesof low thermal ~tabi1ity.I~~ Acylalkylchlorophosphines (107; X=CI) have been obtained from the reaction of the secondary phosphines (107: X=H) with carbon tetrachloride in the presence of triethylamine.lW Aryloxydichlorophosphines have

been

used

to

reduce the organotrichlorophosphonium salts (108) to the related

organodichlorophosphines. 2.2

Reactions.-

The cyclic diene (109) shows considerable reactivity towards

halogenophosphines, with the formation of the cyclic phosphine oxides (110) after the usual hydrolytic work-up.201The chemistry of p-dimethylaminophenyldichlorophosphine (1 11) has received further study. Chlorination and bromination reactions have been investigated, together

I:

Phosphines and Phosphoniirm Salts

Px2 (97) R = Me2N or OEt X = CI or Br

17

(98) n = 1 or 2

(99)

Me Me-CH=C\ CH2PBr2 (100) E - and 2 -isomers

C12PCH=CHC(R)=CH2 (103) R = H or Me

(104)

Dpx2 ,COR2 R1P, X

(107) R1,R2 = Pr', Bus, or But

PRCl (105) R = Me or Ph

+ RPCIS

PC16-

(108)

6 NMe2

(110) R = Et or Ph

(111)

+,SiMe3 R P I\OSiMe3

(113) R = H o r C I

(1 14) R = alkyl or Ph

Organophosphorus Chemistry

18

with the McCormack reaction with isoprene which gave the dihydrophosphole oxide (1 12).2m

Treatment of the chloromethyldichlorophosphines(113) with ethoxymethyldimethylamineyields the corresponding ethylphosphonites.m The phosphonium salts (1 14) are formed in the reactions of iododiorganophosphineswith hexamethyldisiloxane.m Various aminophosphines, e.g., (1 15), have been isolated from the reactions of chlorodiorganophosphineswith 2-amin0pyridine.~~ The curious "poly-onio" phosphine (116) has been obtained from the reaction of phosphorus trichloride with 4-dimethylaminopyridine. However, related reactions do not occur with chloro(organo)phosphines.2" The reaction of phenyldichlorophosphine with isopropylamine has received further study, and a number of intermediate species charackrised.2m The aminophosphineoxide (1 17) has been isolated from the reaction of chlorodiphenylphosphinewith

3Z-hydro~yiminoflavanone.~"Reversible dimerisation of dibutylfluorophosphine occurs in the presence of triethylamine, with the formation of the phosphinodifluorophosphorane(1 18). The nucleophilic and electrophilic properties of the fluorophosphine are also revealed in its reaction with benzaldehyde, which results in the formation of (1 19), again involving trivalent and

pentavalent phorophors

The reactions of chlorodialkylphosphines with hexachlorodisilane

have been investigated.2'0*21' The tetraphosphetane (120) has been isolated from the reaction of

pentamethylcyclopentadienyl dichlorophosphine with the diphosphine (Pf2N)2P-P(SiMq)2.2'Z Phosphorus-nitrogen bond formation occurs in the reactions of N,N'-dimethyl-N,N'-

bis(trimethylsi1yl)ureas with halogenophosphines, and a number of acyclic and cyclic phosphinourea systems, e.g., (121),2'3have been i~olated.~'~.~'' Reductive dehalogenation of halogenophosphines has been observed in the formation of complex metallophosphido systems

in their reactions with iron ~ a r b o n y l s . ~ The ~ ~ *reduction ~'~ of chlorodiorganophosphines to secondary phosphines, and also their conversion to the related fluorophosphines, have been observed in the reactions of coordinated chlorophosphines.21'

3 3.1

Phosphoniurn Salts

Preparation.- The product of alkylation of red phosphorus with iodomethane in the

presence of a catalytic amount of iodine has been shown to be the bisphosphonium triiodideiodine complex (122).2'8 The pyndylphosphonium salt (123) is formed in high yield in the reaction of N-fluoropyridiniumtetrafluoroborate with triphenylphosphine.2'9Cycloquaternization of 1 ,1-bis-[(diphenylphosphino)methyl]ethene with 3chloro-2-chloromethyl-1-propene results in the formation of the cyclic diphosphonium salt (124). which, on treatment with a strong base, undergoes a double exo-endo proton transfer rearrangement to form the cyclic ylide (125). The latter has a puckered tub-like conformation, the two A'-phosphorus atoms acting as barriers to

I:

Phosphines and Phosphonium Salts

19

Ph2

+

PPh3 X I

(133) Z = COR or CN

(134)

(135)

20

Organophosphorus C ’hemistry

full a-electron delocalisation.220A series of propargylphosphoniumsalts (126) has been obtained

by quaternization of propargyl halides with triphenylphosphine in the presence of ammonium chloride in THF.22’ The diphospholium salt (127) has been isolated from the reaction of propargyl bromide with bis(diphenylphosphino)methane.222Routes to zwitterionic phosphonium derivatives, e.g., (1281, have been developed, the final step being quaternization at phosphorus.223Conventional quaternization procedures have also been used in the preparation of benzocrown ethers bearing pendant phosphonium groups,224and in the formation of phosphonium derivatives of brorn~acetylcournarin~~~ and chloromethylbenzimidazole.226 Treatment of the bisphosphonium salt (129; X=OH) (obtained from the reaction of 1,2bisphosphinoethane with formaldehyde in the presence of hydrogen chloride), with thionyl chloride has given the salt (129; X =Cl).227 Evidence of the importance of an oxidative addition step involving the metal halide catalyst has been presented in the nickel(I1) bromide-promoted reactions of triphenylphosphine with aryl- and alkenyl-bromides which lead to the formation of aryl- and vinyl-phosphoniumsalts.22RFull details have appeared of the formation and subsequent reactions of the alkylthiophosphonium salts derived from tris(2,6-dimethoxyphenyl)phosphine sulphide.229The reaction of tetrabutylphosphonium hydroxide with aqueous hydrofluoric acid at pH 8.1 has given the salt Bu,P+ HF2-, which, on treatment with one mole of butyllithium is converted into the unsolvated, simple fluoride Bu,P+ F - . Such salts are freely soluble in water and in most non-polar solvents, and are useful sources of fluoride ion for selective fluorination ~eactions.~”A number of reports have appeared of the formation of phosphonium salts, e.g.. (

and (131)232from the reactions of related iodonium salts with tertiary p h o s p h i n e ~ . ~ ~ ’ - ~ ~

The direct reactions of triphenylphosphinewith aldehydes in the presence of trimethylsilyliodide

(or triflate) offers a new route to the salts (132), which are found to undergo nucleophilic displacement of triphenylphosphine on treatment with a wide range of reagents.235Nucleophilic addition to the vinylphosphonium salts (133) has been used as a route to new phosphonium salts, e.g., ( 134).236Photo-initiatedaddition to vinyltriphenylphosphonium bromide of radicals derived from pyridine-2-thione has been employed in the synthesis of the salts (135).237On treatment with phenylhydrazine, the vinylphosphoniumsalt ( 1 36) is converted to the pyrazolylphosphonium

salt ( 137).23RA new approach to synthesis of I-(acy1amino)vinylphosphonium salts (138) has been developed.239C-alkylation of stabilised ylides is the key step in the synthesis of the salts ( 139).240Similarly, the aminoalkylphosphonium salts (140) have been obtained from the

N-

alkylation of N-phenylph~sphazenes.~~’ The zwitterionic adduct (14 1) results from the reaction of 3-borahomoadamantane with methylenetriphenylphosphorane.”2

An X-ray study has

confirmed that in the reaction of triphenylphosphoniocyclopentadienide with benzenediazonium

salts, the phenylazo group enters the 2-position of the cyclopentadienyl ring.”’ Kinetic studies

I:

21

Phosphines und Phosphonium .'Gilts A.

PPh3 1-

MeS

R1R2C=C- 6Ph3

Clod-

I

N,N
NHCOR

Ph (138) R', R2 = H, Me, or Ph

(1 37)

(139) X = CI or Br Y=OorCO

(140) R = Et02C, H Z e C H , HC-C, or Ar

+

+

PhsP-CH=CH-PPh3

2 OTf-

0

II

0

II

Ph2PCH&H(Ph)PPhz

OEt I ,R2

+

Ph3P4'\OEt R'

(148) M = Ge, Sn, or Zn

(149) M = Ge, Sn, or Zn

(150)

Organophosphorus Chemistry

22

of the reactions of triphenylphosphoniocyclopentadienidewith tetrahalobenzoquinones have also a p ~ e a r e d . ~ " . ~The ' ~ diphosphonium salt (142) has been isolated from the oxidative-coupling reaction of the ylide Ph,P=CPh2 with an organorhenium(VI1) reagent.'*

The preparation of

other phosphonium salts bearing unusual complex anions has also been r e p ~ r t e d . ~ ~ . ~ ' ~

3.2

Reactions.-

The effects of varying concentrations of DMSO in aqueous-DMSO

mixtures on the rate of alkaline hydrolysis of tetraphenylphosphonium chloride have been studied. An increase in the DMSO content of the solvent from 0 to 50% results in a 10"-fold rate increase at 45°.249 Treatment of the salt (143) with triethylamine or sodium hydride in wet acetonitrile results in the formation of a range of compounds which include products of alkaline hydrolysis in which aryl migration from phosphorus to carbon has occurred, e.g., (lM)."50 A reinvestigation of the reactions of oxygen nucleophiles with the vinylphosphonium salts (145) has shown that the product of the reaction with sodium ethoxide in T H F is the phosphine oxide ( 146)251 rather than the ylide (147) previously reported.2s2 Further synthetic applications of

fluorinated 0-ketophosphonium salts have been d e ~ e l o p e d . ~ ~Triphenylphosphonium ~.~" iodide has been shown to be an efficient reagent for the dehalogenation of a-halocarbony1 compounds which are otherwise difficult to reduce.2s5 A study of the reactions of the triphenylphosphonium salts (148) with hydrocinnamaldehyde, which results in the salts (149), has shown that the nature of the counterion is important, the same phosphonium ion product being isolated from the related reaction with triphenylphosphine and hydrogen chloride.2M Two types of radical anion salts have been isolated from the reaction of the salt (150) with tetracyan~quinodimethane.~~~ The readily available l-acylaminovinylphosphonium salts (151) have been used in a synthesis of 5mercaptothimles.2ss Another example has appeared of the use of the salt (152) as a source of difluorocarbene, this time in a synthesis of gem-difluorocyclopropenes from acetylenes.2s9 In aqueous solution, the methylenic hydrogen atoms of the macrocyclic tetraphosphonium salt (1 53) are sufficiently acidic to be selectively deuteriated at different pH values. However, it has not been possible to develop this system for the selective complexation of anions of varying charge.'@

Studies of the CH-acidity and phosphoryl-hydroxylide tautometism of the

phosphonium salts (154) have continued.261-2a Molten tetra-alkylphosphonium salts have been investigated as potential non-aqueous solvents

A surface study of solutions of tetrabutyl-

ammonium and -phosphonium bromides in formamide has indicated a much stronger cation-anion interaction in the phosphonium salt.266 Evidence of micellar catalysis by long chain alkylphosphonium salts has been found in studies of the destruction of toxic phosphorus(V) esters by sodium perb~rate.*~' Further examples of phase transfer catalysis of halogen exchange reactions by phosphonium salts have appeared.2".269 The preparation and applications in synthetic

I:

Phosphines und Phosphonium Suits

23

Ph2

NHCOR

Ph2

+

c12c=c\+

Ph3PCF2Br Br-

PPh3 CI(151) R = Me or Ar

xI I

+

R2P-CH-PPh3

R\ P-P,

Z-

Y (154) X = O o r S

+

Y = PPh3, CN, or COR

Pr

R-P=P-Ar

x'

SiMe3 (155) R = tris(trimethylsily1)hydrazide Ar = 2,4,6-6Ut3C&

ArP =PAr

,P-P' Ar

(156)

Ar

\/

CH2

[(q5-Me5C5)(C0)2Fe]P=PAr

Me2NP=C:

F R

(160) Ar = 2,4,6-But3C6H2

(161) Ar = 2,4,6-But&H2

(162) R = F o r CF3

Me3P=C(X)P(F)CF3

(163) R = Me or Et

(164) X = F, OMe, or OEt CI Bu',P+-

But,

p=c,

,Ph Ph

CPh2

(165)

24

Organophosphorus C'hemislry

chemistry of polymer-bound phosphonium salts bearing nitrite, thiocyanate, and borohydride counterions, respectively, have been investigated.270

4

p,-Bonded Phosphorus Compounds

The literature on this area up to 1990 has been reviewed in a major v~lume.~"The ability of complex metal hydride acceptors to stabilise p,-bonded phosphorus compounds, but without diminishing their reactivity, has also been reviewed.272 A theoretical study has concluded that phosphorus analogues of simple diazonium ions,

e.g., CH,-P=P+, should be detectable in the gas phase, and possibly also in superacid media.273 At temperatures above - I O T , the halogenodiphosphine(155; X =Cl) loses trirnethylsilylchloride to give the tram-diphosphene (156).

Surprisingly, decomposition of

the related

bromodiphosphine (155; X =Br) yields the related cis-diphosphene. Both isomers are stable indefinitely in the solid state but undergo equilibration in sol~tion.~"Diphosphenes are involved as transient intermediates in the dehalogenation of the tetramethylpiperidinyldichlorophosphine

(157) using magnesium in THF, which results in the formation of a range of cycl~polyphosphines.~~~ Improved yields of the diphosphene (158) have been obtained by the

ul trasound-assistedmagnesium-promoteddehalogenationof the precursor aryldichlorophosphine. Ultrasound also assists in the subsequent cyclopropanation of such diphosphenes using metallic zinc and diiodomethane, with the formation of the diphosphiranes (159). Prolonged sonication of such reaction mixtures results in the formation of the phospha-alkene (160) as the sole

product

Diphosphiranes have also been isolated from the reactions of diphosphenes with a

range of diazomethanes.2n A theoretical study of the addition of methylene to the diphosphene HP=PH suggests that the preferred process is .r-addition with formation of the diphosphirane system.278 Interest has continued in the chemistry of diphosphenes bearing complex transition metal substituents at phosphorus, e.g., (161), their cycloaddition reactions with azodicarboxylic acid esters and amides having now been explored.n9.280 A related reaction with Nmethylmaleimide results in cleavage of the P=P bond.281 A diphosphene bearing metallocomplexed phosphido substituents at phosphorus has also been prepared.282The coordination chemistry of both reactive283and stable2" diphosphenes has received further attention. Phosphinyl radicals have been identified by ESR in an X-ray irradiated single crystal of a diph~sphene.~'~ In a review, largely of the work of his own group, Mathey has expanded on the analogy between P=C and C =C bonds.286The difficultiesinherent in the attempted preparation of phospha-alkene systems by the condensation of primary phosphines with carbonyl compounds

I:

Phosphines and Phosphoniurn Sults

have been considered and possible solutions proposed

25 Theoretical treatments of the electronic

and also of the effects of halogen substituents at phosphorus in P-halophospha-alkene~,~~*-~~~ peculiarities of p,-p, conjugation in aminosubstituted phospha-alkenes,2whave appeared. A new route to phospha-Wittig reagents, e.g., (61), has been developed, thereby facilitating their use

in the synthesis of phospha-alkenes.D' The reactive amino-substituted phospha-alkenes (162) have been prepared by gas-phase pyrolysis of related trimethylstannyl(perfluoroalkyI)aminophosphines, and characterised by cycloaddition reactions.292 The one-pot reaction of secondary amines with the alcohol adducts of perfluoro-2-phosphapropeneyields the stable phospha-alkenes (163), which surprisingly do not react with alcohols, amines, and 1,3-diene~.'~~ On treatment with trimethylphosphine, the reactive phospha-alkenes (164) give rise to the ylides ( 165).2p4A new route to 2-phosphapropene (166) has been developed. As would be expected, addition of water and alcohols to this compound take place readily.295On treatment with tin(I1) chloride, the easily accessible ylide (167) is converted into the methylenephosphoniumsalt (168), which then decomposes in solution to form the phospha-alkene (169). The latter gradually dimerises

to form the diphosphetane (170).'"

Treatment of the crowded secondary silylphosphine (171)

with isophthalaldehyde results in the formation of the diphospha-alkene (172), of interest as a new chelating ligand system.297A range of C-halogenophospha-alkenes (173) has been prepared by the reactions of 2,4,6-tri-1-butylphenyldichlorophosphine with butyllithium in the presence of

polyhal~genomethanes.~~~ Thermolysis of the diphosphaspiropentane (174) proceeds not only with the expected spiropentane-methylenecyclobutane rearrangement which yields the phosphaalkene (175) but also with the formation of the diphosphanorbornadiene system (176)? Mathey's group has continued the development of the chemistry of transient terminal vinylphosphinidene complexes, e.g., (177). Generation in the presence of conjugated dienes, e.g., cyclopentadiene, leads to the formation of the complexed bicyclic phospha-alkene (178) viu the [3,3]-phospha-Cope rearrangement of the intermediate phosphirane complex ( I79).'Oo A vinylphosphinidenecomplex is also a likely intermediate in the synthesis of the 2,3-dihydro-1,2diphosphete system (1 80)?" Studies of the keto-enol tautomerism of sterically crowded acyland aroyl-substituted secondary phosphines (and arsines) have c o n t i n ~ e d . In ~ ~related - ~ ~ work, the p,-bonded reagents (1 8 1) and (1 82) have been prepared; doubtless their exploitation in the synthesis of new systems will soon follow.m The reactions of the halogenophospha-alkene(1 83) with complex metallo-anions have given a range of P-metallophospha-alkenes, e.g., (184), which are found to be metastable, undergoing gradual dimensation and subsequent transformation.306 Mathey's group has shown that rhodium complex-promoted catalytic hydrogenation of prochid complexes of phosphaalkenes offers a route to related complexes of chiral secondary phosphines.307.30% The reactivity

Orgunophosphorus Chemistry

26

J?

X

ArHP

Y

x

P A 'r

(172) Ar = 2,4,6-But3C6H2

(173) X = CI, Br, or I Y = H, CI, Br, or I

Ar-P-P-Ar

(1 74) Ar = 2,4,6-But3C6H2

Me I

CH2 =C-P

ArP

=W(CO),

(1 75)

Me

op/ ,C=CH,

H PEC-OLi H

X ArP=C: PYR

(185) Ar = 2,4,6-But&H2 R = Ar or TMS X = CI or Br

CIP=C( SiMe,),

I:

Phosphines und Phosphoniurn Salts

27

of the 1,3-diphosphapropenes (185, Y =Cl) has been explored; with aluminium chloride, the

phosphoniophospha-alkenes (1 86) are formed, and reduction with lithium aluminium hydride gives the phosphinophospha-alkenes (185, Y =H).

Treatment of (185. Y =C1) with

organolithium reagents results in the formation of diphospha-allenes (187).-

The reactions of

a range of C-phosphinophospha-alkeneswith iodomethane have been investigated; in general, quaternization occurs predominantly at the phosphino substituent although, in the presence of excess iodomethane, reaction at the sp*-phosphorusis significant.310 The phosphatriafulvenes (1 88) readily undergo electrophilicattack at phosphorus, implying significant negative charge on this atom as a result of resonance interactions involving the cyclopropene system, canonical forms of type (189) making a significant contributi~n.~”*~’~ With P-halogenophospha-alkenes, compounds of type (188, R2=tms) yield the new cross-conjugated phosphapolyenes (190).”’ Further reports of the reactivity of C-(dialky1amino)phospha-alkenes towards disulphides have appeared.”‘ Related P=C cleavage reactions also occur in their reactions with benzenesulphenyl

chloride

The

photoelectron system

and

dynamic stere~~hemistry~” of

bis(dia1kylamino)phospha-alkenes have also received attention.

C-

The [4+2] cycloaddition

reactions of phospha-alkenes with 1 ,3-butadiene have been considered by a frontier M.O. approach,’” and further work reported on the hydro- and carbo-zirconation of both P=C and

P = N system Various theoretical treatments of phosphabutadiene systems have appeared, including studies of their formation in ring-opening processes undergone by phosphacyclobutenes.320323 Allylphosphines have also found use as precursors of phosphadiene systems.

Thus, e.g.,

pyrolysis of diallylphosphines leads to the formation of the thermally unstable phosphadienes (191) which readily undergo dimerisation to form the cyclic diphosphines (192).324Stable chelate complexes of the diphosphabutadiene (193) have been isolated,325and further examples of diphosphacyclobutadienecomplexes have been characterised.326 Phosphabutatrienes, e.g., ( 194), formed in the reactions of 2,4,6-tri-r-butylphenyldichlorophosphinewith allenyllithium reagents,327undergo conversion to dimethylenephosphiranes, e.g., (199, on treatment with dichlorOcarbene.’28.’29 A route to the iminomethylenephosphenes (196) is afforded by the reactions of the perfluorophospha-alkene (164, X=F) with hindered primary a m i n e ~ . ~The ~’ chemistry of phospha-allenes also continues to attract attention. The diphospha-allene (197) is converted into the novel heterocyclic system (198) on treatment with sulphur

Interest has also

continued in the reactions of coordinated phospha-ally1 systems.332 A new route to the phospha-alkyne (199, R=2,4,6-Bu‘,C6H2)is provided by the reaction of the readily available phospha-alkene (173, X = Y =C1) with a triphenylphosphinepalladium (0) complex.’” The low temperature Lewis base-induced rearrangement of primary

Organophosphorus Chemistry

28

ArP=C=PR

R" (187) Ar = 2,4,6-But3C6H2 R = Ar or TMS

"%P

,P=C,

(188) R' = 1-adamantyl or But R~ = TMS or MES

,SiMe, R2

,yH-CH \\

R-P

CH2

R' (191) R = Ph or But

,R Ar - P 4 ' I 2

::P p H T M TMS s

CPh2

I

Ar (1 93) Ar = 2,4,6-But3C6H2

F,C-P=C=N-R

(194) Ar = 2,4,6-But3C6H2 R = SiMe3 or Ph

(195)

ArP=C =PAr

(196) R = Pr' or But

(197) Ar = 2,4,6-But3C6H2

CO2Et RCHZCIP

RC P :

(200) R = H, Me, or Ph

&OH

But

K Nh

NPri,

H

(203) R = CF3 or C02Me

I:

Phosphinrs attd Phosphoniiirn Salts

20

alkynylphosphines gives a new and efficient route to phospha-alkynes having a primary alkyl substituent at carbon, e.g., 200

Phospha-alkynes continue to find use as building blocks in

synthetic chemistry, and two reviews of this area have a ~ p e a r e d . ~ ~New ~ . ~ developments ’~ include the reaction of the phospha-alkyne (199, R=Bu? with azomethine ylides, which provides a new access to the phosphaindolizine system (201),”’ and with diphenylketene which results in the X3-phosphorin (202).338 The h3-phosphorin system is also formed in the reaction of (199, R=Bu‘) with a spirogermole via a [2+4] cycloaddition process

Cycloaddition reactions of

the amino-substituted phospha-alkene (199, R=Pr‘,N) with dimmethanes lead to the first reported amino-functional 1,2,4-diazaphospholes, e.g., (203).”’ The first representative of the 1,2,4-azadiphosphole system (204)has been formed by the dimerisation of the amino-substituted phospha-alkyne (199, R=Bu‘NH) in an alkaline rnedium.”l Further novel transformations of phospha-alkynes in the coordination sphere of transition metals have also been reported A low temperature structural study of the phospha-alkyne (199, R=Bu’) (a liquid at room

temperature) has revealed a P = C bond length very similar to that determined by microwave ~pectroscopy.”~The first evidence has also been provided of the existence of a phosphorus analogue (205) of an arylisocyanide, stabilised by coordination to a metal.”‘ The chemistry of compounds involving p,-bonds between phosphorus and elements other than carbon has continued to attract attention.

Structural studies of a wide range of

monomeric, sterically crowded, borylphosphines have led to the conclusion that boronphosphorus n-interactions are similar in strength to those in related boron-nitrogen system^."^.""

In contrast, there is little evidence of boron-phosphorus n-bonding in the phosphadiboroles (206), boron-nitrogen a-interactions appearing to be dominant in these less crowded systems. u9*3s0A range of sterically crowded aminoborylphosphines has also been prepared, but as yet no structural information is a ~ a i l a b l e . ~Appreciable ~’ P = N *-interaction appears to be present in the anion (207) obtained by deprotonation of the related phenylamin~phosphine.~~~ P = N systems have also been the subject of MNDO ab inirio quantum chemical calculation^.'^^ Most of the work in the past year in the P=N area has centred around the reactions of Phaloiminophosphenes with nucleophilic reagents, often with the goal of preparing new systems having extended p,-c~nfiguration.~”-~~~ The possibility of stabilising the P =Si bond by intramolecular coordination has been demonstrated in the system (208), which is inert to most nucleophilic and electrophilic reagents, with the exception of oxygen and water.35v Likewise, the sterically crowded system (209) shows remarkable thermal stability, but on treatment with elemental phosphorus gives rise to the new bicyclic system (210).360 A new germaphosphene (21 1) has been prepared, having good thermal stability but being very sensitive to air and moisture, and readily undergoing cycloaddition processes.

A new approach for the generation

30

Organophosphorus C'hemistry

-

-

PhZP-NPh

CEPAr

(205) Ar = 2,4,6-But3C6H2

R' (206) R' = NR2 R2 = Ph or SiMe3

(207)

(209) R = SiPri3 or SiMe2Bu'

R-P=S Mes2Ge=P +Pi

CI(CH2)" 'p=PBu3 J (0C)SW

Pr' (21 1)

(212) R = Ar or Et

(213)

n =2or4

Me

(217)

(218) R' = alkyl, awl, R2N, Cy2P, RO, or RS R2 = TMS

(219)

I:

Phosphines and Phosphonium Salts

31

of thioxophosphenes (2 12) has been described.M2The phospha-ylid complexes (2 13) undergo intramolecular alkylation at the phosphinidene phosphorus, as expected, to give the salts (214) which

readily undergo P-P cleavage to

form cyclic chlorophosphines, e.g.,

1-

chlor~phosphirane.’~~ A new approach to the generation of arylphosphinidenes is offered by the photolysis of the bisazide (215) (an air-stable colourless solid), which, in the absence of other trapping agents, gives rise to the phosphaindane (216).w

Phosphinidenes stabilised by

coordination to zirconium have also been des~ribed.~’ New routes to phosphenium ions, R,P: +, have also been developed. The one-electron electrochemical oxidation of P,P-diphosphines bearing dialkylamino substituents results in the formation of phosphenium ions.-- The products from the replacement of two chlorines of phosphorus trichloride by phosphonium ylides are ionic phosphenium chlorides, e.g., (217), and not covalent halogenophosphine derivatives

The

reactions of phosphenium ions,368and for the first time, those of related arsenium ions,’@’ have also received attention.

Interest has also continued in the chemistry of metal-coordinated

phosphenium ions.37a3n Activity has continued in the chemistry of d - h 5 systems, and further new species, e.g., (218)373and (219),374~haracterised.~”-~~~ Quin’s group has continued to develop the ring fragmentation approach for the generation of pentacovalent low coordination phosphorus specie^.^"^'^^ Di pole moment studies of such systems have also been r e p ~ r t e d , ’ ~ * ~ ~ ~ and the electronic structure of h’-phospha-alkynes considered from a theoretical standpoint.

5

Phosphirenes, Phospholes and Phosphinines

A theoretical study indicates the remarkable ability of halogen substitution at phosphorus to

stabilise the 1 H-phosphirene system (220).387 The 1-chloro-1H-phosphirene system has been obtained directly by the trapping of phospha-alkynes with chlorovinylcarbenes, to give, e.g.,

(22 l).’” A new route to the 1 H-phosphirenes (222) is provided by the elimination of dihydrogen from crowded X3-phosphiranes, intermediates formed in the reactions of dichlorophosphines with

t-butyldimethylsilyl(chloro)methyllithium.389 The phosphirene (223, R =H) undergoes metallation at a ring carbon on treatment with butyllithium, allowing access to C-functionalised systems, e.g., (233, R=CR,OH). In contrast, corresponding treatment of (223, R=Me) results in ringopening to form the allenylphosphide (224), which reacts normally with alkyl halides to form a series of allenylpho~phines.’~ The first example has been reported of the insertion of a d8 Rh’ fragment into the phosphirene (225).39’ The diphosphirenecomplex (226) undergoes dimerisation with the formation of the tetraphosphorus system (227).392A route to the first diphosphirenium salt (228) has also been developed.”’ The intermediacy of I , 1’-biphospholyl systems is implicated in the thermal

0rga n o p h osph orus ( 'hemistry

32

ButMe2Si~SiMe2But

P

X

R

(222) R = Ph or But

(220)X = F or CI

P h y / Ph P Ph

MesPLi

(225)

(224)

cy*N~y..y2 P,r,

But

P Cy2N'

Me

'

\I

W(C0)s

P

Me

Me

Me

w PA P h 2 Ph

(232)

Me

Me

(233)

(234)

I:

Phmphiries und Phosphoniuni Salts

33

tetramerisation of p h o s p h ~ l e s . Electron-rich ~~ arenes or heteroarenes condense with the dienic system of phosphole P-complexes to form 2-substituted phospholene complexes, e.g., (229). Related double condensation reactions, followed by decomplexation at phosphorus and regeneration of the phosphole system, have led to phosphole-thiophen-phospholeand phospholefum-phospholechains, e.g., (230), in which there is apparently little electronic delocalisati~n.~~~ The possibility of extended electronic delocalisation in polythienylphospholes has been investigated by electrochemical technique^.^^ The anion obtained by metallation of 1-phenyl-3,4dimethylphosphole sulphide reacts with chlorodiphenylphosphineto form the phosphole sulphide (231). A gradual exchange of sulphur between the two phosphorus atoms then takes place, with the formation of the phosphole (232), from which the related phospholyl anion can be obtained.397Ring-opening, rather than P-phenyl cleavage, occurs on incorporation of phospholes into tri-osmium cluster systems."* The coordination chemistry of simple phospholes and 5 phenyldibenzophosphole with copper(1) has also been e~plored.~"Phospholyl anion complexes of divalent lanthanides have been prepared by P-P cleavage of the 1 , l -biphospholyl (233) in the presence of the powdered metal at room temperature in THF.4"" The degree of aromaticity of polyphospholyl anions has been assessed in a theoreticalstudy

New routes to 1,3-

diphospholyl anions have been developed, and their use in the synthesis of polyphosphaferrocenes e x p l ~ r e d . ~ ~The * " ~coordination chemistry of phosphaferrocene systems has also continued to attract attention.4w4mThe reaction of 1,3-diphospholylanions with trimethylsilyl chloride yields an equilibrium mixture of diphospholes which arise from 1,5-sigmatropic shifts of the trimethylsilyl group around the ring system, 408 The electronic structure and degree of aromaticity of 1,3-azaphospholes has received attention from the theoretician^.^^ An alternative synthesis of the phospha-indolizine system (201), from the reaction of pyridinium salts with phosphorus trichloride, has undergone further development4" and has also been applied in the synthesis of fused 1,4,2-diazaphospholes,e.g., (234)4"1412 and (235).413,4'4 The 1,2,4,3-triazaphosphole system (236) has been isolated as an adduct with boron trifl~oride.~" Photolysis or thermolysis of 1,2,3-selenadiazoles in the presence of lunetically stabilised phospha-alkynes provides a route to the 1,3-selenaphosphole system (237).4'6 The reactivity of 1,2,3-diazaphospholeshas received further ~ t u d y . ~ ' " ' ~ A new route to the 2-iodophosphinine(238, X =I) has been developed. With zinc, this is converted into the related phosphininyl(iod0)zinc reagent (238, X =ZnI) from which other organometallic derivatives have been prepared. Provided that the phosphorus atom is protected by complexation, the corresponding organolithium reagent can also be generated from (238,

X =I) and used in subsequent syntheticoperations

In related work, two approaches have been

developed for the functionalisation of the 2-bromophosphininesystem (238, X=Br), and a range

Organophosphorus Chemistry

34 R2

[PE NA r]+ AIC14-

(240) Ar = 2,4,6-But3C6HZ

R'

(241) R' = H or Ph

(242)

(243)

1:

Phosphines and Phosyhonium Salts

35

of 2-substituted phosphinines re pa red.'^' Diels-Alder adducts of functionalised dienes with the phospha-alkene (183) can be aromatized in most cases, thus providing a new route to functionalised phosphinines.'" has been studied.

The coordination of the chelating system (239)with platinum(I1)

The coordinated ligand is very susceptible to nucleophilic attack at

phosphorus, leading to addition to the phosphinine ring s y ~ t e m . ' ~Cycloaddition of alkynes to the salt (240) occurs with the initial formation of the phosphirene (241), which then rearranges to form the 2-phosphaquinoline system (242).'%

New A'-phosphinine systems, e.g., (243) have

also been prepared,'2' and the photoelectron spectra of such systems in~estigated."~

References 1

2 3 4 5 6

7 8 9 10 11 12

13 14 15 16 17 18 19 20 21

22 23

M. Formigut and P. Batail, J. Chem. Soc.,Chem. Commun., 1991, 1370. M. Formigut and P. Batail, Bull. Soc. Chim. Fr., 1992, 129, 29. M. W. Haenel, D. Jakubik, E. Rothenberger, and G . Schroth, Chem. Ber., 1991, 124, 1705. K. A. Fallis, G. K. Anderson, and N. P. Rath, Organometallics, 1992, 11, 885. K. Yoshikawa, N. Yamamoto, M.Murata, K. Awano, T. Morimoto, and K. Achiwa, Tetrahedron: Asymmetry, 1992, 3, 13. N. Yamamoto, M. Murata, T. Morimoto, and K. Achiwa, Chem. Pharm. Bull., 1991, 39, 1085. S. D. Perera, B. L. Shaw, and M. Thomton-Pett, J. Chem. SOC., Dalfon Trans., 1991, 1183. S . D. Perera, B. L. Shaw, and M. Thornton-Pett, J . Chem. SOC., Dalton Trans., 1992, 1469. V. Ravindar, H. Hemling, H. Schumann, and J. Blum, Syn. Commun., 1992,22 841. V. Ravindar, H. Hemling, H. Schumann, and J. Blum, Syn. Commun., 1992, 22, 1453. T. Hattori, M. Shijo, S. Kumagai, and S. Miyano, Chem. Express, 1991, 6, 335. D. Wilbrandt, K. Jurkschat, and J. Meunier-Piret, Phosphorus, Sulfur. Silicon, Relut. Efem., 1991, 61, 261. M. Uemura, R. Miyake, H. Nishimura, Y.Matsumoto, and T. Hayashi, Tetrahedron: Asymmetry, 1992, 3 , 213. I. R. Butler, Organometulfics, 1992, 11, 74. L. K. Liu and J. C. Chen, Bull. Inst. Chem., Acud. Sin., 1991,38, 43 (Chem. Absfr., 1992, 116, 59 584). P. H. M. Budzelaar, J. A. Van Doom, and N. Meijboom, Rec. Trav. Chim. PaysBar, 1991, 110, 420. J. A. Van Doom, J. H. G. Frijns, and N. Meijboom, Rec. Trav. Chim. Pays-Bar, 1991, 110, 441. J. A. Van Doom and N. Meijboom, Rec. Trav. Chim. Pays-Bas, 1992, 111, 170. N. Maigrot, L. Ricard, C. Charrier, P. Le Goff, and F. Mathey, Bull. Soc. Chim. Fr., 1992, 129, 76. M. Scheer, St. Gremler, E. Herrmann, U. Griinhagen, M. Dargatz, and E. Kleinpeter, Z. Anorg. Allg. Chem., 1991, 600,203. F. Uhlig, S. Gremler, M. Dargatz, M. Scheer, and E. Herrmann, 2. Anorg. A f f g . Chem., 1991, 606,105. E. Hey-Hawkins and E. Sattler, J. Chem. Soc., Chem. Commwr., 1992, 775. M. Driess, H. Pritzkow, and M. Reisgys, Chem. Ber., 1991, 124, 1923.

36

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59

60

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85 86 87 88 89 90 91 92 93

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94 95 96 97

98 99

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116 117 118 119 120 12 1 122 123 124 125 126 127

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D. W. Allen, Phosphow, Sulfir, Silicon, Relat. Elem., 1992,66, 73.

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I:

193 194 195

196 197

198 199 200 20 1 202 203 204 20s 206 207 208 209 210 21 1 212 213 214 215 216 217 218 219 220 22 1 222

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46

349 350 35 1 352 353 354 355 356 357 358 359 360 36 1 362 363 364 365 366 367 368 369 370 37 1 372 373 374 375 376 377 378

Organophosphorus Chemistry M. Driess, P. Frankhauser, H. Pritzkow, and W. Siebert, Chem. Ber., 1991, 124, 1497. P. Frankhauser, M. Driess, H. Pritzkow, and W. Siebert, Chem. Ber., 1992, 125, 1341. D. Dou, G. L. Wood,E. N. Duesler, R. T. Paine, and H.Noth, Inorg. Chem., 1992, 31, 1695. M. T. Ashby and Z. Li, Inorg. Chem., 1992, 31, 1321. A. N. Chernega, A. A. Korkin, N. E. Aksinenko, A. V. Ruban, and V. D. Romanenko, 22. Obshch. Khim., 1990, 60, 2462 (Chem. Abstr., 1991, 115, 8923). L. N. Markovskii, V. D. Romanenko, A. V. Ruban, A. B. Drapailo, G. V. Reitel, A. N. Chernega, and M. I. Povolotskii, Zh. Obshch. Khim., 1990, 60, 2453 (Chem. Abstr., 1991, 115, 8922). L. N. Markovskii, V. D. Romanenko, A. V. Ruban, T. V. Sarina, M. I. Povolotskii, and L. F. Lur’e, Zh. Obshch. Khim., 1991, 61, 401 (Chem. Absrr., 1991, 115, 92 418). R. Detsch, E. Niecke, M. Nieger, and F. Reichert, Chem. Ber., 1992, 125, 321. R. Detsch, E. Niecke, M. Nieger, and W. W. Schoeller, Chem. Ber., 1992, 125, 1119. J. Hein, C. Gaertner-Winkhaus, M. Nieger, and E. Niecke, Hereroar. Chem., 199 2,409. R. Comu, G. Lanneau, and C. Priou, Acta Chem. Scund., 1991, 30, 1 130. M. Driess, Angew. Chem., Int. Ed. Engl., 1991, 30, 1022. H. Ranaivonjatovo, J. Escudie, C. Couret, and J. Satgk, J. Orgummet. Chem., 199 , 415, 327. P. L. Folkins, B. R. Vincent, and D. N. Harpp, Tetrahedron Lett., 1991, 32, 7009. P. Le Floch and F. Mathey, Sydett., 1991, 743. A. H.Cowley, F. Gabbai, R. Schluter, and D. A t w d , J. Am. Chem. Soc., 1992, 114, 3142. J. Ho and D. W. Stephan, Orgunomfallics, 1991, 10, 3001. 1. Niemann, W, W. Schoeller, V. von der Gonna, and E. Niecke, Chem. Ber., 1991, 124, 1563. A. Schmidpeter and G. Jochem, Tetrahedron Left., 1992, 33, 471. V. D. Romanenko, T. V. Sarina, A . 0. Gudima, A. V. Ruban, L. N. Markowskii, M. Sanchez, M. R. Mazieres, and R. Wolf, Dokl. Akad. Nauk SSSR, 1991,319, 623 (Chem. Absrr., 1992, 116, 59 481). C. Payrastre, Y. Madaule, and J.-G. Wolf, Terrahedron Lett., 1992, 33, 1273. H. Lang, M. Leise, and W. Imhof, 2. Natuforsch., B, 1991, 46, 1650. H. Lang, M. Leise, and C. Emmerich, J. Orgunomf. Chem., 1991, 418, C 9. H. Lang, M. Leise, and L. Zsolnai, Polyhedron, 1992, 11, 1281. P. Becker, H. Brombach, G. David, M. Leuer, H.-J.Metternich, and E. Niecke, Chem. Ber., 1992, 125, 771. A. S. Ionkin, V. M. Nekhoroshkov, and Yu. Ya. Efremov, Izv. Akad. Nauk SSSR, Ser. Khim., 1991, 1654 (Chem. Absrr., 1991, 115, 208 108). H.-J. Metternich, E. Niecke, J. F. Nixon, R. Bartsch, P. B. Hitchcock, and M. F. Meidine, Chem. Ber., 1991, 124, 1973. H.-J. Metternich, E. Niecke, and J. F. Nixon, J. Chem. SOC., Chem. Commun., 1992, 627. H. Bock, M. Kremer, B. Solouki, and M. Binnewies, Chem. Ber., 1992, 125, 315. L. Weber, R. Kirchhoff, H.-G.Stammler, and B. Neumann, J. Chem. Sw.,Chem. Commun., 1992, 819.

I: 379 380 38 1 382 383 384

385

386 387

3aa 389 390 39 1

392 393 394 395 396 397 398 399 400 40 1 402 403 404 405 406 407

Phosphines and Phosphonium Salts

47

C. Etemad-Moghadam, C. Tachon, M. Gouygou, and M. Koenig, Tetrahedron Lett., 1991, 32, 3687. L. D. Quin, S . Jankowski, G. S. Quin, A. Sommese, J. S. Tang, and X. P. Wu, ACS Symp. Ser., 1992, 486,115. L. D. Quin and X. P . Wu, Heterwr. Chem., 1991. 2, 359. S. Jankowski and L. D. Quin, J. Am. Chem. Soc.,1991, 113, 7011. L. D. Quin, R. Bodalski, S. Jankowski, G. S. Quin, N. D. Sadanani, and X. P. Wu, Heterwr. Chem., 1991, 2, 99. A. S. Sherman, I. I. Patsanovskii, E. A. Ishmaeva, A. V. Ruban, V. D. Romanenko, and L. N. Markovskii, 2%. Obshch. Khim., 1991.61, 682 (Chem. Abstr., 1991, 115, 114 646). A. S. Sherman, I. I. Patsanovskii, E. A. Ishmaeva, A. V. Ruban, and V. D. Romanenko, 2%. Obshch. Khim., 1991, 61, 1975 (Chem. Abstr., 1992, 116, 129 086). D. A. Dixon, K. D. Dobbs, A. J. Arduengo, and G. Bertrand, J. Am. Chem. Soc., 1991, 113, 8782. M. T. Nguyen, H. Vansweevelt, and L. G . Vanquickenborne, Chem. Ber., 1992,125, 923. H. Memmesheimer, Juma’a R. Al-Dulayymi, M. S. Baird, T. Wettling, and M. Regitz, Synlett., 1991, 433. H.J. Mettemich and E. Niecke, Tetrahedron Lett., 1991, 32, 6537. F. Nief and F. Mathey, Tetrahedron, 1991, 47, 6673. F. A. Ajulu, D. Carmichael, P. B. Hitchcock, F. Mathey, M. F. Meidine, J. F. Nixon, L. Ricard, and M. L. Riley, J. Chem. Soc.,Chem. Commun., 1992, 750. F. Mercier, L. Ricard, F. Mathey, and M. Regitz, J. Chem. Soc., Chem. Commun., 1991, 1305. F. Castan, A. Baceiredo, J. Fischer, A. De Cian, G. Commenges, and G. Bextrand, J. Am. Chem. Soc.,1991, 113, 8160. M. 0. Revieme, F. Mercier, L. Ricard, and F. Mathey, Bull. Soc. Chim. Fr., 1992, 129, 1. E. Deschamps, L. Ricard, and F. Mathey, Heterm. Chem., 1991, 2 , 377. M. 0. Bevierre, F. Mercier, F. Mathey, A. Jutand, and C. Amatore, New J. Chem., 1991, 15,545. B. Deschamps and F. Mathey, Organometallics, 1992, 11, 1411. A. J. Deeming, N. I. Powell, A. J. A r e , Y. De Sanctis, and J. Manzur, J . Chem. Soc.,Dalton Trans., 1991, 3381. S . Attar, G. A. Bowmaker, N. W. Alcock, J. S . Frye, W. H. Bearden, and J. H. Nelson, lnorg. Chem., 1991, 25, 4743. F. Nief and F. Mathey, Synlett., 1991, 745. E. J. P. Malar, J. Org. Ciwm., 1992, 57, 3694. N. Maigrot, M. L. Sierra, C. Charrier, L. Ricard, and F. Mathey, Polyhedron, 1992, 11, 601. M. L. Sierra, N. Maigrot, C. Charrier, L. Ricard, and F. Mathey, Organometdlics, 1992, 11,459. R. Bartsch and J. F. Nixon, J. Orgummet. Chem., 1991, 415, C 15. R. Bartsch, A. Gelessus, P. B. Hitchcock, and J. F. Nixon, J. Organomet. Chem., 1992,430, c 10. E. Niecke and D. Schmidt, J. Chem. Soc.,Chem. Commun., 1991, 1659. L. Weber, R. Kirchhoff, R. Boese, and H.-G.Stammler, J. Chem. Soc., Chem. Commun., 1991, 1293.

48 408 409 410 41 1 412 413 414 415 416 417 418 419 420 42 1 422 423 424 425 426

Organophosphorus Chemistry

M. L. Sierra, N. Maigrot, C. Chanier, L. Ricard, and F. Mathey, Orgunometullics, 1991, 10, 2835. T. Veszpremi, L. Nyulaszi, R. Laszlo, J. Reffy, and J . Heinicke, J. Phys. Chem., 1992, 96, 623. R. K. Bansal, V. Kabra, N. Gupta, and K. Karaghiosoff, I d . J. Chem., Sect. B , 1992, 31, 254. I. A. Litvinov, K. Karaghiosoff, A. Schmidpeter, E. Y.Zabotina, and E. N. Dianova, Heteroat. Chem., 1991, 2 , 369. K. Karaghiosoff, R. K. Bansal, and N. Gupta, Z . Nafurforsch., E , 1992, 47, 373. R. K. Bansal, D. C. Sharma, and R. Mahnot, Tetrahedron Letr., 1991, 32, 6433. R. K. Band,R. Mahnot, D. C. Sharma, and K. Karaghiosoff, Synthesis, 1992,267. M. Haddad, F. Dahan, J.-P. Legros, L. Lopez, M.-T. Boisdon, and J . Barrans, J . Chem. Soc.,Perkin Truns. 2 , 1992, 671. B. Burkhast, S. Krill, Y. Okano, W. Ando, and M. Regitz, Synfett., 1991, 356. E. N. Dianova, E. Ya. Zabotina, I. Z. Akhmetkhanova, and Y . D. Samuilov, Zh. Obshch. Khim., 1991, 61, 1063, (Chem. Abstr., 1992, 116, 6634). R. Chen, B. Cai, and G. Li, Synthesis, 1991, 783. B. Cai, L. Liu, and R. Chen, Chin. Chem. Lett., 1991,2, 531, (Chem. Abstr., 1992, 116, 214 597). H. T. Teunissen and F. Bickelhaupt, Tetrahedron Lett., 1992, 33, 3537. P. Le Floch, D. Carmichael, and F. Mathey, Orgunometullics, 1991, 10, 2432. M. Abbari, Y. Y. C. Y. L. KO, and R. Carrie, Heteroaf. Chem., 1991, 2, 439. B. Schmid, L. M. Venanzi, A. Albinati, and F. Mathey, Inorg. Chem., 1991, 30, 4693. G. David, E. Niecke, and M. Nieger, Tetrahedron Lett., 1992, 33, 2335. H. Schmidbaur, S. Gamper, C. Paschalidis, 0. Steigelmann, and G. Muller, Chem. Ber., 1991, 124, 1525. R. Gleiter, T. Veszpremi, and E. Fluck, Chem. Ber., 1991, 124, 2071.

2

Pentaco-ordinated and Hexaco-ordinated Compounds BY C.D. HALL

1. lntroductlon - It is gratifying to report that interest in hypervalent phosphorus chemistry has been maintained, especially with regard to structural studies and the synthetic utility of pentacoordinate phosphorus compounds. A novel departure has appeared in the area of hexaco-ordinate phosphorus with the synthesis of further phosphorus derivatives of the porphyrin ring system containing hypervalent phosphorus coordinated by the tetrapyrrole unit. The chapter will take its usual format, however, and the details of this small nugget will therefore appear in the last section.

. .

2. Saucture.Borldiag and L i w Reoreanlsation - Halogen adducts of the phosphines have received considerable attention during the year. For example, mphen ylphosphine reacts with diiodine in dry diethyl ether to produce Ph3PI2 which was shown by X-ray crystallography1 to be a molecular four-coordinate compound, Ph3P-1-1, and not the five coordinate Ph3P12 or the ionic Ph3P'I

I-structures previously proposed. The compound, which is isostructural with its arsenic

analogue Ph3AsI-I, ionises in dichloromethane to Ph3PI' I-(631P,+44.8). An almost identical structure was reported by the McAuliffe group for Ph3PBr-Br which again ionises (to Ph3P'Br

Br-) in dichloromethane.Thus for the series of compounds represented by Ph3EX2 where E= P, As or Sb and X= Br or I, only Ph3SbBr2 has the expected rbp geometry. On the other hand, both ionic and molecular modifications of the three chlorophenylphosphos, PhnPCl5-, where n=1,2 or 3 have been isolated as solids and characterised by elemental analysis, Raman spectroscopy and 31P(MAS) n.m.r. spectroscopy3. It seems that there is a tine energetic balance between the molecular (alleged to be rbp) and ionic forms of these compounds. A new theoretical study of pseudorotation in HnPF5-,, (n=2-5), MenPF5-, (n=1,2), P ( O Z C ~ H ~ ) P(oC3H6)H3 H~. and PO5H4- has appeared. The potential surface for the lowest pass of the pseudorotation pathway was calculated for each compound using ab initio SCF and MP4 methods and not unexpectedlyJigands such as H, Me and CH2 preferred the equatorial p ~ s i t i o n .In~ fact the authors claim that the stabilisation of the equatorial plane of the pentacoordinated structure determines the stability of the whole molecule and that fluorine substituents have a significant effect on the 3d A 0 of the central phosphorus. On a more experimental note, the cations of compounds (1) and (2) exhibit dynamic behaviour at room temperature and the two fluorine atoms cannot be distinguished by 31P n.m.r. At -3OoC, however, the intramolecularexchange process in is slowed down and the 31Pn.m.r. spectrum becomes a doublet of doublets indicating the non-equivalence of the fluorine atoms.The X-ray crystal structure of (2) displays rbp geometry with the ring system spanning one equatorial (NMt,P-N=l84.4 pm) and one apical (NMe2,P-N=198.7 pm) position and the fluorine atoms also situated apical (P-F=159.9 pm) and equatorial (P-F=155.6 ~ m ) . ~

Organophosphorus C'hemistry

SO Me, ,Me

Me, ,Me

-,'N Me-12N-P(+] F'

,y1 .

F:

CI-

F\ NaBPhL Me2N-P

?J

I

Me

Me

e

7

BU' - P = C R I R ~

;

(3a-c) a, R' = H; R~ = P i b, R' = Me; R2 = Et c, R' = Me; R 2 = Et

-

+

RPC13

+

PC16

F

Br

I

l3~0-P;

PhOPF2

+

Br

-

2C13CCHO

F I

RP-7:

PhOPF2CI2

OCHBrCC13

F OCHBrCC13

O

R

II I

(PhCH=CH), P(OCHCH,C1)3-,

(13ab) a, n = 1 b,n = 2

(15ab)

+

e

J

+

( 3 4 ) RCHCICH2CI

0 (14) R = H or CH2CI

MeP(C1)30N=C:

+

PhPC12

-

(PhCH=CH), PCIs,

(3-n)

(5a-c)

(4a-c) a, R3 = Et b, R 3 = M e C, R3 = B d

R' CI

2:

Pentaco-ordinated and Hexaco-ordinated Compounds

51

3. Acvclic PhosDhoranes - Ylides (3) containing the P-F bond react with alcohols (4) to form stable alkoxydialkyldifluorophosphoranes( 5 ) which were isolated by distillation and characterised by multinuclear n.m.r.6 In a further discussion of the ambident reactivity of chlorophosphonium derivatives it has been shown that the course of the reaction between organotrichlorophosphonium hexachlorophosphates (6) and arylphosphorodihalidites depends on the nature of the halogen in the latter.7 Of particular relevance here is that (7) with (6, R=Ph) in weakly polar media reduces (6) to (8) with the formation of the fluorophosphorane (9). In a comprehensive paper devoted to the insertion reactions of the P-halogen bond in halophosphoranes. especially those containing a five-membered dioxaphospholane or dioxaphospholene ring, it is reported that acyclic halophosphoranes (e.g. 10) react with chloral (1 1) to form difluorouialkoxyphosphoranes ( 12).8 The reactions of chlorostyrylphosphoranes (13a,b) with epoxides (14) in the presence of catalytic amounts of titanium tetrachloride produced bis-(2-chloroalkyl)styrylphosphonates ( 15a) or 2-chloroalkyl- distyrylphosphinates (15b) together with the corresponding dichloroalkanes in high (>90%) yield9 The reactions of mchloromethylphosphoranes of type (16) with sulphur nucleophiles take a number of quite intricate routes amongst which, for example, is the formation of (17) on reaction with hydrogen sulphide. lo Finally in this section, McAuliffe et al. have provided a route to new and existing transition metal complexes of Ni, Fe and Mn by the reaction of coarse-grain metal powders with halophosphoranes as exemplified by the formation of (19) from nickel powder and (18).'

..

4. p

4.1 - Pentaco-ordinate phosphorus compounds containing fourmembered rings are scarce this year but one example is provided by an extension of the reaction of N-substituted mas with PC15 in which, for instance, the reaction of (20) with excess PC15 gives (211.12 Insertion of aldehydes into the P-halogen bond of phosphoranes referred to in Section 3 ( ref.8) is also e x ~ m p l i f i e dby l ~ the reaction of the pyrocatecholmbromophosphorane(22) with fluoral (23) to give (24) with 531P,-55ppm. Further studies in this area by Pudovik et al. have shown that the reaction of the phosphite (25) with one mole of pyruvic ester (26) results in the formation of (29) via (27) and (28) but with two moles of (26) the phosphorane (30) is formed.14 The reaction of (25) with tetrachloro-benzoquinone to form a cyclic phosphorane (531~,-53)is also reported in this paper. An interesting paper by Moriarty et al. describes the isolation and characterisation of stereoisomers of pentaco-ordinated phosphoranes together with a study of the hydrolysis of c h i d monocyclic oxyphosphoranes. The stable pseudorotamers of chiral monocyclic oxyphosphoranes (3 1ab) and (32ab) were synthesised according to a previously published procedure16 and were separated either by column chromatography on silica gel under basic conditions (31a.31b and 32b) or by fractional crystallisation (32a). The X-ray diffiaction analysis of crystalline (32a) rtvealed an almost regular rbp and the first-order interconversion of (32a) and (32b) at 90°C had k = 2 . 4 ~ 1 O - ~ m i n corresponding -l to a AGS value of 27kcal mol-l. Diastereomer (32a) reacted immediately with 0.1M HCI to give a 1:l mixture of the two diastereomeric phosphonates (33ab) but surprisingly (32b) under the same conditions gave (33a)

52

+

Ni

2Me3PI2

-

(1 8 )

+

a 0 \ P B r 3

’

+

Ni I3(PMe&

3PCI5

3CFSCHO

0’

-

a

we

0=cvpc >

P

( OC HBrCF3)3

Me (CF3CH20)3P

+

1/2~2

(1 9)

+

MeNHCONHCOCH2CI

Organophosphorus Chemistry

MeC0.C02Et

2 : Pen tuco- ordinuted and Hexuco - ordinated Cornyo i l t i Cis

53

Me-P'\

I ..h I

OMe

0.

(31) R~ = H; R~ =

0 (32) R' = Me; R 2 =

n02

(34ab)

(33ab)

Ph3P-CH2 + (35)

+

R

(36a-g)

ph3p3 (37a-g)

a, R = H; b, R = Me; c, R = Et; d, R = Ph; 8 , R = CH(OEt)2; f, R = CH(OMe)$ g, R = oxiranyl

54

Organophosphorus Chemistry

and (33b) in a ratio of 27:73. Isotopic labelling studies proved that the nucltophilic attack by water was at phosphorus (not carbon) and the selectivity was ascribed to the relative stabilities of the two hydroxy phosphorane intermediates (34ab). A series of 2.2.2-triphenyl- 1.2-~5-oxaphospholanes(37a-g) were synthesised from methylene phosphorane (35) and suitable epoxides (36a-g).17 An X-ray analysis of (37e) showed a rbp configuration with the phenyl group and the ring oxygen atom as apical ligands and according to n.m.r. data the pentaco-ordinate structurt was retained in non-polar solvents whereas in polar solvents there existed an equilibrium with an open chain form The 2.2.2-methoxy- 1.2A5-oxaphospholene (38) behaves as an enolatc ion and reacts under mild neutral conditions with a number of electrophiles (e.g.Br2) to form Phrno-y-ketophosphonatc (39) in high yield.18 In further studies relevant to the mechanism of the Mitsunobu rtaction, the reaction of diphenylphosphine (40) with di-isopropyl azodicarboxylate (41) was found to give a mixture of products one of which was assigned structure (44)formed via (42) and (43).19 The reaction of mco-ordinate phosphorus compounds with orthoquinones,P-ketoalkenes and 0-ketoimines is also a well-established source of pcntaco-ordinate phosphorus compounds but in some cases the dipolar ion structure is more stable. Thus the reaction of (45ab) with (46)produced the dipolar ion structures (47ab) but on the other hand, reaction of (45b) with the quinone imine (48) produced what appeared to be an equilibrium mixture of (49) and the pentaco-ordinate structure (50).20 The 1,3.2-A5d-diazaphospholencs (51ab) have proved to be useful synthetic reagents in that on hydrolysis they yield the bis-hydroxylamine ( 5 2 ) which reacts with benzaldehyde to form the imidazoline (53).21 X-ray crystallographic studies o n oxyphosphoranes containing eight-membered rings have revealed the first isolated rbp structure (54) with the ring in a diequatorial position22a which confirms the earlier conclusions from n.m.r. studies of analogous systems in solution.22b A similar situation was found for ( 5 5 ) but in contrast the eight-membered ring in the pentaoxyphosphorane (56) was disposed axial-equatorial and a pseudo-octahedral structure was found for (57).23 Eight-membered rings also feature in pcntaco-ordinate compounds of antimony (58) prepared from the reaction of diethanolamine with pentaphenylstibane or methoxytetraphcnylstibane. The 3Cn.m.r. spectra in solution cannot distinguish between (%a, facial) or (58b. meridonal) as the appropriate structure but X-ray crystallography reveals that (58a) is the correct structure in the solid state.24 The pseudo hexaco-ordinate structure is thus, once again. in evidence. Reactions of fluorophosphoranes (59ab) with the bis-trimethylsilyl derivative of 2,3dihydroxynaphthalene(60) produced the monocyclic phosphoranes (61ab) and the structure of (61b) was confirmed by single crystal X-ray analysis of its dichloromethane solvate at -95OC. The geometry is rbp with, as expected, the ring disposed axial-equatorial and the fluorine atom in an axial position.25 Similar chemistry involves the reaction of (59ab) or (62ab) with (63) to form the monocyclic phosphoranes (64ab) and (65ab) respectively.26

. . - The work of Schmutzler et al. reported in references 25 4.2 Bicvclic and 26, also includes the preparation and characterisation of a number of spirophosphoranes. For example the reaction of (60) with (66a-e) produced a range of spirocyclic phosphoranes (67ae).25 Likewise the reaction of (66ae) with two moles of (63) produced a series of

2:

pen taco-ordinated and Hexaco-ordinated Compounds

Br2, CCI4 P

0 "C,90%

P(OEt),

8 (39)

ppi

Ph2PH

+

Pr'02CN=NC02Pi

(411

(40)

(44)

/

H

,C02Pt

I

L

0 (cN)2c%

(45ab)a, R = NMe,; b, R = Ph

/

8

o R(NMe2)2

/

(47ab)

Organophosphorus C’hernistry

(45b)

MeJN,0SiMe3 “--p-oR I

P(NMe2),Ph

+

H20

___t

RA‘.. (51ab)a, R = Et; b, R = SiMe3

Mexi:-

OH

Me

PhCHO

Me

yH

OH

(52)

Me OH

(53)

2: Pentaco-ordinated and Hexaro-ordinated <70rnpoimds

O%, '*. OCH2CF3 I

/'i -

0CH2CF3 0 OCH2CF3

57

yo% '.OCH2CF3 I

/7-oCH2CF3

0 OCH2CF3

(54)

1

qrJ

CF3CH2O.. 0

"P-0 CF3CH20'

I

OCHzCF3

OCHZCFS

Ph I

Ph

OSiMe3

OSiMe3

(59ab) a, R = Me; b. R = P h

(61ab)

58

Organophosphorus Chemistry

+

(59ab)

Me3SiOCH2C0.0SiMe3

-

R

-

(63)

+

I

F

(64ab)

(63)

RPF4.

4 5

R-.. ,P-00I

R.., 0 I ,P-0 F I F

(65ab)

(62ab) a, R = Me; b, R = Ph

+

RPF4

-4Me3SiF

-

[

m

(66a-e)

:

)

R

2

(67a-e)

a, R = F; b, R = Pr‘;c, R = CH2SiMe3;

(66a-e)

+

-4Me3SiF

0 (68a-e) R’

R’ 4

OH

(69a-e) a, R’, R2, R3, R4 = CI;

R’

2:

Pentaco-ordinaled and Hexaco-ordinated ( b t n p o u n d s

59

spirophosphoranes of structure (68a-e) which were again characterised by multinuclear n.m.r.26 Extension into the field of hypervalent arsenic chemistry is afforded by the reaction of catechols (69a-e) with malkylarsenates (70) to form either (71a-e) or (72a-d) which were characterised by elemental analysis and i.r. specaa.*' Conformational effects of ring fusion and heteroatom substitution in six-membered rings of spirocyclic oxyphosphoranes have received further attention during the year. The spirooxyphosphoranes (73-77) were synthesised by oxidative addition and in each case X-ray crystallography revealed rbp frameworks with the phosphorinane ring occupying apicalequatorial positions in a boat conformation.28 Variable temperaturelH n.m.r. data indicated retention of the solid state structures in solution and rapid pseudorotation with the exocyclic group as pivot.There was, however, evidence of a higher temperature process for (77) which supports the intermediacy of a diequatorial dioxaphenanthrene system (78). In a related paper29 phosphoranes (79-81) were prepared in which hydrogen bonding interactions between N-H and remote ring substitutents were possible. X-ray crystallography again revealed the phosphoranes in tbp geomemes with the rings situated in axial-equatorial sites. In the case of (79). however, a hydrogen-bonded chain structure was found with the phosphorinane ring in a chair conformation. Furthermore, for (80)a hydrogen-bonded dimer was reported with the six-membered ring in a twisted or half-chair form. Variable temperature l H n.m.r. showed all three molecules undergoing ligand exchange via an intermediate with the six-membered ring diequatorial and with activation energies in the range of 10.5- 12.5 kcal.mo1-l. There was, however, no evidence from solid-state studies for a diequatorial orientation of the dioxaphosphorinane system and hence it was stated28 that "proposed phosphorane tbp models for enzymatic action on c-AMP that contain such diequatorial ring orientations, are not supported by the present structural data". The debate has been sharpened by the recent report of a mcyclic tetraoxyphosphorane (82) prepared from the reaction of [CH2(CH20)2PC=CH] with (CF3)2CO at -78°C.30 The Xray analysis revealed a distorted rbp configuration with the 1,3,2-dioxaphosphorinaneattached diequatorially to phosphorus in a chair conformation, contrary to models and MNDO calculations which predicted a half-chair conformation flattened about phosphorus. ThelH n.m.r. data in solution clearly support the X-ray structure and the authors point out that the results have implications regarding the structures of (83)31and (84)32 studied previously. The latter two phosphoranes, derived from thymidine, are models for the transition state or intermediate in the enzyme-catalysed hydrolysis of c-AMP. Phosphorane (83) was assigned a twist conformation in solution with the six-membered ring axial-equatorial3 but for (84) it was postulated3* that a significant proportion of molecules populated a ring which was attached diequatorially to phosphorus in a pseudorotational equilibrium mixture. If the diequatorial form of (83) and (84) is a chair conformation as found for (82) then the observed coupling constants for (83) and (84) which are almost identical, "exclude the possibility that either ion can have the 1.3.2dioxaphosphorinane ring diequatorial to any considerable extent."30 Therc may be m a n to tell ! Bicyclic phosphoranes (87a-d) prepared by the reaction of (8%-d) with (86) were isolated and then characterised by m.s., elemental analysis, i.r. and rnultinuclear n.m.r. spectroscopy; no pseudorotation was observed at ambient t t m p e r a t ~ r e In . ~ a~ related study, mcyclic phosphoranes (89a-d) were obtained from the reaction of (88a-d) with (86).34 An analogous reaction between (Wa-i) and (86) furnished another series of mcyclic phosphoranes ( 9 1 a - i 1 . ~The ~ single crystal X-ray structure of (91a) revealed a rbp configuration about phosphorus with a 26% distortion along the Beny coordinate using P-01 as the pivot.

Organophosphorus Chemistry

a(69a-d)

+

2(R0)3As=0

-

(70)

-

--’2

(72a-d)

2:

61

Pentaco-ordinated and Hexuco-ordinuted C 'ompounds

qg s\ Io \

/

o/P-o

9

HA

&'

T

1

C F3

H2CH20Me

Organophosphoriis Chemistry

62

cF3,c,’o

b”” -

R’O, P-N=C=O

+

R’O‘

OH/N-Y O ’“p-0 * RO ’ I‘ OR’

(85a-d)

(86)

a, R’ = Me; b, R’ = Et; C , R’-R’ = CH2CH2 d, R’-R’ = CH2C-CMe2

R2NPC12

+

(86)

(87a-d)

7-

gF3

R2N-p-----

(88a-d) a, R = Me; b, R = Et;c, R = Pr‘; d, R-R = CH2(CH2CMe2)2

\

(89a-d)

R

(9Oa-i) a, R = Me; b, R = Et; C, R = P i ; d, R = But; e, R = PhCH2;1, R = Me3SiCH2, g, R = Ph; h, R = CF3 i, R = CCI3 (91a-i)

(R10)2PCE C R 2

+

(92ab) a, R’,R2=Me; b, R’ = Me; R2 = Ph

(94ab)

OC(C02Et)2

(93)

(95ab)

2:

Pentuco-ordinated und Hrxaco-ordinuted C'ompounds

63

In a continuation of their studies of alkynylphosphonites, Pudovik et of. have shown that the reaction of (92ab) with the ketoester (93) in the presence of alcohol produces (95ab) via the ylids (94ab).36 An X-ray crystal stNCtUn of the 2chloromethylspirophosphorane (96) shows a distoned rbp configuration with the oxygen atoms in axial positions and within the crystal, the spirophosphoranes are connected along a fourth-order screw axis to form infinite hydrogenbonded helical chains represented by (97).37 The synthesis and chemistry of hydridophosphoranes has continued to attract attention. The reaction of the phosphoramidite (98) with hydroxysuccinimide (99) or hydroxyphthalimide (100) gave the novel phosphites (101) and (102) which in turn gave the hydridophosphoranes (103) and (104) r e ~ p e c t i v e l yThey . ~ ~ are rtadily solvolysed by, for example, methanol back to a phosphite (e.g.106) via (105). The reaction of bicyclic phosphoramidites with alcohols offers a simple route to hydridoph~sphoranes.~~~'% particular the oxidative addition of a variety of alcohols (ROH) or phenol (PhOH) with bicyclic phosphoramidites of type (107) give a wide range of bicyclic phosphoranes of type (108) with the P-H bond in an equatorial position. A number of addition reactions with activated double (e.g. fumaric ester) and mple (e.g. acetylene dicarboxylic ester) bonds are also described.40 The reaction of hydridophosphoranes (1 09) with alcohols ( 1 1Oa-f) takes a further step in the presence of diphenyl disulphide to generate the alkoxylated products (1 1 la-o.41 The synthesis of the tetrazaspirophosphoranes (1 13, X=Br or I) was achieved by the reaction of (1 12) with trimethylsilyl halides whereas (1 13. X=CN) was obtained by metathesis of (1 12) with NaCN. The route to (1 13,X=F). however, involves the reaction of the fluorophosphorane (1 14) with the silyl urea (1 15). The compounds were characterised by mass spectrometry, ix., multinuclear n.m.r. and X-ray cry~tallography.~~ Pro-azaphosphatranes (1 16a-c) show the unexpected Lewis base sequence (1 16a) > (1 16b) > (1 16c) with respect to protonation which gives rise to the azaphosphatranes(1 17a-cI.The rationale o f f e d for the unusual weakness of the protonic acid (1 17a, pKa in DMSO = 29.6) is the stability of the axial thrte-cenrre, four-elecmn bond, signalled by the unusually high-field 31P n.m.r. shift of the cation at - 4 2 ~ p m . 4 ~ The first example of a transition metal complex containing a W-tbp 10-P-4 phosphorus centre (120) results from the reaction of (1 18) with ( 1 19). X-ray crystallography reveals that all four ADPO units have y-tbp phosphorus centres and multinuclear n.m.r. in solution is consistent with this structure.44 5 . H e x a c o - o f d i n a t e H o u n d s , - The acceptor properties of perchloroalkylchlorophosphoranes,Cl~P(CCl~)~, C14PCC13 and ClqP(C2C15) towards Lewis

bases have been investigated by 'P n . m . and ~ ~the ~ same technique has been used to study the reaction of azide ion with RPCl4 and RPCI6- ions.46 In the second of these papers, however, no new pentaco-ordinate or hexaco-ordinate species were detected. Chlorotropism in a series of N,N-disubstituted amidinium chlorophosphorates (12 1- 123) has been investigated by a combination of i.r. and U.V. s p e c t r o s ~ o p y . ~ ~ Finally a new depanure in an unusual aspect of hypemalent phosphorus chemistry has been provided by the synthesis of water-stable dialkoxy phosphorus(V)-tetraphenylporphyrins (1 25) from (124). The six-co-ordinate phosphorus porphyrin (125) with R=Et, has

Organophosphorus Chemistry

64

MeCN 20 "C

0'

\ e : O H ,

THF, 20 "C

+"P--OMe

I

sj(& THF, 20 "C, Me2NH

NMe2

P

O

-

-Me2NH MeOH

___t

+

MeOH

2:

Pentuco-ordinuted und Hexaco-ordinuted Compounds

(1lOa-f)a,R=Me; b , R = E t ; C, R = P f ; d, R = Bu", e, R = Hex", f, R = Pr' Me

Me

>O

I

Me

+

MesSiX

I

Me

lNaCN I

Me

1

Me

(1 13, X = CN)

Me

I

Me

Me

(llla-f)

Me

X = Br or I

Me

65

I

Me

Organophosphorus Chemistry Me 1 oPF3 N

Me

I

+

I

NSiMe3

'="

NSiMe3

-

I

Me

Me

(1 14)

(1 15)

(1 16a-c)

(1 1 7a-c)

a, R = H; b, R = Me; C, R = CH,Ph

But I

[Ag(MeCN),]'SbF&

But

Me

Me

Me

Me

(113, X = F)

2:

Pentaco-ordinated and Hexaco-ordinated Compounds

67

a3lP= - 180.1, which suggests that the ethoxy groups are attached to the central phosphorus at the fifth and sixth co-ordination sites.The bis-hydroxymethyl derivative (R = HOCH2) is water soluble and very stable even under acidic and basic aqueous conditions, a property which may be useful in photorcdox catalysis.48

Interest in hypervalent phosphorus chemistry has been maintained especially with regard to structural studies and the synthetic utility of pentaco-ordinate phosphorus compounds. Conformational effects of ring fusion and heteroatom substitution in six-membered rings of spirocyclic oxyphosphoranes have received further attention and hence added fuel to the debate over the occmnce of diequatorial six-membered ring orientations as tbp models for enzymatic action on c-AMP. Finally, a novel departure has occurred in the area of hexaco-ordinate phosphorus chemistry with the preparation of further derivatives of the porphyrin ring system containing hypervalent phosphorus coordinated by the tcaapyrrole unit.

68

Organophosphorus Chemistry

REFERENCES 1.

2. 3 4.

5. 6.

7.

8. 9

10. 11. 12. 13.

14.

IS. 16. 17. 18.

19. 70. 21. 37 --.

23. 24. 25. 26.

S.M. Godfrey. D.G. Kelly, C.A. McAuliffe. A.G. Mackie, R.G. Prichard and (the late) S.M.Watson, .I. Chem. Soc., Chem. Commun., 1991, 1163. N. Bricklebank, S.M. Godfrey, A.G.Mackie, C.A. McAuliffe and R.G. Pnchard, J. Chem. Sot:. Chem. Comm., 1992, 355. M.A.H.A. Al-Jaboori, P.N. Gates and A.S. Muir. J . Chem. Sot.., Chem. Commun., 1991, 1270. A. Wasada and K. Hirao, J . Am. Chem. Soc., 1992, 114, 16. T . Kaukorat, P.G. Jones and R. Schmutzler. Phosphorus Sulfur und Silicon. 1992, 68, 9. 0.1. Kolodyazhnyi and S.N. Ustenko, J. Gen. Chem. USSR, (Engl. trans.) 1991, 61. 464. B.V. Timokhin, M.V. Kazantseva, G.V. Ratovskii, D.V. Chuvashev and V.I. Donskikh, .I. C e n . Chem. USSR, (Engl. trans.) 1991, 61, 2007. V.F. Moronov. T.N. Sinyashina, E.N. Ofitserov, F.Kh. Karataeva, P.P. Chernov, I.V. Konovalova. and A.N. Pudovik. .I. Gen. Chern. USSR, (Engl. trans.) 1991, 61, 527. V.V. Komiachev. Yu.N. Mitrasov, and G.B. Arsent'eva. J. Gen. Chem. USSR, (Engl. Trans.) 1991, 61, 2187. Y1i.E. Lyashenko and V.B. Sokolov, Phosphorus Sulfur and Silicon, 1992, 69, 153. S.M. Godfrey, D.G. Kelly, A.G. Mackie, P.P. MacRory, C.A. McAuliffe, R.G. Prichard, and (the late) S.M. Watson, J . Chem. Soc., Chem. Comrnun., 1991, 1447. B.V. Timokhin, V.K. Dmitriev, M.Yu. Dmitrichenko and G.V. Dolgushin, Bull. Soc. Chem. USSR, (Engl. trans.) 1991, p. I7 1 . V.F. Mironov. I.V. Konovalova and A.N. Pudovik, J . Gen. Chem USSR. (Engl. trans.) 1991, 61, 23. I.V. Konovalova, L.A. Burnaeva. I.V. Loginova and A.N. Pudovik, J . Gen, Chern. USSR, (Engl. trans.) 1991, 6 1 , 2298. R.M. Moriarty, J . Hiratake and K . Liu, J . Am. Chem. Soc., 1991, 113, 9374. R.M. Moriarty, J . Hiratake and K. Liu, .I. Am. Chem. Soc., 1990, 112, 8575. H.J. Bestmann, C. Riemer, and R. Dotzer, Chem. Ber., 1992, 125, 225. C.K. McClure and C.W. Grote, Tetrahedron Letters, 1 9 9 1 , 3 2 (No.39), 5313. D. Camp, P.C. Healy, I.D. Jenkins, B.W. Skelton and A.H. White, J. Chern. Soc., Perkin Trans I. 1991, 1323. M.F. Zayed. Y.O. El-Khoshnieh. and L.S. Boulos, Phosphorus Sulfur and Silicon. 19Y1, 6 2 , 251. H. Hund and G.-V. Roschenthaler, Phosphorus, Sulfur and Silicon, 1991, 62, 71. a) T.K. Prukasha, R.O. Day, and R.R. Holmes, Inorg. Chem., 1 9 9 2 , 3 1 , ( N O S ) , 725. b) W.M. Abdon, D.B. Denney and S.D. Pastor, Phosphorus, Sulfur, Relat. Chem., 1985, 22. 99. T.K. Prukasha, R.O. Day, and R.R. Holmes, Inorg. Chem, 1992, 3 1 , (No. 10). 1913. D.Kraft and M. Wieber, Z.Anorg. Allg. Chern, 1991, 605, 137. M. Well, A . Fischer, P.G. Jones and R. Schmutzler, Phosphorus. Sulfur and Silicon, 1992, 69, 231. M. Well, W . Albers, A. Fischer. P.G. Jones and R. Schmutzler, Chem. Ber.. 1992, 125, 801.

27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

V.S. Gamayarova. Z.M. Fazliakhmetova. A.V. Il'yasov, V.I. Morozov, I. Kondrat'eva, and F.G. Khalitov, J. Gen. Chem. USSR, (Engl. trans.) 1991, 6 1 , 1636. R.R. Holmes, K.C. Kumara Swamy, J.M. Holmes and R.O. Day, Inorg. Chem, 1991, 30,1052. J. Hans, R.O. Day and R.R. Holmes, Inorg. Chem, 1 9 9 1 , 3 0 , 3928. Y . Huang, A.M. Arif, and W.G. Bentrude, J. Am. Chem. Soc.. 1991, 113, 7800. H.Yu. A.M. Arif, and W.G. Bentrude, J. Am. Chem. SOC., 1990, 112, 7451. N.L.H.L. Broeders, L.H. Koole, and H.M. Buck, J . Am. Chem. Soc., 1990. 112, 7475. R.-D. Hund and G.-V. Roschenthaler, Phosphorus, Sulfur and Silicon, 1 9 9 1 , 6 2 , 6 5 . R.-D. Hund and G.-V. Roschenthaler, Phosphorus, Sulfur and Silicon, 1992, 66, 301. R.-D. Hund, U. Behrens, and G.-V.Roschenthaler, Phosphorus. Sulfur and Silicon, 1992, 69, 119. V.N. Christobletov and A.N. Pudovik, .I. Gen Chern. USSR, (Engl. trans), 1991, 61. 554.

2: 37.

38. 39. 40.

41. 42. 43. 44. 45. 46. 47. 48

Pentaco-ordinated and Hexaco-ordinated Compounds

69

A.N. Chekhlov, A.N. Bovin and F.N. Tsvetkov, J . Gen Chem. USSR, (Engl. trans), 1991. 61 1344. T. Bailly and R. Burgada. Phosphorus, Sulfur and Silicon, 1991, 63. 33. D. Houalla, K.EI Adeb. Z. Bounja and R . Wolf, Phosphorus, Sulfur and Silicon, 1992, 6 9 , 13. 2. Bounja. D. Houalla, M. Revel and M. Taieb. Phosphorus. Sulfur and Silicon, 1992, 69. 4 3 . L. Liu. G . Li, and M. Huang, Phosphorus, Sulfur and Silicon, 1992, 69, 1. J. Breker, P.G. Jones and R. Schmutzler, Phosphorus, Sulfur and Silicon, 1991, 62,

139. M.A.H. Laramay and J.G. Verkade. 2.Anorg. A&. Chem., 1991,605, 164. J. Arduengo, H.V. Rasika Dias, andJ.C.Calabrese, J. Am. Chem. Soc.. 1991,113,1071. R. Ali and K.B. Dillon, Phosphorus, Sulfur und Silicon, 1992, 66, 37. R.M.K. Deng and K.B. Dillon, Phosphorus, Sulfur and Silicon, 1992,66,95. L.M. Sergienko, G.B. Ratovskii, B.V. Timokhin, V.K. Dmitriev and V.I. Kal'chenco, .I. Gen. Chein. USSR..(Engl. Trans.) 1991, 61. 579. H.Segawii, K. Kunimoto. A. Nakamoto. and T. Shimidzu, J . Chem. Soc., Perkin Trun.s,l* 1992. 939.

3

Phosphine Oxides and Related Compounds BY B. J. WALKER

1 Preparation of Phosphine Oxides Diastereomerically pure menthyl phosphinates (1) are reduced stereospecifically by lithium 4,4'-di-tert-butylbiphenylidewith retention of configuration at phosphorus. The phosphine oxide anion produced in this reaction can be trapped by benzyl bromide to provide a new synthesis of optically active phosphine oxides with optical purities as high as 958.1 The method was also applied to the synthesis of ( S , S ) and (R,R)-1,2ethanediylbis(methylpheny1phosphine oxide) ( 2 ) . The vinylphosphonium salt (3) has now been shown to react with ethoxide ion to give exclusively the phosphine oxide ( 4 ) * and not the ylide (5) as previously reported.3 Depending on the nature of the reagents, the reaction of nitrones with vinylphosphines can provide the cycloadducts ( 6 ) and (7) or lead to initial oxidation of the phosphine by the nitrone to give the corresponding phosphine oxide.4 In the latter cases cycloadducts of the phosphine oxide with nitrone were also isolated in low yield. 1-Phenyl-1 -benzophosphepine oxide ( 9 ) has been prepared by flash vacuum pyrolysis of 2a,2b-dihydro-3-phenyl-3H-cyclobut[b]phosphindole 3-oxide (8) (Scheme l).5 Treatment of ( 9) with trichlorosilane provides the first example of a 1-benzophosphepine (10) which, unlike (9). is thermally unstable in solution and gradually decomposes to naphthalene. Full details have appeared of the synthesis of the cis-isomer ( 1 2 ) of the tetracyclic phosphine oxide previously prepared as the t r a n s - i s o m e r (13).6 The isomeric mixture obtained depends on the conditions used for hydrolysis of the intermediate salt ( 1 1 ) to give (12) and ( 1 3 ) . I n addition to investigating a number of reactions of (12) and ( 1 3 ) which retain the tetracyclic structure the authors report detailed 13C, IH, and 3 1 P n.m.r. studies which not only allow determination of stereochemistry but, due to the rigidity of the ring system, provide useful data relating coupling constants to geometry. The macrocycles ( 1 4 ) 7 and ( 1 5 ) g containing the phosphine oxide function have been prepared. Oxidation of ( 1 5 ) produces only the d , l - f o r m (16) of the disulphoxide. This differs from the corresponding oxidation of the acyclic analogue ( 1 7 ) which gives all four possible stereoisomers of ( 1 8 ) . It is suggested that the selective formation of ( 1 6 ) is due to the

3.

Phosphine Oxides and Related Compounds

71

R2

pI

+

R

I (8)

Reagents: i, FVP, 550 OC, 6 x

(9) mmHg; ii, SiHCI3, PhH, 55 OC Scheme 1

(1 0 )

72

Organophosphorus Chemistry

qL@

.But

s

o

s

GH CH3 N-N X

CH H3C I I X\\ ,N-N IP \ Ph' 'N-N

' //

/I P N-N Ph ' 1 CH3

-78

"C

H

3:

Phosphine Oxides and Related Cbmpounds

73

macrocycle ( 15 1 being conformationally strained in solution and this is supported by variable temperature 13C n.m.r. studies and X-ray diffraction data. T h i o x o p h o s p h i n e s ( 1 9 ) have been generated by the reaction of dibromotriphenylphosphorane ( 2 0 ) with bis(triphenylmethylmercapt0)phosphines (21) as evidenced by trapping with 1.3-dienes to give cyclic thiophosphinate ana logues, e.g. ( 2 2 ) i n low yield.9 Oxidation of d i p h o sphiranes ( 2 3 ) with ozone at low temperature has been used to generate the dioxide ( 2 4 ) which decomposes at room temperature to give the phosphaalkene oxide ( 2 5 ) and products apparently derived from ArP=O.lo 2 S t r u c t u r e and Physical Aspects Structural studies on a variety of phosphine oxide binary and ternary cocrystallization compounds have been reported. The molecular structure of the highly stable HMPA-primary amine adduct ( 2 6 ) has been determined by X-ray crystallography and molecular orbital calculations have been used to make structural comparisons with adducrs of other phosphine oxides.] 1 The isotropic 31 P chemical shift for hydrogen-bonded co-crystals formed between triphenylphosphine oxide and aryl sulphonamides has been correlated with the number of NH---OP hydrogen bonds formed and this data can now be used to derive information on the hydrogen bonding patterns in related co-crystals.12 The ternary co-crystallization compound formed by mixing N,N-dimethyl-o-phenylenediamine, triphenylphosphine oxide and aqueous fluoroboric acid has been shown by X-ray crystallography to have an unusual structure (27) where the oxygen atom of the phosphine oxide acts as a double acceptor through hydrogen bonding.13 A range of diastereomeric 2-diphenylphosphinoyl-l,3-dioxanes have been synthesized either by Arbuzov reacti o n s of i s o p r o p y I d i p h e n ylphosphinite with the appropriate ( 1 . 3 - d i o x a - 2 - y 1 ) t r i m e t h y l ammonium iodide (Scheme 2) or by transacetylization between 1,3-diols and diphenyl(diethoxymethy1)phosphine oxide (Scheme 3).14 The anomeric effect i n these compounds was studied by n.m.r. spectroscopy and X-ray cry st a 11o g r a ph y . The conform at i on a I be h a v i o u r of 2 -(diph e n y 1p h o sp h i n o y 1 ) 1,3-dithiane ( 2 8 ) has been studied between 2 2 3 K and 258K by IH n.m.r.15 The linear plots of In K versus 1/T obtained allowed assessment of both the enthalpic and entropic contributions of the S - C - P ( 0 ) anomeric effect. Comparison with the corresponding data obtained from the cyclohexyl analogue ( 2 9 ) suggests that the enthalpic anomeric effect i n ( 2 8 ) is approximately 3.4 kcal/mol.

Organophosphorus Chemistry

74

Scheme 2

!? + (EtO)&HPPh2 f

H PhS03H

Scheme 3

i-iii

(30)

(31)

Reagents: i, 2 x Bu'Li, THF, 0 "C; ii, Ar2C0, 0-50 "C; iii, H30' Scheme 4 R' PPh2

I

TBSO"' &TBS

H 0' 0 It (33) R' = Me2P, R2 = H;

::

R' = Me2P, R2 = OH

3: Phosphine Oxides and Reluted ('orrtpouncis

75

A detailed study of 77Se and 3 ' P nuclear spin relaxation in tri( rertbuty1)phosphine selenide has been reported16 and the kinetics and mechanism of formation of tetracoordinate P(V) sulphides from the reaction of tricoordinate phosphorus compounds with diary1 trisulphides have been investigated.17

3 Reactions at Phosphorus The isolable oxaphosphetanes ( 3 1 ) have been prepared by treatment of the phosphine oxide ( 3 0 ) with two equivalents of butyllithium followed by reaction with substituted benzophenones (Scheme 4).18 It has been reported that treatment of triphenylphosphine oxide with organolithium or Grignard reagents leads to ligand exchange even at -9SOC.19 Although no such examples are given i n the report, a similar reaction occurring with mixed arylalkylphosphine oxides would obviously pose problems in phosphine oxide carbanion chemistry. 4 Reactions at the Side-Chain A number of phosphine oxide derivatives of the A-ring of vitamin D3 and

related compounds have been synthesized20 and used in the synthesis of vitamin D and its analogues. These include the phosphine oxide (32), which has been used in the synthesis of 25-phosphorus analogues (33) of vitamin D3.21 The 1,25-dihydroxy vitamin D3 metabolite ( 3 6 ) and the l a - f l u o r o analogue (37) have been synthesized from vitamin D3 by conversion to the phosphine oxide ( 3 4 ) followed by olefination with the ketone ( 3 5 ) , itself obtained by degradation of vitamin D3.22 Attempts to prepare 9-fluoro vitamin D3 using the standard olefination reaction of the appropriate carbonyl compound (39) with the A-ring phosphine oxide ( 3 8 ) gave instead the 9-hydroxy derivative (40).23 9-Fluoro vitamin D3, prepared by the corresponding Wittig reaction using the ylide analogue of ( 3 8 ) , did not undergo hydrolysis to the 9-hydroxy derivative. Phosphine oxide-based olefinations with ( 4 1 ) have been used in the synthesis of l a , 25-dihydroxy19-nor-vitamin D3 2 4 and its side-chain homologated analogue (42).*5 The phosphine oxides ( 4 3 ) and ( 4 4 ) . which are enantiomeric synthons for the preparation of dihydrotachysterols, have been synthesized from the appropriate di hydrocarvones.2 6 In continuing studies of stereoselectivity i n reactions of phosphine oxides, Warren has shown that the introduction of a diphenylphosphinoyl group to create a chiral centre next to the hydroxyl group in allylic alcohols allows epoxidation with high diastereoselectivity, especially in the eryrhroisomers, e.g. (45) (Scheme 5).27 This high diastereoselectivity was retained when a third chiral centre was introduced. The epoxides produced could be ring-opened with thiolate anions i n a highly diastereoselective manner and

76

Organophosphorus Chemistry

'H\3

PPh2

,CH3 (CH2)3C, OH

I

R3SiO"'

&

Base ____t

0

(35)

(34)

(36) X = F (37)X = OH

Oe PPh2 I

TBSO"'

(CH2)3CH

&

i, BuLi, THF

c

HO"

ii, TBAF

0

(39)

PPh2

I

R3SiO**'

OSiR3 HO"

OTBDMS (43)

OTBDMS

(44)

3: Phosphine Oxides and Related Compounds

77

the hydroxy phosphine oxides produced undergo the expected stereospecific Horner-Wittig elimination to provide compounds, e.g. (46), with all stereo centres defined. The reaction of the bis(phosphine su1phide)-stabilized carbanion ( 4 7 ) with aldehydes depends on the counter cation involved.2 8 Reactions with the lithium salt of ( 4 7 ) lead to the vinylbis(phosphine sulphides) ( 4 8 ) whereas the potassium salt of (47) gives the expected olefination product (49) (Scheme 6). I t is worth noting that the lithium salt of the corresponding phosphine oxide does not react under the same conditions whereas the potassium salt gives the product analogous to (49), although in lower yield than that obtained from the sulphide. A new route to 2 4 5 2 ) and 3 4 5 1)-(2-aminovinyI)indoles in excellent yield is provided by the reaction of 2 - and 3-acylindoles with the carbanions of 1-aminoalkyldiphenylphosphine oxides (50) (Scheme 7 ) . 2 9 The previously established method of diene synthesis using tandem Wittig reactions of the phospholanium salt (53) has been applied to the synthesis of the sex pheromone ( 5 4 ) from the pedal gland of the bontebok (Darnaliscus dorcas dorcas) and to various 1,4-diketones (Scheme 8).30 Diphenyl coumarin-3-phosphinyl oxides ( 5 5 ) and the corresponding phosphonates ( 5 6 ) have been synthesized i n one-step via a Knoevenagel reaction of acetoxysalicylaldehydes with diphenylphosphinyl- and triethyl phosphonoacetate, respectively.31 2,5-Dimethoxyphenyldiphenylphosphine oxide ( 5 7 ) undergoes lithiation, predominantly at the 6-position of the dimethoxyphenyl ring, on treatment with tertiarybutyllithium in THF under conditions of thermodynamic control at low temperature.32 The carbanion ( 5 8 ) formed can be trapped with a variety of electrophiles. The corresponding phosphine sulphide, although less reactive, is lithiated exclusively at the 4-position. The (E,E)-isomer of 1,2,5-triphenylphospholane oxide (60) has been identified as the product obtained by catalytic hydrogenation of the phosphole (59).33 Compound ( 6 0 ) can be isomerized exclusively to the thermodynamically more stable (E,Z)-isomer ( 6 1) by catalytic amounts of strong base. Treatment with one mole equivalent of base leads to a mixture of isomers. The individual isomers of the (E,Z)-isomers (61) were obtained by chiral supercritical fluid chromatography. The reaction of phosphole sulphide derivatives ( 6 2 ) with ethyl diazoacetate has been investigated with a view to providing a new route to phosphinines (64).34 Reaction at high temperature provided the corresponding homophosphole ( 6 3 ) which could be converted to the phosphinine ( 6 4 ) by heating with triphenyl phosphite. The stereochemistry of ( 6 3 ) , which was determined by X-ray crystallography, led to suggestions for the mechanism of the rearrangement of (63) to ( 6 4 ) .

78

Organophosphorus Chemistry

(75: 25/syn : anti)

(100 : O/syn : anti )

(45)

Scheme 5

S

(Ph2P)2C=CHR

$ (Ph2P)2CH2 (47)

9

(48)

>

fi + Ph2pMH

H R (49) Reagents: i, Bu"Li, PhH; ii, RCHO; iii, BU'OK, THF

Scheme 6

~

-

CHNR32

!

c

Ph2PCH2NR32 o ~

R2

R2

(511

(50) Reagents: i, Bu"Li, THF, -78 "C; ii, BU'OK, THF, -78 "C Scheme 7

(52)

0 i, ii

P

fh

2

P- m

R-L

PhNp\ Ph Clod-

(53)

4 v i

0

V

R SMe

(54) R = n-C5HI1

Reagents: i, BU'OK; ii, RCHO; iii, LDA; iv, MeSSMe; v, HCHO; vi, HgCI2,50 "C Scheme 8

3: Phosphine Oxides and Related ('ompounds

79

RippR32 0 II

0 II

CH2Ci2 NaOH

R32PCH2C02Et

0

R2

Ph

Ph

Ph

Ph

Ph

Ph

MeLi

Ph

Ph

+

RX

?

Bu3SnH * AlBN

pblPh2

? 0

I

s

hv

Buty p \ - MAre

-78 "C

SyJ

O Y BU'O ,Me

0rga n o phosphorus Chemistry

80

0-N

0-N

Ph2+!R2 Ph2P

+

Ph+ 2!

R’

R’ anti -(70)

1

syn -(70)

1

ii

OH Ph + 2!

NH:,

+

-

OH

NH2 R2

R’

R’ anti -( 7 1)

S Y -(71) ~

!

1

iii, iv

( E )-(72) (Z1472) ultrasound; ii, NiC12.6H20,NaBH,; iii, NaH, DMF; iv, HCI

Scheme 9

ReCI(N2)(Ph2PCH2CH2PPh2) (76) (W4

(77)

ii

P p ,h ),2!

R2

iii, iv

Reagents: i, R2CEN-0,

R2

(78)

3: Phosphine Oxides and Related Compounds

81

Boron trifluoride catalyses the 1,3-phosphotropic rearrangement of the a-phosphorylated imine (65) to give (66).35 This reaction takes place at room temperature, whereas the uncatalysed reaction requires heating to 150-2OOoC. High yields of the addition products ( 6 7 ) have been obtained from the reaction of carbon-centred radicals with diphenylvinylphosphine oxide.36 Radical addition to the chiral phosphine oxides (68) using Barton‘s method provides diastereomeric ratios of up to 9:l in the case of ( 6 9 ) . Allylic diphenylphosphine oxides undergo 1,3-dipolar cycloadditions with nitrile oxides to give A*-isoxazolines ( 7 0 ) with a n t i - p r e f e r r e d stereoselectivities of up to 5:1.37 Separate reduction of syn-and a n t i - ( 7 0 ) to the hydroxy amines (71), followed by Wittig-Horner elimination provides stereoselective syntheses of the homoallylic amines ( 7 2 ) (Scheme 9). A study of the effect of substituents on phosphorus on t h e diastereoselectivity in the cycloaddition of nitrones to vinylphosphine oxides (73) and sulphides ( 7 4 ) has been reported.38 In certain cases diastereoselectivities of >90% were achieved. Interestingly, while 2-hydroxyalkylphosphines undergo Rabbit gastric lipase-catalysed acylation, the corresponding phosphine oxides and sulphides either react more slowly or not at all.39 5 Phosphine Oxide Complexes The synthesis and X-ray crystal structure of the macrocyclic bisphosphine oxide manganese complex ( 7 5 ) have been reported.40 A stable P-bonded phosphinidene oxide complex ( 7 7 ) of rhenium ( I ) has been prepared from ( 7 6 ) by nitrogen replacement with C-tertiarybutylphosphaalkyne followed by hydrolysis.41 X-Ray crystallography was used to determine the structure of ( 7 7). What is reported to be the first complex (78) with a PO ligand has been prepared.42 The molecular structure of ( 7 8 ) , determined by X-ray crystallography, shows an exceptionally short PP distance. REFERENCES

1.

Y . Koide. A. Sakarnoto, and T. Irnarnoto, Terrahedron Letters. 1991. 3 2 . 3375.

2.

S.M.Ruder and B.K.

3. 4.

Norwood. Tetrahedron Letters. 1992. 3 3 , 861. H.J. Bestrnann. K. Roth, and M . Ettlinger, Chem. B e r . , 1982. 115. 161.

K.M. Pietrusiewicz. I. Salarnonczyk, W. Wieczorek,

A . Brandi. S. Cicchi, and A.

Goti, Tetrahedron. 1991. 4 7 , 9083. 5.

6. 7.

J. Kurita, S. Shiratori, S. Yasuike. and T. Tsuchiya. J . Chem. Soc., Chem. C o m u n . . 1991, 1227. S.E. Crerner. J.M.Cowles. F.R. Farr, H - 0 . Hwang, P.W. Krerner. and A.C. Peterson, J . Org. Chem., 1992, 57, 511. F. Gonce, A-M. Carninade. F. Boutonnct, and 970.

J-P. Majoral. J . Org. Chem., 1992, 57.

82

O r g a n o p h o s p h o r u s Chemistry

8.

P.B. Savage, J.M. Desper. and S.H. Gcllman. Tetrahedron Letters, 1992. 33. 2107.

9.

P.L. Folkins. B.R. Vincent, and D.N. Harpp. Tetrahedron Letters, 1991. 32, 7009. G . Etemad-Moghadam. C. Tachon, M. Gouygou. and M. Koenig. T e t r a h e d r o n

10.

Letters, 1991, 32. 3687. 11.

D.R. Armstrong, S. Bennett. M.G. Davidson. R. Snaith. D. Stalke, and D.S. Wright, J . Chem. SOC., Chem. Commun.. 1992, 262.

12.

S. Ammugam. C. Glidewell, and K.D.M. Harris, J . Chem. SOC., Chem. Commun., 1992, 724.

13.

A.L. Llamas-Saiz. C. Foces-Foces, J. Elguero, P. Molina. M. Alajarin. and A. Vidal. 1 . Chem. SOC., Chem. Commun., 1991. 1694.

14.

M. Mikolajczyk. P.P. Graczyk. M.W. Wicczorek, and G. Bujacz. T e t r a h e d r o n , 1992, 48, 4209.

15.

E. Juaristi and G. Cuevas, Tetrahedron Letters, 1992. 33, 2271.

16.

G.H. Penner, Can. J. Chem.. 1991, 69. 1054.

17.

C.D. Hall, B.R. Tweedy, R. Kayhanian, and J.R. Lloyd. J . Chcm. SOC. Perkin Trans.2,

18.

T. Kawashima, K. Kato. and R. Okazaki. J . Am. Chem. SOC.. 1992. 114, 4008.

19.

N. Furukawa, S. Ogawa. K. Matsumura. and H. Fujihara, J. Org. Chem., 1991. 5 6 ,

1992, 775.

6341. 20.

G.H. Posner and T.D. Nelson, J . Org. Chem., 1991, 56, 4339.

21.

W.G. Dauben, R.R. Ollmann, Jr., A.S. Funhoff. S.S. Leung. A.W. Norman. and J.E.

22.

J . Kiegiel, P.M. Wovkulich. and M.R. Uskokovic, Tetrahedron Lerters, 1991, 3 2 ,

Bishop, Tetrahedron Letters, 1991, 32. 4643. 6057. 23.

W.G. Dauben and L.J. Greenfield. J. Org. Chem., 1992, 57. 1597.

24.

K.L. Perhman, R . Swenson. H.E. Paaren, H.K. Schnoes. and H.F. DeLuca, Tetrahedron Letters, 1991. 32, 7663.

25.

K.L. Perlman and H.F. DeLuca, Tetrahedron Letters. 1992. 33, 2937.

26.

R.B. Rookhuizen. J.C. Hanekamp, and H.J.T. Boz, Tetrahedron

Letters, 1992, 3 3 ,

1633. 27.

D. Hall. A.F. Sevin and S. Warren. Tetrahedron Letters. 1991, 32, 7123.

28.

M.B. Goll and S.O. Grim, Tetrahedron Letters, 1991. 32, 3631.

29. 30.

U. Pindur and C. Otto, Tetrahedron, 1992. 4 8 . 3515. T. Fujimoto. Y. Hotei, H. Takeuchi, S. Tanaka. K. Ohta. and I. Yamamoto. J . Org.

31.

C h e m . , 1991, 5 6 , 4799. P. Bouyssou and J. Chenault, Tetrahedron Letters, 1991. 32. 5341.

32.

J.M. Brown and S. Woodward, J . Org. Chem., 1991, 5 6 . 6803.

33.

J-C. Fiaud and J-Y. Legros, Tetrahedron Letters, 1991. 32. 5089.

34.

S . Holand. L. Ricard. and F. Mathey. J. Org. Chem.. 1991. 5 6 . 4031. P.P. Onys'ko. T.V. Kim, E.I. Kiscleva. and A.D. Sinitsa, Terrahedron Letters, 1992,

35.

33. 691.

3:

Phosphine Oxides and Related Compounds

83

36.

A. Brandi, S. Cicchi, A. Goti. and K.M. Pieirusiewicz. Tetrahedron Letters, 1 9 9 1 , 32,

37.

S.K. Amstrong, S . Warren, E.W. Collington, and A. Naylor. Tetrahedron Letters,

38.

A. Brandi, S. Cicchi, and A. Goti, 1. Org. Chem., 1991. 5 6 . 4383.

39.

H.B. Kagan, M. Tahar,

40.

B. Beagley, G. Dyer, C.A. McAuliffe, P.P. MacRory, and R.G. Pritchard, J . Chem.

3265. 1991, 32, 4171. and J-C. Fiaud, Tetrahedron Letters, 1991, 32, 5959.

SOC., Chem. Commun., 1991, 965. 41.

P.B. Hitchcock. J.A. Johnson, M.A.N.D.A. Lemos, M.F. Meidine. J.F. Nixon. and

42.

O.J. Scheser, J. Braun. P. Walther, G. Heckmann. and G. Wolmershauses. A n g e w .

A.J.L. Pombeiro, J . Chem. Soc.. Chem. Commun., 1992, 645. Chem. Int. Ed. Engl., 1991. 30. 852.

4

Tervalent Phosphorus Acid Derivatives BY 0. DAHL

1 Introduction Several reviews of relevance to this chapter have appeared this year. One describes recent advances in the Staudinger reaction;l another is about the Perkow and related reactions2 A comprehensive review has been published on advances in the synthesis of oligonucleotides by the phosphoramidite a p p r ~ a c h and . ~ a survey has appeared on the synthesis and cyclisation reactions of tervalent phosphorus acid derivatives containing an oxoalkyl group.4

2 Nucleophilic Reactions 2.1 Attack on Saturated Carbon.- A study of the preparation of phosphonates related to the antiviral adenallene (1 ) by Arbuzov and Michaelis-Becker reactions has shown that Arbuzov reactions on such unsaturated systems are sometimes followed by eliminations o r rearrangement^.^ Thus the chloroalkene (2) reacted normally to give the phosphonate (3), but the corresponding alkyne (4) gave 9-ethyladenine and presumably (6), and the allene (7) gave the rearranged phosphonate (8). In the presence of iodide ions the alkyne (4) gave a diphosphonate (9). probably because the better nucleophilic iodide ions promoted dealkylation of the intermediate (5) instead of elimination. The chiral acetals (10) are attacked by triethyl phosphite at low temperatures in the presence of titanium(1V) chloride to give l-alkoxyphosphonates (1 1a.b) with a high degree of diastereoselectivity;6 the main diastereomers (1 la) were purified and used to prepare pure (S)-enantiomers of aaminophosphonic acids. Phosphono-, phenylphosphinico-, and diphenylphosphinoyl-sarcosine( 12) have been prepared in improved yields by Arbuzov reactions on the protected sarcosine derivative (1 31.7

2.2 Attack on Unsaturated Carbon.- Bis(trimethylsily1)phosphonite (14), prepared from ammonium phosphinate and hexamethyldisilazane, adds to a,&unsaturated ketones (15) to give high yields of mono- or disubstituted phosphinic acids.* Low yields were obtained for enolisable ketones if (14) was prepared in situ from trimethylsilylchloride and triethylamine instead. Diethyl trimethylsilyl phosphite (16) reacts readily with a,p-unsaturated imines to give solely 1,Zaddition products (17), even in the presence of bulky N-substituents, provided R1 is an aryl group.9 Formaldehyde dimethylhydrazone and phosphorus tribromide gave the unstable phosphonous dibromide (1 8) which could be converted to a distillable phosphonous diamide (19).'O Phosphorus tribromide reacts with 2-methylfuran in a 1: 1 molar ratio to give 5-methyl-2-furanylphosphonous dibromide (20); a 1:2 molar ratio gave the pure bis(furany1)phosphinous bromide. Unsubstituted

4:

Tervalent Phosphorits Acid Derivatives

85

B-CHzCzCH-CH20H ( 1 ) 6 = adenin-9-yl

B-CH2-CEC-CH2CI

+

(Et0)3P

c

110 "C

'3

n-

+

[B- CH2- CHz CH- CH-P(OEt ) kI

H

CI-

(5)

(4)

1

B-Et

+ CH2=C=C=CH-P(O)(OEt)2 (6) not isolated

(1 3)

(12) n = 0 - 2

Organophosphorus Chemistry

86

,'AR3 +

(Me3Si0)2PH

!(O)OH

R1&

0

0

R3

i, (Me&i),NH

1

0

R'

h

)2 P(0)OH

R3

AR3

+

R'

(1 6)

PBr3 + CH2=N-NMe2

/

ii, (15)

' R

(R

(Et0)2P-OSiMe3

1

R'

-% Br,P-CH=N-NMe2 0 "C

(18 )

-

Me2NH

P(O)(OEt)*

(Me2N)2P-CH=N-NMe2 (19)

(25) R' = Me0 (26) R ' = Ph

4:

Tervalent Phosphorus Acid Derivativrs

87

furan required higher temperatures and gave product mixtures, and thiophen required more severe conditions still; phosphorus trichloride was unreactive in all cases.l Triethyl phosphite and tris(alkylthio)cyclopropenyl cations (21) gave the allenic phosphonates (22) in refluxing acetonitrile. Some dicarbonyl(q5-cyclopentadieny1)iron substituted alkylphosphonates (23). containing one or two nucleosidyl groups, have been prepared from the ironethylene complex (24) and trialkyl ph0sphites.l

2.3 A t t a c k o n Nitrogen, Chalcogen, or Halogen.- Trimethyl phosphite. or methyl diphenylphosphinite, reacts with azides in the presence of water to give phosphoramidates (25) or phosphinamides (26) in high yields.14 The amides could be transformed to primary amines under nonaqueous acid conditions without hydrolysis of sensitive groups in the R2 group, e.g. ester groups. Isomerization of (Z)-azobenzene to the (E)-isomer is catalysed by trico-ordinate phosphorus compounds. A kinetic study of this reaction has concluded that the isomerization probably occurs by N-inversion in an intermediate (27).15 Alkanes are transformed to alkyl dimethyl phosphates when veated with trimethyl phosphite under GifIV conditions (oxygen, ferrous chloride, zinc, pyridine-acetic acid). The formation of the alkyl phosphate is explained by attack of trimethyl phosphite on the alkyl oxygen of a peroxide complex (28), in which the usual attack at the terminal oxygen is hindered by co-ordination of iron. The possibility of preparation of chiral phosphorus compounds from racemic mixtures by selective oxidation of one of the enantiomers of a tervalent compound has been examined with chiral Nsulphonyloxaziridines as the oxidising agents. Dimethyl aroylphosphonates (29) give ylidphosphonates (30) with trialkyl phosphites probably via initial oxygen-attack and elimination of trimethyl phosphate. The involvement of a carhene (3 1) was shown by the formation of dimethyl indan-1-phosphonates (32) from (29. Ar = 2-ethylphenyl), in which case carbene-insertion in the ethyl group competed with trapping by trialkyl phosphite. Kinetic data, activation parameters, and Hammett p values have been reported for the reaction of trico-ordinate phosphorus compounds with diphenyl trisulphide, and the results discussed in terms of a biphilic mechanism.19 A dithymidyl 3 ' 4 phosphorothioate (33) has been prepared from a thymidin-3'-yl disulphide and a dimethyl 5'-thymidyl phosphite.20 Tervalent phosphorus acid esters, and triphenylphosphine, attack 2-bromothiazole (34) at bromine in alcoholic solvents to give thiazole and the oxidised phosphorus compounds.21 A similar attack of tris(diethy1amino)phosphine on the bromine atom of bromopentafluorobenzene was used to prepare a series of main-group-four pentafluorophenyl derivatives, e.g. (35).22 A full paper has appeared o n the fluoridation of trimethylsilyl phosphites, or phosphoramidites, with sulphuryl chloride fluoride.23 The mild conditions allowed the preparation of sensitive nucleoside derivatives, e.g. (36) and (37).

3 Electrophilic Reactions 3.1 Preparation.-Some rare tervalent phosphorus acid derivatives, e.g. (38). with two P-OH

groups have been prepared as shown;24 their 31P n.m.r. chemical shifts and the absence of P=O

Ph

N '

I :PAr,(OPri)3-,

Ph"

fi' Ar-C-P(0)(OMe)2

-

+ (R0)3P

(29)

P(O)(OMe)2

@

(32)

+OR),

Ar

-C- -P(0)(0Me)2

-

+ 0 -P(0R)3 Ar -C - -P(0)(OMe)2

1 (R0)3P

A

Ar-C-P(0)(OMe)2

(311

(30)

'""P

MMTro -

OAc

(33)

OAc

4:

Tervalent Phosphorus Acid Derivatives

DMTaYbz vb= i vbz -Pbz SO2CIF

t

o\

Py., -30

MTro

"C

P-NPS2

Me3SiO'

dT,

tetrazole

DMTro

DMTro

SOZCIF

c

/P\

OAc

*v

o\ + !

OAc

(37)

N

N

K

+

PC13

-

3N N - P : H

@N-PC12

0

0

OH

0

(38)6, 142.5

Oo\P-NEt2

'

0'

+

RCOOSiMe3

-

oo\P-OSiMe3 0'

'

+

RCONEt2

90

Organophosphorus Chemistry

absorptions in their i.r. spectra seems to exclude the usual tautomeric H-P=O structure. A large number of phosphites with two different alkyl or aryl groups, and several phosphoramidites, phosphorochloridites, and sulphur analogues have been prepared for evaluation as antioxidants and characterized by n . m . ~ - Trimethylsilyl .~~ phosphites are usually prepared from a suitable H-P=O compound and trimethylsilyl chloride in the presence of a base; a new route to such compounds is illustrated by the reaction of a phosphoramidite (39) with trimethylsilyl acetate or benzoate26 An alternative to the Arbuzov route to P-keto phosphonates (40). alkylation of diethyl phosphorochloridite (4 1) with enolates followed by air-oxidation of the phosphonite, has been e v a l ~ a t e d Although .~~ some enolphosphate was formed, the ratios of P-C to P - 0 products were better than 12.5:l under optimized conditions, and the products were easy to purify. The reaction is also useful for preparation of a-phosphono esters (42). A full paper has appeared on a new reagent

(43) for the determination of optical purities of chiral alcohols or thiols.28 It is superior to previous reagents because of the large chemical shift difference between the diastereomeric products (44). 4-Dimethylaminopyridine (DMAP) and phosphorus halides give "onio"-phosphorus compounds, e.g. (45). as poorly soluble salts.29 Phosphorus trichloride with two equivalents of DMAP gave the salt (46)which upon storage or upon heating in toluene decomposed to the "onio"-phosphide (47) and chlorine! 30 The driving force for this remarkable reaction seems to be the cationic substituents which strongly stabilize the phosphide center by inductive and field effects. Methyl phosphorodichloridite (48) and DMAP gave the salt (49) in another remarkable reaction which seems to include a spontaneous Arbuzov demethylation of the tervalent derivative (50).30 In a search for tervalent phosphorus acid derivatives with better phosphitylation properties than usual aminophosphines or phosphoramidites Nifant'ev et a f . have prepared several new reagents. These include pyrazole derivatives, e.g. (5 2-aminopyridine derivatives, e.g. (52)?2v 33 amidine derivatives, e.g. (53),34 and hydrazine derivatives, e.g. (54).35 They were prepared by standard methods and examined for their reactivity towards alcohols and, in the case of the amidine derivatives, for their tendency to isomerize by migration of the phosphorus group to the other nitrogen atom. Another type of reactive tervalent phosphorus acid derivative is phosphites derived from hydroxylamine. Several stable derivatives, e.g. (55) and (56). have been prepared and substitution reactions with alcohols studied.36 Tervalent phosphorus derivatives are normally reactive towards thiocyanate groups, but (57) could be prepared as shown and purified by d i ~ t i l l a t i o n .Attempts ~~ to prepare the phosphorodiamidite (58). however, failed, because the more nucleophilic phosphorus atom in (58) attacked the thiocyanate group, giving the product (59) after ring-opening by chloride ions present in the reaction mixture. Some thermally stable cyanothiophosphites. e.g. (60).have been prepared as shown.38 The corresponding oxygen analogues are thermally unstable towards exchange of cyan0 and acetate groups. The thioacetyl group is substituted when (60) is treated with ethanol under kinetic control to give the cyanophosphite (6l), but at room temperature the thermodynamically stable thiophosphite (62) is formed. 3.2 Mechanistic Studies.- The kinetics and mechanism of the acid catalysed alcoholysis of phosphoramidites and aminophosphines has been studied.39 The rate of methanolysis in methanol

4:

91

Tervalent Phosphorus Acid Derivatives

Me

Me

Me

Me

(44)

(43)

+

PCI3

+

PCI3

EtOAc r t.

-

(Me2NCN+-)P

3CI-

r.t.

(Me2N
2cI-

+

(46)

I

A toluene

2 M e 2 N q N

+

MeOPCI2

a

--i&&-[ ( M e 2 N c N + - ) 2 P - O M e

o

l 0P - NH

2Cl-1

-0 N

N 1

Me

(53) 0

X o ;0P - O - N B

0 (54)

(56)

92

PCI3

Organophosphorus Chemistry

+

-

Me3SiOwSCN

C12P-0-SCN

(59)

(58)

(Et0)2P-CN

EtO-P(CN)*

+

MeCOSH

-

,SCOMe

XC

+ MeCOSH

(61)

EtO-P, CN

1.

(Et0)2P-SCOMe + HCN

(60)

(62)

/ 0 O N O 2

, 0 0 N O 2 tetrazole *

Me-P\

Me-P,+

NPr'2 (66)6,128.7

NP$2

H'

N N ,, -N V

I

N

(67)6,181.6

/ ! 3 O N O 2 Me-P,

(68)6,186.6

4:

'I'ervulent Phosphorus Acid Derivutives

9.3

was proportional to the concentration of acidic catalyst (e.g. Et2NH2+ Cl-), and the catalytic ratc constant for different catalysts obeyed the Bronsted equation with an a of 0.13, corresponding to a small degree of proton transfer in the transition state. Great care was taken to purify the phosphorus compounds for residual dialkylammonium salts in order to know the amount of catalyst present. W i h strong acids (e.g. anhydrous HBF4) tris(diethy1amino)phosphine and other aminophosphines are protonated on phosphorus, as is evident from a large P-H n.m.r. coupling constant, and from an Xray crystal structure of (63). These phosphonium salts do not react with methanol, and (63) may even be recrystallized from methanol! Alcoholysis occurs, however, as soon as bases (e.g. triethylamine or aminophosphines) are added. Phosphonium salts like (64) are inert towards alcohols, also in the presence of bases. The mechanism proposed is therefore not substitution on a phosphonium salt like (63), but on an aminophosphine-acid complex with a small degree of proton transfer, e.g. (65). The proton is thought to activate phosphorus for nucleophilic attack as well as to assist the cleavage of the P-N bond. In another study the acid catalysed rate of methanolysis of the hydrazine derivative (54) was shown to be three times higher than that of the corresponding diethylamino d e ~ i v a t i v e The .~~ activation of 4-nitrophenyl N,N-diisopropylmethylphosphonamidite(66) with tetrazole is claimed to proceed in two discrete steps as seen by the appearance of 3 P n.m.r. signals from two intermediates, (67) and (68).40 No undecoupled 3 l P n.m.r. data or other evidence were given to support the unique protonation at nitrogen in (67). The rate ratio for substitution of phenoxy groups by methoxide ions in (69) and (70) has been shown to be very solvent dependent4l Although a high rate ratio (k(69):k(70) = 1 . 8 ~ 1 0 was ~) found in methylene chloride, the ratio was only 14 in methanol. The authors propose an ion-pair stabilized phosphorane-like structure (7 1 ) for the transition state or intermediate in methylene chloride, which has a favourable axial-equatorial placement of the five-membered ring, to account for the high ratio in this solvent, and an in-line S N mechanism ~ to apply in methanol, where ion-pairing is unimportant. The different stereochemical expectations (retention in methylene chloride and inversion in methanol) could not be verified because phosphites isomerize under the reaction conditions. 3.3 Use for Nucleotide, Sugar Phosphate, Phospholipid, or Phosphoprotein Synthesis.- A new phosphorodiamidite (72) has been used to prepare a p h o ~ p h a t i d y l i n o s i t o l ; ~ ~ after oxidation to the phosphate the 2-trimethylsilylethyl group was easily removed with hydrogen fluoride in acetonitrile-tetrahydrofuran.The phosphoramidite (73) was prepared in a standard way and used to prepare ribonucleosidyl ethyl ph0sphates.4~ The cyclic phosphoramidite (74) was superior to several other reagents to make inositol trisphosphates;44 the same reagent could be used to prepare various unsymmetrical dialkyl phosphates by a four-step procedure involving alcoholysis, oxidation of the phosphite (75) with pyridinium uibromide, alcoholysis of (76). and reductive removal of the benzylic s ~ b s t i t u e n t . 4The ~ well-known phosphorodiamidite (77) has been used to prepare mannosyl nucleosidyl alkyl phosphate^?^ and (78) to obtain a dimannosyl peptidyl phosphate.46 Further work has been published on the preparation of phosphoproteins; the phosphoramidite (79) has been used to prepare protected phosphotyrosine monomers for use in Fmoc solid phase s y n t h e ~ i s 4as~ well as to phosphitylate a tyrosine-containing resin-bound p e ~ t i d e ; ~ ~

94

Organophosphorus C 'hem istry

(Me0)2P-

[>P-OPh

-O-P( Me3Si

EtO\ P-NPr',

NPri2)2 NC-6

(72)

(73)

(74)

PyHBr3

0 (75)

YH

OR'

Br

But I

y

RO-P( NPr'2)2 (77) R = CH2CH2CN (78) R=CH2Ph

RSH (87)

P-CI

(R' O ) ~ -P- N R ~ ~

CI,C-C-O--PCI;! I CH3 (81)

(79) R ' = Bu', R2 = Et (80) R' = CH,Ph, R2 = P t

0

- 3 0 " ~[ i P - S R

[pRMe3N

v>5

"C

N [o;P-cl

3

(82)

t

+ NMe3

R-P-OI 0-

(84)

CH20COC17H35 I

R = CHOCOC17H35 I

CH2-

0

Me3N

+ NMe3

E

R-P-OI

0(85)

4:

Tervalent Phosphorus Acid Derivutives

95

the phosphoramidite (80) has been used to phosphitylate serine, threonine, and tyrosine after solidphase assembly of peptides up to 15 residues in length.49 Some ether phospholipids with serine and threonine polar headgroups have been synthesized using 2.2.2-trichloro- 1,l -dimethylethyl phosphorodichloridite (8 1)?O N-rerr-Butylphospholipids were obtained by alcoholysis of (82), followed by oxidation and hydrolytic opening of the ring.51 A high-yield synthesis of the thiophosphatidylcholin (83) and two phosphonate analogues, (84) and (85), has been d e ~ e l o p e d 2-Chloro.~~ 1,3.2-dioxaphospholan (86) and the thiol (87) gave an unstable thiophosphite which could be oxidized with dinitrogen temxide at low temperature and ringopened with trimethylmine to give (83); the thiophosphite rearranged at room temperature or below to a thiophosphonate which furnished the thiophosphonate analogue (84) or, if oxidized, the phosphonate analogue (85). Binding of reporter groups or other active groups to oligonucleotides is simplified if the group is attached to a phosphoramidite. New examples of such functionalized phosphoramidites are dinitrophenyl substituted phosphoramidites, e.g. (88)?3 useful to detect an oligonucleotide by anti-dinitrophenyl antibodies, Vitamin E containing phosphoramidites, e.g. (89).54 which make the oligonucleotide very lipophilic, and a phosphoramidite (90)containing a reduced form of the intercalator fagaronine.55 Deoxyribonucleoside phosphoramidites (9 1) without protection groups at adenine, cytosine, or guanine, and a uridine phosphoramidite (92). have been prepared and tested as monomers for oligonucleotide synthesis.56* 57 The syntheses with (91, B = G and T) gave fairly pure moderate length oligonucleotides under ordinary coupling conditions and tetrazole catalysis, but (91, B = A or C) gave complex mixtures due to competing phosphitylation at the amino groups. The best procedure, which allowed synthesis of at least 2Gmers containing all four bases without base-protecting groups, was to use a 1:2 pyridine hydrochloride-imidazole catalyst instead of tetrazole, and to remove small amounts of N-phosphitylated biproducts by a wash with 1:1 pyridine hydrochloride-aniline in acetonitrile. Ribonucleoside phosphoramidites (93) with diethy lamino groups have been shown to give higher coupling yields than the corresponding diisopropylamino compounds, and solid-phase RNA syntheses of oligomers with up to 74 bases have been r e a l i ~ d . ~ ~ Deoxyribonucleoside phosphorodiamidites (94) have been prepared from the protected nucleoside and chlorobis(diethy1amino)phosphine. the latter giving rise to products of a higher purity than tris(diethy1amino)pho~phine;~~ the phosphorodiamidites were used to prepare oligonucleotides containing one isopropyl phosphotriester linkage. A methylphosphonamidite (95) with two orthogonal leaving groups has been prepared and used to obtain thymidine methylphosphonate or methylthiophosphonate dimers4O The Cnitrophenoxy group of (95) and (96) was the sole leaving group in the presence of sodium hydride whereas teuazole only activated the diisopropylamino group. The alkylbis(diisopropy1amino)phosphines (97) have been prepared as shown and used to prepare the phosphonamidites (98)i60 they were successfully used to prepare deoxyribonucleoside dimers and hexamers containing alkylphosphonate or alkylthiophosphonate linkages. In a stereocontrolled synthesis of oligodeoxyribonucleoside phosphorothioates, the monomers (99) were prepared from the cyclic thiophosphoramidite (100) as shown.61 The preparation of a deoxyadenosine 3'-S-thiophosphoramidite (101) has been described, and its use to obtain a

96

NPf2

OMe Me0

Me (90)

DMTroTJDMTro 9

P-NPr’2 Me0 (91) B = A, C, G , T

0 OSiBu‘Me2

R’,N--P/ \

0r2 (92) R’ = Pf, R2 = Me, B = U (93)R’ = Et, R2 = CH2CH2CN, B = AbZ,CbZ,GbZ,U

DMTroYJ

0, P-NEt, Et2d (94) B = AbZ, CbZ,Gib,T

4:

97

Tervalent Phosphorus Acid Derivutives

DMTropT tetrazole

DMT

9P-NPrI2

DMTrdT

Me/

/

0

0

N

0

9

2

.!-OV

Me-P, NPri2 (95)

YrdT

tetrazole

ODMTr

DMT CI-P( NP112)2

RLi RMgX or

m

R- P(NPf12)2 (97) R = Me, Bu, octyl

9P-NPr', R' (98) R = Me, Bu, octyl

DMTro

98

OrganophosphorusChemistry

dinucleoside 3'-S-pho~phorothioate.~~ A full paper has appeared on the preparation of oligodeoxyribonucleoside phosphorodithioates up to 20-mers by solid-phase synthesis, using the thiophosphoramidite monomers ( The stepwise coupling yield was 96-9846 after 2x1 min coupling with tetrazole catalysis, but the products, after oxidation with sulphur, contained 8-9% of phosphorothioate linkages. 3.4 Miscellaneous.- New optically active phosphites (103)64 and derived from R- or S-2.2'-binaphthol have been prepared by standard methods and used as ligands for asymmetric hydroformylation or hydrocyanation reactions. Low to moderate asymmetric induction was achieved in the synthesis of 5.6-disubstituted cyclohexadienes from benzene chromium complexes when the optically active phosphites (105) were ligands.66

4 Reactions involving Two-co-ordinate Phosphorus Phosphenothious fluoride ( 106) was formed on pyrolysis of phosphenodithioic fluoride (1O7), as shown by photoelectron s p e ~ t r o s c o p yPhenylthioxophosphine .~~ (108) has been generated at 0 O C as shown and trapped by dienes.68 The chloroiminophosphine (109) is stable at room temperature, but the less hindered (1 10) dimerized to the diazadiphosphetidine (1 1 1).69 The conjugated aminoiminophosphine (1 12) and phosphinoiminophosphine (1 13), both obtained from (109), were stable at mom t e ~ n p e r a t u r eThe .~~ aminoiminophosphine anion ( 1 14) reacts with chlorodiphenylphosphine at nitrogen or at phosphorus depending on the solvent7l Similar anions react with the chloroiminophosphine (1 15) in pentane to give 1,3,5-triaza-2,4-diphospha1,4-pentadienes (1 16).72 The 2-h3-phosphaquinolines (1 17) were surprisingly the products when a phosphinidyneammonium salt (1 18) and an alkyne were stirred together in toluene, followed by addition of a base;73 a mechanism via a phosphirene as shown was given. Attempts to prepare 4.5-disubstituted 1,2,4.3-triazaphospholesfrom amidrazones ( 1 19) and tris(dimethy1amino)phosphinegave tetramers (1 2 0 ) ; ~monomeric ~ boron trifluoride complexes (121), however, could be obtained. Several condensed 1,4,2-diazaphospholes ( 122)75 and ( 123)76 have been prepared. Electrochemical oxidation of dialkylamino substituted diphosphines, e.g. ( 124). gave phosphenium ions (125) readily.77 One equivalent of the phosphonium salt (126) and phosphorus trichloride gave the dichlorophosphine (127), but a phosphenium chloride (128) was obtained with two equivalents of ( 126);78 another phosphenium chloride (129) was formed from diethyltrimethylsilylamine and (127). The first diphosphirenium salt (130) has been prepared and the X-ray crystal structure dete1mined.7~ A diphosphene (131) has been prepared for the first time as both the pure E- and the pure Zisomer;80 the chloro- and bromo-diphosphane (132) probably gave different isomers by a cis elimination of trimethylsilyl halide because different rotamers were primarily occupied. The activation enthalpy for the isomerization of (13 1) was found to be 25.5 kcal/mol, and the equilibrium mixture was (131a):(131b) = 11:6.

4:

Tervalent Phosphorus Acid Derivatives

99

g

0- P(OAr),

\

/

0- P(OAr)2

(103) Ar = Ph, Me+

(105) n =0,2

Ph-P(SCPh&

+

Ph3PBr2

0 "C

[ Ph-P=SI (108)

R e N = P - C I

R (109) R = Bu' (110) R = P +

tq

N=P-E*

(112) E = N (113) E = P

NMe2 NMe2

+

2 Ph3CBr

+

Ph3PS

1ou

Organophosphorus Chemistry

PPh2 I R’-N-P=N-#

+

R’-N-P=N-R2 Li+

PhZPCI

(1 14)

L

PPh2 I R’--N=P=N-R~

R’ = 1-adamantyl, R2 = 2 , 4 , 6 - ( 6 ~ ‘ ) ~ C ~ H ~

+

PhCfCR

PEN

AICI,

%

R (1 17) R = H, Ph

R2yT=? R’

R

4:

Tervalent Phosphorus Acid Derivcitiws

101

NPt2

I

SiMe,

R' = ( Me3Si)*N-

P= P ,

'R

(133)

R2 (1 31 b)

N'

\

Organophosphorus Chemistry

102

? ( H 0 Ph ) 2 p Y B

(137) B = C , G

-

o-P(oR~),

Et3N

R’R2SiCI2

+

2 (R30)2PH0

R’R2Si:

o-P(oR~)~ (138)

4:

Tervulent Phosphorus Acid Drrivatives

I03

5 Miscellaneous Reactions A paper on new approaches to the generation of arylphosphinidenes has been published.81 The stable bis-azide precursor (133) upon photolysis, or vapour phase thermolysis. gave (134). obviously via the phosphinidene (135); the same product was obtained by photolysis of the phosphaketene (1 36). The reduction of aryldiazonium salts to a r e n a with triethyl phosphite or triphenylphosphine is shown to proceed by a radical-chain mechanism.82 The previously described photo-Arbuzov rearrangement of benzyl phosphites has been used to prepare several acyclic phosphonate nucleotide analogues, e.g. ( 137).83 A series of dialkylsilylene diphosphites (138) has been prepared for use as chelating l i g a n d ~ Chlorophosphines .~~ react sluggishly with trialkyl phosphites, but the reaction has now heen shown to be catalysed by Lewis acids and then to give high yields of diphosphine oxides, e.g. ( 139).85

References 1.

2. 3. 4.

5. 6. 7.

8. 9. 10.

11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

23. 24. 25.

26. 27.

Y. G. Gololobov and L. F. Kasukhin. Tetrahedron, 1992, 48, 1353-1406. G. B. Borowitz and I. J. Borowitz, in R. Engel, ed., Hundbouk of Organophosphorus Chemistry, Marcel Dekker, Inc.: New York, 1992, Chapter 3. S. L. Beaucage and R. P. Iyer. Tetrahedron, 1992.48.2223-231 1. F. S. Mukhametov, J. Gen. Chem USSR, 1991.61. 8-33. S. Megati, S. Phadtare, and J. Zemlicka, J. Org. Chem, 1992, 57, 2320. T. Yokomatsu and S. Shibuya, Tetrahedron: Asymmetry, 1992.3.377. K. Burger, E.Heistracher, R. Simmerl, and M. Eggersdorfer, 2 Nuturforsch., 1992,47b, 424. E. A. Boyd, A. C. Regan, and K. James, Tetrahedron Lett., 1992, 33, 813. K. Afarinkia, J. I. G. Cadogan. and C. W. Rees, Synlett., 1992,. 123. A. A. Tolmachev. L. M.Potikha, A. A. Yurchenko. E. S. Kozlov, and A. M . Pinchuk, J. Gen. Chem. USSR, 1991, 61, 2189. A. A. Tolmachev, S.P. Ivonin, A. V. Kharchenko, and E. S. Kozlov, J. Gen. Chem USSR, 1991, 61. 778. H. Kojima, K. Ozaki, N. Matsumura, and H. Inoue, J. Chem Res. (5’). 1991, , 324. D. Bergstrom and T. Schmaltz, J. Org. Chem, 1992,57, 873. A. Zidani, R. Carrie, and M. Vaultier, Bull. SOC. Chim Fr.. 1992, 129, 71. C. D. Hall and P. D. Beer, J. Chem. SOC., Perkin Trans. 2, 1991, , 1947. D. H. R. Barton, S.D. BCvitre, and D. Doller, Tetrahedron Lart., 1991, 32,4671. U. Verfiirth and I. Ugi, Chem. Ber., 1991, 124, 1627. D. V. Griffiths, P. A. Griffiths, B. J. Whitehead, and J. C. Tebby, J. Chem SOC., Perkin Trans. I , 1992, ,479. C. D. Hall, B. R. Tweedy, R. Kayhanian, and J. R. Lloyd, J. Chem SOC., Perkin Trans. 2 , 1992, , 775. J. S. Vyle, X. Li, and R . Cosstick, Tetrahedron Lett., 1992.33, 3017. D. W. Allen, Phosphorus, Sulfir, and Silicon, 1992,66,73. V. V. Bardin. L. S. Pressman, L. N. Rogoza, and G. G. Furin, J. Fluorine Chem.. 1991, , 213. W. Dabkowski. F. Cramer, and J. Michalski, J. Chem Soc., Perkin Trans. 1 . 1992,. 1447. S. A. Mamedov, A. B. Kuliev, B. R. Gasanov, and A. M. Mirmovsumova. J. Gen. Chem USSR, 1991, 61, 2474. T. KUnig, W. D. Habicher. U. Hahner, J. Pionteck, C. Ruger, and K. Schwetlick, J. Prakt. Chem., 1992, 334, 333. M.A. Pudovik, L. K. Kibardina, and A. N. Pudovik, J. Gen. Chem USSR, 1991.61, 1347. K. Lee and D. F. Wiemer, J. Org. Chem, 1991. 56, 5556.

I04

28. 29. 30. 31. 32.

33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.

46. 47 * 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69.

Organo phosphcirus Cherniary A. Alexakis. S. Mutti, and P. Mangeney, J. Org. Chem, 1992,57, 1224. R. Weiss and S. Engel, Synthesis, 1991, , 1077. R. Weiss and S . Engel, Angew. Chem. Inr. Ed. Engl., 1992. 31. 216. V. Y.Iorish, M. K. Grachev, A. R. Bekker, and E. E. Nifant'ev, J. Gen. Chem USSR, 1991, 61, 92. M. K. Grachev, G. I. Kurochkina, S. G. Sakharov, A. R. Bekker, and E. E. Nifant'ev. J . Gen. Chem. USSR, 1991,61, 1564. E. E. Nifant'ev. V. V. Negrebetsky, M. K. Gratchev, G. I. Kurochkina, A. R. Bekker, L. K. Vasyanina. and S. G. Sakharov, Phosphorus, Suffitr, and Silicon, 1992,66,261. E. E. Nifant'ev, V. V. Negrebetskii, and M. K. Grachev, J. Gen. Chem. USSR, 1991,61, 1450. M. K. Grachev, A. R. Bekker, and E. E. Nifant'ev, J. Gen. Chem USSR, 1991.61, 1441. T. Bailly and R. Burgada, Phosphorus, Sulfur, and Silicon, 1991.63, 33. R. M. Kamalov, G. S. Stepanov, D. V. Ryzhikov, M. A. Pudovik, and A. N. Pudovik, J. Gen. Chem USSR, 1991,61. 1614. A. N. Pudovik, V. N. Nazrnutdinova, and L. P. Chirkova, J. Gen. Chem. USSR,1991.61, 551. E. E. Nifant'ev, M. K. Gratchev, S. Y. Burrnistrov, L. K. Vasyanina, M. Y. Antipin. and Y . T. Struchkov, Tetrahedron, 1991.47.9839. J. Helinski. W. Dabkovski, and J. Michalski, Tetrahedron Lett., 1991,32, 4981. G . Aksnes and P. Frgyen. Phosphorus, Sulfur, and Silicon. 1991.63, 45. S . P. Seitz, R. F. Kaltenbach III, R. H. Vreekamp, J. C. Calabrese, and F. W. Perella, Bioorg. Med. Chem Lett., 1992, 2, 171. C. Sund. P. Agback, L. H. Koole, A. Sandstrom, and J. Chattopadhyaya, Tetrahedron, 1992, 48, 695. S. Ozaki. Y. Kondo, N. Shiotani, T. Ogasawara. and Y. Watanabe, J. Chem Soc., Perkin Trans. I , 1992,, 729. Y. Watanabe, Y. Komoda. and S. Ozaki, Tetrahedron Lett., 1992.33. 1313. R. Verduyn, J. J. A. Belien, C. M. Dreef-Tromp, G. A. van der Marel, and J. H. van Boom, Tetrahedron Lett., 1991.32, 6637. J. W. Perich and E. C. Reynolds, Int. J. Peptide Prot. Res., 1991,37,572. J. W. Perich, D. L. Nguyen, and E. C. Reynolds, Tetrahedron Lett., 1991,32,4033. D. M.Andrews. J. Kitchin, and P. W. Seale, Int. J. Peptide Pror. Res., 1991. 38, 469. A. B. Kazi and J. Hajdu. Tetrahedron Lett., 1992,33,2291. C . McGuigan and B. Swords, J. Chem. SOC., Perkin Trans. 1 , 1992,. 51. B. Mlotkowska and a. Markowska, Liebigs Ann. Chem., 1991, ,833. D. W. Will, C. E. Pritchard, and T. Brown, Carbohydrate Res., 1991, 216, 315. D. W. Will and T. Brown, Tetrahedron Lett., 1992.33, 2729. J. Chen, D. V. Carlson, H. L. Weith, J. A. OBrien, M. E. Goldman. and M. Cushman, Tetrahedron Lett., 1992. 33. 2275. S. M. Gryaznov and R. L. Letsinger, J. Am. Chem. Soc., 1991, 113. 5876. S. M. Gryaznov and R. L. Letsinger, Nucleic Acids Res., 1992, 20, 1879. M. H. Lyttle, P. B. Wright. N. D. Sinha, J. D. B i n , and A. R. Chamberlin, J. Org. Chem., 1991, 56, 4608. K. Yamana, Y. Nishijima. K. Negishi, T. Yashiki, K. Nishio, H. Nakano. and 0.Sangen, Tetrahedron Lett., 1991, 32, 4721. H. C. P. F. Roelen, H. van den Elst, C. E. Dreef, G. A. van der Marel, and J. H. van Boom, Tetrahedron Lett.. 1992.33.2357. W. J. Stec, A. Grajkowski, M. Koziolkiewicz, and B. Uznanski, Nucleic Acids Res., 1991, 19, 5883. X. Li, D. M. Andrews, and R. Cosstick, Tetrahedron, 1992,48,2729. K. Bjergkde and 0. Dahl, Nucleic Acids Res., 1991, 19, 5843. N. Sakai, K. Nozaki, K. Mashima, and H. Takaya, Tetrahedron-Asymmetry, 1992,3,683. M. J. Baker and P. G. Pringle, J. Chem SOC., Chem. Commun.. 1991,. 1292. G. Bernardinelli. A. Cunningham, C. Dupre, E. P. Kundig, D. Stussi, and J. Weber, Chimia, 1992. 46, 126. H. Bock, M. Kremer. B. Solouki, M. Binnewies, and M. Meisel, J. Chem Soc., Chem Commun., 1992, , 9. P. L. Folkins, B. R. Vincent, and D. N. Harpp. Tetrahedron Lett.. 1991,32.7009. V. D. Romanenko, A. B. Drapailo, A. N. Chernega, and L. N. Markovskii, J. Gen. Chem. USSR, 1991. 61, 2260.

4:

70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85.

Trrvalent Phosphorus Acid Derivutives

I05

L. N. Markovskii, V. D. Rornanenko, A. V. Ruban, T. V. Sarina, M.I. Povolotskii, and L. F. Lur'e, J. Gen. Chem. USSR, 1991, 61. 363. R. Detsch. E. Niecke. M. Nieger, and W. W. Schoeller, Chem. Ber., 1992, 125, 11 19. R. Detsch, E. Niecke, M.Nieger, and F. Reichert, Chem Ber., 1992, 125, 321. G. David, E. Niecke, and M. Nieger, Tetrahedron Lett., 1992,33,2335. M. Haddad, F. Dahan, J.-P. Legros, L. Lopez, M.-T. Boisdon. and J. Barrans, J. Chem. SOC., Perkin Trans. 2, 1992, , 671. K. Karaghiosoff. R. K. Bansal, and N. Gupta, 2 Nuturforsch., 1992, 47b. 373. R. K. Bansal, R. Mahnot. D. C. Shanna, and K. Karaghiosoff, Synthesis, 1992,, 267. J. Niernann, W. W. Schoeller, V. von der GiSnna, and E. Niecke. Chem Ber.. 1991, 124, 1563. A. Schmidpeter and G. Jochern, Tetrahedron Lett., 1992.33,471. F. Castan, A. Baceiredo, J. Fischer, A. D. Cian, G. Cornrnenges. and G. Bertrand, J. Am. Chem Soc., 1991, 113, 8160. E. Niecke, 0. Altmeyer, and M. Nieger, Angew. Chern., Int. Ed. Engl., 1991,30, 1136. A. H. Cowley, F. Gabbai. R. Schluter, and D. Atwood, J. A m Chem Soc., 1992, 114, 3142. S. Yasui, M.Fujii, C. Kawano, Y. Nishimura, and A. Ohno, Tetrahedron Lett., 1991.32, 5601. K. B. Mullah and W. G. Bentrude. 1. Org. Chem., 1991,56,7218. T. P.Kee and M. T. Patel. Polyhedron, 1992.11, 135. N. N. Demik, M. M. Kabachnik, Z. S. Novikova, and I. P. Beletskaya. J. Gen. Chem U S S R , 1991, 61, 460.

5

Qu inq ueva Ie nt Phosphorus Acids BY R. S.EDMUNDSON

Results presented during the year appear to indicate a further shift in interest away from fundamental phosphate ester chemistry towards that of phosphonic and phosphinic acids and. in all area%, towards compounds of potential pharmacological interest. The chemistry of phosphoric and phosphonic pseudohalides has been reviewed.

I . Phosphoric Acids and their Derivatives 1.1. Synthesis of Phosphoric Acids and their Derivatives.--The use of sulphuryl

chloride fluoride for the preparation of phosphorofluoridates from trimethylsilyl phosphites (cf. Orgunophusphom.~Chemisny,

1990, 2 1 , 123) h a s now been described

fully, particularly with regard to nucleoside derivatives2

Other carbohydrate

phosphorofluoridates have been obtained from the corresponding hydrogen phosphates by the use of 2.4-dinitrofl~orobenzene.~ An improved procedure for the preparation of monoalkyl (and also monoaryl) dihydrogen

phosphates

involves

the

treatment

of

the

corresponding

phosphorodichloridates with aqueous MeCN containing silver nitrate4 The cryptand (2) was obtained from ( 1) by hydrogenolysis. 5 Two highly unusual procedures for the preparation of trialkyl phosphates have been described. In the first, alkanes are made to react with trimethyl phosphite in a medium consisting of FeC12.4H20:Zn(0):02 in pyridine

-

acetic acid. The essential reaction

appears to be one of Fe(1I)-catalysed oxidation of the tervalent phosphorus ester by an alkyl hydroperoxide to afford an alkyl dimethyl phosphate6

In the second procedure.

described in considerable detail, a Cu(I1) catalyst aids in the interaction of red phosphorus and an alcohol, ROH, when the products are the alkyl chloride RCI (from 7 CuCI2) and an almost quantitative yield of the phosphate ( R 0 ) 3 P ( 0 ) . A procedure thus far used extensively in the synthesis of biological phosphates has now been applied at a more fundamental level. When acted upon by an alcohol R'OH in the presence of 1 H-tetrazole, the cyclic phosphoramidite (3) yields the P(II1) ester (4). Oxidation of the latter with rn-chloroperoxybenzoic acid (mCPBA) then affords the cyclic

5:

Quinquevalent Phosphorus Acids

107

0-0-0

W

(3) X = lone pair, Y = NEt2 (4) X = lone pair, Y = OR’ (5)X = 0 , Y = OR’

(1 ) R = 4-CI-CsH4 (2) R = H

(7)R = OPh or NMe2

( 8 ) R = 0-alkyl

or NMe2

(1 1 ) R = CH(OMe)CH20R’ (12) R = Ar

(9)

(1 3) R = CH(OMe)CH20R’ (14) R = Ar

r

1

Me’

(15 )

F

C

(1 6)

H

J

(1 7 )

A

COOR2

R3

(1 9) X = CH2, R’ = PO3H2, R2 = R3 = H

(1 8 )

(20) X = 0 , R’ = P03Ph2,R2 = Bn, R3 = Cbz (21) X = 0, R’ = P03H2,R2 IR3 = H

I ox

Organophosphorw Chemistry

phosphate ester (5) from which the phenylenedimethylene moiety may be removed by hydrogenolysis to give a monoalkyl dihydrogen phosphate. Alternatively, the treatment of (4)with pyridine.HBr3, followed by the alcohol R 2OH in the presence of Et3N, affords the acyclic triester (6); hydrogenolysis of the latter yields the mixed diester

(R

o)(R~o)P(o)oH.X Phosphate triesters diester amides (7) and ( 8 ) based on the 1,3,2-dioxaphosphepane

ring system previously

Again, using

have been obtained by conventional procedures.9'10 characterized

N-methylisatin

or

procedures

the

radicals

acenaphthenequinone

have

obtained been

from

made

to

sodium

and

react

with

phosphorodifluoridates or phosphorodifluoridothioates to give the fused phosphates (9) and ( lo)( R = Et or Ph; X = 0 o r S).1 1 Monoaryl and diary1 phosphate analogues, ( 1 3) and ( 14). of platelet activating factor, have been synthesized by reactions between the cyclic phosphates ( 1 1 ) or ( 12) and nitrogen-containing heterocyclic systems. Larger

ring

phosphate

systems

12H-dibenzo[d,g][ 1,3,2]dioxaphosphocins

recently ( 15:

R2

described =

include

H)

and

16H-dinaphtho[2,1 -d; 1 ',Z'-g][ 1,3,2]dioxaphosphocins ( 15; RZ2= C4H4);'

the the

they were

obtained conventionally from the diol and R1P(0)C12 (R1 = aryloxy), a procedure likewise used to obtain the crown ether type (16; X = 0 or S, R = EtO or PhO). 15 Interestingly,

the

reaction

between

the

metacyclophane

( 17)

and

diphenyl

phosphorochloridate with triethylamine results in the phosphorylation of all eight hydroxy groups whereas with diisopropyl phosphorochloridate the acylation process stops at the symmetrical tetraphosphate stage. compounds ( 18; n

=

Similarly the phosphorylation of

4 or 6) with diethyl phosphorochloridate-triethylamine proceeds

only to the symmetrical halfway stage. 17

Cis-4-(Phosphonomethyl)-2-piperidinecarboxylic acid ( 19) is a powerful and selective N-methyl-D-aspartic acid (NMDA) antagonist. The phosphate analogue, (2 1 ) has now been described, having been obtained via the N-protected diphenyl ester (20) by

hydrogenolysis. The replacement of X = CH2 by X = 0 has a very marked detrimental effect on NMDA-antagonist activity.' Descriptions

have

been

given

(>-phosphoserineI9, 0-phosphothreonine,

for

syntheses

of

peptides

and 0-phosphotyrosine?'

based

on

and several

O,O-(diary1 phosphoryl) derivatives of 0-phosphoserinecontahing peptides have been evaluated with regard to the ease of removal of the aryl groups and hence also to the value of

the latter for protection purposes during solid-phase phosphopeptide

5:

Quinquevalent Phosphorus Acids

synthesis.:! more

109

Thus for Boc.Ser[P(0)(OAr)2]OBn, phenyl and 2-methylphenyl groups are

readily

removed

2-tcn-butylphenyl groups.

by

hydrogenolysis

than

are

2,6-dimethylphenyl

and

22.23

Phospholipid type compounds have been synthesized through a reaction sequence based

on

the

hydrolytic

cleavage

of

the

P-N

bond

3-ten--butyl-1.3,2-

in

oxazaphospholidines. 24 The chemical synthesis and biological applications of monophosphoryl and 25 diphosphorylpolyprenyl compounds have been reviewed. Interest in the chemistry of the phosphates of myo-inositol (22) continues to prow.

In addition to reviews?6v27 a new book on the subject has appearedz’ The first of two routes adopted for the synthesis of D-myo -inositol 1 -(dihydrogen phosphate) involved the

initial preparation

of

the ketal

(23). its subsequent

monophosphorylation to (24) by means of either dibenzyl phosphorochloridate or phosphitylation

using the N,N-dimethyl

analogue of

(3), and finally complete

deprotection. The enantiomeric phosphate wa? likewise prepared. 29*30 The second synthesis started with L-quebrachitol (25); its di-U-cyclohexylidene derivative (26; R1

=

Me, R2

=

H) was benzoylated and the product was then treated with aluminium

chloride and sodium iodide, when loss of the methyl group and one cyclohexylidene group occurred to give (27: R 1 = H, R 2 = Bz). Further manipulation afforded the pentabenzoate (28) which was phosphorylated (Scheme 1) to give (29) and the latter was then hydr~genolysed.~Using appropriate modifications to the starting materials in the first of these two procedures, and employing the equilibrium-driven (self-resolving) 30 synthesis of the camphanylidene ketals, the 3- and 4-mono(dihydrogen phosphate)s, 30 the 1 ,4-di-.30’32 the 1 , 4 . 5 - t r i ~ - , ~and ~ ) ’the ~ ~3.4.5,6-tetrakis-(dihydrogenphosphate)s of myo-inositol were also obtained. The same camphor ketal (23) was also used in yet another synthesis of myo-inositol 1,4-bis(dihydrogen phosphate) via the intermediates (31 )-(34) and as outlined in Scheme 2.32 A fourth synthesis of the same bisphosphate (38) relied on the inosi to1 derivative (35) (Scheme 3), the latter compound being chosen specifically because of its additional value in the preparation of certain phosphonate analogues o f 33

myo-inositol 1,4.5-tris(dihydrogen phosphate)(see later).

Extensive use has been made of ally1 groups for protection purposes in the conversion of

the di-0-cyclohexylidene

derivative (26; R 1

=

R2

=

H) into

D-myo-inositol 1.3,4-tris- and 1,3,4,5-tetra.kis(dihydrogenphosphate)s using conventional 34 phosphitylation methodology.

Orgunop hosp horus Chemistry

110

HoQ

dQ X-0

H

HO".

"OH

R

HO"'

'OH

HO..-@t-I

MeO'**

'"OH

OH

OH

OH

(22)

(23) R = H, X = C10H16 (24) R = (0)P(OBn)2, X = C1&i16

(25)

Reagents: i, (3),1H -tetraole; ii, then m -CPBA; iii, (a) H2, Pd/C (b) MeO-, MeOH

Scheme 1

Reagents : i, Me2ButSiCI,imidazole, MeCN; ii, Me2C(OMe)2,DMF,p -TsOH; iii, Bu4N F-,THF; iv, (3), 1H-tetrazole, CH2CI2; v, m -CPBA +

Scheme 2

5.

Quinquevalent Phosphorus A c i h

"OR2

111

i , i i ~ ( 3 5 )R' (36) R' iii K(37) R' " K ( 3 8 ) R'

= H, R2 = Bn, R3 = 4-Mt3OC6H4CH2 = (BnO),P(O), R2 = Bn, R3 = 4-MeWsHdCH2 = (BnO),P(O), R2 = Bn, R3 = H = PO3H2, R2 = R3 = H

Reagents: i, (B~IO)~PNP~'~, 1H -tetraole; ii, Bu'OOH; iii, 2% CF3COOH, CH2CI2; iv, H2, P&C, EtOH

Scheme 3

(23) R1 = R2 = H R' = Me3C.C0,R2 = H (40) R1 = Me3C.C0, R2 = Bn i i i c (41) R' = H, R2 = Bn iv, v (42) R' = (O)P(OCH2)2C6H4- I , & R2 = Bn vic(43) R' = P03H2, R2 = H iL(39)

iic

' - 0 ~ 2

OR'

Reagents: i, Me3CCOCI, py.; ii, BnBr, Ag20, DMF; iii, NaOH, MeOH; iv, (3), CH2CI2,1H 4etrazole; v, rn -CPBA; vi, H2, P&C, MeOH

Scheme 4

(44) (45) (46) (47)

R=H R = (O)P(NHPh)2 R = (0)P(OBn)2 R = (O)P(OCH2)2CGH4-1,2

OH (48)

112

0rganophosp horus Chemistry

The important D-myo-inositol 1,4,5-tris(dihydrogen phosphate) has received its fair share of attention during the year. In another of many reported syntheses, the intermediate (23)served as the starting material, protection in the second step (Scheme 4) being afforded by the use of the pivaloyl group.32 Elsewhere, the same compound was synthesized from enantiomerically pure I -C)-(-)-menthoxycarb~nyl-rnyo-inositol~~ as well as through the use of the tr-(fen-butyldimethylsily1oxy)phenylacetylgroup36 for protection purposes. In a study by Japanese workers, myo-inositol was converted into

LA-1,2,4-tri-O-benzyl-myo-inositol (44) through seven steps, and an examination was then made of the ease of synthesis of the phosphorylated products (45)-(47)using. respectively, the phosphoryl chloride (PhNH)2P(0)Cl, tetrabenzyl pyrophosphate (TBPP),

or (3),standard procedures being used in the ultimate deprotection stages. In the deprotection of (45), sequential removal of the anilino and benzyl groups yielded only 17% of the target compound, and this was accompanied by a comparable amount o f the pyrophosphate (48). The slowness of the reaction involving the phosphorodiamidic chloride, taken in conjunction with the concomitant side reactions, forced the rejection o f this reagent for the phosphorylation step. 37 Syntheses

of

myo-inositol

1,4,5-tris(dihydrogen

phosphate)

and

1,3,4,5-tetrakis(dihydrogen phosphate), using phosphitylation methodology, have been 38 reviewed. The 1 -(dihydrogen phosphate) 4,5-cyclic pyrophosphate (48) also results from the N-bromosuccinimide oxidation of the 1-phosphate 4,5-bisthiophosphate (5 2 );synthesis of the latter compound was achieved according to the Scheme 5.39

Deoxy analogues of myo-inositol 1.4.5-tris(dihydrogen phosphate) have also captured some attention. The 2,3-O-cyclohexylidene derivative of the 6-deoxy analogue i.e. compound (5 6 ), was obtained through the intermediates (53)-(55)as outlined in Scheme

6.39 A

further

analogue

(59)

was

prepared

via

(58)

from

40 ( 1 RS,2RS,4RS)-cyclohexanetriol(57) (Scheme 7). of the penta-U-benzoyl-D-my-inosi to1 (60) yielded Hydrogenolysis 1.3,4-tri-O-benzoyI-L-myo-inositol (61 ), phosphorylation of which (Scheme 8 ) afforded

D-myo-inositol 2,4,5-tris(dihydrogen phosphate) (63)via its hexabenzyl ester (62). A similar sequence of reactions in the chiro-inositol series commenced with (64) and gave

(65)4' L-Quebrachitol (66)( = 25) may be converted into (67) which is then a source (Scheme 9) of L-chiro-inositol 2,3,5-tris(dihydrogen phosphate) (69), a potent inhibitor 42

of inositol I,4,5-triphosphate 5-phosphatase and 3-kinase enzymes. Syntheses of racemic, D-, and L-2-deoxy-2,2-difluoro-myo-inosi to1

5 : Quiri qu e valent Phosphorus A cids

" ' 0 ~ 2

I13

(49) R' = H, R2 = Bn, R i = CMe2 iic(50) R' = (0)P(OCH2CC13),, R2 = Bn, R3 = H (51) R' = (0)P(OCH2CC13)2,R2 = Bn, R3 = (S)P(OCH2CH2CN)2 i i i c (52) R' = PO3H2, R2 = H, R3 = P02SH2

Reagents: i, (C13CCH20)2P(0)CI,py., then Me2CO/MeOH/1M HCI; ii, (NCCH2CH20)2PNPr'2,1H -tetrazole, MeCN, then S/py.; iii, Na/NH3(1),then PSOH

Scheme 5

OR2

(54) R' = R2 = (BnO),P(S) iiiE(55) R' = R2 = P02SH2 iv (56) R', R' = (O)(HO)POP(O)(OH), R2 = PO3H2

E

R'O'

OR' Reagents: i, (Bn0)2PNPi2,1 H -tetrazole;ii, S/py.;iii, Na/NH3(1),then PiOH; iv, NBS, dioxan/H20, then HSCH2CH20H

Scheme 6

OR i, i

i (57) ~ R

=H ( O ) P ( O C H ~ ) ~ C-G 1 ,H2~ (59) R = PO3H2

i i i (58) ~ R=

OR Reagents: i, (3), 1H -tetraole, THF/CH2CI,; ii, m -CPBA, CH2C12;iii, H2, Pd/C, EtOH aq.

Scheme 7

114

Organophosphorus Chemistry (60) R1 = H, R2 = R3 I BZ "(61) R1 = R3 = H, R2 = Bz ii, iiiE(62) R1 = R3 = (0)P(OBn)2, R2 = Bz

"OR2

i v K ( 6 3 ) R' = R3 = P03H2, R2 = H

Reagents: i, H2, Pd/C, EtOH; ii, (BnO)*PNPi2, 1 H -tetrazole; iii, rn -CPBA; iv, NaOH aq.

Scheme 8

-..OR2

"'OR2

'*OR2

(64) R' = H, R2 = R3 = BZ (65) R' = R3 = P03H2,R2 = H

(66) R' = Me, R2 = R3 = H ic(67) R' = R3 = H, R2 = Bz ii, iii c(68) R' = R2 = (O)P(OEt)2, R2 = Bz ' ' K ( 6 9 ) R1 = R2 5 P03H2, R2 = H

Reagents: i, Several steps; ii, (Et0)2PCI, MeCN; iii, Bu'OOH; iv, Me3SiBr, CH,CI,; v, NaOH aq.

Scheme 9

OH BnOQ

H "OBn

HOQ

!R

H

H0'-

"OBn OH

HO'.'

"OH OH

5:

Quinquevalent Phosphorus Acids

11s

1,4.5-tris(dihydrogen phosphate) have been achieved starting from (70). resolved as its 0-camphanyl derivative, and with subsequent deprotection to (7 1 ). The 2-mono-fluoro compounds were similarly obtained.43,44

Myo-inositol phosphorothioates are readily accessible from appropriately protected precursors

following

( NCCH2CH20)2PNPr'2.

initial

phosphitylation,

(generally

with

or

(BnO)2PNPr'2

in the presence of tetrazole). and subsequent addition of

sulphur, either directly or by reaction with a disulphide such as (PhCH C0S)2. The methodology allows the preparation of mixed phosphate-thiophosphates. 3 9 2 5 Designed as substrates for the spectrophotometric assay of

phosphatidyl

inositol-specific phospholipax C. the racemic compounds ( 7 ~ and ) ~(73: ~ C 6H9

=

1 - p ~ r e n y l ) were ~ ~ synthesized from (74). Both syntheses (Scheme 10) involved

phosphitylation, and the final dealkylations, (76) to (72) and (78) to (73), were achieved using lithium bromide in acetone. Syntheses of nucleoside phosphorothioates and -dithioates have been reviewed.48 At a simpler level, descriptions have been of convenient syntheses of S-alkyl

phosphorodichloridothioates from sulphenyl chlorides and methyl phosphorodichloridite in liquid S02f9 of dialkyl S-phenyl phosphorothioates from trialkyl phosphites and phenylsulphenyl chloride5') of S -[2-(dialky1amino)ethyll dialkyl phosphorothioates by a similar procedure5

and of S-alkyl 0-aryl and U,U-diary1 phosphorothioates from 52 appropriate dialkyl 0-aryl or S-alkyl diary1 thiophosphates and POC13. Cyclic trithiopyrophosphates and related compounds (79; n and the benzo derivatives from (79; n

=

=

0 or 1. Y

=

0 or NH)

0, Y = 0 or NH) are readily available from the

interaction of metal or pyridinium salts of the corresponding hydrogen dithiophosphate and 2-bromo- 1 -methylpyridinium iodide.53 The 1,3,2dioxaphosph(III)olanes (80) are a convenient source (Scheme 1 1 ) of the thiophosphatidyl cholines (81), and it is worth noting, at this stage, that the compounds (8 1 ) readily undergo a thermally-catalysed transformation into the phosphonothioic i ~ o m e r . 5 The ~ quinone (82) readily converts hydrogen phosphorodithioates into

bis(dialkoxyphosphinothioy1) disulphides.55 Malathion, the well-known insecticide, and the much more toxic isomalathion, (83) have one and two chiral centres, respectively. Chiral forms of the former have been prepared

from

the

appropriate

diethyl

malate

trifluoromethanesulphonic anhydride and sodium

by

sequential

reaction

with

0,O-dimethyl phosphorodithioate:

thus, for example, (-)-malic acid yields (RC)-malathion (84). Monodemethylation of the malathion enantiomers with strychnine, and methylation (dimethyl sulphate) of the

I Ih

Organophosphorus C'hemistry

(74) R = H (76) R = (O)P(SC16H33)OMe (77) R = P(OMe)NPt', (78) R = (0)P(OMe)O(CH2)4C16H9

MeOCH20'*'

Reagents:i, (MeO),PCI, Et3N; ii, ~ N S C W ; iii, H (MeO)(Pr',N)PCI, ~ ~ Et3N; 0

iv, HO(CH2)&6H9, 1 H -tetrazole, Bd4N

+

lo3-

Scheme 10

RCH2S-F??]

i

0

-

RCH2J):

ii

0

-

!,o-

+

i?

COOEt

RCH2SP\ 0QNMe3

(80)

Reagents: i, N204;ii, Me3N

Scheme 11

0

Me0.l p*S*CH.COOEt I

MeS'

~

&H2COOEt

MeO-y-SI-(

oMe

'COOEt

5:

117

Quinquevalenr Phosphorus Acids

resolved strychnine salts affords the diastereoisomers of isomalathion56 ‘The fused thiadiazaphospholidines ( 8 5 ; X from

the

appropriate

amino(or

=

0 or S) are obtainable conventionally

mercapto)- 1 ,2,4-triazoIes7

Interaction

of

4-amino-2-hydroxybenzoicacid with (PhSPS )2 o r Lawesson’s reagent (L. R.) yields the compounds (86; R

=

PhS or 4-MeOC6H4)5’ The treatment of the quinonemethide (87)

with L. R. or 0 , O - tiimethyl dithiophosphoric acid yields the products ( 8 8 ; R

=

Me0 or

A general synthesis of Sr-(2-oxoalkyI) 0,O-dialkyl phosphoroselenoates (89)

involves the interaction of enol silyl ethers and the pseudo phosphonium salts derived from O,O,O-trialkyl phosphoroselenoates and sulphuryl chloride.6‘) When

cysteine

reacts

with

diisopropyl

hydrogen

phosphonate

and

1M

Et3N-MeOH-H20 in CCI4 at -5 to 00 , the amino acid is phosphoryiated only at nitrogen to give (90). In the presence of a larger amount (>3M) of triethylamine and at a slightly higher temperature, the corresponding disulphide results. There is no evidence for N to S migration analogous to that observed in the similar treatment of serine or 61 t h reon ine.

Two long papers have dealt with syntheses and biological activities of analogues of cyclophosphamide (CPA) and of aldophosphamide. Scheme I 2 indicates simple reactions which

have

been

carried

out

on

the

ether

(91);

the

products

were

1,32-oxazaphospholidines (92) o r perhydro- 1,3,2-oxazaphosphorines (93). depending on R (H o r Bn), with each type being obtained as a mixture of stereoisomers. For the compounds (93), stereochemical differences are thought to reside at the phosphorus atom. with the 5-hydroxy group being axially sited in all cases. Scheme 13 outlines a synthesis

of

the 4-hydroxy

and

4-hydroperoxy

derivatives

of

5-methoxyCPA;

cis-4-hydroxy-5-methoxyCPAequilibrates very slowly, and only to a small extent, with the corresponding ring opened aldophosphamide. 4-Hydroperoxy-6-substitutedCPA stereoisomers were prepared according to Scheme 14; they undergo deoxygenation at C(4) when acted upon by dimethylsulphide to give the corresponding 4-hydroxy compounds. Stereoisomers of 4-hydroxy-6-phenylCPA (94), when produced according to Scheme 15, are epimeric at C(4).6’ In the second paper, descriptions are given of the reactions summarized in Scheme 16.63 An extensive discussion is addressed to the question of stereochemistry in the compounds (95) and their mode of degradation and release of (96);in respect of the latter, the three routes (a), (b), and (c) in Scheme 17 are considered. Route (a) represents the direct attack by HO- on the iminium ion and results in the hydrolytic generation of an aldophosphamide and subsequent cyclization to a CPA

Organophosphorus Chemistry

118

Se R2L

R

3

II

(R'0)2POR'

I

SO2C12 - 78 "C

SH

8

(CICH2CH2)2NPC12

+

YR

H2NCH2CHCH20H

(92)

(93) Scheme 12

R', R2 = OBn, OH,or H

5: Quinquevulenr Phosphorus Acids OMe i ii

OMe

I

HO+oR ' :Z2 OH

MeO---

d

NR2

jl

iii

0

V

MeO---

R = CH2CH2CI Reagents: i, 03;ii, H202;iii, Os04, O: N : :

; iv, Me2S or (Et0)3P; v, Na104

Scheme 13

R' R2 = CH2CH2CI R' = Me, P i , PhCH2CH2, CGH~X(X = H, 4-Me, 4-F, 4-N02), 3- or 4-CSHdN

Reagents: i, 0,; ii, H202

Scheme 14

R = CH2CH2CI Reagent: i, Na104

Scheme 15

I20

Organophosphorus Chemistry

\ iv-vi

R’ = Et or CH2CH2CI; R2 = H, Et, or CH2CH2CI;R; = (CH2CH2)20;R3 = H or Ph Reagents: i, BuLi, THF; ii, R&P(O)CI2; iii, R:NH; iv, 03,CH2C12;v, Me2S; vi, 4-Me-4-H2N-2-pentano1,K2CO3; vii, R3CHO;viii, NaBH,, pH 6-8

Scheme 16

1

Scheme 17

5:

Quinquevalent Phosphorus Acids

121

derivative. or, as a minor process, @-elimination to (06); this route is not particularly significant, nor is route (b). The direct attack of HO- on the ,r-hydrogen (route (c)) results in the direct expulsion of (96). and from the kinetics, this is evidently the favoured route for the hydrolytic breakdown and the formation of (96). 1 -2. Reactions of derivatives of Phosphoric Acids.-The interaction of a Grignard

reagent, R 1 MgX, and an allylic compound, R 2CH=CHCH2L, where L is an appropriate leaving group e.g. halogen or phosphate diester anion, results in the displacement o f I, with substitution at either C( 1 )(@-substitution)o r C(3)(y-substitution, SN 1 ' replacement). A

comparative

has

study

2-methyl-2-butenylmagnesium

been chloride

made

of

the

reactions

(prenylmagnesium

between

chloride)(R1

=

Me2C=CHCH2) and a variety of allylic phosphate esters in the presence of CuCN.2LiCI

in 'I'HF. For the primary allylic compounds (97: L =

=

(RO),P(O)O, R

Ac), displacements at -78O afforded 82-95% of mixtures of

y

=

Et, Pri, or Ph; R2

and

(1

substitution

products, (98) and (99) in the ratios 87-88: 13- 12. With ten-butylmagnesium chloride (97; R = Ph, R2 = SiMe2But), the ratio was 96:4. For the secondary compounds (100;

R2 = SiMe2But) with L = ( R 0 ) 2 P ( 0 ) 0 (R (Me2N) P(0)O. the with R3

=

Y:~Y

=

Et, Pri, cyclohexyl. or Ph) or

ratios were >99:1, in favour of ( 1 0 1 ) , as they were for L

=

CI

Ac. Other esters such as the mesylate did not furnish such high

stereoselectivities. For L

=

CI, the ( E ) l ( Z )ratio in ( 1 0 1 ) could be as low as 1 : I but

might reach 85:15, and was improved (to 96:4) when L = ( R 0 ) 2 P ( 0 ) 0 ( R

=

Et, Pr', or

cyclohexyl); for L = (Me2N)2P(0)0. the ratio was 59:4 1. Several examples were given of the essentially complete (>95:5) transfer of chirality, e.g. when using (102) with either of the above mentioned Grignard reagents. In reactions with prenylmagnesium chloride, stereoselectivity was slightly greater for ( 104) than for ( 103), with increased

y:(r

yield.

With methylmagnesium iodide, ( 105) gave < 1% reaction product, whereas ( 104) reacted readily to give an 85% yield of a product containing Y and n isomers in the ratio >99:1. Thus, in general, excellent coupling with high regio-, ( E ) - and enantio-selectivity has been observed. The methodology h a . been applied to the synthesis of coenzyme Q using the ester ( 106).64*65 In a development, Fe(acac)3 was used as a catalyst, when the reactions between Grignard reagents and allylic phosphates were highly SN2 selective. Using diphenyl esters, the SN2:SN2' ratios were 90:lO - 99:1, although with the corresponding diethyl

or diisopropyl esters, the ratio generally approximated to 3: 1 6 6 Reactions between Me3SiM

(M

=

Li or Cu) and 3-phosphoryloxyalkenes (1-substituted ally1 dialkyl

122

Organophosphorus C'hemistry

(97)

(102)

(103) L = CI (104) L = 0P(o)(OP~)2 (105) L = OAC

I

+ NMe3

(109) R = CI (110) R = OH (1 11) R = OPr, OPh, or NEt2

(108)

OH

(1 12) R = OH (1 13) R = OPr, OPh, or NEt2

R

(1 14)

5:

Quinquevalent Phosphorus Acids

phosphates) were also stereoselective. For M

123 =

Cu. the main, or even exclusive. product

was the allylsilane, obtained through the sN2' reaction. whereas the use of the lithiated silanes afforded the more highly substituted alkene.b7 Hydrolysis of the esters (107) and (108) involves concomitant cleavage of both C-0 and P - 0 bonds, the relative contributions of such fragmentations depending on experimental conditions. The reaction at carbon is favoured by an increase in temperature and is accelerated (60 times) by thiosulphate. Reaction at the P-O bond is favoured relative to that at the C-O bond by the addition of an organic solvent (acetone) to

the aqueous medium. Only P-0 cleavage occurs in THF, in which the process is

accelerated by fluoride anion ( 1 0 0 times).68 Divalent metal cations accelerate the hydrolysis of bis(6-hydroxyquinolinyl) and bis(8-hydroxyquinolinyl) phosphates. 69 Secondary 180and IsN isotope effects have been studied for the hydrolysis of 3.3-ditnethylhutyl 4-nitrophenyl phosphate under alkaline or acid conditions, under both of which the SN2(P) mechanism appears to operate. The secondary "0 effect is a measure of changes in bonding of the non-bridging (i.e. P=O) oxygen in the reaction transition state: that of "N

is a measure of the cleavage of bonding to the departing

4-nitrophenoxy group in the transition state. It appeared evident that the extent of weakening in the bonding to the departing group is little affected during the course of association with a weak nucleophile but that, during the process, bonding to the non-bridging phosphoryl oxygen weakens7"

Concurrent cleavage of P - 0 and C - 0

bonds by water occurs during the hydrolysis of 1 -phenylethenyl dihydrogen phosphate. At pH 1 - 8.3 and at room temperature, the hydrolysis is extremely rapid. Various

possible mechanisms for the process have been discussed.

71

The reaction between the cyclic phosphorochloridate ( 109) and a strictly equimolar amount of water yields o-phenylene hydrogen phosphate ( 1 10); in the presence of excess water. both ( 109) and ( 1 1 0 ) afford the acyclic phosphate ( 1 12). On the other hand, the cyclic esters and amide ( 1 1 1 ) with one mole of water each yield the corresponding ( 1 13) which. in turn, are then rapidly hydrolysed to ( 1 12). Alcoholysis of the esters ( 1 1 1 ) yields diesters of the acid ( 1 12).72 In spite of its high reactivity, with or without ring opening, the cyclic diester ( 1 1 0 ) nevertheless reacts very slowly with 2-phenylethanol in the presence of ethyldiisopropylamine, suffering ring opening to give ( 1 14; H

=

H).

However, association of the acid ( 1 1 0 ) with an amidine grouping in close proximity to a 2-phenylethanol moiety, as in ( 1 15), results in a rapid ring opening phosphorylation to give ( 1 16), characterized by X-ray analysis. The effect of the amidinium cation is thus

I24

Organophosphorus Chemistry

OH HO

0

I1 @ = (EtOj2P

(122) x = o (124) X = O (123) X = OCH2CH20 (1 25) X = OCH2CH,O

Quinquevalent Phosphorus Acids

-5:

12s

comparable to that produced by a coordinated metal ion.73 A calorimetric study of the hydrolysis of the esters ( I 17; R

=

Me or Et) and of

dimethyl 2-hydroxyethyl phosphate (and also of the phostonic esters ( 1 18; R Et)

and

comparison

of

their

hydrolytic

behaviour

with

that

Me o r

=

of

dialkyl

(2-hydroxyethy1)phosphonates) has been carried out so allowing a full analysis of thermodynamic aspects of the hydrolysis p r o c e s s e ~ 7 ~ The thermally initiated rearrangement of the esters ( 1 10; R

=

(a) CF3CH20, (b)

PhO, ( c ) Me3CCH20 ) and of the phosphinate ester ( 1 19; R = Bu), results in the formation of the esters (120). During 5 h at 200" , the four compounds rearrange to the extents of 36, 5 8 . 59. and 46% respectively. The esters (121: R

=

(a) Me3SiCH2, (b) Ph,

(c) Me3CCH2) similarly rearrange with isomer yields of 54, 59, and 59%respectively7' The

regiochemistry

(2-oxoalky1)phosphonate

of

the

rearrangement

of

an

enol

phosphate

to

a

has been examined for a series of monocyclic and bicyclic

substrates. Surprisingly. (122; R

=

H) failed to rearrange to (124: R

=

H) when treated

with lithium diisopropylamide (LDA). However, protection of the carbonyl group by ketal formation allowed the rearrangement of ( 1 23; R

=

H) to ( 1 25; R

=

H)

to

proceed

with 67% yield. An unsatisfactory mixture of products was obtained when ( 123;

R

=

OMe) was similarly treated with LDA. The dienol (126: X

( 1 27; X

=

OCH2CH20) afforded

OCH2CH20). Other substrates based on the decalin system, ( 128) - ( 130), also proved susceptible to rearrangement. 76 =

Further examples have been cited of the LDA-initiated rearrangement of aryl phosphates ( 1 3 I : R I , R2

=

Me or MeO) to arylphosphonic diesters ( 132) at -78" .

Acidolysis of the di-fen-butyl esters yields the free phosphonic acids7' Surprisingly, the di-rut-butyl ester ( 1 33; R = But, R 1 = COOBu', R 2 = R 3 = H) failed to rearrange whereas the corresponding diethyl ester rearranged satisfactorily7' No incorporation of deuterium took place when the initial treatment of the phosphate ( 1 33) with LDA was followed by addition of D 2 0 and it was therefore felt that a carbanionic charge was not produced onhu to the phosphate group. No rearrangement occurred when R R2

=

R3

=

Br, but rearrangement took place readily when R2

=

H and R3

=

Et and

=

Br. In

summary, the rearrangement appeared to be suppressed with increased steric hindrance and electron withdrawal. Yet another rearrangement involving phosphate esters is that of oxiranyl phosphates following their formation by oxidation of enol phosphates ( 1 34) by peroxy acids or dimethyldioxiran; the products are (2-oxoalky1)phosphonic diesters ( 1 35). A preliminary communication concerning the reaction sequence was included in last year's

126

Organophosphorus Chemistry

H

0

II

OP(Bu')p P(OBU')~ -78

R2

R'

"C R2

R'

5:

Quinquevalent Phosphorus Acids

127

X

II

(R’0)ZP-SY

+

-

x=s

H2C=CHOR2

Y = Br

S

II

(R’0)2PSCH2CHBr(OR2)

(136)

(1 37)

S

II

L +SP 2 ) o ’ R (

H

(1 37)

(138)

y

s

S

II

(140)

(139)

x x

0

X

II

(R’0)2PSCYR2R3

X

II

(R’ O)2PSCHY(COR2) (142)

(141 )

X

II

II

(RO),PSCHPhSP(OR)2 (144)

l2

or

(R’0)2PSCH2CH0

(145)

II II

(R’ 0)2PSSP(OR1)2

(143)

Organophosphorus ( 'hernistrl.1

128

Heport, and a full paper has now appeared.70 0,O- Dialkyl thioxophosphoranesulphenyl bromides (136; X = S, Y = Br) add to

vinyl ethers to give the dithiophosphate esters ( 1 37); when heated in a dry atmosphere,

the latter esters undergo dehydrobromination to give a mixture of cis and rruns-( 138). Traces of 2M HCI convert ( 1 37) into the thic)phosphorylated acetaldehydes ( 139) or the dimer ethers ( 140); acidolysis of the latter ethers affording the aldehydes ( 1 39).'() The (di)thiophosphate esters (141; X

=

0 o r S) and (142) are the products of the

reactions between. respectively. the diazoalkanes R 2 R 3CN2 and the sulphenyl halides (136; X

=

0 or S. Y

=

C1 or Br). and between the latter (136; X

ciiazoketones R2COCHN2." 32 The reaction between ( 1 36; X

=

=

0,Y

0, Y

=

=

CI) and the

Br) and ethyl

diazoacetate is somewhat unusual since the formation of the expected (142; Y

R2

=

=

Br,

EtO) is accompanied by P ( 0 ) S to P(S)O rearrangement as well as by production of

ethyl dibromoacetate and ( 143; X X

=

=

O).'

The disulphides and tetrasulphides ( 143;

0 or S ) react with phenyldiazomethane to give exclusively (144; X

=

0 or S).83

The products from the first two stages in the peroxy acid oxidation of the 2 = 1 -piperidino) have been = 1 -pyrrolidino, R

phosphorodiamidothioate ( 145: R

tentatively identified by spectroscopic means as the S -monoxide and the S , S -dioxide hut the ultimate reaction product is the anhydride ( 1 46).84

When [

a

concentrated

solution

of

(Rp)-(2-hydroxymethyI-4-nitrophenyl)

16 18 0 , Olthiophosphate (147) of at least 95% e.e. was rapidly diluted with rerr-butyl

alcohol, there resulted a mixture of comparable amounts of ( 1 48) and ( 14Y)/( 1 SO). The rcrr- butyl ester (148) was present in racemic form thus confirming a contribution from

the full dissociation of ( I 47) into a free monomeric thiometaphosphate intermediate. The composition of the ( 149)/(150) mixture, indicating roughly 60% racemization with 40% retention, is the first demonstration of a dissociative phosphoryl transfer process occurring with retention of configuration at phosphorus. 85 In a 2:l mixture of 2,2,2-trifluoroethanol (TFE) and water at 20" containing lutidine, 0-geranyl 0.0-dimethyl phosphorothioate ( IS I ) undergoes rearrangement mainly to the S-geranyl ester ( 152), but also, to some extent, to the S-linalyl ester ( 1S3), whilst at the same time undergoing solvolysis to smaller amounts of free alcohols and their TFE ethers. At a slightly higher temperature (40-65" ), ( 153) affords ( 152) together with the S-neryl ester (154). At a still higher temperature (>90" ) demethylation of the S-geranyl ester ( 152) is observed. The relative reactivities of ( 151), ( 152). and ( 153) are I : I x lo-':

6x

The formation of ( 153) shows that the allylic 1

+

3 rearrangement

accompanies thione-thiol rearrangement to ( 152),and it would thus appear probable that

5:

129

Qiiiriquevalent Phosphorus Acids

-s,

.*,,

-

PH S=P

NO2

'..,O-

I

(149)

I

t

s-

v ' % O -

D

(Me0)2P-S

:d

( Me0)2P-S

(153)

I

Organophosphorus Chemistry

130

isomerization occurs in both anions and cations in the ion pairs. A similar situation ( 152)

would also appear to hold for the formation of respect,

it

is

interesting

that

geranyl

tosylate

and ( 154) from (15 I ) . and

I n this

lutidinium O,O-dimethyl

phosphorothioate in a similar medium at room temperature yield ( 151 ) and. mainly, ( 152): ( 154) is not formed. I t would seem that different product ratios reflect different

structures within the intermediate ion Salts of mono- and dithiophosphoric

acid 0,O-dialkyl

esters react with

N -benzylidene-2,2,2-trifluoro-1 -chloroethylamine at the sp3 carbon to give compounds (155:a-c): when X

=

S. these can isomerize to (156; a,b) in the presence of triethylamine

and are then rapidly transformed into (157; a,b). When R

=

EtO. an equilibration occurs

between ( 157; a) and ( 158: a)?7 The reactions indicated briefly in Scheme 18 are well established in principle, and indeed

possess

synthetic

utility.

However,

the

isolation

of

the

intermediate

p-mercaptoalkyl phosphorothioates derivable from ( 1 59) has generally not been achieved. Using sugar @-hydroxyalkylphosphorodithioates, conditions have now been found under which the intermediate p-mercapto phosphorothiolates are isolable in high yields. A series of monocyclic or bicyclic 8-hydroxy dithiophosphorylated carbohydrates having diequatorial, axial-equatorial, or diaxial conformations. was treated with pyridine at room temperature, and the migration of the phosphorus centre followed using 3 1 P n.m.r spectroscopy;

for

convenience.

the

phosphorus

atom

wac

part

of

a

1,3,2-dioxaphosphorinanering. Typical of the reactions studied were those involving compounds ( 160) in which the thiophosphorylthio group h a s adjacent equatorial and axial hydroxy groups; migration occurred to the equatorial hydroxy group to give ( 16 1 ) rather than to the axial hydroxy, when (162) would have been the product. Such axial to equatorial migrations were observed to occur rapidly and were complete within ca. 1 h. The

mechanism

proposed

involved intermediate

P(V) species

possessing

the

1,3,2-oxathiaphospholanering. Those migrations from equatorial to equatorial positions were accomplished within 5 minutes. Axial to axial migrations failed to occur within one month. An unusual reaction pathway was observed for compound (163); here, after 48 h

in pyridine at room temperature, the products were the sugar phosphate ( 164) together with

(165) and

phosphorothioate.

the

pyridinium

salt

of

the

cyclic

neopentyl

hydrogen

8X,89

The mode of interaction of benzonitrile with a dithiophosphorus acid (166) is also well established; the reaction leads, via the initial adduct (167) to the amide (pathway a),

o r by further reaction with (166) to the anhydrosulphide (169) and thiobenzamide

5:

Quinquevalent Phosphorus Acids CI

131

SP0()R2

I

RzP(X)SM

CF3CHN=CHPh

I

EtBN

CF3CHNZCHPh

C6H6

-

SP(S)R2

I

CF3CHZNCHPh

(155) (a) X = S , R = EtO (b) X = S, R = Ph

(156) a,b

(c) X = 0, R = EtO

J SP(SF2

E

I

CFBCH*N=C Ph (157) a,b

CF3CHZN-CPh

I

S=P(OEt),

(158a)

S

II

\

/s

(R0)2P<.0

(R0)zP- SH

/

S II

Y-K

S-P(OR)*

-H+

*

It

S

i,

+

s(159)

ii, Scheme 18

-

Organophosphoriis C'hemisrrv

132

Scheme 19

HO

' Me

HO

5 : Qic in y ue valent Ph osp horu.y A cids

PhCN

+

133

R2P(S)SH

PhF=NH

*

I

S-PR2

II

S

PhCNHPR2

IIs sII

+

R2P-S-PR2 II

;

0

II

(RO), PSeR’

R2lqX S

+

(R0)2P-O-P(OR)2 I

8

SeR’

-X

(171)

PhCSNH2

s

(172) (a) X- = S02CI-

(b) X- = Br- (813133 (c) x- = I- (Is-)

0

II

0

II

(RO)~P-O-P(OR)Z

0

0

Se

II (R0)pPX

II

ROPX;!

OR

I

II

0

II

0

II

(R0)2P-O-P(OR) I

(1 79)

Scheme 20

!

(Me2N),P-7=Cr

OH

JJ

Ar

II

(RO)~P-O-P-O-P(OR)~ II

(RO)3P=0

0

134

Organophosphorus Chemistry

(pathway b). The effects of the addition of a third component to the system containing ( 166: R =

Pr '0) have now been examined (pathway c). The presence of phenol leads to

the formation of (169) and (170; X

=

PhO). With acetic acid, the three routes are

involved to the relative extents of 1 : I :8, but more complex reactions are involved in the presence of halogenated acetic acids. When aniline is added to the initial reaction mixture at ambient temperature, only the anilinium salt of (166; R = Pr'O) separates out and this undergoes no reaction with the benzonitrile: reaction does occur, however, at higher temperatures with the formation of the benzamidinium salt of the same acidPo In reactions between (166: R

=

alkoxy) and isothiocyanates, the initial step again occurs at

the CN group9' Studies of the halogenation of higher chalcogen-containing phosphorus acid esters have been extended to include a detailed examination of the selenium-containing esters ( I 7 1: R I = (i) Me, or (ii) Ph: Scheme 20, R

=

Me3CCH2 ). Reactions are fa5ter than

those already recorded for the analogous thio esters, and reactions of the phenyl esters are slower than those of the methyl esters. The relative reactivities of the halogens are, as might be expected, chlorine > bromine > iodine, and the common intermediates in all reactions appear

to

be the phosphonium salts (172). which are then the sources,

depending on the particular reaction conditions and halogen, of the final products ( 173) ( 1 80). The main products from the reactions of ( 1 7 1 i) involving SO2CI2 or CI2 (fast

even at -80" ) are ( 173) and ( 174); with bromine. ( 1 78) is also an important product. The nature of the products from (17 1 i ) and iodine are markedly dependent on reactant ratio, solvent, time, and temperature. With ( 17 I ii) and sulphuryl chloride, chlorine, or hromine. the main products are again ( 1 73) and ( 174), although ( 177) - ( 1 80) are also to be found. Reaction with iodine is slow, leaving much unreacted starting material, but furnishing ( 173) and ( 174) together with traces of ( 1 78)92 Lithiation of hexamethylphosphoric triamide with MeLi in ether followed by addition of dimesityl- or mesitylphenylketene yields the stable enols (181; Ar mesityl) together with the amides MesCHArCONMeR (R

=

=

Ph or

Me or Et). The structures of

both products ( I8 1 ) were confirmed by X-ray a n a l y ~ i s 9 ~ In pyridine containing H2I8O, the phosphoramide (182) is gradually converted into the free cyclic acid (183) from which I8O is absent. A general scheme for the reactions of ( 1 82) with the nucleophiles YH ( Y

=

HO, RO, or PhNH) is summarized in

Scheme 21. Aniline yields the anilinium salt of (183) but no phosphoramidate (RO)*P(O)NHPh. It thus appears that the compound ( 1 82) possesses no phosphorylating properties, as has been suggested by earlier workers who favoured attack at the carbonyl

5:

I35

Quinquevalent f’hosphorus Acids

-

?H (R0)2?-NPh

L

-O+Y Ph

f (R0)2P,

YHPh ,C-Ph 0 1 Y

f

(R0)2P-OH

OR I ,,OR 0-P I ’OH Ph,+ NPh

*

’?

RO-P;

-

lPh

(RO), = OCH2CMe2CH20

Scheme 21

CICH&H2NHP(O)X2 (184) X = CI (185) X = NHR

5

MeOH, BF,

z

r.t.

*

fi

MeO-7-Z

MeS-P-N.

COOEt O2N

NPh

i.

(1 83)

R’ R~N-T-

I

L

Y

+ PhCY

,OH

Me (191)

I36

Organophosphorus Chemistry

centre as the preferred mode of reaction by n u c l e o p h i t e ~ 9 ~ When treated with four molar equivalents of a primary amine RNH2, the phosphoramidic dichloride ( 184) yields the triamicte ( 185). When these (R

=

Me or Bn)

are further treated with NaH, the sole products are the N-phosphorylated aziridines ( 186). but for ( 185; R = aryl), a mixture of ( 186) and the cyclic triamide ( 187) results.

More of the same base converts (187) into (186) by deprotonation and internal nucleophilic attacksg5

In general, methanolysis of the amides (188; Z Y = MeS, Ph, or Me N; X 2

=

S. Y

=

MeO, EtO, or PhO; X

=

=

0,

M e 0 or EtO) in the presence of BF3 yields the

corresponding methoxy compounds ( 189). Loss of the L-pyrrolidino group from diastereoisomers of ( 190) under mild conditions occurs with retention of configuration at phosphorus. Interestingly, MeOH/BF3 fully degrades the cyclic ester/amides ( 19 1 ; from (+)-ephedrine)back to ephedrine?6

2. Phosphonic and Phosphinic Acids and their Derivatives 2.1 .Synthesis of Phosphonic and Phosphinic Acids and their Derivatives-The

synthesis of allylic phosphonic acids and their derivatives by the photoisomerization of ally1 phosphites has been r e ~ i e w e d 9and ~ aspects of the chemistry of oxaphosphetanes. thiaphosphetanes, azaphosphetidines, and diphosphetanes, have been reviewed98 The macrocyclic compound (192; X

=

0. R

=

H) has been prepared by conventional means

from the diphenol; it is also said to be obtainable by acidolysis of its cyclic dimer99*100 The

hydrogen

phosphonate

(193;

R

1,2-bis(2-hydroxyethoxy)benzene through

its

=

H)

reaction

is

obtainable

with

from

PC13/tc~-BuOH,101

although the initial reaction yields a mixture of this and the monomer (16; X

=

0. R

=

fI), only the dimer is isolated here. 2. I . 1 . Alkylphosphonic Kids-The monomeric cornpounds ( 194: X

prepared conventionally. I

New syntheses of

=

0 or S ) have been

1 -adamantylphosphonic dichlorides

through the replacement of other functional groups e.g. O N 0 2 and halogens using sulphuric acid followed by PCIs. have been reported. 103'104 The reactions between

I ,3-didehydroadamantane and dialkyl 1 -adam ant y lphosp honic acid. OS

hydrogen

phosphonates

yield

esters

of

Dialkyl hydrogen phosphonates have been added to cyclopentene and its alkyl-substituted derivatives under homolytic conditions in regiospecific. and to some

5:

137

Quinquevalent Phosphorus Acids

(197) R’ = EtO, R2 = R3 = Ph (198) R’ = R2 = Ph, R3 = EtO

(195)

(199) R = H (200) R = OAC

(201) X = NO2 (202) X = NH2 (203) X = OH (204) X = CI (205) X = OAC

I38

Organophosphorus c'h em istrv

extent stereospecific, reactions. The

addition

of

diethyl

hydrogen

bisphosphonic acid esters (195; R 1

=

trisphosphonic acid derivatives (196; R 1 ester nor ( 195; R

=

R2

=

=

phosphonate

R2

=

R2

=

to

the

quinonemethide

OEt) occurs readily to give the R3

=

OEt);lo7 although neither this

EtO) can be dealkylated to the corresponding free acid by the

use of Me3SiBr/H 0. dealkylation can be achieved using Me3SiBr/Na2C03.108 The compound (195; R2l = Ph, R 2 = EtO) is unusual from the point of view of its reactivity

in addition reactions; this compound does not add Ph2P(0)- to give (196; R 1 = R2 R3

=

=

Ph.

EtO), but instead affords (197). Analogous compounds are produced when diethyl

hydrogen phosphonate adds to ( 195; R 1 = R2

=

Ph) to give ( 1 98).'(I7

The addition of dimethyl hydrogen phosphonate to ( 199) yields (20 1 ), convertible. by conventional means, into (202); deamination of the latter, using NaN02/HOAc yields 6 1 % of a 2: 1 mixture of the 3,5-dideoxy-D-ribo- and L-lyxohexofuranoside derivatives (203), together with 12% (206), 8% (204), and 7% (205). The interaction of (204) with DBU yields (206); that of (205) and NaOMe yields (203). Other transformations (Scheme 22) allowed the conversion of (203) into the diastereoisomeric pentapyranosides (207, 208; R

=

H). Further reactions yielded the phospholanic acids (209) and (210),

characterized as their U,U,U-triacetyl methyl ester derivatives. O9 Other transformations have been based on the compounds (21 1)-(2 14) obtained through the initial addition of In principle the addition of a hydrogen

methyl phenylphosphinate to (200).l

phosphonate to a 1 -nitroalkene gives mixtures of stereoisomeric products derived regioselectively. The stereochemistry of the addition reaction can be altered by modifications

to

the

experimental

conditions.

5,6-dideoxy-6-nitro-D-hex-5-enofuranoses,the

use

Using

of

p.m.r

a

range

of

spectroscopy

has

demonstrated that, at room temperature and in the presence of triethylamine, reactions yield mixtures in favour (66-89:34-1 1 ) of the (5R) compound, whilst at 100" and in the absence of a base, the product ratios are 22-48:78-52. in favour of the (5s) compound. 1 1 1 The alternative approach. namely the addition of an appropriate compound to an unsaturated phosphonic derivative, has been exemplified by the additions of active methylene compounds, XCH2Y, ( X

Y

=

=

Y

=

COOEt; X

=

H, Y

=

NO2; X

=

COOEt,

N=CHPh) to 1 , l -bis(diethoxyphosphinyl)ethene.Such additions afford compounds of 112

the type (215) having the potential for modifications in functionality at CHXY.

Recent examples of the use of the Arbuzov reaction in the synthesis of phosphonic and phosphinic esters include the reaction of (216) with ethyl diphenyl phosphite to give

5:

Quinquevalent Phosphorus Acids

(203)

139

OH 0

J

HovoH Scheme 22

[( Et0) 2P(0)]2CH*CHXY

(215)

(211) X = NO2 (212) X = NH2 (213) X = OH (214) X = OTHP

OAc (216) R = I (217) R = (O)P(OPh)2

OMe (218) R = I (219) R = (O)P(OEt)Ph

140

Organophosphorus c'h emistry

(217).' l 3 and of diethyl phenylphosphonite with (218) to give (2 lo).' l 4

The new

hexakis[(diethoxyphosphinyl)methyl]calix[6]arene (22 1 ) was similarly obtained from the chloride (220), and converted into the free acid (222), a powerful uranophile.' l 5 I t is possible to carry out successive Arbuzov reactions on the dibromides (223; X Ph) when the products (224; R1

=

alkyl; R2

=

=

Me or

alkoxy or Ph) may be obtained.' l 6

Anomalous Arbuzov reactions have been reported to occur between triethyl phosphite and unsaturated N-substituted derivatives of adenine and cytosine (225-23 1 : B = adenin-N9-yl or cytosin-NI-yl).' l 7 Thus, both (E) and (Z) forms of (225) yield the corresponding (226). However, (227) yields the N-ethyl derivatives of the heterocycles, although in the presence of iodide anion the phosphonates (228) can be obtained. The chloroallene (229) yields (230); in the presence of iodide anion an additional product was (E,E)-(231 ). In Michaelis-Becker reactions, (229) affords (23 1 ) with or without (230), depending on solvent, and (227) in DMF affords (23 1). The Michaelis-Becker reaction has also been applied in the synthesis of 2-propynylphosphonic acid diesters;' 2-propynyl esters of conditions.'

phosphinic acids have been

made under phase-transfer

Further applications of the Arbuzov and Michaelis-Becker reactions are

indicated later in this Report. The

cathodic electrolysis of

mixtures

(or pheny1)phosphonates in the presence of

of

alcohols and

dialkyl

methyl

tetraethylammonium perchlorate in

acetonitrile yields mixed esters of the corresponding phosphonic acids. The yields and product ratios of mono- and di-exchange esters are functions of the starting materials and current. 2o Bis(2,2.2-trifluoroethyl)esters of phosphonoacetic acids have been prepared by the acylation of anions derived from the bis(trifluoroethy1) esters of methyl- and ethylphosphonic acids. I The anion from diethyl (cyanomethy1)phosphonate was employed in the synthesis of stereoisomeric cyclopropane-fused deoxypyranosides (Scheme 23).122 Syntheses of pyrophosphonate analogues of farnesyl pyrophosphate were achieved starting from methyl methylphosphonomorpholidate (232) and through the intermediate (235)(Scheme 24),123 When compound (37) was made to react with (238) followed by treatment with BnOH in the presence of I-methylimidazole, (236; X could be hydrogenolysed to (237; X

=

=

H) resulted, and this in turn

H). The analogous reaction between (37) and

(239) did not take place, but the use of (240) allowed syntheses of (236; X (237; X

=

F) to be achieved.33

=

F) and

5:

Quinquevalent Phosphorus Acids t-

141

1

Ph

X

OMe

(223)R = Br (224)R = (0)P(OR')R2

(220)R = CI (221)R = PO3Et (222)R = PO3H2

CICH2CH=C H CH@

CICH2CECCH@

(225)R = CI (226)R = P03Et2

(227)

8

(Et0)2PCH=CHCH=CH@

CICH2CH=C =CH@

(2311

(229)

Q."

TfO

0

+

II

-

(EtO)*PCHCN Li

t

+

0

OH Scheme 23

142

Organophosphorus Chemistry

?

Me-Y-OMe

iiic (233) R = Me

- (234) R = SiMe3 ivL (235) R = H

?::

FarCH2~-O-~-OH OH

4

vi

”

(235)

-

? I :

FarCH2P-0-P-Me I

OH

OH

OH

Reagents:i, BuLi, THF; ii, Farnesyl chloride (FarCI); iii, Me3SiBr; iv, Bu,N’F; vi, MeP03H2

v, H3P04;

Scheme 24

“r=r R’O”‘

“OR2 R’

OR^

(37) R’ = P03Bnn,R2 = Bn, R3 = H (238) R’ = PO3Bn2, R2 = Bn, R3 = BnOP(0)CHX2 (237) R’ = PO3H2, R2 = H, R3 = HOP(O)CHX2

(238) R’ = CF3, R2 = Me (239) R’ = H, R2 = CHF2

i.ii

ROH

-

8

iii

RO-?-Me H

Reagents: i , Me,CCOCI; ii, MeP(O)H(OH),EtSN; iii, 12, py., H20

Scheme 25

t

* RO-7-Me

OH

5: Quinquevalent Phosphorus Acids

143

Conventional intermediates based on my)-inositol have been adapted for the synthesis of

methylphosphnnate

analogues of

inositol phosphoric acids. Thus,

I .2.3,4,6-pentabenzoyI-myo-inositol was the source (using reactions indicated in Scheme 25) of

the 5-methylphosphonate

(24 1 ): 3,6-di-O-benzyl- 1,2-O-isopropylidene-myo-

inositol furnished the 4,5-bis(methylphosphonate)(242), and compound (44) yielded the

1,4,5-tris(methylphosphonate) (243).' 24 Several steps are required to convert D-mannose (244) into compound (245) from which. by phosphorylation

with diphenyl phosphorochloridate

and triethylamine,

followed by hydrogenolysis. (246) may be obtained. Attempts to modify this latter substance at C( 1 ) so as to introduce a further phosphoruscontaining function have not been successful. The bis(isopropylidene) derivative (247) reacted with tetraethyl methylenebisphosphonate to give (248), together with its C( 1 ) epimer and (249). Treatment of the anomers of (248) with p-toluenesulphonic acid in acetone so as to remove the 4,6-isopropylidene group, and further phosphorylation (same reagents), deprotection, and de-esterification (Me3SiBr followed by hydrogenolysis) gave individual anomers of the diphosphate phosphonate (250). I25

2.1.2.Alkene-,alkyne-,aryl-phosphonicand phosphinic acids.-(a-Stannylalky1)phosphonic acid diesters have been employed to prepare alkenylphosphonic diesters. Treatment of the tin compounds (251) (generated in situ) with an aldehyde R 3CHO at -70" yielded a mixture of (E) and (2) isomers of (252). the proportions being controlled essentially by R2 126 Reactions between triethyl phosphonoacetate and the nitriles RCN (R

=

CN or

C13C) are catalysed more effectively by M n ( a ~ a cor ) ~MnAc;! than by NiAc2 or ZnAc2. Using Mn(acac)2 in toluene at room temperature (R (R

=

=

CN) or in hot chloroform

CI3C) the products are (253) as (E)l (2) mixtures.127 Benzylic phosphonic diesters of the type (254; X

function) are oxidized to (255) by Pb02

=

H or another phosphoryl

or potassium ferrocyanide.

I28

Scheme 26 outlines a synthesis of shikimic acid (257) starting from the D-lyxose-5-aldehyde derivative (256) involving an initial Knoevenagel condensation of 129 the aldehyde with tetraethyl methylenebisphosphonate. Vinylidenebisphosphonic acid derivatives and homologues have been prepared from methylenebisphosphonic acid tetraalkyl esters by the routes A,' 30 B,l

and C 32

exemplified in Scheme 27. The [2,2-bis(alkylthio)ethenyl]bisphosphonic tetraethyl esters provided a source of novel (en4iamine)bisphosphonic esters. The novel compound (260)

144

Organophosphorus C’hemisrry

“‘OH

OR’

OH

(241) R’ = OP(O)(OH)Me,R2 = R3 = H (242) R’ = R2 = OP(O)(OH)Me,R3 = H (243) R’ = R2 = R3 = OP(O)(OH)Me

(244)

BnoHO..

”‘OH

8

(E~O),PCHR’(S~IR~~)

E

(Et0)2PCR’=CHR2

8

( Eto) pPC(COOEt ) =C( NH2)R

(253)

OH

(254)

(255)

5:

Qirinquevalent Phosphorus Acids

145

i

-x/

OBn

II

/

\

13571 1--. I

Reagents: i, [(Et02P(0)]2CH?,M ~ N ( C H Z C H ~ )TiCI4, ~ O , CCI4/THF; ii, Ho, Pd/C, EtOH; iii, NaOEt, EtOH; IV, Me3SiBr, CHCI3, H 2 0 Scheme 26

#.

C (Et0)2P(0)CH2CH=CH2

__.------ --..

[(EtO),P(0)]2CH-CH-CH2

Li'

[( Et0)2P(0)12 C =CHCH Reagents:i, (Et2N)2CH2;ii, heat; iii, PhNCO; iv, Ph3PBr2,Et3N;v, CS2; vi, R'X; vii, H2N(CH2),NH2; viii, PhCHBrCHBrPh; ix, LiN(SiMe3)2;x, (Et0)2P(O)CI; xi, H30+ Scheme 27

Organophosphorus Chemistry

146

exemplifies a group of related compounds.'

j3

A useful review describes the synthesis and utility in synthetic organic chemistry of

vinylphosphonic acids and their derivatives. 134 Two papers describe cycloaddition reactions leading to P-C(sp2 ) systems. Pudovik et d. have continued their work on the cycloaddition of carbonyl compounds to

unsaturated phosphonic derivatives with a study of the interaction of mesoxalic acid esters and dialkyl 1 -alkynyIphosphonites (R 1 0)2PC=CR 2 , when the cyclic phosphonates (261; R 1

=

H or alkyl) were isolated.' 35 Reactions between vinylphosphonites and

ni trilimines lead to diazaphosphorines (262) or diazaphospholines (263), depending o n the substituent R (Scheme 28).136 The salts (264; R

=

Ph, PhCH=CH or PhOCH=CH), derived from the aryl or vinyl

tetrachlorophosphoranes and PC15. undergo further reaction with aryl dichlorophosphites to furnish the salts (265); these are acted upon by formic acid, the final reaction products

being aryl(or viny1)phosphonochloridic acids

a5

their aryl esters.' 37 The salts (264) also

react with epoxides in the presence of TiCI4 to give di(2-chloroethyl) esters of the 138 aryl(or viny1)phosphonic acid. A 31P n.m.r study h a s been made of the PdC12-catalysed reactions between

unactivated aryl halides and trialkyl phosphites which lead to dialkyl arylphosphonates. Several Pd-containing species have been recognised as participating in the general reaction scheme.' 39 Other applications Pd(0)-catalysis are to be found later in this Report. Ni(I1)-catalysis has been used in reactions between aryl halides and P(II1) esters: 1 = 0 or 1 ) and (267; n = 1 or 2). in which R and R2 = alkoxy or

the systems (266; n

Ph, were so prepared. 140p141The indolines (268; X the bromides (268; X

=

=

(Et0)2P(0) ) were obtained from

Br) using NiC12 as catalyst.142 Reactions between aryl bromides

and P(II1) esters in the presence of NiCI2 are fa5ter for trimethylsilyl esters than for 143 alkyl esters. The novel resorcinol-based 25-crown-8 ether compound (269) possesses a pendent lipophilic phosphonic acid moiety, and was synthesized from the macrocyclic tert-butyl ester

tosylate

and

diethyl

(2-hydroxy-5de~ylphenyl)phosphonate.~ 44 Esters 13,15,145

of

arylphosphonic acids analogous to ( 15) and ( 16) have been listed.

The keteneimide (258) is a useful starting point for the synthesis of several types of

phosphorus

compounds;

with

the

a-hydroxyketones,

2-anilino-3-(diethoxyphosphinyl)furans (270) are formed.' sodium salt of salicylaldehyde yields (271; X

=

R 1R2C(OH)COR3,

whilst reaction with the

NPh) from which (271; X

=

0) can easily

5:

Quinquevalent Phosphorm Acids

+

R&NNAr

147

(Et0)2PCH=C(SEt)CI

I

Ar I

,CH=C(SEt)CI (Et0)2P\ CR=NNAr +

R

-

several steps

- EtsyJR

1

O? 'OEt (262)

Ar Et3N, HCI

Ar

Scheme 28

+

-

R(ArO)PCI2PCls (265)

0

HO,I I R

d \ /

OCH2COOH

0

(269)

0rganophosp h orus C 'hemis try

I48

Phl,

.OH

(R'0)2PONa

OTs

0

II

(R10)2P-I(OH)Ph

( R'0)2PCZ CR2

(272)

(273)

OCSOPh

i.ii,iii

(Et0)ZPCHFz

f

5)

-

f

iv

(EtO)ZPCF2CH*R

Reagents: i, BuLi, THF; ii, RCHO, THF, -78 "C; iii, PhOCSCl; iv, Bu3SnH, AlBN

Scheme 29

t

(Et0)2PCHF2

-

f HO OBu' (EtO)2P+OBut

i, ii

F

+

cvi--

\

I

0

1'

RO Me ( E t O ) 2 P ~ O B u t F

(275) (R = Me3Si)

iii, iv

0

5)

(274)

-

0

+

( EtO2 )& !

0But F

0 (274)

(275)

vii. iii

\

0

CH2 COO-Na'

Reagents:i, LDA, -70 "C; ii, (Bu'OOC)~,then H30'; iii, NaHCO,(aq.); iv, C6H6,azeotrope; v, Tebbe reagent; vi, N,Obis(trimethylsilyI)trifluoroacetamide;vii, TFA

Scheme 30

5:

Quinquevalent Phosphorus Acids

he obtained. I

149

I -Alkynvlphosphonic diesters (273) are obtainable by the interaction of

the iodonium phosphonate (272) and the I -alkynes, K2C'CH.I 46 2.1.3. (Hu1ogm)ulRyl hphosphonic unci -phosphinic. ru-ids-Mono- and di-tr-fluorinated

alkylphosphonic acids have been prepared by fluorination of the phosphonic ester anions with N-fluorosultams, (RS02)2NF. (R

=

CF3)147 o r (R

=

Ph).14'

An alternative

synthesis of ( 1 , I -tlifluoroalkyl)phosphonic diesters is summarized in Scheme 29. 40 The use of lithiateci (t1ifluoromethyl)phosphonic diesters in this area is illustrated in Section 2.1.9. (Perfluoroalky1)phosphonic acids, as their diethyl esters. have been obtained from diethyl phosphorochloriclate and the Grignard reagents, RfMgX 50 o r from tetraethyl pyrophosphite in the presence of a peroxide.

K f I and

151

Scheme 30 outlines a synthesis of an isopolar and isosteric analogue of phosphoenolpyruvate, stabilized as its disodium salt. (276). in which the inseparable mixture of (274) and (275) is used directly; the use of the Tebbe catalyst, /I-chloro-~-methylenebis(cyclopentadieny1)-titaniumdimethylaluminium,is noteworthy. 52

Methylenebisphosphonic acid tetraalkyl esters have been fluorinated with acetyl hypofluorite, 53 and brominated o r chlorinated with the sodium hypohalite. 54 Reduction of the dihalogenated compounds with sodium sulphite or stannous chloride yields the monohalogeno compound. 54 Mono-tr-brominated alkylphosphonic esters were also obtained using N-bromosuccinimide (NBS) 55 and a synthesis of the dibromo esters (R0)2P(0)CBr2CHY (Y

=

COOalkyl o r CN) employed

dimethylhydantoin as brominating agent

I ,3-dibromo-5,5-

Scheme 3 1 indicates how enones are

convertible into (2-bromo-3-oxoalkyl)phosphonic esters (278; E

=

Br); the direct

interaction of (277) with NBS at -5" yields diethyl (3-0x0- 1-alkenyl)phosphonates, also formed when the esters (278; E

=

Br) are heated 157

Reactions between diethyl trimethylsilyl phosphite or tris(trimethylsily1) phosphite and the appropriate 1 , I -difluoroalkene yield the esters (279) and (280)(R Me3Si).158

=

EtO o r

2. I .4. Hydroxp- und cpoxyulkyl-phosphonic and phosphinic acids, und related sulphur o r sclcnium compounds-Conventional reactions between 1,2-propadienylphosphinicacid and substituted

benzaldehydes

yield

[(a-hydroxybenzyl)(1 ,2-propadienyl)]phosphinic

acids.' 59 Reactions between ( I -oxoalkyl)phosphonic esters and nitromethane in the presence of a base (K2C03) yield the esters (281).16' The compounds (282: n 2), 1 6 '

=

I or

and (283) 162 are obtainable conventionally from the cyclic ketone and dimethyl

Organophosphorus Chemistry

150

Reagents; i, (Et0)3P;ii, Electrophile E

Scheme 31

HO

! ? P(OR2)2

R'CHzNO2

(279) R2 = CFS (280) R2 = SFS

0

F?

Me (287) X = OH (288) x = NHCR~R~CECH

5:

IS1

Quinquevalent Phosphorus Acids

phosphonate anion. Of rather greater structural interest are the derivatives (284)-(286) of squaric acid. The addition of lithium diethyl phosphonate to squaric acid diethyl ether yields a mixture of the expected adduct (284) (this is, in fact, the main product when the reaction is carried out at -70°), together with the C-phosphorylated compound, (285); the latter becomes increasingly important with raised reaction temperatures. Without separation,

the

mixture

of

(284)

and

(285)

is

acidolysed and (cyc1obutenedione)phosphonic acid stabilized as its tripotassium salt (286).163

the

Mixtures containing N-methyl-4-piperidone.a dialkyl hydrogen phosphonate and a 3-amino- 1 -propyne afford the two product types (287) and (288). the former predominating irrespective of the order of mixing of reactants. 64 Conventional reactions between 3-formyl-4-chromone and dialkyl or trialkyl phosphites yield the expected dialkyl (tu-hydroxymethyl)- or (a-alkoxymethyl)- phosphonates. 165 Normally, dialkyl hydrogen phosphonates act upon 1 ,4-diketones only at the more reactive carbonyl group and successive additions to each carbonyl group do not occur; thus the diketones (289) yield the ( 1 -hydroxy-4-oxoalkyI)phosphonic diesters (290).

Exceptionally. when R1

=

R4

=

Ph, and R2

=

R3

=

H,

cyclization of the initial

monoadduct to the C-phosphorylated tetrahydrofuran (29 I ) and formation of the double addition product (292) both occur.'66 On the other hand, bis(trimethylsily1)phosphonite adds to (293) to give both the double addition product (294)(as its bis(trimethylsily1) ether ) and the phospholane (295; R 1 = H). The reaction scheme wa., at least partly, confirmed by an X-ray crystal structure determination on (295; R1

its 5-trimethylsilyl ether.

=

Ph. R2

=

Me) as

167

When hypophosphorous acid adds to the I,4diketones (296), the course of the reaction evidently depends, to some extent, on the nature of the group R, and the product types (297) and (298) are each isolahle.168 The addition of bis(trimethylsily1)phosphonite to the 1.5diketones (299; X = 0 or

CH2 , n

=

0 or 1 , R

=

H or Me) has also been examined, the products being

characterized as their methyl esters. The products (300) resulted from initial reaction at the ring carbonyl group followed by cyclization through the enol form of the initial product. Compounds (301) were obtained by initial reaction at the benzoyl group followed by cyclization. The 1,5-diketones (302; n 169 at the ring carbonyl group to give (303).

=

0 or 1 , R = H or Ph) react initially

An enantioselective synthesis of ( 1 -hydroxyalkyl)phosphonic diesters commences with

the cleavage, using (Et0)3P/TiC14 , of

the acetal (304) derived from

(2S,4S)-pentanediol. to give (305) and (306) in the ratio 9 1 -94:94, relative yields

152

Organophosphorus Chemistry

R'-

R'COCHR2CHR3COR4

?H C-CHR2CHR3COR4 i

' O=P(OR)2

(289)

\

[ /

[ ( R 0 ) 2 p -

1

PhCOCH2CHR'COPh

(2931 .

(290)

R'-

]

C- CHR2CHR3COR4

(R0)J:O

-

t .;aP:iH +

(W2L 0 (291)

HI, P, HO

0 OH I

-CCH~ I

Ph

Th

Ph 0

OH

OH

II

I

(R0)2P-?CH2CH2?-P(OR)2

(292)

?H!? H H R -~P : C I OH Ph

r

(294)

(295)

R = Bu'

0 OH

Ph

R R

(299)

Ph

Ph

5:

Quinquevalent Phosphorus Acids

% 0

R'

153

0

HO

R'

0

154

Organophosphorus Chemistry

depending on R. Swern oxidation of (305) affords (307) with >95% e.e. 17()

In an approach to dialkyl esters of (a-hydroxy(heterocyclo)methyl]phosphonates, the oxiranes (308) were made to react with thiobenzamide to give the thiophen derivatives (309), and also with the pyridine or pyrimidine derivatives (310; X Y = C(CO0Et) or N ; X

=

Y

=

CH,

N). For both systems, (309) and (31 I ) , subsequent

=

sequential reactions with p-Tol.OCSCI and tributylstannane result in the removal of the tr-hydroxy groups. 171 Several methoxy-substituted o-formyldiethylbenzamides( 312) have been converted into phthalide-3-phosphonic diesters ( 3 1 3) following initial reaction with dimethyl (rcn-hutyldimethylsilyl) phosphite.' 72

An

easy

conversion

of

methylenebisphosphonate (314; X -dithioacetal derivatives (3 14; X

triethyl = =

H, R

phosphonoacetate =

and

tetraethyl

COOEt o r P03Et2) into the gcm

SMe) employed AI2O3/KF/MeSSO2Me under

microwave irradiation.' 73 The 2-phosphono- 1,3-diselenanes ( 3 16) are obtainable from 174 the diselenolanes ( 3 15) and dimethyl (diazomethy1)phosphonate with BF3.Et20. A recently reported synthesis of C-phosphorylated oxiranes (3 17) involves initial chlorination of a dialkyl alkylphosphonate anion with benzenesulphonyl chloride and subsequent reaction of the tr-chloro anion with a ketone R2R3C0. 175 Hammerschmidt has continued his interesting studies on the biosynthesis of organophosphorus compounds using isotope labelling techniques. His earlier work has shown that when ( 1 , I -dideuterio-2-hydroxyethy1)phosphonicacid is fed to Srrepromyces fradiue the deuterium is incorporated into the fosfomycin derived therefrom, via phosphonoacetaldehyde.

Fosfomycin,

(32 1 ),

is

thought

to

be

produced

from

phosphoenolpyruvate ( 318) via (3 19) and the aldehyde (320) through interaction of the last of these with a one carbon species. The present study was designed to discover the origin of

the epoxide oxygen. Deuterium-labelled (RS), ( R ) , and

(S)-(2-hydroxypropy1)phosphonicacid (322) were fed separately to S. fradiue when it was shown that the (S) form wa. incorporated into the cell fosfomycin, 37% of the deuterium being attached to the C(1) of (324). the substance through which the fosfomycin was estimated and obtained from the latter by ammonolysis. Moreover, by using (323). it appeared that the epoxide ring could be derived from the C-hydroxy oxygen of (2-hydroxypropy1)phosphonic acid. Since this had the (2s) configuration, it also appeared that the C(3) fragment was derived from the carbonyl group of (320) by the addition of a one carbon species to the pro-(S) face of that group.'76 Diastereoisomers of isotopically-labelled ( 1 .2-di hydroxypropy1)-phosphonic acid, although

5 : Quinquevalent Phosphorus Acids

H.

T!(OH)2 XH

0

M e q P(0)(OH)

OH

(322) X = “ 0 , R = D (323) X = ” 0 , R = H

(324)

RO

L

(325) R = H, X = OBn (326) R = Bu‘Me2Si, X = OBn (327) R = H , X = POSH2

(329)

R2

(Et0 & !)2

R’ (3311

H

(332)

Organophosphorus Chemistry

1%

taken up by S. frudiue

, were

not specifically incorporated into the fosfomycin.' 76

Only the (S) form of (2-h~droxy-[2-~H 1ethyl)phosphonic acid (327), synthesized

in four steps from (325) via (326), was incorporated into the fosfomycin of S. frucfiuc.

I77

2.1 3. (Oxoulkyl )phosphonic aids-Reference has already been made to syntheses of some compounds in this subgroup e.g. squaric acid derivatives rearrangements derivatives.76

of

enolphosphates

to

and through the

[2-oxo(cyclo)alkyl]phosphonic acid

give

The reaction between cyclic ketone enolates and diethyl phosphorochloridite followed by aerial oxidation of the intermediate P(II1) esters, yields mixtures of C - and 0-phosphorylated products. The formation of the ( 1 -oxoalkyl)phosphonic diesters was optimized using diethyl ether as solvent (although hetter yields were sometimes obtained for reactions in Et20/THF when hexamethylphosphoric triamide was added) when the

C:O ratio could be raised to 12.5-14:l. The methodology was also appropriate for the preparation of tr-phosphonoaldehydes and tr-phosphono-carboxylates.' 78 and

2-thiophosphonocycloalkanones

chloro-phosphination hydrolysis. 170 Oxidation

of

(Cr03

the

in

are

conveniently

obtained

ketone enamines followed by

acetone/acetic

(tu-hydroxycycloaIkenyl)phosphonates (328; n

acid =

or

in

2-Phosphono-

aq.

by

direct

oxidation and

sulphuric

mild

acid)

of

1 or 2) yields the rearranged enone

phosphonic diesters (329), oxidizable (H202) to the (epoxya1kyl)phosphonic diesters (330).

161

The (2-oxoalkyl)phosphonic diesters (33 1 ) may be acylated (NaH, o r LDA,

R3COCI) to the (2,4-dioxoalkyl)phosphonic diesters (332: R 1 and R2 €2 ,K2=(CH,),; R3

=

=

H or Me,

H. EtO, Ph, or rert -Bu).

2. I .6. (Aminoulkyl) -phosphonic a i d s and -phosphinic ucids-Several general preparative methods have been further exemplified during the course of the year. 2.1.6.1. Reducrion merhods-These have included the reduction of oximes of the esters of ( I -oxoalkyl)phosphonic acids,"

and of ( 1 -azidoalkyl)phosphonic acids.lS5* 7() in both

cases to ( I -aminoalkyl)phosphonic diesters. and the reduction of nitro groups at C(2) 182 with hydrogen/Pt02 109. I '() or Raney nickel.

2.I h.2. Use of rhc Arhuzov recurtion-This was applied to the introduction of the phosphono moiety into 'ippropriate intermediates, e.g. in the conversion of (333:R'

=

H

5:

Quinquevalent Phosphorus Acids

o r Me) into (334; R 2

=

IS7

Me o r Et).lx3

2.I h . 3 . Addition merhocis -The addition of dialkyl hydrogen phosphonates to compounds possessing actual o r potential imine bonds has been applied to the preparation o f esters of ( I -amino- 1 -aryl-2,2,2-trifluoroethyl)phosphonic acids, 84 (tr-anilinohenzy1)phosphonic 185,186

and

related I x7

acids;

[( 1 -aminoalkyl)( 1.2-propadieny1)phosphinic

acids];lX8 and [[tr-(arylamino)-tr-2-thienyl]methyl]phosphonicacidss8 Other examples include the initial introduction of phosphorus in a synthesis ultimately of pyrrolidinyl and (piperidin-2-y1)phosphonic acids.18'

and the preparation of (N-methylaminomethyl)-

phosphonic acid diethyl (but not dimethyl) ester from (CH2NMe)3.190 The interaction of dialkyl hydrogen phosphonates with ketones and N-substituted h ytlroxylamines yields [[(N-hydroxy-N-substitute~i)amino]methyl]phosphonicdiesters. I

Other phosphorus (111) compounds, including PCI3. alkyl phosphorodichloridites, dialkyl

pho~phorochloridites,")~~ !I3

and

dialkyl

trimethylsilyl

phosphites O4

have been used in similar reactions to give N-acyl o r N-phenyl derivatives of ( 1 -aminoalkyl)phosphonic acids. The use of diethyl phosphoramidate as nitrogen source

together with diphenyl hydrogen phosphonate, and o f BnOCONH2 with PCI3

,

each in

conjunction with an aldehyde, affords N-phosphono or N-carboxy derivatives.'

''

Dialkyl and bis(trimethylsily1) esters of N-phosphonomethylaminoacetaldehyde acetals (336) are obtainable by the additions of the corresponding hydrogen phosphonic diesters to (335). The esters (336) suffer monodealkylation when allowed to stand at room temperature, and in the presence of HCI fail

to

yield the target aldehyde. However, the

bis(trimethylsilyl) esters may be desilylated, using an alcohol, to (336; R2 = H) and the latter with IM HCI yield (336; R 1 = R 2 = H) as a brown resin. I t is worth the reminder that aminoacetaldehyde hydrochloride itself exists in the gem-diol structure.' 96

In the alternative general approach, dialkylamines add to C-phosphorylated quinonemethides to give ((u-aminobenzyl)phosphonicdiesters. 128 2.1 6.4. Amiwmerhylurion methods-That of phosphonite esters has provided polyaza

macro cycle^;"^

that of phosphorous acid with N-benzylglycine and formaldehyde has

provided a route to N-[(dihydroxyphosphinyl)methyl]glycine (glyphosate) (337).198 Phosphonomethylation of N-(2-cyanoethyl)glycine yields (338) after appropriate work up. 199 2.1.6.5.Miscellunecous compounds und synrhcses-These include the preparations of [ 1 -amino-2-(4-pyridinyl)ethyl]phosphonic esters'

and symmetrical and unsymmetrical , bis(aminoalky1)phosphinic acids from H3P02/R CH(NHCORL)2 in aqueous acetic 200 acid.

'

.?

Organophosphorus Chemistry

158

OTE*0 X

H2c-toR’ OR’

N R’

(336)

(333) X = Br (334) X = (R20)2P(0)

(335)

OEt

0

0.,

( H 0 ) 2 1 AR N 3 0 H

?<

MeYPXN F3C CF3

0

ii

t i

MeOOC

I

CF3

NHR

-

(342) R = BOC

1

1

(342) R = H

iv

aoAC

0

I

P-C-NHCOOEt

(339)

! (341)

RO’

0 CF3

(340)

(337) R = H (338) R = CH2CH2COOH

0

Me,l

0

OH ‘NH3

OH

Reagents: i, P(OMe)3; ii, MeOH, HCI; iii, CICOOBn; iv, LiBH4, MeOH, B(OH),; v, HBr, HOAc

Scheme 32

Reagents: i, (R2C0)20,py.; ii, (MeO)*P(O)H, DMF; iii, Bu4N+Br-, K2C03; iv; 6M HCI or HBr-HOAc Scheme 33

NHR

5:

Quinquevalent Phosphorus Acids

IS9

The I .4,2-diazophospholines (339) are reactive towards alcohols, ROH, and yield 20 1 the linear esters (340; R = C - C6). ( 1 -Amino-3-hydroxypropyl)phosphonicacid, an analogue of homoserine, has been

synthesized from

the azetidinonephosphonic dimethyl ester (34 1 ) according to the

reactions in Scheme 32.202 The synthesis of ( I -hydroxy-2-aminoethyI)phosphonic diesters by reduction of the 2-nitroethylphosphonic diester ha5 already been referred to. 82 Other ( I -alkyl(or aryl)-2-amino- 1 -hydroxyalkyl)phosphonic acids have been prepared

according

to

the

reactions

presented

in

Scheme

33.203

( 1-Hydroxy-4-aminobutyl)- 1 , l -bisphosphonic acid ha5 been synthesized from trimethyl

phosphite. dimethyl hydrogen phosphonate, and 4-phthalimidobutanoyl chloride, followed by acid hydrolysis of the tetramethyl ester: its crystal structure h a s been determined.204 Here it is worth noting that, while removal of the phthalimido group (as a protection moiety) can generally be accomplished by the use of hydrazine hydrate, the attempted removal of this group from diisopropyl (4-phthalimidobutanoyl)phosphonate suffered complications because of attack at the carbonyl group. 205 A simple example of the control of chirality at the amino carbon atom

is that

experienced in the conversion of the ( 1 -hydroxyalkyl)phosphonic diesters (307) into the (azidoa1kyl)phosphonic diester (343) using the Mitsunobu reaction: the interconversion occurs with inversion of configuration at C( 1 ); reduction of the azido group provides the ( 1 -aminoalkyl)phosphonic

diester

of

established

chirality.

Whilst

diethyl

(tr-anilinobenzyl)phosphonate has been resolved using an appropriate column for h.p.l.c., the compounds (345; R

=

H or Me) were not resolvable using an identical procedure. It

seems that the compounds (345) are formed from (344) and diethyl hydrogen phosphonate i n a stereospecific way; one chiral centre ( R or 3) is formed initially, and the addition of the second hydrogen phosphonate molecule occurs in such a way as to generate a second chiral centre with the opposite configuration so producing the meso molecule a5 the major (9:1) reaction component. 186 The use of chiral Schiff bases based upon terpene moieties has already been reported, but their applicability h a s now been extended. Thus the Schiff base (346; R2

=

H). derived from (+)-oxopinic acid, and (aminomethy1)phosphonic acid diethyl ester,

was alkylated

in

the

usual way and

the products

hydrolysed

to give the 2

(S)-( 1-aminoalkyl)phosphonic diesters with 15. 62, 93, and 92% e.e. for R = Me, Et. Bn, and ally1Zo6 The reaction between (347:R2 the (13)-(347; RL

=

=

Li) and diethyl vinylphosphonate gave

CH2CH2P03Et2) which was acidolysed ( aqueous acetic acid) to

a

160

Organophosph ori4s Chemistr-v

CH =N(CH2)2N=CH

(307)

R

-2 R

F(OEt)2 0

R

(344)

(343)

(EtO)27'=0 O= P(OEt), a C H . N H ( C H 2 ) I N H CH I

R

R (345)

(346)R' = COOH (347)R' = Me

B

(! 0Ef)2

N

R (349)

5 : Quirt q ue valent I'h osp horids A cid.7

lhl

R

(S)-( I -acetylamino- 1,3-propane)hisphosphonic acid tetraethyl ester (348;

=

Et)

hydrolyzable to the free acid. a phosphonic acid analogue of glutamic acid.207 The Schiff base (349; R

=

H) from pinan-3-one. when alkylated with 2-iodoethanol THP

ether yielded (340; R

=

CH2CH20THP) and this, when worked up, gave the phosphonic

acid analogue of homoserine2')' A new, and novel. approach t o the preparation of chiral

(aminoalky1)phosphonic

acids, used sugar amines as chiral templates, and which, through reaction with aldehydes, were converted into Schiff bases. The base was then allowed to react with a dialkyl hydrogen phosphonate in the presence of S K I 4 to give a mixture of diastereoisomeric products, chiral at C* and having (350; R 1

=

H. R 2

=

(r

or p conformations on the sugar moiety. The base

Me3CC0, R3

=

Ph) (containing 12% of the p-anomer) from

D-arabinopyranosylamine, gave a diastereoisomeric R2

=

Me3CC0, R 3

=

mixture of

(35 1 ; R

=

H,

Ph) containing 67.7% N R , 13.6% trS. 15.7% g R , and 3.0% p S forms;

acidolysis yielded diethyl (tr-aminohenzy1)phosphonate having the (R)-form as the main component. Other

experiments

were

fucopyranosylamine base (350; R 1

=

carried

Me, R2

=

out

with

Me3CC0,R3

2,3,4-tri-C)-pivaloyl-g-I,=

Ph or other aryl groups,

o r 2-furyl) and 2,3.4,6-tetra-~9-pivaloyl-~-D-glucopyranosylamine base.

A particularly

useful example appears to be the base from fi-D-galactopyranosylamine, (352; R2

=

Me3CC0, R 3

R3

=

Ph), contained 89.5% p S , 7.1% g R , 2.3% trS. and 1 . I % (rR, forms. High selectivity

=

Ph), when the products, of the composition (353: R2

=

Me3CC0,

was also obtained with some substituted (4-CI, 4-Me) aryl groups, but otherwise the enantioselectivity varied extensively.209 An improved synthesis has been developed for the synthesis of tetraalkyl diazomethylenebisphosphonates and alkyl diazo(dialkoxyphosphiny1)acetates using the phosphonic anion and 2-naphthalenesulphonyl azide.2 1 0 2. I .7. Sulphur und srfenium-containing compounds-The enzyme, phosphoenolpyruvate

phosphomutase,

from

Terruhymenu

pvriformis.

catalyses

the

transformation

of

phosphoenolpyruvate (PEP) into its P-C bond-containing metabolite, phosphonopyruvate. During the course of a study of the mechanistic details of this process using isotope labelling techniques, chiral [ 80]-labelled forms of

thiophosphonopyruvate were

synthesized. The reactions employed in the syntheses are indicated in Scheme 34 for one enantiomer

(356). Separation

0-2-(trimethylsilyl)ethyl

of

the

(SpSc)

and

( RpSC)

diastereoisomers of

N,P-dimethyl-N-( 1 -phenylethyl)phosphonamidothioate was

carried out by h.p.1.c.: the former isomer is illustrated (354). Stereochemistry was

Organophosphorus Chemistry

162

s Me-P-CI I OCH2CH2SiMe3

s

i

iii

R’-pdCH2COCOOR2

0CH2CH2SiMe3

1

R’ = Me-C--NMe i

OCH2CH2SiMe3

/

f

H

* R’L-p-Me

Ph

(354)

=180

s

2 R1-~~CH2CoCOOPr‘ R =PI’ 0-

(355)

s

1

iii R2 = CH2CH2SiMe3

s

CH2COCOO-

R’-P-

* -0~PaCH2C00-

iv

0-

0-

(356) Reagents: i, (S )-PhCHMeNHMe, HPLC; ii, BuLi, Cul, CICOCOOR2; iii, CsF, 18-crown-6, MeCN; iv, H 2 a Scheme 34

-ooc\ ! //c -0-P I -0H2C

0-

[

0

-ooc\ II H2c4c- 0- -0-7 -enzyme 0Scheme 35

1

PhCNH OMe

(357)

(358)

5:

Quinquevalent Phosphorus Acids

checked

by

an

X-ray

163

of

analysis

S(4-nitrophenacyl)

N-( 1 -phenylethyl)-phosphonamidothioate obtained

from

(354)

N,P-dimethyl-

with

CsF

and

4-nitrophenacyl bromide. The O-2-(trimethylsilyl)ethyl protecting groups in (355) were removed with CsF/ 18-crown-6. It was concluded that the PEP phosphomutase reaction proceeds with retention of configuration at phosphorus, and hence by a stepwise mechanism (Scheme 3 5 ) 2 ' Several cyclic trithiophosphonic acid systems have been prepared using Lawesson's reagent (LR) and similar reactants. Such products include (86; R

4-amino-2-hydroxybenzoic acid5' (87) affords (88; R (357). LR

and

=

whilst

=

C6H40Me-4) from

1 -diphenylmethylene-2-( 1 H)-naph thalenone

C6H4-OMe-4). With diphenylphosphinodithioic acid, (87) yields

N,N'-dibenzyl-p-benzoquinonediimide yield ( 358).21

Sometimes

included in the products from such reactions is the symmetrical triphosphorinane [4-Me0C6H4P(S)l3 which is also formed when esters of phosphonoformic acid are treated with LR; its crystal structure has been determinedz' When treated with sulphur and DBU. (359: Ar

=

2,4,6-tri-ten-butylphenyl)yields

(360) together with a mixture of cis and trans forms of (361). An X-ray crystallographic examination was made of the dithiadiphospholane ( 360)214 Monomeric ethyldithioxophosphorane (362) was obtained by the gas phase thermolysis of its cyclic dimer (363).21

The reaction between 2-methyl-4.6-di-ten-

butylphenylphosphine and sulphur afforded (364) as a bright orange solid, stable for several months under argon. Under similar conditions, the corresponding selenide is unstable and yields ( 3 6 5 ) z Compound (366) formed during the thermolysis of (367). undergoes cycloaddition reactions with dienophiles X=Y (X

=

CH2, Y

=

CMeCOOMe. CMeCN, etc) to give the

products (368) and ( 3 6 9 ) z 2.1 .8. Compounds wirh phosphorus-nitrogen bonds-Unlike other simple phosphonic dichlorides, allylic phosphonic dichlorides are reported to undergo replacement of only a single chlorine atom when acted upon by an excess o f diethylamine in the presence of triethylamine to give the phosphonamidic chloride which, however, is then reactive 218 towards sodium alkoxides. The initial products from oximes and chlorophosphines rearrange readily to the phosphinic

amides (370)219*220 which

N-phosphinylaziridinesz2'~

Simple

may

then

be used a. precursors

N-(dialkoxyphosphiny1)hydroxylamines

to

are 22 1

obtainable from the phosphinic chloride and N,O-bis(trimethylsi1yl)hydroxylamine.

Organophosphorus C’hrmisrry

164

S EtP4 *S

(363)

qe \ 1

Me Ph,

P-SeH

0 Ph

Ar

Ar

0 EtO II

&2tJAMe

0

0

( R C H 2 ) 2 N N2 ‘ p p Ph

Ph

Me

Et0,I

0

0

I

(RCH2)2N/‘+OH Ph

R

(374)

(375)

5:

Quinquevalent Phosphnrirs Acids

165

Diastereoisomers of P-mesityl-P-phenyl-N-( I -phenylethyl)phosphinic amide were succesfully separated but attempts to remove the I -phenylethyl group from nitrogen by catalytic hydrogenolysis o r by using Na/NH3(1) were not successful. However, when the ( RP RC )-(-) diastereoisomer was methanolysed, (S-(+)-methyl mesitylphenylphosphinate

was obtained: this with Na/NH3 i n 'THF afforded (R)-(-)-mesitylphenylphosphinicamide. An X-ray analysis of the minor N-(1 -phenylethyl)phosphinic amide stereoisomer showed

the major form to have the ( R p R C ) configuration, (37 1 )z22 Photolytic or Rh-catalysed

decomposition of

(I-diazo-2-oxoalkyl)phosphonic

amides (372) leads to the phosphinylphenylacetic acid (374)(presumably by way of a Wolff

rearrangement

to

(373)

after

initial

carbene

formation)

and

to

1,2-azaphosphetidines (375), the latter being formed diastereoselectively in favour ( 1 0 : I ) of the (SP)form.22 3 Dialkyl phosphorocyanatidites (R0)2PNC0 react with nitrilimines, ArC+=NN-Ph in

a I :I ratio t o give the reduced triazaphosphorines (376): linear phosphinic esters are isolable when the reactant ratio is I :2.224 Chinese workers have announced syntheses of compounds based on the heterocyclic skeleton (377).225 Several new macrocyclic systems have been constructed in reactions between the phosphonic dihydrazides (378; X

=

0 or S) and 3 3 - or 4,4'-dialdehydes (379). The final

products (380) possessed ring sizes of from 28 to 36 annular atoms, and in which the bridging groups Z and Z' may be identical or different and have the structures indicated.226,227

2.1.9. Compounds o f hiologicul interest -In this section, discussion is centred around the syntheses of the compounds and their biological effects are not discussed in any detail. The first group of such compounds comprises those

phosphorus-containing

analogues of amino acids, either synthetic o r natural, and the peptides derived from them. Such analogues are made up of two types; the first consists of compounds in which the carboxyl group has been replaced by the dihydroxyphosphinyl moiety, whilst the second group consists of those substances derived from an amino acid by "addition" of the phosphinyl moiety and thus carry both functional groups. Reference has already been made to the successful use of Schiff bases based on terpene

nuclei

as

reagents

for

the

synthesis

of

optically

active

chiral

(tu-aminoalkyl)phosphonicacids, (38 1 ), several of which are amino acid analogues: they include the analogues of alanine (R

(R

=

(HO),P(0)CH2CH,)?07

=

Me)?06 phenylalanine ( R

and homoserine (R

=

=

Bn)?06 glutamic acid

CH2CH20H)Zo8 Other syntheses

Organophosphorus Chembtry Ph I

Ar

(376)

(377)

PhP(X)(NMeNH&

(378)

Z,Z’ = (a) -OP(X)PhO-,

(379)

(b) -P(O)Ph-,

\s, (C)

-0

P ,

N ,, P, N

s,. 0-

5:

Quinquevalent Phosphorus Acids

167

already indicated have also yielded analogues of homoserine202 and phenylalanine. Treatment of the Schiff base (346: RZ

=

CH2CH2COOEt) with aqueous acetic acid

affords 5-(diethoxyphosphinyl)pyrrolidinone which, by reduction with LiBH4, yields the proline analogue (382)207 The phosphono isostere of histidine, (383), was prepared from I -triphenylmethyl- 1 H-imidazole-4-carboxaldehyde and N-[bis(dimethoxyphosphinyl) methyl]f~rmarnidez~~ Analogues of amino acids e.g. alanine, valine. and tryptophane, have been resolved using dibenzoyl-D-tartaric acid.229 A series of aminophosphonic acid derivatives of vinblastine h a s been synthesized as potential tumour inhibitors: some are said to exhibit “remarkable activity” towards cancer cells both in v i m and in viva 229 Peptides have been constructed from amino acid phosphonic analogues using conventional techniques and protecting Of

the

general

methods

elaborated

for

the

synthesis

of

tr-amino-

o-phosphonoalkanecarboxylic and related acids (384a). that described in Scheme 36 is probably amongst the most generally applicable, and uses as starting materials (384; X

CI or Br; Y

=

=

(CH2)4-10, (CH2)20(CH2)2. or 1.4-CH2C6H4CH2)z32 The

reactions in Scheme 37 were applied to the synthesis of one specific compound. (387), but no doubt the procedures could be more widely adapted: to be noted is the control of asymmetic hydrogenation in (386) through the use of ( 1 $2R)-(385). The final product, 233 (S)-(+)-2-amino-4-phosphonobutanoicacid, exhibited 67% e.e.. In the general Scheme 38, the immediate precursors to the phosphonoamino acids,

viz.

(389),

were

obtainable

by

two

possible

routes

from

4-benzylidene-4,5-dihydro-5-oxazolones (388). Moreover. the intermediates (389) could themselves be transformed into the target compounds (391; Ar 3,4-(Me0)2 derivatives; R

=

=

Me. Et, Pr’, or Bu) through

Ph or its 4-Me0 or two routes. The

diastereoisomeric ratio of the esters (39 1 ) depends on experimental conditions, including the use of acidic or basic reaction media.234 The analogue, (393). of O-phosphotyrosine, (392), has been obtained by reaction of the benzaldehyde (395) with azidoacetic ester, followed by hydrogenation to give (394), transformed under alkaline conditions into (393)235 The same acid, and again in racemic form. was also obtainable from w.w’-dibromoxylene using two other routes, in one of which the phosphono group was introduced through the use of the Arbuzov

2-Amino-4-hydroxy-5-phosphonopentanoicacid (3Y7) has been synthesized in a 237 short reaction sequence from the aminobutanedioic diester (396) (Scheme 39).

Organophosphorus Chemistry

168

X-Y-y(COOEt)2

-

I

r-I

(Me3Si0)2P-Y-y(COOEt)2

1

NHAc (384)

?

ii

?

111

(H0)2P -Y -CH(C00H)2

NHAc

(H0)2P-Y-C(COOEt)2 I

I

NH2

NHAc

(384a) Reagents: i, H3P03, (Me,Si),NH;

ii, EtOH; iii, HCI, aq.

Scheme 36

0

0

11

(EtO),PC H2CH2

f

(Et0)2FCH2CH2COOEt

+

PhCH(NH2)CH(OH)Ph

-

(385)

1

Ph

ii

?

(EtO)2PCH2CH2+o

?

iv

(HO)2PCH2CH2$HCOOH NH2

E

-

0

iii

(EtO),PCH2CH2$HCOOH

+ ' Ph

NH2

(387)

Ph (386)

Reagents: i, BuOH; ii, AI/Hg, MeOCH2CH20Me;iii, H2, PdIC; iv, 4M HCI,

Scheme 37

4

5:

Quinquevalent Phosphorus Acids

169

!

( R ’ 0 ) 2 P G

-,:O t

NYo

NYo

Ph

Ph

(388)

Na+

Ar

i

\

/ iii

R

(R’o)z%NYo / \ OSiMe,

3(;8:

t

(390) R2 = H

(R10)2P-CH-CHCOOR2 I

Ar

I

NHBz

(390)

8

(HO)2P-CH-CH-COOH I

Ar

I

NH2

(391) Reagents: i, (R’O),PONa; ii, (RO),POSiMe,;

iii, Me,SiCI; iv, R20H; v, H20; vi, H30t

Scheme 38

tJJCH \ O

(Bu‘O)~~

(392) X = 0,R’ = R2 = R3 = H (393) X = CH2, R’ = R2 = R3 = H (394) X = CH2, R’ = But, R2 = H, R3 = Me

(395)

Organophosphorus Chemisrry

170

Reagents: i, (Et0)2P(0)CH2Li,THF; ii, NaBH4,MeOH; iii, 6M HCI, 100 "C

Scheme 39 NHR~

Me-P AR1

(398) R1 = R2 = R3 = H (399) R' = CH2CH2CI,R2 = Bz, R3 = Me (400) R' = CH2CH2CI, R2 = Bz, R3 = H

0

H&O

~

0 II-CHO Me-P

+

I

O-CI

!r

Me-P

O-CI

0

HO, II P(CH2) R'

O 4 C I

ntH.COOH NH2

0 11

X(CH2) 'P " R'

OEt R,I

0

HO'PYNHC0cF3 Ph

BocXNH(COOB~)(CH~)~CHRP(O)(OE~)~

(407)

(408) R = NHCHBnCONH2 (409) R = --N

3

CONH2

171

5: Quinquevalent Phosphorus Acids

‘The hydroformylation and amidocarbonylation of esters of methylvinylphosphinic acid have been studied i n relation to the synthesis of probably the best known molecule of the types under consideration. viz. 2-amino-4-(hydroxymethylphosphinyl)butanoic acid, (398), also known as phosphinothricin or glufosinate. The outcome of

the

hydroformylation of the ester (401 ) depends on the nature of the catalyst employed. Thus the use of Rh4(CO), 2, Rh2C12(C0)4. o r HRh(CO)(PPh3)3,leads to relatively high total yields of (402) and (403) but with low selectivity; in contrast, when C O ~ ( C Ois) ~ employed, high selectivity with relatively low total yields are observed. Reactions in methanol afford a 90% relative yield of (402), Subsequent amidocarbonylation using the same catalysts and benzamide/H2/C0 gives a mixture of (399) and (400) from which an 8% yield of (400) can be obtained: subsequent hydrolysis of this gives (398).238 Interesting of

results

homophosphinothricin

have (404:

been R

reported =

w-phosphonoalkanecarboxylic acids (404; R

=

for

an

asymmetric

synthesis

=

3)

and

a-amino-

n

Me,

OH, n

=

higher

2.3, or 4). Glycine can be

alkylated using the Ni-containing catalyst (405) by the halides (406). The use of (406; R

=

Me, n

=

2, X

=

Br) and (406: R

=

EtO. n

=

2 or 3, X

diastereoisomeric products separable by t.1.c.. but (406; R

=

=

Br) leads to mixtures of

EtO, n

=

1, X

=

I) affords

only the (2s) product. The same complex also undergoes Michael additions to diethyl vinylphosphonate

to

give

(,$)-2-arnino-4-phosphonobutanoicacid, and

to

ethyl

methylvinylphosphinate to give homophosphinothricin. from which the enantiomerically pure forms can be obtained.239 Ethyl [2-amino-4,4-bis(diethoxyphosphinyl)]butanoate has been synthesized by a route already discussed. I12 Esters derived from N-hydroxy-2-thiopyridone and, for example. a-amino acids, react with vinylphosphonic diesters on irradiation to give complex phosphonic derivatives from which the thiopyridine group can be removed with tributylstannane. In this way, the protected amino acid Boc-X-OBn, where X = asp or glu, with diethyl 240 vinylphosphonate, ultimately yields the compounds (407). The phosphonic amides (408) and (409) and some of their derivatives have been prepared as potential inhibitors of H I V - p r o t e a ~ e 2 ~ The biological activity of aminoalkanephosphonic acids, both natural and synthetic, has been reviewed.242 A second area of considerable synthetic activity is the search for antagonists of

N-methylaspartic acid (NMDA). Receptors for glutamic and aspartic acids have been implicated in the pathology of several neurological and neurodegenerative illnesses,

172

Organophosphorus Chemisiry

including, for

example,

Alzheimer’s disease,

epilepsy,

spasticity,

stroke, and

schizophrenia. Several phosphonic acids have been characterized as being specific for NMDA antagonism in vitru ; they include 4-phosphonomethylpiperidine-2-carboxylic acid, 4-(3-phosphonopropyl)piperazine-2-carboxylicacid, 2-amino-5-phosphonopentanoic acid, and 2-amino-7-phosphonoheptanoicacid. Several papers have been devoted to analogues of 4-(3-phosphonopropy1)piperazine-2-carboxylic acid. One sequence, (Scheme 40), is initiated by the addition of Me or Et, n

(nitroalky1)phosphonic diesters (410: R

=

cr-aminoacrylic ester, and

the

leads, on

diaminoalkanecarboxylic acids (41 1; n

=

one 1

=

2 or 4) to N-protected

hand, to

the ~phosphono-2.4-

or 3). and, on the other, to the 237 = 1 or 3).

4-(w-phosphonoalkyl)tetrahydropyrimidinyl-6-c~boxylicacids (4 12; n

Homopiperazine analogues (4 14) were obtained from the heterocycles (4 13: n

m

= 0;

n

= 0.

m

= 1)

followed by acid hydrolysis. The compounds (414; n = 0, m inactive, but (414; n

I. m 24 3 compounds ( n = m = 0). =

=

1,

by initial reaction with diethyl (dromoalky1)phosphonates =

0, y

=

= 1,

y = 2 or 3) are

3) is weakly active, relative to the piperazine

As indicated in Scheme 41, the anhydride (415) can be used to prepare the esters (416) which are obtained as a ca. 2:l mixture of cis and

trm

forms: hydrolysis of the

mixture gives a mixture ( 1: 1 ) of cis and nuns-(4 17). The stereochemistry of the products was decided following a sequence, also illustrated in Scheme 4 I , in which (R)-aq)artic acid was converted into the cis compound (418), also a potent NMDA a n t a g o n i ~ t 2 ~ ~ A series of papers, each describing the synthesis and biological evaluation (in respect of their NMDA-antagonist activity) of several groups of compounds, also describe modelling studies. Scheme 42 indicates, in outline, the syntheses of phosphono(420).

phosphonoalkenyl-( 42 1 ),

and

wphosphonoalkyl-(422)

N-phenylglycines

obtainable from single intermediates (4 19) each, in turn , being readily available from the appropriate b r ~ m o a n i l i n e z Other ~~ aromatic-based compounds also prepared from readily available starting materials are (423; n

=

0 or 1 ) and (424: n = m = 0 or 1). The

same paper also described compounds in the series (425) and (426)(Scheme 43). Another paper covers compounds of a like nature but based on the tetrahydroisoquinoline n ~ c l e u s zModelling ~~ studies245*247 suggest that, for a molecule to bind and thus be successful as an NMDA antagonist, it is necessary that it be capable of considerable folding so that the phosphonic and carboxylic acid groups can be brought into close proximity. Yet a third group of compounds extensively reported on during the year are those

5:

Quinquevalent Phosphorus Acids

173

H

Reagents: i, KF-AI2O3,THF; ii, HZ,Pd/C, HCI, MeOH; iii, 6M HCI, 110 "C; iv, AcOCH(OM~)~, DMF

Scheme 40

cx 0

Cbz

i,ii

*

d:0

i i iH

I74

Organophosphorus Chemistry

n:--k - ocooMe 0

COOH

i

several steps

H2NC ’ OOH

“COOBu’

R

0

kOEt),

t

y

“COOBU‘

R

J iv, v, vi

0:::Zo3 0

R = phenylfluorenyl

H

H2

(418 )

Reagents: i, (EtO),P(0)CH2Li; ii, BnBr, (C6H,1)2NH;iii, 6M HCI, heat; iv, TFA; v, Me3Sil; vi, MeOH, 6M HCI,

4 Scheme 41

1

vi

Reagents: i, (Et02)P(0)H, NEt3, (Ph3PkPd, toluene, 120 OC;ii, 6M HCI, heat; iii,H2C=CH(CH2),P(O)(OEt)2, Et3N, (Ph3P)2PdC12,DMF, 90-100 “C; iv, Me3SiBr, MeCN; v, KOH,aq.; vi, H2, Pd/C, EtOH

Scheme 42

5:

Quinquevalent Phosphorus Acids

c;; COOH

I75

d'". P03H2

R

(423)

Reagents: i, MeOOCCHR.NH2,NEt3,DMAP, EtOH; ii, 6M HCI, heat; iii, Dowex 50; iv, H2, Pd/C, EtOH

Scheme 43

(427) R' (428) R' (429) R' (430) R'

= R2 = H = CHZOH, R2 = H = H, R2 = P03H2 = CH20H, R2= P03H2

176

Organophosphorus ('hcni istry

designed to have antiviral activity. Acyclovir (427) and gancyclovir (428) are potent :inti selective agents active against herpes virus; during the course of their metabolism they are converted into the monophosphates (429) and (430) by thymidine kinase. The monophosphates may then undergo further phosphorylation to triphosphates which exert the antiviral effect by inhibition of a DNA p o l y m e r a ~ e 2Efforts ~~ thus far designed to create other reactive molecules analogous to (429) and (430) have centred around the interaction of an active phosphonate moiety with a purine or pyrimidine base, generally guanine (Gua), cytosine (Cyt), or adenine (Ade). The dimethyl phosphite esters (43 1 ) undergo a photochemically catalysed Arbuzov isomerization to the phosphonates (432: n

=

1-3). The silyl protecting groups may be

removed with Ph3P/CBr4 and the resultant (aAmmoa1kyl)phosphonic esters made to react with an activated heterocyclic base, the example of adenine being illustrated (Scheme 44). The products are conveniently dealkylated at phosphorus using silicon reagents to give the target molecules (434: R

=

Ph)24y The cytosine analogue is

reported to have selective activity against human cytomegalovirus, an infection observed

in AIDS patients, and a condition against which (434; R

=

activity. A [ I4C] ring labelled cytosine analogue of (434; n

H) is also said to have some =

I, R

=

CH20H) has been

~ynthesized2~') The phosphonate (435) reacts with bases e.g. 2-amino-6-chloropurine o r cytosine in the presence of Cs2C03 to give (436; R 1 = Et, R2 = Trm) which can be dealkylated using Me3SiBr to give (436; R 1

=

R2

=

H). Similar compounds, (438) and

(439) were prepared from the sodium salts of the bases and (437), the latter itself being obtained by way of a Michaelis-Becker r e a ~ t i o n . 2 ~ ~ Similarly, the phosphorylated alcohols (440: R

=

H or CH20Ac) react with

1 -hydroxyuracil or 1-hydroxythymidine in the presence of Ph3P/diethyl azodicarboxylate

in DMF (Mitsunobu reaction) to give the compounds (441). Removal of the acetyl group CH20Ac) with NaOEt, is accompanied by the formation of the 1,2,4-dioxaphosphorinane(442).2 5 1

from (441; R2

=

An alternative route to the phosphonate moiety suitable for the synthesis of compounds (441) starts with diethyl "2-(phenylseleno)ethoxy]methyl]phosphonate which, when acted on by Na104 affords diethyl (vinyloxymethy1)phosphonate.The latter, with the appropriate N-hydroxy base e.g. 9-hydroxyd-(dimethoxytrity1)-adenine,in the presence of N-iodosuccinimide, yields (44 I ; R2 = CH I). readily convertible, using tetraethylammonium acetate, into (44 1 ; R 2 = CH20Ac).2& Arbuzov reactions performed on (443)(Scheme 45) furnished (444) and (446) from which the alcohols (445) and (447) were obtainable. Mitsunobu reactions of the latter

5:

177

Quinquevalent Phosphorirs Acids

qO::M

e2But

I

0=P(OMe) ph&OSiMe2Bu'

(431)

(432)

0 =P (0Me) 111

P h h n B r

iv

(433)

(434)

Reagents: i, hv; ii, Ph3P, CBr,; iii, NaH, DMF, Ade; iv, H30+

Scheme 44

(436)

(437) X = CI, R2 = H (438) X = 9-Ade, g-Gua, or Cyt; R2 = H or Me (439) X = 9-Ade or Cyt, R2 = CH20H

Organophosphorus Chemistry

178

1

i

ii

0

iv

i (444) ~ R = AC

(445) R = H

0

[5:(446) R = Bn (447) R = H

Reagents: i, BrCH20CH2CH20Ac;ii, H30+;iii, CICH20CH(CH20Bn)2;iv, H2, PdC, EtOH

Scheme 45

zvodA

Me

(449) Z = Br (450) Z = (RO)2P(O)

(448)

(451) i

iii' iv

= Et, R2 = H (453) R' = Et, R2 = MeS02 (454) R' = Na, R2 = MeS02

i (452) ~ R'

c

Reagents: i, (Et0)2P(0)CH2Li,BF3Et20,THF, r.t., ii, MeS02CI, Et3N, CH2CI2; iii, Me3SiBr, DMF; iv, NaHC03;v, 1M NaOH aq.

Scheme 46

5: Quinquevalent Phosphorus Acids

with

179

I -hydroxyuracil or related bases, followed by ester dealkylation. gave the

rliphosphonic acid derivatives analogous to (44 1 ).253

2,3-Didehydro-Z',3'-dideoxythymidine (448) is an HIV reverse transcriptase inhibitor currently under investigation in its relation to AIDS in humans. Ultimately, its triphosphate is responsible for antiviral activity. Analogues have now been prepared. Thus, the phosphonic acid (450; R

=

H) was prepared from (450; R

=

Et), the latter in

turn obtained in an Arbuzov reaction involving (449). A second sequence (Scheme 46), commencing with (451), leads to (455: X compounds (455: (a) X

=

CH2, Y

=

=

CH2. Y

0; (b) X

=

0. Y

the last exhibited antiviral activity comparable

(B

=

0, B

= =

=

thymidine). Of the three

CH2, and (c) X

to

that of

=

Y

=

0),only

(456) and

(457)

thymidine)zs4 Analogues of the general structural types (456) and (457) were

prepared from an appropriate epoxide. Cis and trans

forms of (456) were

characteri~ed.2~~ Artheriosclerosis and coronary heart diseaw are associated with high serum cholesterol levels, and one proven approach to the treatment of hypercholersterolemia lies in reducing the cholesterol level in plasma by increasing its level in the liver. The compounds (458: X-Y

=

G C , HC=CH, CH2CH2, or CH20) have been examined for this

purpose. Their syntheses result from the attachment of a pyridine nucleus to an appropriate phosphonic acid derivative, (462), the synthesis of which is illustrated in Scheme 47. The mode of attachment of (462) to the pyridine nucleus depends on the individual X-Y Current interest in the biological activity of fluorine-containing analogues of biologically active molecules is further exemplified by the synthesis (Scheme 48) of the 257 = 4-chlorophenyl).

difluoro analogue (465) of phaclofen (46: Ar

2.2. Reactions and Properties of Phosphonic and Phosphinic Acids and their

1,3.2-oxazaphospholiDerivatives.-The diastereoisomers of 3-henzyl-4-isopropyl-2-vinyldine 2-oxide, derived from valinol, react ;is dienophiles with cyclopentadiene to give the 1:l adducts (467). The (2R,4S) and (2S,4S) compounds each give mixtures of endo and exo

products, formed with marked diastereofacial selectivity. The structures of the

products were confirmed by X-ray analysis.258 Two novel reaction sequences have been noted for allenephosphonic diesters. The course of the reaction between the [ 1 -(methoxymethyl)allene]phosphonic diesters (468) and 2-aminopyridines depends on the presence of C and N substituents in the latter. Products of types (469), (470), and (471), have been identified259 In the second

Organ op h osp h orus Chemistry 0

(456)

OSiPh2Bu' R ' A C O O M e

II

iii, iv

*

0 OSiPh2Bu' Meo,b(&COOMe R2'

- (461) R2 = OH

(459) R' = I

iK(460) R1 = (O)P(OPr'),

" L (462) R2 = CI

Reagents: i, (Pr'0)3P; ii, Me3SiBr, BSTFA, CH2C12;iii, MeOH, DCC, py.; iv, 5% KHS04,then TMSDEA, CH2C12;v, (COC1)2, DMF

Scheme 47

i

(465) R = F (466) R = H

i (463) ~ X = NO2

(464) X = NH2

Reagents: i, (Et0)2P(0)CF2Li,ii, H2, Ni, EtOH; iii, 12M HCI, then

Scheme 48

4

5:

Quinquevalent Phosphorus Acids

1x1

Me

0 (468)

\

(469)

R2 = Me, R3 = alkyl,R4 = Me

0 (470)

$3

(477)

(478)

Organophosphorus Chemistry

182

sequence, the ( 1 -methoxyallene)phosphonic diesters (472) have been converted into C‘-phosphorylated dihydrofuranyliodonium salts (473), structures which were confirmed by

X-ray

analysis. 260

The

addition

of

C,N-diphenylnitrilimine

allenephosphonate yields mixtures of the C-phosphorylated (475). the

regioselectivity

being

different

from that

to

diethyl

pyrazoles (474) and

observed

when

diethyl

1 -propynylphosphonate is used as the phosphorus reactant. This suggests that

isomerization

of

allenephosphonate

propynylphosphonate

to

does

not

precede

addition to the nitrilimine, and that the initial adducts from the former are probably of the type (476)261 Two papers discuss the hydrolysis of catechol cyclic phosphonic esters. The ring opening of the compounds (477; R 1

=

Me or CPh3. X

=

0) is accelerated by either acid

or alkali, and similar behaviour is observed with the compound having the 4,6-di-tert-hutylsubstituents.Alcoholysis (R2 compounds (X

=

=

Pr) or phenolysis (R2

0) affords the corresponding (478; X

proceeding much more slowly. The products (478; X

=

=

=

Ph) of the same

0), the latter reaction . = Pr’ or Ph) show a

0, R2

marked tendency to recyclize. A similar treatment of the thiophosphonate (477;

R 1 = Me, X

=

S) yields the same (478; R 1

=

Me, R2

=

H,X

=

0),evidently through

thione-thiol tautomerism and hydrolysis of the resultant P-SH bond, although i t should

be said that the thiol structure could not be detected in the reaction r n i ~ t u r e s . ~ ~ ~ ’ ~ ~ ~ The rates

of

hydrolysis

of

2-substituted- 1,3,2dioxaphosph(V)orinanes and

2-substituted-I ,3,2dioxaphosph(V)epanes are affected in much the same way by a change in the ~ u b s t i t u e n t z ~ ~ The cyclic phosphinate ester (479) hydrolyses < 100 times faster than an acyclic analogue and ca. 1 05 times slower than the phosphonic ester (480).265 A preliminary report describes the behaviour of the phosphinic ester (481), as a mixture of diastereoisomers, in aqueous Na180H. One mechanistic possibility for hydrolysis (with ring retention) is that the reaction proceeds with inversion (route A) when the trans ester (481) would yield (482); these might then be characterized as a mixture of the methyl esters (483)and (484) following methylation with diazomethane. Alternatively,

reaction

with

retention

(route

B)

would

yield

(485) similarly

characterizable as (486) and (487). The observed products were (483) and (487) with the ratio of isotopomers being roughly the same as that of the cis and nuns forms in the initial substrate; (483) w a ~ the , main product. Consequently, the hydrolysis appears to occur stereospecifically with inversion of configuration, thus excluding a mechanism in which the five-membered ring spans the equatorial-axial positions in a P(V) intermediate,

5:

Quinquevalent Phosphorus Acids

183

(479) R’ = H, X = CH2, R2 = Et (480) R’ = H, X = 0 , R2 = Me

=

I8o

0 (490)

184

Organophosphorus Chemistry

and the results would appear to negate the long held assumption that, even for rings

without P-0 bonds, a mechanism involving pseudorotation holds good.266 A study of the alkaline hydrolysis of the phosphonate ester(480) examined the

possibility of involvement of dianionic or hexacoordinate species during the reaction. Compound (488) was formed by P - 0 bond cleavage rather than by cleavage of the C - 0 bond. Also observed was (480), formed under locally high concentrations of (480) by its reaction with (488). (49 I ) was also observed; its formation could result from the cyclization of (480) to (490) with subsequent hydrolysis. The formation of intermediate hexacoordinate species was thought not to take place.26s Four independent reaction pathways have been identified to account for the hydrolysis of the phosphonoformic triester (492), two of which, k3 and k4, involve P-C bond fission. Reactions k l and k4 are the principal ones. The unusual formation of (493) was explained by postulating the involvement of a pentacoordinate species based on a phosphorus-containing three-membered ring.267 The appropriately placed amide group in the esters (494) has a powerful accelerating effect on the hydrolysis of those esters. Although cyclic intermediates of type (495) could not be detected in this study, nevertheless intramolecular nucleophilic catalysis was thought to account for the kinetics of both acid and alkaline hydrolysis of 268 such monoaryl esters. The diethoxyphosphinyl group has only a weakly stabilizing effect on an adjacent C=C bond, and the composition of a mixture of unsaturated phosphonic acid esters produced by the dehydrohalogenation of (2-chloroa1kyl)phosphonic diesters is determined mainly by the potential substitution patterns and hyperconjugation.

A mixture of

2691270

phosphonic dichlorides, consisting of (496; R (2)-(498; R

=

=

Cl), (E) + (2)-(497; R

Cl)

=

CI), in the ratio 44:46:10, was obtained from PrMeC=CH2 and PCI5,

followed by P4OIo, and was converted into a mixture of diethyl esters the ester mixture contained 70% (497; R R

=

and (E) +

=

EtO), and 30% (498; R

,

using EtONa;

=

EtO) + (499;

EtO). A plot of product composition during the course of the reaction between (496)

and base revealed that, as the amount of the latter fell, that of (498) increased, whilst that of (497) initially increased, but then decreased, with the curves crossing. Thus, production of the nb-unsaturation is kinetically controlled, whereas the formation of py-unsaturated products is thermodynamically controlled. Equilibration of the reaction mixture with rert-butyl alcohol gives a mixture containing 12% of (E) R

=

EtO), 84% (E)

+

(2)-(498;R

=

EtO), and only 4% of (499; R

+

(2) -(497;

=

EtO). The

thermodynamically favoured structure has the greatest number of substituents on the

5: Quinquevalent Phosphorits Acids

185

!

+

Bn0-P-COOMe I

BnOH

0-

t

f:

!i

k2

BnO-P-I

BnO-~-COOBn

0-

k3

COOMe

OBn

(493)

-

f:

BnO-7-0OBn

(492)

f:

RCONHCH2P-OH I

OAr

R

(494)

(495)

f:

PrMeCCH2PR2 I

CI (496)

Li+

(500)

8

PrMeC=CHPR2

(497)

8

EtCH=CMeCH2PR2

(498)

H2C=CEtCH$’R2

(499)

::

186

Organophosphorus Chemistry

C=C bond.270 Some properties of diethyl allylphosphonate have been investigated, in particular the behaviour of its anion (500) towards tg-unsaturated ketones and carboxylic esters. Although in some cases the conjugate addition o f the anion has been observed. e.g. in the formation of (501 ) and (502), in most cases the reaction leads to carbocyclic products. 7-Nucleophilicity. with addition-elimination, has been observed in reactions with e.g.

(E)-4-methoxybut-3-en-2-one, when the final product is ( 5 0 3 ) , following

expulsion of the methoxy group. A third mode of reaction consists of multiple addition: thus with (504; R 1

=

R2

=

Me, or R 1

=

H, R2

=

Ph)(i.e. a p-substituent but no b-leaving

group) reaction with (500) leads to the cyclohexane derivatives (505)z7 Pd(0) catalyses the isomerization of (506) into (507)?72 and the interaction of

R1

ester (508;

EtO or Ph) with a ketone R2COR3 in the presence of

=

Pd(Ph3P)4/Sm12 yields mixtures containing the isomeric deacetylated compounds (SOY) and ( 5IO), together with the related pair ( 5 1 1 ) and ( 512), all presumably produced through a common allylic ~ a t i o n . 2 Lithiation ~~ of the triazolephosphonic diesters ( 5 1 3; R1

H or Ph.) yields the rearranged phosphonic diesters (514) after a period of warming.274 =

It has previously been established that the Claisen rearrangements. ( 5 15) to ( 5 16), proceed 10-20 times more rapidly (under comparable degrees of substitution) when A

=

(R0)2P(0) than when A

diamide moiety, A

=

=

ArS02. In a new study, the influence of a phosphonic

(R2N)2P(0), has been explored, more particularly with A

comprising a cyclic phosphonic diamide grouping, in order to exploit the potential controlling

effects of ring size and the relative electronic features of P-N and P - 0

bonds. In this study, a series of (X

=

CH=C=CR3R4: R 1 or R2

=

allenephosphonic

diamides (517) t o (520)

Me, Pri, But. Ph or Bn; R 3 or R4

=

H, Me, or Pri) was

prepared; their reactions with the ally1 alcohols RSR6C=CHCH20H furnished various products depending on the starting material. Thus (517) gave (522) and (523); (520) 2 2 gave (522); (510: R = H) gave (522), (524), and (525); (519; R = Ph) gave (522) and (523); and (518) gave (522). When subjected to treatment with BuLi in THF, the phosphonic diamide ethers (522) rearranged to the ketones (523) significantly faster than comparable phosphonic diester ethers. From the preparative aspect, the N ,N '275 dihenzyl- I ,3,2-diazaphospholidine ring system proved to be the most useful. An unusual example o f steric selection has been demonstrated; following the

addition to sulphur to racemic 0-(-)-menthy1 phenylphosphinothioate (526) to give O-(-)menthy1

phenylphosphinodithioic

acid,

iodine

oxidation

then

afforded

5:

Quinquevalent Phosphorus Acids

187

0

MeoTo

-MeO-

? (RO)ZPCHCH=CH2

f? (RO),PCH=CHCH20Ac

OAc I

0 I,R ’ ,PCHCH=CHR’ I

&Ac

(507)

(508)

(506)

R’

0 11

)PCH2CH=CHR2

EtO

0 I ,PCH=CHCHR~ EtO RI,‘

R‘ 0 11 \PCH= EtOO

R2 CHCH ’CH(OH)R3R4

R’

0 II )PCHCH=CHR~

k(OH)R3R4

Organophosphorus Chemistry

CHZR

N-N

0 (513)

R6

R’

(523)

5:

Qiiinquevaient Phosphorus Acids

(529)

(Arc H2) P(0)NHOS02Me

BU‘N~( o P” ArCH; ‘NHPh

(532)

E

Ph-~-~-NHCHR’COOR2 N OMe t

OH

100 “C *

E

PhCONH-~-NHR1COOR2 OMe

Organophosphorus Chemistry

1 YO

(.SpSp)-his[-(-)-mentho~(phenyl)thioph~~sphonic] disulphide (528); the same product was

ohtained from (Sp)-(526) via (527) and its reaction with either the phosphinodithioic acid or with Me3SiN3. No other diastereoisomers were formed in this unexplained reaction, confirmed by the X-ray analysis of (S28).276

It is known that. when treated with NaOMe in MeOH, the mesylates (520;

R

=

alkyl or Ph) react to give the phosphonamidic

esters (531) via the

metaphosphonamidate intermediates ( 5 3 0 ) ,and a similar migration also occurs when the dihenzylphosphinic R

=

amide derivatives

(532) are similarly

treated. When

(520:

4-MeC H CH ) is so treated. two products are ohtained, one being identified as 6 4 2 = 4-MeC6H4CH2) and isolated in 90% yield: the minor product was methyl

(531; R

phenyl[(4-methylphenyl)methyl]phosphinate. An analogous reaction occurred with potassium ten-butoxide in ten-hutyl alcohol. and with ten-hutylamine the product of the rearrangement

was

(533). These

experiments

thus

demonstrate

that

phenyl

groups migrate in preference to benzylic groups.277 Migrations of alkyl groups have

been

observed

during

the

treatment

of

4-nitrohenzenesulphonates 22 1

of

N-(dialkylphosphiny1)hydroxylamines with an alkoxide base.

The reaction between diastereoisomerically enriched samples of the thiophosphonic chloride

(534) and

phosphonothioic

isopropylamine

diamides

or

(536), and

rcw-butylamine is

thought

to

ultimately

affords

the

proceed

through

the

metathiophosphonamide intermediate (535);the reaction ha5 now been investigated with particular regard to the influence of reaction medium. In dilute solutions, reactions involving both amines are completely non-stereospecific; nevertheless, the ratio of product diastereoisomers differs markedly from the 1 : I ratio which might he expected. As the solvent polarity is increaed (cyclohexane to acetonitrile), there is comparatively little change in the product diastereoisomer ratio for isopropylamine (from 65:35 to 55:45), hut a greater change (from 80:20 to 55:45) for ten-butylamine. The reaction is thought to proceed via a 'free' intermediate (535) when the concentration of amine is low.278 At 100" the oximes (537; R 1 = H or Me, R2 = Me or Et) undergo a 279 Reckmann-like rearrangement to the phosphorodiamidic esters (538). Amongst other examples of P-C bond fission which have been commented upon, are the loss of phosphorus from (539),280 and that occurring during the hydrolytic degradation of the herbicide, Buminafos, (540), to cyclohexanone and C6H o = N B ~ 2 IX The microbial cleavage of the P-C bond, e.g. in 1 -(Y-(ethylphosphono)ribose, can be facile 282 in comparison with chemical cleavage.

5: Quinquevalent Phosphorus Acids

191

8 EH2

(Et0)zPCHRClq(OEt)2

K2C03

R = Me or El

EtOCH2CECR

~6

BuN

(0Bu ) ~

*;

(541) R’ = 1 - A d 0 or Me3CCH20,X = 0, R2 = Me, R3 = H (543) R’ = Mesityl (542) EtO, X =NH, 0 or X =S,0, R2 R2 = =Me, Me,R3 R3 = =HH (544) R’ = Et2N,X = 0, R2 = Me , R3 = H (545) R’ = Ph, X = 0, R2 = R3 = H

N\

0

1

(549)

Organophosphorus C'hemistry

I92

A novel rearrangement accompanies the extrusion of a metaphosphate ester during

the low temperature photolysis of the 2,3-oxaphosphahicycl~)[2.2.2loctane derivatives (54 I ). In addition to the metaphosphate intermediate (546) trapped as the corresponding

(547) hy reaction with ethanol, and the indication of the formation of polymers of (546).

a compound having the new ring system (548; R 1

=

I-adamantyloxy, R2

=

Me) was

isolated and characterized hy X-ray analysis.2X3 'The amide (542) has been used to generate a metaphosphoramidate species by either thermolysis or photolysis; the intermediate could, once again. he trapped as the corresponding (547).284*2X5 The modes of extrusion of (546) from (543) and (544) have been studied from the point of view of the kinetics, and the effects of temperature and solvent286 The sequence has now heen extended to include (545) which extrudes a metaphosphonate (546; HI 287 X = 0)as a polymer and characterized as (547; R 1 = Ph, X = 0).

=

Ph,

Evidence has heen obtained which suggests the formation of a carhene intermediate when a djalkyl aroylphosphonate (549) is acted upon hy a trialkyl phosphite. The evidence includes the further reaction of the proposed carhene (550) with more trialkyl phosphite to yield the ylide (55 I ); in some cases, the ylide then undergoes thermal rearrangement to an ester of the type (552: e.g. R

=

Me, X

=

4-Me0).

Interaction of the ylide with more of the aroylphosphonic diester sometimes results in the formation of a 1,3,2-dioxaphosph(V)olane (553; e g . R

=

Me. X

=

4-CI). For the

(2,4-dichlorobenzoyl)phosphonic diester, the formation of the ylide (55I ) takes place slowly and there is no tendency to form the corresponding (553). In the reaction between (549; X

R

=

Me, X

=

=

2-Et) and trimethyl phosphite, not only is much of the ylide (5S1;

2-Et) produced, hut much of (554) is also formed, evidently through

cyclization of the carbene (550; X ohserved from (549; X

=

=

2-Et). Similarly, the formation of (555) has heen

2-Ph); in this case the reaction occurs under mild conditions,

with no sign of ylide formation. The 4-phenyl compound yields ylide only2" A further. and fuller, account has now heen given of the photolysis of the diary1

esters of phosphonic acids (556; R 1

=

Me, vinyl, ally], or Bn; R2

=

MeO, EtO, SMe, o r

€ 3 ~ ~ ) ~ and " ) of the isomeric his(methoxypheny1) esters of methylphosphonic acid.290 I n

the latter study, the formation of biphenyls and dihenzo[ 1,4][b,e]dioxins is important for (556; R 1

=

Me, R2

=

2-Me0), with the transient species (557) and ( 5 % ) being

detectable through their reactions with methanol. Several interesting

systems have heen ohtained during the photolysis o f

thiophosphoryl diazo compounds, as exemplified in Scheme 49 using (559; R

=

PrI2N).

The products may he cyclic or acyclic and, in some cases the yields are very high. 'l'he

5:

Quinqurvulent Phosphorus Acids

(554)

MeOOC'

(555)

(562)

(560) = MeOOCCECCOOMe

Scheme 49

194

Organophosphorus Chemistry

structure (56 1 ) was confirmed by X-ray analysis. Cyclic systems such as (562) can undergo ring opening e.g. when acted upon by benzaldehyde, or ring expansion e.g. through reaction with (560). The authors consider their results in terms of the possible transient existence of phospha(V)thiirene intermediates.29 1 The Curtius-like photocatalysed rearrangement of the diarylphosphinic azides (563)

in methanol is thought to proceed, at least partly, through (564) which can be trapped as (565). The formation of nitrene intermediates is evident and can lead, by means of internal insertion, to the cyclic phosphonic amides (566). In the c a e of (563; Ar

=

2,4,6-Me3C6H2) the main product is (565) (51% yield), but (566; R 1

=

2,4,6-Me3C6H2,

R3

=

H)

can

also

be

isolated

in

20%

=

Me, R2

yield.

When

rcw4wtyl(mesityl)phosphinic azide is photolysed under similar circumstances, the ‘Curtius’ products (567) and (568) are dominated by the former, indicating the lower migratory ability of the mesityl group: also isolated was ca. 30% of (566; R 1 = Me, R2

Rut, R3

=

(566; R 1

H). For (563; Ar =

Pr’, R2

=

=

s

=

2.4,6-Pri3C H2), the products were 28% (565) and 51%

2.4.6-Pj 3C 6H 2 , R

=

Me), and it would thus appear that an

increase in steric interference at the aryl onho alkyl group allows the insertion process to compete more effective1y.2~~ 3. U s e s of Derivatives of Quinquevalent Phosphorus Acids in Synthesis There have been few recorded novel applications of organophosphorus compounds based on quinquevalent phosphorus acids in conventional synthesis. A further use of diethyl phosphorocyanidate has been noted, here in the synthesis of allenic nitriles from acetylenic k e t 0 n e s . 2 ~ ~Bis( 1,3-oxazo1-2-one)thiophosphinicchloride has been used in the one-step synthesis of amides, B-lactams. esters, and thioesters from carboxylic acids?94

and pentafluorophenyl diphenylphosphinate h a s received attention

~5

an

effective peptide forming re~tgent.2~’ Lawesson’s reagent has been employed in the thiation of flavones and related ~ o m p o u n d s 2and ~ ~ a new reagent for the thiation of amides is (569)297

N-(Diphenylphosphinyl)-3-aryl-1-phenyl-2-propeneimines derivatives when acted upon by p-toluenesulphonic acid.298

(570)

yield

pyridine

5:

Quinquevalent Phosphorus Acids

(567)R’ = Ar, R2 = But (568)R’ = But, R2 = Ar

ir -A

Ph

‘y

Ph

O=PPh,

9 7

(R0)2P- CH,

+

N

Ar

ArCHO Ph

R

R2PCH=CHOEt

F1

RZPCHXCHO

P’Ph3X-

(571)

(572)

(573)

196

Organo phnsp horus C’hemistry 4. The Structures of Quinquevalent Phosphorus Acid Derivatives

The tautomeric involvement of the phosphoryl group in phosphonic esters of the (571) has

type

been

re~iewed.2~’ The

(2-ethoxyviny1)phosphonic diesters (572; R corresponding diamides (572: R

=

addition =

of

halogens,

X2,

to

the

P r o , PriO, or sec- Bu) 300 and the

R 2N)30’ yields the phosphorylated acetaldehydes

(573). and the enolization of these has been studied. The structures and stereochemical interrelationships

between

the

diphosphonic

esters

(574)

(E)

and

and

(2)-1,2-ethenediylbisphosphonic tetraalkyl esters have been examined.302

Several reaction schemes discussed in this Report have been confirmed by X-ray analyses of the intermediates or products in those schemes. X-Ray analysis was also used, together with spectroscopic techniques, to assign structures to the four stereoisomeric products (575) and the two C(3) epimeric linear phosphonates (576) which resulted from the reaction between 4-hydroxy-2-pentanone and dimethyl phosphorochloridi te.303 X-Ray

analyses

have been

performed

on

salts of

diphenyl phosphoric,

phenylphosphonic, and trichloromethylphosphonic acids;304 phosphorylated urea and thiourea derivatives;305 phenyl[[t~-acetyloxy(4-nitrophenyl)]methyl]phosphinicacid;306 and the diethyl esters of the rhreo forms of

(2-hydroxy- 1,2-diphenylethyI)phosphonic 307

and [( 1 -hydroxycyclopenty1)(2-methylphenyl)methyl]phosphonic acids.

Amongst five-membered ring compounds examined by diffraction techniques are a series of six 1,3,2-oxazaphospholidines with 2-phenoxy-2-0x0, Z-phenyl-2-oxo-, o r 2-phenyl-2-thioxo

substituents

and

derived

from

(-)-ephedrine308

as

well

(2R,4R,5R)-2-chloro-3-isopropyl-4-methyl-5-phenyl1,3.2-0xazaphospholidine 30y 3 10 3,3-diethyl- 1,2-diphenyl- 1.4.2-diazaphospholidin-5-one2-oxide.

as and

Six-membered ring compounds which have been examined include a pair of diastereoisomeric

salts from

ephedrine

and

dimethyl- 1,3,2-dioxaphosphorinane 2-0xide,~I

4-(2,6-dichlorophenyI)-2-hydroxy-5,5and

7,7-dimethyl- 1-oxo- 1 -phenyl-3(diphenylphosphiny1)hexahydro-1 H-pyrrolo[ 1,2-c][1,3,2]oxazaphosphorine.312 Seven-membered and larger ring compounds examined include trans-(7; R P h ) 9 the 5,6-benzo[1,3,2]dioxaphosphepins(577; R 1 R1

=

R

=

H , R2 Me, R2

=

H, R2

=

=

PhO o r

Ph, X = O)?’313 (577;

= MeO, X = O);314 and the 5,6-benzo[l,3,2]dithiaphosphepin (577: =

Ph, X

=

!$I 4 8-(2.3-dimethylphenoxy)- 16H-dinaphtho[2,1-d: 1 ‘,2’-g]

[1,3,2]dioxaphosphocin %oxide (15; R 1

=

2,3-Me2C H30, RZ2 = C4H4)I4 and a 3P 5

phosphorus-containing dibenzo- 17-crown-6 compound.

197

(574)

(575)

Organophosphorus Chemistry

198

P acids,3

n.m.r.

( IS;R

( I -aminoalkyl)-

and ( 1 -hydroxyalkyl)phosphonic

and p.m.r. and c.m.r. data for many 2-methoxy-2-oxo- 1,2-oxaphospholan-3-ols

and related ( 1 5; R

data for many

1 1

= =

compound^.^

and for several 12H-dibenzo[d.g][ 1,3,2]dioxaphosphocins.

aryloxy, alkyl, o r Ph)’ and 16H-dinaphtho[2,1-d:1’.2’-g][ 1,3,2]dioxaphocins aryloxy, RZ2 = C4H4), have been presented.14

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96.

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Organophosphorus C’hemistry

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Z. N. Vostrokmutova, V. I. Evreinov, and L. N. Markovskii, J. Gen. Chem. USSR, 1990, 60, 240 1 . 142. P. A. Stepanov, P. A. Gurevich, A. I. Razumov, and T. V. Zykova, J. Gen. Chem. USSR, 199 I , 6 1, 74. 143. N. N. Denik, M. M. Kabachnik, Z . S . Novikova, and I. P. Beletskaya, Bull. Acad. Sci. USSR, Div. Chem. Sci., 199 1 , 1300. 144. B. P. Czech, H. Huh, and R. A. Bartsch. J. Org. Chem., 1992, 57, 725. 145. C. D. Reddy, R. S. Reddy, and C. N. Raju, Asian 1. Chem., 1991, 3 , 63. 146. J. Lin, Xiamen Dame Xuebao, Ziran Kexueban, 1990, 29, 356 (Chem. Abstracts., 1991, 1 1 5 , 136196). 147. Ze-Qi Xu and D. D. DesMarteau, J, Chem. Soc., Perkin Trans. I , 1992, 313. 148. E. Differding, R. 0. Duthaler, A. Krieger, G . M. Ruegg, and G. Schmit, Synlett., 1991, 395. 149. S. F. Martin, D. W. Dean, and A. S. Wagman, Tetrahedron Len., 1992, 3 3 , 1839. 150. W . Cen and Y. Shen, J. Fluorine Chem., 1991, 52, 369. 151. B. L. Rice, C-Y. Guo, and R . L. Kuchmeier, Inorg. Chem., 1991, 3 0 , 4635. 152. D. P. Phillion and D. G . Cleary, J. Org. Chem., 1992. 57. 2763. 153. D. Hebel, K. L. Kuk, J. Kinjo. T. Kovads, K. Lesiak, J. Balzarini, E . De Clercq, and P. F. Torrence, Bioorg. Med. Chem. Len., 1991. 1, 357. 154. J.Veps&Iainen, H. Nupponen, E. Pohjala. M. Ahlgren, and P. Vainiotalo, J. Chem. Soc., Perkin Trans. I t , 1992, 835. 155. S. K. Chakraborty and R. Engel, Synth. Commun., 1991, 21, 1039. 156. D. Direktov and R. Effenberger, J. Chem. Technol. Biotechnol., 199 1 , 5 1, 253. 157. C. K. McClure and C. W. Grote, Tetrahedron Len., 199 I , 32, 53 13. 158. H. Wessolowski, G. Roeschenthaler, R. Winter, and G. L. Gard, Phosphorus, Sulfur, Silicon, Relat. Elem., 1991, 60, 201. 1 S9. V. V. Belakhov, and B. I. lonin, Khim. Primen. Elementoorg. Soedin., 1990, 8 1 (Chem. Abstracts, 199 1, 1 1 5 , 7 1740). 100. C. Yuan, S. Cui, G. Wang, H. Feng, D. Chen. C. Li, Y. Ding, and L. Maier, .S-ynthcsis, 1992, 258. 16 1. E. Oehler and E. Zbiral, Synthesis, 1991. 357.

5:

Quinquevalent Phosphorirs Acids

203

162. J . Lon and N. Amrhein, Justus Liebigs Ann. Chem., 1992, 625.

163. C. U. Kim abd P. F. Misco. Tetrahedron Lett., 1992, 33, 3961. 164. S. K. Tukanova. B. Zh. Dzhiembaev, and B. M. Butin, J. Gen. Chem. USSR, 1991, 61. 1015. 16s. W . M. Abdou, M. D. Khidre, and M. R. Mahran. Phosphorus, Sulfur, Silicon, Relut. Elcm.,, 1991, 61, 83. 166. M. F. Rostovskaya. V. V. Isakov, M. G. Slabko, and V. I. Vysotskii, J. Gen. Chem. USSR, 1991, 61. 827. 167. V. 1. Vysotskii, S. V. Biryukov, M. F. Rostovskaya, B. K. Vasil’ev, S. V. Lindeman, and Yu. T. Struchkov, J. Gen. Chem. USSR, 1991, 61, 352. 168. Yu. V. Prikhod’ko, A. S. Skobun, M. F. Rostovskaya, and V. I. Vysotskii, J. Gen. Chem. USSR, 1991, 61, 1147. 169. V. I. Vysotskii, and S. V. Lovan’kov, J. Gen. Chem. USSR, 1991, 61, 1 196. 170. ‘I. Yokomatsu and S. Shibuya, Tetrahedron:Asymmetry, 1992, 3, 377. I 7 1 . M.Drescher, E. Oehler and E. Zbiral. Synthesis, I99 1, 362. 172. M.Watanabe and S. Furukawa, Synlett., 199 I , 48 1 . 173. D. Villemin, A. B. Alloum, and F. Thibault-Starzyk, Synrh. Commun., 1992. 22, 1359.

174. M.Mikoiajczyk, M. Mikina. P. Graczyk, M. W. Wieczorek, and G. Bujacz, Tctruhedron Lett., 199 1 , 32, 4 189. 175. K. Lee, W. S. Shin, and D. Y. Oh, Synrh. Commun., 1992, 22. 649. 176 F. Hammerschmidt, J. C k m . Soc., Perkin Trans. I , 199 1, 1993. 177. F. Hammerschmidt, Justus Liebigs Ann. Chem. , 1992. 553. 178. K. Lee and D. F. Wiener, J. Org. Chem., 199 1 , 56. 5556. 179. A. A. Tulmachev, A. N. Kostyuk, L. N. Morozova, R. D. Dampeka, E. S. Kozlov, and A. M. Pinchuk, J. Gen. Chem. USSR, 1991.61. 1475. 180. D. Fouqut?, E.About-Jaudet. N. Collignon, and P. Savignac, Synrh. Commun., 1992, 22, 219. I8 I . L. Maier and P . J. Diel. Phosphorus, Sulfur, Silicon, Relar. Elem., 199 1, 62, 15. 182. C. Yuan, G. Wang, S. Chen, and L. Maier. Phosphorus, Sulfur,Silicon, Relat. Elem., 1991, 63, 1 1 1. 183. N. A. Meanwell, H. R. Roth. E. C. R. Smith, D. L. Wedding, and J. J. K. Wright, J . Org. Chem., 1991, 56, 6897. 1x4. 1,. N. Markovskii, Yu. G. Shermolovich, G. G . Barashenkov, V. P. Kukhar’, V. A. Soloshonok, and A. B. Rozhenko, J. Gen. Chem. USSR , 1990, 60. 2005. 185. H-J. Ha and G-S. Nam, Synrh. Commun., 1992, 22, 1 143. 186. S. Caccamese, S. Failla, P. Finocchiaro, G. Haegele, and G. Principato, J. Chem. Rcs. ( S ) , 1992, 242. 187. K.Kellnet and L. Rodevald, 2. Anorg. Allg. Chem., 1991, 600, 189. 188. V. V. Belakhov, V. I. Yudelevich, B. I. Ionin, and M.A. Shneider, Khim. Primen. Elemenroorg. Soedin., 1990, 86 (Chem. Abstracts, 199 I , 1 15, 7 174 1 ). 189. F. Le Moigne, A. Mercier, and P. Tordo, Tetrahedron Len., 199 1 , 32, 384 1. 190. L. Maier, Phosphorus, Sulfur, Silicon, Relat. Elem., 1991, 62, 29. 191. S. D. Pastor, R. Ravichandran, and R. Mewwly, Tetrahedron, 1992, 48, 291 I . 192. L. K. Lukanov and A. P. Venkov, Synth. Commun., 199 1, 21, 195 1. 193. L. K. Lukanov and A. P. Venkov, Synrhesis, 1992,263. 194. K. Afarinkia, J. I. G. Cadogan, and C. W. Rees, Syden., 1992, 123. 195. C. Yuan, S. Chen, and G. Wang, Synthesis. 1991, 490. 196. L. Maier and T. Winkler, Phosphonrs, Sulfur, Silicon, Relar. Elem., 1991, 63, 6 5 . 197. C. J. Broan, E. Cole, K. J. Jankowskii, D. Parker, K. Mukkody, B. A. Boyce, N. R. A. Beeley, K. Millar, and A. T. Millican, Synthesis, 1992. 63. 198. L. Maier, Phosphorus, Sulfur, Silicon, Relat. Elem., 1991, 61, 65.

204

Organophosphorus Chemistry

109. V. V. Negrebetskii. V. A. Kolesova, R. G. Bobkova. A. L. Chimishkyan, and N. I. Shvetsov-Shilovskii,J. Gen. Chem., USSR , 1991, 61, 104.

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5: Quinquevalent Phosphorus Acids

20s

230. V. Solodenko, T. Kasheva, and V. Kukhar, Synrh. Commun., 1991, 21, 1631. 231. R. M. Valerio, J. W. Perich, P. F. Alewood. G. Tong, and R. B. Johns, A m . J. Chem., 1992, 45, 777. 232. V. V. Ragulin, M. E. Bofanova, and E. N. Tsvetkov, Phosphorus, Sulfur, Silicon, Relat. Elem., 199 1 62, 237. 233. X-Y. Jiao. W-Y. Chen, and B-F. Hu, Synth. Commun., 1992, 22. 1179. 234. C. Preussler, K. Schnepp. and K. Kellner, Jusm Liebigs Ann. Chem., 1991, 1 165. 235. T. R. Burke, P. Russ, and B. Lim, Synrhesis, 1991, 1019. 236. C. Garbay-Joureguiberry, I. McCon-Tranchepain, B. Barbe, D. Ficheux, and B. P. Roques. Tetrahedron.Asymmeny, 1992, 3 , 637. 237. C. F. Bigge. J-P. Wu. and I. R. Drummond, Tetrahedron Len., 1991, 32, 7659; CF. I

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206

Organophosphorus Chemistry

259. V. K. Brel’ and E. V. Abramkin, Bull. Acud. Sci. USSR, Div. Chem. Sci., 1991, 409. 260. N. S. Zefirov, A. S. Koz’min, T. Kasumov. K. A. Potekhin, V. D. Sorokhin, V. K. Brel’, E. V. Abramkin, Yu, T. Struchkov, V. V. Zhdankin, and P. J. Stang, J. Org. Chem., 1992, 5 7 , 2433. 261. N. G. Khusainova, Yu. G. Trishin, 6. A. Irtuganova, L. A. Tamm, V. N. Chistokletov, and A. N. Pudovik, J. Gen. Chem. USSR, 1991, 61, 545. 202. I. A. Soldatova. T. S. Kukhareva, and 6. E. Nifant’ev, J . Gen. Chem. USSR, 1990, 60, 1807. 263. 6. E. Nifant’ev, T. S. Kukhareva. I. A. Soldatova, and L. K. Varyanina, Phosphorus, Sulfur, Silicon, Relat. Elem., 1991, 60, 125. 264. C. Yuan, S. Li. and X. Liao, Hlraxue Xuebao, 1991, 49, 272 ( C k m . Abstracts, I99 1 , 1 15, 49827). 265. R. Kluger and S. D. Taylor, J. Amer. Chem. Soc., 1991 , 1 1 3, 57 14. 266. P. M. Cullis and A. D. Kaye, J. Chem. Soc. , C k m . Commun., 1992, 346. 267. A. G. Mitchell, D. Nicholls, I. Walker, W . J. Irwin, and S. Freeman, J. Chem. Soc., PerAin Trans., ff, 1991, 1297. 268. J. Rahil and R. F. Pratt, J. Chem. Soc., Perkin Trans. If, 199 1, 947. 269. J. P. Gerber, T. A. Modro, C. C. P. Wagener. and A. Zwierzak, Heterout. Chem., 1991, 2, 643. 270. M. P. Belciug, A. M. Modro, T. A. Modro, E. R.Rohwer, and A. Zwierzak, Phosphorus, Sulfur, Silicon, Relut. Elem., 1991 , 63. 57. 27 1. Ana M. M. M. Phillips and T. A. Modro, J. Chem. Soc., Perkin Trans. I , 199 I , 1875. 272. J. Zhu, X. Lu, X. Tao, and X. Sun, Chin. Chem. Lett., 1991, 2 , 839 (Chem. Absrracts, 1992, 1 16, 174267). 273. S. Ma and X. Lu, Chin. Chem LRtt., 1991, 2 , 673 (Chem. Abstracts, 1992, 116, 174266). 274. D. K. Anderson and J. A. Sikorski, J. Heterocycl. Chem., 1992, 29, 177. 275. S. E. Denmark, H. Stadler, R. L. Dorow. and J. Kim, J. Org. Chem., 199 I , 56, 506 3. 276. A. topusinski, L. Luczak, J. Michalski. A. E. Koziol, M.Gdaniec, J. Chem.Soc., Chem. Commun., 1991,889. 277. M. J. P, Harger and A. Smith, J. Chem. Res. ( S ) , 1991, 358. 278. M.J. P. Harger, J. Chem. Soc. ,Perfin Trans. I I , 1991, 1057. 279. E. Breuer, H. Zaher, and Z. Tashma, Tetrahedron IRtt., 1992, 33, 2067. 280. T. D. Abramyan, A. M. Torgemyan. and M. Zh. Ovakimyan, Arm. Khim. Zh., 1990, 4 3 , 739 (Chem. Abstracts, 1991, 115, 8906). 28 1 . B. Schneider, A. Porzel. R. Weidhase, and H. R. Schuette, J. R u b . Chem., 199 I , 333, 85. 282. L. Z. Avila, K. M.Draths, and J. W . Frost, Bioorg. Med. Chem. Lett., 1991, 1, 51. 283. L. D. Quin, X-P. Wu, I. Lukes, and R . 0. Day, Tetrahedron Lett., 1992, 33, 3975. 284. L. D. Quin, C. Bourdieu. and G . S. Quin, Phosphorus, Sulfur, Silicon, Relat. Elem., 199I , 63, 349. 285. L. D. Quin. J. Szewczyk, and K. M. Szewczyk. J. Org. Chem., 1991, 56, 5965. 286. S. Jankowski and L. D. Quin. J. Amer. Chem. Soc., 1991 , 1 13, 701 1. 287. L. D. Quin and X. Wu, Heterout. Chem., 1991. 2, 359. 288. D. V. Griffiths, P. A. Griffiths, B. J. Whitehead, and J. C. Tebby, J. Chem. Soc., Pcrkn Trans. I , 1992, 479. 289. M. Shi, K. Yamamoto, Y. Okamoto, and S. Takamuku, Phosphorus, Sulfur, Silicon, Rclat. Elem., 199 I , 60, 1. 290. M. Shi, Y. Okamoto. and S. Takamuku, Tetrahedron Lett., 1991, 32, 6899.

5:

Quinquevalent Phosphorus Acids

207

291. M. Soleilhavoup, A. Baceiredo. F. Dahan, and G. Bertrand, Irwrg. Chem., 1992, 31, 1500. 292. M. 1. P. Harger and P. A. Shimmin, J . Chem. Soc., Chem. Commun., 1991. 1187. 293. R. Yoneda, N. Inagaki. S. Harusawa. and T. Kurihara, Chem. P h . Bull., 1992, 40.21. 294. T. Otsubo. C. Matsukawa, T. Ishizuka. and T. Kunieda, Heterocycles, 1992, 33. 131. 295. S. Chen and J. Xu, Terruhedron Letr., I99 I , 32, 67 1 1 . 296. T. S. Hafez, Phosphorus, Sulfur, Silicon, Relat. Elem., 1991, 6 3 , 249. 297. 0. N. Nuretdinova and F. F. Guseva. Bull. A c d . Sci. USSR, Div. Chem. Sci., 1991, 1423. 298. H. Kakiuchi, T. Kobayashi, and H. Kato, Bull. Chem. Soc. Jpn.,, 1991, 64, 2588. 299. T. A. Mastryukova and M. I. Kabachnik, Hererout. Chem., 199 1, 2, 6 13. 300. R. R. Shagidullin, V. A. Pavlov, B. I. Buzykin. A. Kh. Plyarnovatyu, K. M. Enikeev, M.P. Sokolov, and V. V. Moskva, J . Gen. Chem. USSR, 1991,61, 1459. 301. M. P. Sokolov, B. I. Buzykin, and G. V. Mavrin, J. Gen. Chem. USSR, 1990, 60, 1773. 302. G. M. Blackburn, A. R. Forster, M. Guo, and G . E. Taylor, J. Chem. Soc., Perkin Trans. I , 199I , 2867. 303. A. E. Wrbblewski, W. T. Konieczko, J. Skoweranda, and M. BukowskaStrzyzewska, J. Crystullogr. Spctros. Res., 1991, 21, 581. 304. R. R. Holrnes, R. 0. Day, Y. Yoshida, and J. M. Holmes. J . Amer. Chem. Soc., 1992, 114, 1771. 305. R. Richter, J. Sieler, H. Borrmann, A. Simon, Nguyen T. T. Chau, and E. Herrmann, Phosphom, Sulf w, Silicon Relat. Elem., 1991 , 60, 107. 306. V. V. Tkachev, Zh. Srrukt. Khim., 1991, 32, 125 (Chem. Abstracrs, 1992, I 17, 5948 1). 307. 0. Angelova, J. Macicek, N. Vasilev, S. Momchilova, and I. Petrova, 1. Crystullogr. Spectrosc. Res., 1992, 22, 253. 308. C. H. Schwalbe, G. Chopra, S. Freeman, J. M. Brown, and J.V. Carey, 1. Chem. Soc. Perkin Trans. I I , 1991 , 208 1. 309. P. D. Robinson, D. H. Hua, and D. Roche. Actu Crystullogr. Sect. C, Crysr. Strucr. Commun., 1992, C48, 923. 3 10. X. Liu, M. Sun, F. Miao, K. Feng, and R. Chen. Actu Crystallogr. Sect. C, Crysr. Srruct. Conuruua., 1992, C48,947. 3 1 1 . H. J. Bruins Slot, F. J. J. Leusen, A. D. van der Haest. F. Van Bolhuis, Actu Crystallogr. Sect. C,Cryst. Snuct. Commun., 1992. C48.925. 3 12. K. M. Pietrusiewicz, I. S a l a r n o k y k , W. Wieczorek. A. Brand;, S. Cicchi. and A. Goti, Tetrahedron 199I , 47, 9083. 3 13. I. A. Litvinov, 0. N. Kataeva, V. A. Naumov, R. P. Arshinova. and S. G. Gnevashev, Bull. Acad. Sci. USSR, Div. Chem. Sci., 1991, 196. 3 14. I. A. Litvinov, 0. N. Kataeva, V. A. Naumov, R. P. Arshinova, and S. G. Gnevashev. 2%. S W . Khim., 1990, 3 1, 75 (Chem. Abstracts, 199 I , 1 15, 2947 1 ). 3 15. T. N. Kudrya, V. V. Tkachev. L. 0. Atovmyan, E. S. Gubnitskaya. A. A. Chaikovskaya, and A. M.Pinchuk, Zh. St&. Khim., 1991, 32, 175 (Chem. Abstracts. 1991, 1 1 5 , 2 8 0150). 3 16. 2.Glowacki, M. Hoffrnann. M. Topolski, and J. Rachon, Phosphorus, Sulfur, Silicon, Relat. Elem., 1991. 6 0 . 6 7 . 317. A. E. Wrdblewski, Phosphonrs, Sulfur, Silicon, Relur. Elem., 1991, 61. 97.

6

Nucleotides and Nucleic Acids BY R. COSSTICK AND A. M. COSSTICK

1.

Introduction Work in this area continues to be dominated by studies which are relevant to the use of

nucleic acids as therapeutic agents. There is increasing interest in the synthesis and evaluation of phosphonate and phosphotriester analogues of mononucleotides as potential anti-viral drugs and some important developments have now been made in this field. It appears increasingly likely that triple helix formation, between a single strand which is complementary through Hoog-

steen base pairing to an existing DNA duplex, will be exploited in the therapeutic development of oligonucleotides. Triple helical structures of RNA homopolymers fustappeared in the litera-

ture more than twenty-five years ago, yet the number of papers devoted to this subject has grown dramaticallyduring the last two years, with many elegant studies being reported, particularly from the laboratory of Dervan. Interest in the structure of DNA and its interaction with other molecules has been spurred by world-wide initiatives in the study of recognition processes. Undoubtedly investigations in this area have been aided by developmentsin nmr spectroscopy, such as multidimensional experiments and the use of isotopically labelled substrates. It can now be forcefully argued that nmrbased techniques are the singularly most important method for the elucidation of DNA structure.

Mononuclaotides 2.I Nucleoside Acyclic Phosphates - It is well established that most nucleoside analogues become biologically active as a result of cellular conversion to phosphomonoesters. For this reason there has been increasing interest in the synthesis of nuclemide phosphotriesters and in 2.

some cases, phosphodiesters which might act as membmne soluble pn>-drugs of the bioactive nucleotides.

The diethyl-, dipropyl- and dibutyl-phosphates (1) of 2',3'-dideoxy-3-de-

adenosine have been synthesked and shown to possess anti-HIV-1 activity at non-cytotoxic doses.

Phosphate triester derivatives of the anti-leukaemic nucleoside arabinu-cytidine have

also been prcpared and in an in rim assay the trichloroethyl derivative (2) was found to possess g r a m biological activity than the parent nucleoside.* Interestingly, the bis-trichloroethylphosphates undergo fluoride ion-mediated transesterificationreactions in the presence of nucleophilic

6: Nucleotides and Nucleic Acids

209

(1) R = Et, Pr", or Bun

!

CCI3CH20-7-0

RO

/

(? CCl3CH20--Ff-O CC13CH20

-yyC" \ HO

(2)

HO

(3)

fi'

CC13CH20-P-O I H RN

y k f HO (4)

R = Me, Et, Pr", or Bun R'= Pr" or Bu"

0

(?

Eto-r-o II

0F

M

OMe

I N~

0

OMe

210

Organophosphorus Chemistry

alcohols or amines, that have been used to prepare phosphate (3)and phosphoramidate analogues (4), and a clear structure activity relationshiphas emerged with anti-leukaemicactivity increasing

as the length of the

chain increases.3

More complex esters of 3’-azido-3‘deoxythymidine (AZT) carrying carboxylic ester-

containing side chains, have been prepared and evaluated as potential anti-HIV agents.

In

particular, the bis-(methyl lactyl) triester (5) was shown to be more selective in its anti-viral action than the parent n~cleoside.~Several phosphoramidatederivatives of AZT containing amino acids have been prepared since it was postulated that HIV proteases might be able to assist in the hydrolytx release of the active nucleotide. Of those Containing the trichloroethyl group, the methoxy alaninyl derivative, (6) was the most effective inhibitor of HIV replication although its activity was significantly less than that of AZT.5 In studies on the ethyl methoxy-L-valinyl phosphoramidate derivatives of AZT, a ten-fold difference in ~ t i - H 1 Vactivity was observed for the two diastereoisomersof (7) with the more lipophilic diastereoisomer possessing the greater activity.6 A series of closely related AZT Gary1 phosphoramidares has been prepared from the corresponding phosphorochloridates and evaluated for their efficacy against HIV.

The

methoxy alaninyl phosphoramidate (8) was found to have significant activity against HIV-I infected JM cells, a cell line in which AZT has very low activity due to paor phosphorylation of the nucleoside.’

This observation is consistent with a proposed mode of action which

involves membrane penetration followed by hydrolysis to release the free nucleotide. As an extension to this work, the same group has prepared a series of phosphorodiamidatederivatives of AZT.* These compounds were prepated by reaction of AZT with phosphoryl chloride and subsequent addition of the appropriate amino acid methyl ester.

The bis-phenylalaninyl

compound (9)was found to possess the most potent inhibitory effect against HIV- 1 proliferation. A similar series of phosphate (lo),phosphoramidate (11) and phosphorodiamidate(12) deriva-

tives of the anti-HIV nucleoside 3’-fluoro-3’-deoxythymidinehave also been prepared.9 Of these analogues the phosphate triester (10) was found to be the most potent inhibitor of HIV- 1 replication in a human T-cell line. A series of aryl bis-(nucleoside-5‘-yl)phosphates in which the nucleosides are either

2’,3’-dideoxy (d2)or 2’,3’-didehydm2‘,3’-dideoxy(d4) has been prepared by coupling the nucleoside moieties together using a standard phosphotriesterapproach.lo Only the 4-(methylsulphony1)phenyl derivatives of d4T (13) and d2A ( 14) showed anti-HIV activity that was comparable with the parent nucleosides. The activity of these compounds can be explained by uptake of the triesters into cells followed by a slow release of the nwleoside and nucleotide. A similar strategy has been

adopted by Meier and Huynh-Dinh based on the recent observa-

6: Nucleotides and Nuclric Acids

21 1

l?

0

I

0

F

F

N3

(15)

:4 AcO

0

R = C6H13or Cl6H%

0-P-OR ~

O

A

C

212

Organophosphorus ( ’hemiI Irv

tion’ ’ l2 that the combination of anti-viral and antibiotic agents may be useful in the treatment of AIDS. To match this requirement O-alltyl-5’,5’-dinucleoside phosphates (15) have been prepared as combined pro-drugs of the anti-viral nucleoside AZT and the antibiotic nucleoside cordycepin.l3 The compounds were synthesised by initial preparation of the dinucleosidephosphate, using the phosphoramidite approach, and subsequent alkylation of the phosphodiester using the appropriate alkyl iodide. Lipophilic phosphate triester derivativesof 5-fluorouridine(16) and arabino-cyhdine(17) have been prepared as potential anti-cancer pro-drugs. l4

The 3’-protected nucleosides were

phosphitylated with the glycosyl phosphoramidite (18). oxidised using aqueous iodine and the phosphodiester alkylated with iodohexadecane following removal of the cyanoethyl group. A series of 6‘-(3-sn-phosphatidyl)neoplanocinanalogues (19 - 21) have been prepared by a one-

The phosphatidyl group was donated from the appropriate phos-

step enzymatic procedure. I5

phatidylcholinein a phospholipaw D-catalysed transphosphatidylation. All the compounds ( 19 21) exhibited significant anti-tumour activity which surpassed that of the parent compound.

The nucleoside monophosphate sugar GMP-&fucose (22) which participates in enzymatic fuco-

’

sylation has been synthesised.

Reaction of U-2,3,4-(tri-U-acetyl-a-L-fucopyranosyl)trichloro-

acetamide (23) with acetyl-protectedGMP gave, after deacetylation, the a- and 8-anomers of (22) which were separable by preparative hplc.

Nucleoside phosphonate analogues continue to attract attention as therapeutic nucleotide analogues since the phosphorus-carbon bond is resistant to enzymatic hydrolysis. A general procedure has been developed for the synthesis of 5’-C-phosphonomethyl nucleosides (24) which are isosteric with nucleoside 5’-monophosphates. Phosphonate derivatives of the dideoxynucleosides were prepared by initially condensing the nucleoside 5’-aldehydes with the diphenyl triphenylphosphoranylikmedlylphosphonate (Scheme I ) . l7 The resulting mixtures of E- and Z-alkenes were reduced to the saturated diphenylphosphonate,which was then depro-

tected in a two-step procedure using aqueous sodium hydroxide followed by hydrolysis with C.arox phosphodiesterase. The phospllonate derived from dihxyadenosine showed weak inhi-

bitory activity against HIV-1 in a T-lymphocyte cell culture.

The 5’-C-phosphonomethyl

analogue of 3’-deoxy-3’-fluorocytidine(25) has also been prepared using the same Wittig-type reaction.

’*

An alternative approach to the synthesis of 5’-C.-phosphonomethyl nucleosides has

been developed starting from the WNC acid derivative (26, Scheme 2).19 Conversion to the N-hydroxy-2-thiopyridoneester (27) and in sim photolysis in the presence of diethylvinylphosphonate gave, after reduction, the thymidine monophosphate isostere (28). Compound (28) was readily elaborated to produce (29), an analogue of AZT 5’-monophosphate. A series of 3’,5‘-

213

6: Nucleotides urid Nucleic Acids

(19) R = myristoyl (20) R = stearoyl (21) R = oleoyl

? M~F$NPYP

vG

HO

HO

OH

AcO

0

n

Ph,P=CHPO(OP,h)*

O

w

B

a

s

OANH

OAc

.-

( p h o ) 2 p ~ o ~ B a s e

e

0 II

O

Scheme1

Organophosphorus Chemistry

214

0

0

Scheme 2 0 I1

Base = Cyt, Ade, Thy OH

Ho-0

Ho0

- 01

(34) Y = CH20, CF2,or CH2

6:

21s

Nudeorides and Nuc*lei.icAcids

dideoxy-5’-C-phosphonomethylnucleosides (30) has also been prepared and evaluated for antiHIV- 1 activity.”

The key synthetic steps involved an Arbusov reaction between triethylphos-

,2-O-isopropylide~-c~-D-eryrhro-hexafur (31), followed phite and 3,5,6-trideoxy-6-iododo-l by condensation with the appropriate nucleoside base. The closely related 2‘,5‘-dideoxyuridine-5’-phosphonates(32)have been prepwed by condensation of the 5’diethoxyphosphoryI sugar (33) with bis-trimethylsilyluil in the presence of trimethylsilyltrifluoromethane sulphonate

.’

Some similar carbocyclic nucleoside

phosphonates (34) have been synthesised by purinoselenylationof functionalised cyclopentenyl derivatives.22 In the key step, a seleniranium salt (35)was opened by 6-chloropurine in the presence of silver tetrafluoroborate with good control of stereoselectivity (Scheme 3). A range of nucleoside 5’-hydrogen- and 5‘-methyl-phosphonates has been prepared and

their ability to inhibit the replication of HIV-1 investigated. In particular, the 5’-hydrogenphosphonates of AZT and 3’-deoxy-3’-fluorothymidineexhibited potent anti-HIV-1 activity ~ ~general with selectivity indices similar to, M better than,those of their parent n ~ c l e o s i d e s .A method for the synthesis of 5’-O-(alkoxycarbonyl)phosphonate esters (e.g. 36) of 2’,3’-dideoxynucleotideshas been presented.24 The 4-methoxy-4-(methoxycarbonyl)phosphinylchloride

(37)was generated in sinc by reaction of trimethylphosphoroformateand K l 5 , and condensed directly with the nucleoside.

Treatment of the fully esterified nucleotide with sodium iodide

in THF selectively removed the phosphate methyl group leaving the carboxylate ester intact. The 2’,3‘-dideoxy-3‘-C-@methyl)nucleosides

(38) of the five common nuclm

tide bases have been prepared by a condensation of the nucleobases with l,Zdi-O-acetyl-5-0-

bemyl-3-deoxy-3-(methoxyphosphorylmethyl)-6-D-ribofuranose(39).25 Conversion to the deoxyribosederivative was accomplished by reduction of the Z’-thiomcmbonateand hydrolysis of the phosphonic ester groups using bromotrimethylsilane. 9-( 1-Deoxy- 1-phosphono-B-D-

p i s c o - f u r a n o s y l ) - l , 9 - d i h y ~ ~ - p u r(40, i n ~ Scheme ~ 4)has been prepared as a potential transition state inhibitor of purine nucleoside phosphorylase.26 The crucial step in the synthesis involved the carbon-phosphorusbond formation by reaction of the hemiacetal(41) with triethylphosphite. Nucleotide (40)proved to be very susceptibleto hydrolysis of the glycosidic bond (half-life of thirty-nine minutes, pH 7), but showed weak inhibitory activity (Ki= 26 pM) against purine nucleoside phosphorylase. A method for the alkylation of dinucleosidyl phosphates via stannyl phosphate intermed-

iates has been described.27 The tributylstannyl phosphate (42) was prepared quantitatively by

the addition of a stoichiometric quantity of tributylstannyl methoxi& to a solution of thymidiylyl(3’-5’)thymidinein methanol.

Alkylation was achieved by heating (42) in acetonitrile

Organophosphorus Chemistry

216

SeC6H5

Scheme 3

Me0

P-CI 1

OMe N3

(37)

(36)

0 HO

phA EtOHPkE1

(38)

(39)

6: Nurleotides und Nucleic Acids

217

F!

CHz-P-OH

HO

OH

0-

Scheme 4

HovT OH (42)

(43) x = o (44) X=CH2

Organophosphorus Chemistrv

218

with a large excess of the appropriate alkylbromide in the presence of triethylammonium

bromide. Several nucleotide analogues based on acyclic sugar moieties and containing a phosphonate group are known to possess potent anti-viral activity.

The anti-viral properties of the

I@hosphonomethoxy)alkyl] purines have been

and several new members have

been added to this family of compounds. 1-ha-HPMPA (43), an analogue of the potent antiviral agent (S)-9-(3-hydroxy-2-phosp~methoxypropyl)adenine(HPMPA, &), has been prepared and shown to exhibit potent anti-herpeticactivity.3o In the key synthetic step (Scheme 5 ) the enol ether (45) was coupled with N4-trityl-9-hydroxyadenine in the presence of N-iodo-

succinimide to give the i d d e (46) in 65% yield. Compound (43) (KsO2.6 pM) was found to have greater activity than HMPA (KsO40 pM) against HSV-2 and showed no sign of

toxicity up to 100 pg/ml.

Harnden er ul. have prepared an analogous series of compounds

containing pyrimidine bases (47).31 In this case the synthesis was achieved by a Mitsunobu coupling of the 1-hydroxy pyrimidines with the alcohol (48).

The same group has also

synthesiseda variety of (hydroxy)@hosphonomethyI)phosphorylmethoxyalkoxy-pyrimidines (49) and purines (50) which contain a diphosphonate unit and can be considered 1s analogues of nucleoside d i p h ~ s p h a t e s . ~The ~ requisite phosphonate (51) required for the synthesis was

obtained by means of an Arbusov reaction between (diethoxyphosphin0yl)methyldiethoxyphosphine (52) and 1,3dibenzyloxy-2-choromethoxypropane(Scheme 6). After removal of the benzyl protecting groups the alcohol derived from (5 1) was coupled to either a l-hydroxypyrimidine or a 9-hydroxypurine by a Mitsunobu reaction. Compound (50) (base 1 shown to be active against visna virus at 0.3pg ml- .

=

adenine) was

Unsaturated p h o s p h o ~ t ehave ~ been preparedas acyclic n u c l d d e analogues. Reaction of the (Z)-unsaturated guanine derivative (53) with triethyl phosphite followed by deprotection with trimethylsilyl iodide gave (Z)-N-9-(4-phosphoro-2-buten1-yl)guauine (54) in 65 % yield (Scheme 7).33 Attempts at a similar Michaelis-Arbusov reaction using the butynyl chloride (55) unexpectedly gave 2-amino-6-chl~N-9-ethylpurine(56) as shown in Scheme 8.

The

phowArbusov rearrangementhas been used as the key step in the synthesis of a series of acyclic nucleoside phosphonates related to 9-(5-phosphonopentyl)guanine (57), a potent inhibitor of human erythrocyte purine nucleosidc ~hosphorylase.’~The benylphosphonate diester (58)was obtained in 72% yield by irradiation of a benzene solution of the phosphate (59) with a medium pressure mercury lamp (Scheme 9).

After desilylation and brominationthe intermediate (60)

was readily converted to the guanine nucleotide analogue (61).

6:

Nucleotides and Nuc-lrir Acids

219

(45) Scheme 5

Base = Cyt, Thy, or Ura

! !

Base I

HO-T-Y-0

-0

yo

-0 HO’

(49) Base = Ura, Thy, or Cyt

(50) Base = Ade or Gua

Scheme 6

C

I-

V Gua

i, P(OEt), ii, TMSl

(53) Scheme 7

! rn

HO-7-0

(54)

Gua

Organophosphorus C'hemis try

220

0 B -Et (56)

Scheme 8

-0

(57)

Scheme 9

II

+ (Et 0)2P-

CH=C =C =CH2

6: Nideotide.7 and Nucleic Acids

22 1

A synthetic raeptor (62) has been developed for the recognition of ~ ( A P A ) . ~The ~

receptor forms a cleft and binds to the dinucleoside monophosphate through a combination of a salt bridge and hydrogen-bonded interactions. The crystal structure of sodium 2’-deoxyinosine monophosphate has been determined by X-ray dihction methods.36 This deoxynucleotide shows many expected features, namely an ann’-conformationabout the glycosyl bond, a C2’-endo pucker of the deoxyribose sugar, and a gauche-gauche orientation for the phosphate POUP.

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 - Monophosphorylation of 2’-protectedribonucleosides

with the bifunctional reagent bis-((6-bifluoromethyl)benzotriazol-1-yl]methylphosphonate (63)

or the analogous phosphonothioate (64)and subsequent addition of N-methylimidazole,has been shown to produce exclusively the (Sp)-configurationof both the nucleoside 3’,5’-cyclic methyl phosphonate (65) and the correspondingphosphonothioate (66)respect~vely.~~ The stereospecificity of the cyclisation has been rationalised in the following manner. The initial phosphorylation gives the (@)- and (Sp)-diastereoisomers of the intermediate (67) in almost equal amounts. Addition of N-methylimidazole activates the 3’-hydroxy group which reacts specifically with the (Rp)-diastereoisomerof (67) to give the (Sp)-diastereoisomerof the cyclic product with the methyl substituent in the thermodynamically more stable equatorial position. The (@)-diastereoisomer that is consumed is rapidly replenished by ( 6 - b i f l u o r o m e t h y l ) 1-~1-yl oxidemediated inversion of the (Sp)-diastaeoisomer. Another group has independently described the synthesis of adenosine 3’,5’-cyclic methylphosphonate by an almost identical route.38

(It

should be noted that the authors also reported that only one diastereoisomer was formed and although there is no configurational assignment it is assumed that it also has the (Sp)-configura-

tion.) This cyclic AMP analogue was found to inhibit both cyclic AMP phosphodiesteraseand cyclic AMP-dependent protein kinase at millimolar concentrations. A series of adenosine 3’,5’-cyclic phosphoramidates (68) has been synthesised from

adenosine 3’,S‘-cyclic phosphate in a one-pot procedure.39 The reaction proceeded by treatment of the cyclic AMP tributylammonium salt, in dimethylformamide, with PC15 and the appropriate alkylamine. The compounds showed significant cytotoxic activity against some tumour cell lines.

lnterestingly, studies on mouse mastoqWma P-815 cells showed the

cytotoxic effect of the compounds inmased with an increase in chain length up to ten carbon atoms and decreased in compounds having longer chain lengths.

The conformations of the

Organophosphorus Chemistry

222

Pr

X

II

P-Me

(63)X = 0 (64) X = S

(65) X = 0 (66)X = S

223

6: Nucleotides and Nucleic Acids

o*s d’ \o

NHR

OH

(68) R = CH3 up to n-CIBH3,

(69) -03s

Vh

0

0 II

HoY7Base POC13, PO(OEt),

HO

OH

w

HO

OH

1

t ri-n-butylarnmniurn

phosphate

0

0

vB / vBas ii

II

-0-P-0-P-0 I

- O - 0-P=O

A-

r

! R

- 0-7-0-7-0 0, o”p‘oo,

HO

HO

OH

OH

L

H*O/pH 7.5

HO-TO-7-0-7-0

HO

Scheme 10

OH

224

Organophosphorus C'hrmistrjl

phosphorus-containing rings of a series of nucleoside cyclic 3',5'-phosphoramidates have been studied by detailed 'H nmr experiments.@

To complement this work the solid-state

conformations of several nucleoside cyclic 3',5'-phosphates and their electrically neutral analogues have been studied and The SO2 group has been examined as a stable, uncharged, isosteric replacement for PO2in 3',5'-cyclic nucleotides.

Treatment of either the 5'-@tosyl or 5'-O-mesyl derivative of

3'-O-mesylthymidine with the lithium acetylide-ethylenediamine complex in DMSO has been used to prepare the cyclic sultone (69).42 The sultone (70) derived from a similar reaction with the corresponding 8-D-fhreo-pentofuranosyl thymine nucleoside was shown to react with azide ion (and other nucleophiles) in DMF at 96C to give the sulphonate (71). The sultone (69) was much less susceptible to ring opening by nucleophilic attack.

3.

Nucleosidc Polyphosphates An unusual one-pot procedure for the synthesis of ribonucleoside 5'-triphosphates has

been reported that is based on use of the Yoshikawa intermediate (72, Scheme

Treat-

ment of the unprotected nucleoside with phosphoryl chloride in triethylphosphateand subsequent addition of tri-n-butylammonium phosphate in DMF, gave, after aqueous work-up, the h-iphosphate in good yield ( >60%). The reaction is thought to proceed via the intermediacy of a cyclic metatriphospbate (73)which was initially proposed by Michelson and Todd.

A fully

protected 2'-O-methyl ribonucleoside bound to a controlled-pore glass support via the 3'position has been used in an efficient synthesis of 2'-O-methyl ribonucleoside 5'-triphosphates (74).44 After liberation of the 5'-O-dimethoxytr1tyl group the triphosphate moiety was intro-

duced using salicyl phosphorochloriditeand pyrophosphate. Following deprotection and cleavage from the support, yields of the triphosphate were generally better than 60%. The corres(75) could be prepared as a mixture of diastereoisomers in ponding 5'-O-c~-thiotriphosphates

a yield of 40 - 45% using a modification of this procedure. In an attempt to develop improved anti-HIV agents many nucleoside 5'-mphosphate analogues have been synthesised and studied as inhibitors of HIV reverse transcriptase. The effect of an N-3-substituent on the anti-HIV-1 activity of AZT has been investigated through the preparation of a series of N-3 alkylated AZT deri~atives.'~ Of the compounds prepared N-3ally1 AZT was shown to be the most active (EC50

=

0.9 pM). However, 3-allyl-AZT-5'-tri-

phosphate (76),prepared by Yoshikawa phosphorylation and subsequentreaction with carbonyl diimidazole and tri-n-butylammonium phosphate, exhibited no inhibitory effect against HIV-1 reverse transrriptase. A series of dideoxyribodeazapurinenucleoside 5'-triphosphates (e.g. 77

6:

22s

Nucleotides arid Nucleic Aciris

? 8 ;

HO-P-0-7-0-7-0 I

HO

OMe

x=o (75)x = s

(74)

0

-0

-0

-0

\

(77) R = H, NH2,or NO2

226

Organophosphorus <'hemistry

and 78) has been prepared by Yoshikawa phosphorylation followed by condensation with tetra-

kis(tri-n-buty1ammonium)diphosphate.46 Studieson the ability of thesenucleoside triphosphates to inhibit HIV-1 reverse tranbptase suggest that the purine N( 1) atom is required for inhibitory

activity. Similar studies on the deazaguanosine series have revealed that the triphosphate (79) is a potent inhibitor of HIV-1 reverse transcriptase (ICs0 = 0.27 P M ) . ~ The ~ triphosphates of 2-amine5-ethyl-2'-deoxyuridineand 2-amino-(E)-5-(2-bromovinyl)-2'-deoxyuridinehave been prepared and evaluated as substratedinhibitorsfor different DNA p o l ~ m e r a s e s . Neither ~~ of these compounds proved markedly inhibitory to herpes simplex virus type 1 (HSV-1) DNA polymerase or cellular DNA polymerase a and they were not incorporated into DNA. The triphosphate (80) of a carbocyclic nucleoside has been prepared as a racemate in eight steps from 6-oxabicyclol3.1.Olhex-2-ene (Scheme 1l).49 Unexpededly this triphosphate ester, derived from a secondary alcohol, acted as a moderately good inhibitor of HIV-1 reverse transcriptase (ICsO

=

7.9 PM). The same group has synthesised the 5'-triphosphate of the 6-

fluorocarhocyclic analogue of thymidine (81); it was found to be a poor inhibitor of this enzyme.50 Several 5'-triphosphates of modified nucleosides have been prepared and evaluated as substrates for DNA polymerases. The ability of E. cofi DNA polymerase I (Klenow Fragment) to utilise 2'deoxy-6-thioguanosine 5'-triphosphate (S6dGTP) has been i n ~ e s t i g a t e d . ~Kinetic ~ 6 studies demonstratedthat S dGTP is readily incorporated into DNA in place of dGTP and is also misincorporated in place of dATP at a low, but detectable frequency.

N-2-Alkyl and N-2-

phenyl 2'deoxyguanosine 5'-triphosphates have been synthaised and evaluated as substrates for E. cofi DNA polymerase I.52 N-2-methyl dGTP and N-2-ethyl dGTP were efficiently incorporated in place of dGTP, whereas N-2-phenyl and N-2-(4-n-butylphenyl)dGTPwere poor substrates for DNA synthesis.

Melting temperatures obtained for oligodeoxyribonucleotides

containing N-2-alkyl deoxyguanosine residues annealed to complememtary single stranded DNA were lower than those obtained for the equivalent unmodified duplexes. Symmetrical dinucleoside S'-pyrophosphates (82) have been prepated in high yields ( > 80%) from the

free acid of the nucleoside 5 ' - ~ h o s p h a t e . ~This ~ one-potprocedure is most

efficient when performed in DMF or DMSO using about four equivalentsof triphenylphosphine and 2,2'-dipyridyldisulphide as the coupling agent and a large excess of N-methylimidazole as the catalyst. The cap portion (83) of messenger RNA has been synthesised in 37% yield by Mn2+ ion-catalysed pyrophosphate bond formationbetween7-metbylguanoSine5'-phosphorimidazolide and a nucleoside S'-diphosphate in neutral aqueous solution.s4

In the absence of

Mn2+, hydrolysisof the phosphorimidazolide was predominant. The role and effect of varying

6: Nucleotides and Nucleic Acids

oo--8 steps

227

! R R

HO-7-0-7-0-7-0 -0 - 0 -0

Scheme 11

HO

(83)

OH

228

Organophosphorus (’heniisiry

the metal ion in this pyrophosphate bond forming reaction has been investigated by Sawai er al. and the metal ions Mn2 , Mg2+ and Cd2 +

+

were found to be the most effective.55

The

yields obtained with Cd2 were found to vary depending on the nucleoside base, suggesting that +

this metal is also coordbating to the base moiety. It is thought that the M2+ ions assist pyre phosphate bond formation through organisation and activation of the substrates by coordination. Carbohydratederivatives of nucleoside polyphosphates are attractive targets for enzymatic synthesis as the products can be obtained under mild conditions, usually with absolute control

of regiochemistry.

A practical method has been developed for the gram-scale synthesis of

uridine 5’-diphosphoglucuronicacid (84) from uridine 5’-diphosphoglucose(85) using uridine 5’-diphosphoglucose dehydrogenase (UDP-Glc DH) isolated from bovine liver (Scheme 12).56 The required cofactor, NAD, was regenerated in sinc using a coupled pyruvate/lactate dehydrogenase system.

Four equivalents of pyruvate were used in order to force the reaction to

completion. This enzymatic procedure was found to be superior to a platinum-catalysedoxidation of (85).

Efficient enzyme-based routes have also been developed for the synthesis of

c o ~and ~ ~ ~uridine 5‘-diphosphogala~tose~~ (87). uridine 5 ’ - d i p h o s p h ~ N - a c e t y l g l ~(86) A series of glucose-adenosinediphosphate hybrids, in which carboxamide (88). acetylene (89)

and allene (90) groups link the two moieties, has been prepared and evaluated as potential inhibitors of h e x o k i n a ~ e . ~Both ~ the ciuhxamide (88) and acetylene (89) derivatives were effective inhibitors of yeast hexokinase (k,

=

0.2 and 2.5 mM, respectively) and were competi-

tive with glucose and non-competitive with ATP. The synthesis of the two diastereoisomers of

91-(2-nitrophenyl)ethyl adenosine 5’-@i-

phosphate (91) has been achieved using resolved (R)- and (S)-l-(2-nitropheny1)01.~

The

alcohols were converted to (R)-and (S)-1-(2-nitrophenyl)ethyl phosphates by phosphitylation with N,Ndiisopropyl-bis-(2-cyanoethyl)phosph(92) and subsequent oxidation with 3chlorobemic acid. Each of the monophosphates was activated with carbonyldiimidazoleand condensed with adenosine diphosphate to give the desired triphosphate. These ATP analogues can be used for the rapid release (by flash photolysis) of ATP in biological systems. The 8-

azid0-3’-O-ant.hraniloylderivatives of 2‘dADP (93) and 2’-dATP (94)have been prepared in seven steps from 8-azido-2’deoxyade1~mine.~~ These compounds are of interest as fluorescent and photoactivatable probes for the nucleotide binding site of kinases and cyclases. In particular, (94) was shown to be a competitive inhibitor of Bonierelfupcmsis adenylate cyclase and the observed Ki (74 pM) was close to that predicted from the Kivalue of 3’-0-anWloyl2’-dATP.

6:

229

Nudeorides clnd Nuc-leic Acids

x

2 NAD

2 NADH

L-lactate DH

UDP-GkDH

coo 0-P-0-P-0

HO

I

HO

OH

(84) Scheme 12

HO

(86) R = HO

HO-HO AcHN

OH

(87)R = HO

Organophosphorus Chemistry

230

0

HO

OH

OH

HO

OH 0 (88) X =

PN H

(89)X =

\

E

?

-s

-s

R-7-0-7-0

&*

vG HO

OH

E

NH2

(95) R = HO-7-0

-0

(93)R = OH 0

(96)R = OH

II

(94) R = HO-7-0

-0

AcO

OAc

6: Nucleorides and Nucleic Acids

23 I

Thiotriphosphatescontinue to be both challenging targets for organic synthesis and useful substrates for enzymatic and biological studies. The synthesis of the four diastereoisomers of guanosine 5’-0-(1,2-dithiotriphosphate)(95) has been described using a combination of chemical and enzymatic techniques.63 The (JQ,@)- as well as the (s;O,@)-diastereoisomers of (95) were most conveniently obtained by phosphorylation of (@)- or (Sp)-GDPaSBS (96) respectively, with acetate kinase. Phospbrylation of (%) with pyruvate kinase only provides a route to (Sp,Sp)-GTPaSBS,since only (Sp)-GDPcrSBS is a substrate for this enzyme. How-

ever, all four diastereoisomers can be preparedby a second method in which (97) is reacted with thiopyrophosphate and contaminating GTPaSyS is selectively removed by hydrolysis. It is a well established property that many enzymes interact in a stereospecific manner

with the different diastereoisomersof nucleoside phosphorothioates. For example, when AMP is substituted by adenosine 5‘-O-monaphosphororhioate(AMPS), adenylate kinase-catalysed phosphorylation occurs specifically at the pro-R oxygen atom to give (Sp)-ADPaS. The stereospecificity results from the restricted orientation of the P-0 and P-S bonds in the enzyme active site. While it is known that changing the metal ion can perturb the stereose.lectivity,Tsai and co-workers have dramatically established that site-directed mutagenesis on adenosine kinase can alter the enzyme-substrate interactions and change the stereospecificity of the

A

mutant of the chicken muscle adenosine kinase with arginine 44 (a residue previously proposed to interact with the negatively charged phosphate moiety of AMP) replaced by methionine has

been shown to have a completely reversed stereospecificity at the AMP site. Thus, phosphorylation by this mutant enzyme produced (Rp)-ADPaS almost exclusively. A series of thymidine triphosphate analogues (98 a - e) has been prepared in which the

a/B or B/y bridging oxygen atom is replaced by the imido grwp (Schemes 13 -

Compound (98e)was shown to be a surprisingly potent inhibitor of HIV-1reverse tnmaiptase (Ki = 87 nM). A difluoromethylphoqhnate analogue (99) of AZT 5’-triphosphate has been

prepared and evaluated as an inhibitor of HIV-1 reverse t r a n s c n p t a s ~ . ~Difluoromethylenebis-phosphonic acid was prepared using acetyl hypofluorite-mediated fluorination of tetraiso-

propylmethylene-bis-phosphonateand dealkylation using mmethylsilyl iodide. The bis-phosphonic acid was coupled with the 5’-phosphoromorpholidateof AZT under standard conditions, to give (99) quantitatively. The phosphonate analogue (99) was thirty-fold less effective than AZT 5’-tripbsphate as a competitive inhibitor of HIV- 1 reverse transrriptaSe,but interesthgly ten-fold more effective than the methylenephosphonateanalogue (100). ADPBF (101) has been prepared by tbe reaction of AMP morpholidate With excess bis-(tri-n-butylammonium)flumoThis nucleotide analogue, which is comparatively stable in aqueous solution, was

Organophosphorus C'hemistry

232

HO-P-X-P-Y I

0

-P-

I

R X

(98a) (98b) (98c) (98d) (98e)

Y R 0 N OH 0 N N3 0 N H N N OH N 0 N3

CI-P-N=P-CI

+

I

I

CI

CI

HO

vT R

1

i, PO(OEt,), - 20 "C ii, NaOWH,O

(98a-c)

H O -FP 1 - NH- P R- O y 0 7 T h y

i, Carbonyldiimidazole ii, (BU)~N-H,PO,

I

-0

I

-0 R

Scheme 13

8

CI-P-N=P-N=Y-CI I

CI

I

CI

? CI

+

HO

i, PO(OEt),

YThY ii, NaOWH20

OH

Scheme 14

(gee) Scheme 15

(98d)

233

6: Nucleotides and Nucleic Acids

(99) X = F (100) X = H

R7- 0- R7- 0

8 R

F-

-O-~-O-~-O 0 0

HO

OH

pA HO

(101)

(1 02)

NH2

R

0-7-0

OH

234

Organophosphorus Chemistry

found to be a good mimic of adenosine 5'-phosphosulphate (APS) (102) and was a substrate

for adenosine phosphosulphate kinase. In contrast, ADPBF was a poor analogue of ADP and these results suggest that the major dtterminant in enzymatic discrimination between APS and ADP is the charge difference between the terminal sulphuryl and phosphoryl groups.

It has

been suggested that organic vanadates are likely to be good analogues of organic phosphates. Kinetic studies have been used to demonstrate that nicotinamide adenine dinucleotide 2'vanadate (103) is able to act

w

a cofactor for bakers' yeast glucose-&phosphate

dehydrogenase .68 X-ray crystallography has been used to investigate the humidity-dependent transition of disodium adenosine 5'-triphosphate between the dihydrate and trihydrate forms.69 The study reveals useful information about the dynamic aspects of ATP which are useful in understanding ATP-enzyme interactions. The 13C nmr line-shapes of 12- 13C)ATPhave been studied in both viscous solutions and enzyme complexes.70 The results show that glycosidic rotation persists at high viscosity, but is arrested in enzyme complexes. It has been demonstrated that ATP and AMP bind to a guanidinium-functionalisedmonolayer derived from (104) viu specific hydrogen bonding and electrostatic attraction.71 4.

Oligo- and Poly-nucltotides

4.1

DNA Synthesis - The chemical synthesisof DNA is now highly developed and relatively

few papers are appearhg on the synthesisof unmodified DNA. A genenil review has appeared on the synthesis of DNA and DNA aaalOgue~:~* a more focused article on the application of the phosphoramiditeapproach to the synthesis of oligodeoxyribe and oligoribonucleotideshas also been ~ublished.'~ An optimised polystyrene support for DNA synthesishas beea developed which uses polystyrene spheres (50

-

100 pm diameter) with a pore size of loo0 A and 50% cross-linked by

di~inylbenzene.~~ The 3'-tetminal residue is attached viu a succinate linker to a support-bound benzylamine moiety. In a direct comparison with a controlled-pore glass (CPG) support, the polystyrene support gave equal or superior results. Side reactions on the polystyrene support are thought to be minimised due to the lack of reactive functionality on the support surface. A procedure has been reported for the preparation of oligonucleotidesthat does not require the

~~ CPG solid support was used in which the 3'-tenninal use of ammonia for d q o t ~ t i o n . A nucleoside was attached through a 4-(2'-hydroxyethyl)-3-nitrobenzarm'de linker (105). Chain elongation was carried out using cyandylphospbramidite monomers in which the heterocyclic amino groups were protected with the 4-nitrophenylethoxycyl group. Complete wow-

6:

Nucleotides and Nucleic Acids

235

tion was achieved by treatment with a 0.5 M solution of DBU in pyridine for three hcnrrs. This sfrategy has been successfully applied to the synthesis of short oligodeoxyribonucleotidescontain-

ing the ammonia-sensitive mutagenic bases 0 4 p r o p y l and 04-butyl thymine. Liquid-phase synthesis of oligonucleotides using a polyethylene glycol support (previously named High Efficiency Liquid Phase synthesis) has been applied to the large scale preparation of short oligomers using the hydroxybenzotriazole phosphotriester appr~ach.’~ In a reprtsentative synthesis, the octamer d(TAGCGCTA) was prepared with an average coupling yield of greater than 93% and

from 1.9 g of the support 150 mg of tbe deprotected and purified product was obtaiaed. Using phosphoramidite reagents a procedure has been developed for the synthesis of short oligonucleotides which does not necessitate the use of base protecting groups.77 The nucleoside 3‘-phosphoramidites (106) were obtained in about 90% yield by phosphitylating the 5’-DMTprotected nucleoside with MeOP[N(Ri)2J2. Activation of this phospboramidite with pyridine hydrochloridelimidle was shown to lead to preferential phosphitylation of hydroxyl groups in the presence of the exocyclic amino groups.78

The use of this activating agent and the

incorporation of a pyridine hydrochloride/aniline wash step (which cleaves any P(l1I)-N bonds) permits the synthesis of mixed-base 20-mer oligonucleotides from non-base-protected nucleoside monomers.

31P nmr studies on the thymidine monomer show that a nucleoside phospboro-

monochloridite (107) is formed when the arnidite is treated with pyridine hydrochloride. Medium size oligodeoxyribonucleotides have been pr-

on a solid-phase support from

deoxyriboaucleoside 3‘-bis-(1,1, I ,3,3,3-hexaflw~2-propyl)pbosphite (108) Unitsby activation with ~-methylimidazo~e.’~This procedure results in internucleotide ~-phosphonatelinkages which are oxidised in the normal manner once the synthesis is complete.

RNA Synthesis - By comparison with DNA synthesis, the preparation of RNA oligomers is not a trivial task. In particular, the selection of a suitable protecting group for the 2’hydroxy functions of the ribonuclaoside building blocks is of critical importance. The 1-(2-

4.2

chlor0ethoxy)ethyl (Cee) (109) group has been employed, in conjunction with the 5’-O-DMT group, for the synthesis of oligoribonucleotides by the phoybramidite approach.m

The Cee

group was shown to be completely stable to the acidic conditions required to remove the DMT groups, but was removed in a frnol debloclring step using acidic hydrolysis at pH 2.0.

This

group has been evaluated in the synthesis of a series of RNA oligomers cOntaining UP to twenty ribonucleotides. The use of the acid labile 4-metboxytetrahydmpymnylgroup for permanent 2’-protection in combination with the 5‘-O-fluorcnylmcthoxycuboayl(Fmoc)group which is removable under basic conditions has some attractions as a strategy for oligoribonucleotide

236

Organophosphorus Chemistry

DM 0, ,OMe

7

CI (107)

6:

Nitcleotides and Nucleic Acids

synthesis.

237

To further this work the 3’/5’-regioselectivity for the introduction of the Fmoc

nucleosides has been investigated.” group into 2’-0-(4-rnethoxytetrahydropyranyl-4-yl)

The

desired 5’-O-Fmoc nucleosides (1 10) were shown to be the major products and were isolated in yields of 52 - 65%. A new and general method for the introduction of the [[2-(methylthio)phenyl]thio]methyl

(MPTM) protecting group into the T-position of ribonucleosides (111) has been published

nucleoside (Scheme 16).82 The procedure utilises a fully protected 2’-0-1,3-benzodithiol-2-y1 ( I 12) which is reduced with tri-n-butyltin hydride, S-methylatedwith methyl iodide and desilylated to give the 3’,5‘-diol (1 1 1).

The usual 5’-O-dimethoxytritylationof (1 11) followed by

phosphorylation with S,S-diphenylphosphorodithioate and mesitylenesulphonyl chloride gave the nucleotide unit (113).

The chemical synthesis of RNA has been accomplished using base

protecting groups that are rapidly removed under basic conditions.83 The standard blocking groups for the exocyclic amino functions have been replaced by dimethylformamidine for adenosine and guanosine and isobutyryl for cytidine.

Removal of these groups using

concentrated aqueous ammonia is complete within one hour at 55% and eight hours at room temperature. It is established that the efficient synthesis of RNA requires a delicate balance between steric bulk of the 2’-protecting group and reactivity of the phosphoramidite. The application

of 2-cyanoethyl-N,Ndiethylphosphoramidates to RNA synthesis, in combinationwith triakylsilyl blocking of the 2’-hydroxy group, has been examined.@ In comparison with the diisopropyl derivatives they were found to be sufficiently stable, easier to prepare and gave higher coupling efficiencies. The diethylphosphoramiditeswere generally used in combination with r-butyldimethylsilyl protection of the Z‘-hydroxy group; with the exception of guanosine, where the triisopropylsilyl group was used.

The authors report that using these. synthons

oligoribonucleotides with chain lengths in excess of seventy residues can be prepared with acceptable purity and yield.

The solution phase synthesis of oligoribonucleotides has been

investigated using phosphotriester chemistry and a cellulose acetate support.85 Improvements to this strategy have been made by incorporating a (3-ca1-boxy)propiony1 spacer into the cellulose support and using 2‘-cyanoethyl protection for the 0-6 position of guanosine. The expression of proteins containing site-specific non-natural residues is obviously an important goal in the design and production of novel proteins/enzymes.

A general strategy

involves engineering one of the termination codons (a nonsense mutation) into a gene at the position of modification. Under normalcircumstancestranslation of mRNA transcribed from this gene would result in a truncated protein product since there is no tRNA corresponding to the

0rganop h osph orus Chernistrv

238

o0 ,.-\

0vS*

-&.J

u)3SnS

"

O

w

B

a

s

e

0

MeS

MeS

MeS

Scheme 16

6: Nucleotides and Nucleic Acids

239

termination cadon. However, the translationsystem can be supplemented with a semisynthetic nonsense su~pressortRNA whose anticodon is complementary to one of the termination codons

and is charged with a non-natural residue. Crucial to the success of this strategy is the requirement for efficient and simple procedures for the construction of the nomeme suppressor tRNAs. The most widely used strategy involves enzymatic ligation of a chemically synthesised 2'(3')-U aminoacyl-CpA unit to a tRNA lacking the 3'-tenninal CpA unit.

The synthesis of 2'(3')-@

(L-pheny1alanyl)CpA (1 14) and 2'(3')-O-(D-pbenylalanyl)-CpA (1 15) has been investigated and a general route has emerged which uses the trichloro-t-butoxyabnyarbonyl group (removable with zinc-acetylacetooe under neutral conditions) for protection of the amino groups of cytidine

and adenosine and the acid labile ethoxyethyl group for blocking the 2'-hydroxy function.86

The internucleotide linhge was introdwed by the phospbattiesterapproach using the pbenylthio group to protect the phosphate and the amiaoacetylation of the 3'-hydroxy group accomplished with the N-benqloxycarbmyl-proteckdamino acid using DCC. This combination of protecting groups enabled complete deblocking to be achieved without fesofting to hatsh acidic or basic conditions. In an additid study, four different procedures, based on either run-off transrrip tion or solid-phase. synthesis, have been compared for the preparation of a wnsense suppressor ~ R N Aacylated with ~-3-iodotyrosine.~~

(2'-5')-Linked adenylate oligonucleotides consisting of three or more monomer units and carrying a 5 ' 4 - or triphosphate are involved in an anti-viral respoase by activation of the endoribonuclease, RNase L, which inhibits translation through cleavage of messenger aad ribosomal RNA.

This anti-viral effect is only transitory Since the 2'-5'-adenylates am rapidly cleaved

by cellular phospbodiestaases. To suppress the digestion of these mokcules and to investigate the effect of structure on biological activity a number of analogues of 2'-5'-obgoadenylates have been prepared. The chemical synthesis of the diastereomerically pure phospborottu'oate 2'-5'-A trim~ore~ (1 16) has been achieved by the phosphorarm'dite approach using sulphur oxidation and subsequeot separation of the isomers by silica-gel ~ h r o m p t o g r a p h y . ~It~ was established that the configuration of the intemucleotidephosphorotht'oate linkage Qes not affect binding to RNase L, but has a signrficant effect on the activation process. Activation decreases in the order (l@,l@)>(&l@)>(l@,Sg). The (&~,Sp)-(2'-5')-A-trimer-core is an effective inhibitor that binds to RNase L,but does not activate the enzyme. A sfffeoselective synthesis

of (2'-5')-oligoadenylates umtaining pbosphorothr'olatelinkages with the (@)configurahon has been obtainedusing the hydrogen phoapboarteapproach followed by oxidative SulphUri~ation.~~

The stereaektivity of the reaction is dependent on the 3'-protecting group: for example, use

240

Orguriop hosp horus C 'hernistry

Howcy' O \, O ,

HO O\\

OH

/

0

-o'p'oY7Ade - -s'p'oY7A 0

R'+

0

0

HO

0

H '

NH2 (1 14) R' = PhCH2, R2 = H (1 15) R' = H, R2 = PhCH2

HO (1 16)

i, pivaloyl chloride ii, Se

(117)

BZ = COPh

t

(118)

Scheme 17

OH

6:

Nuckotides and Nucleic Acids

241

of the 3’,5’-0-( 1,1,3,3-tetraisopropyl-1,3disiloxanediyl)adenosinemonomer (1 17) gave the (Sp)-diastereoisomerof (1 18) exclusively (Scheme 17). 8-Methyladenosinesubstituted analogues of (2’-5’)-A 5‘-triphosphate were prepared by using a lead ion-catalysed ligation reaction.90

The analogue containing 8-methyladenosine

residing in the 2’-terminal position (1 19) showed the strongest binding affnity to RNase L and was several times more effective than the unmodified bimer as an inhibitor of translation. A series of uridine-substituted analogues of (2’-5’)-oligoadenylates have been prepared and evaluated for their ability to bind and activate RNase L.91

Substitution of the 5’-terminal

adenosine by uridine caused up to a hundred-fold loss of both binding and activation of RNase L, whereas the effect of replacing the 2‘-tenninal adenosine residue was to dramatically reduce activation of the enzyme. These results reinforce earlier studies which had indicated that structural elements of the 5‘-adenosine nucleotide are involved in binding to RNase L, whereas activation is dependent upon structural determhmts of the 2’-residue. Studies on self-replicating systems, includmg template directed synthesis of oligoribonucleotides using phosphorimidazolide monomers, have been reviewed.92

4.3

Modified Oligonucleotides

4.3.1

Oligonucleotides contliaing modified phosphodiester m g e s - Activity in

this area continues unabated particularly with regard to the synthesis and evaluation of modified oligonucleotides as potential chemotherapeuticagents. several reviews93-97 have appeared in the area of antisense technology and the importance of this therapeutic principle can be readily appreciated from the appeamce of a journal dedicated to “Anriseme Researrh and Developmenrs”.

Attention continues to be focused on the pbsphorothioate, phospborodithioate and

phosphonate modifications although there is aiso increasing interest in intemuclcotide linkage replacements that do not contain phosphorus. An elegant stemontrolled synthesis of oligodeoxyribonucleosidephosphomthioates has been reported that is based on the use of 5’-0-(2-thio-1,3,2-oxathiephospho lane) intermediates

(120, Scheme 18.)98 Chromatographic isolation of the diastereomeridy pure thiaptmqholane

synthons enables them to be used in a stereospecific (> 99%) DBUcatalysed reaction with the 5‘-hydroxy function of a support-bound nucleoside. This procedure allows tbe Preparation of internucleosidephospho&oate

linkages with predeterrmned . configuration at eacb phosphorus

-H centre. The oxidation of diastereomeridy pure diribonucleoside-

‘oatediesters

with 3H-2,l-benzoxathiol-3-one has been investigated and found to be stereospecific,proceeding

with reteation of configuration at phosphorus (Scheme 19).99 Both the oxidation of H-phos-

242

Organophosphorus C'hemistry

? ! ? ?

HO-P-0-P-0-P-0 I

I

HO

o+

0

/

HO

0

HO

OH

vB HovBa 'ow MTo

0, /sP

O" '

O

'p'

w

B

0

a

s

s"

e

k

Scheme 18

ase

I

0

0

+s-

6: Nucleotides and Nircleic Acids

TBDMSO

243 TBDMSO

0

OTBDMS

BzO

o

OBz

w

a

BzO

OBz

s

e

Scheme 19

DM

MTo V : 0, e aK ,s e

7

Me

s -CN

O

?i

R’O-P-OR~ I -S

v

B

a

s

e

+

(1 24) 0

E

R10-P-OR2 I

+

?i

R10-y-OR2

(124)

H

+

e

o

-0

(125) S

II

R10-P-OR2 I H

+

(125)

Scheme 20

244

0rganoph ospho rus (Yi ('tn ivlry

phonothioate diesters with iodine in aqueous acetonitrile/triethylamine and oxidative coupling of H-phosphonotluoate diesters with ethanol under similar conditions, have also been found to be stereospecific reactions. loo

It is thought that the reactions proceed with overall retention

of configuration. Extensive epimerisation was observed when the reactions were carried out in the presence of pyridine.

Although phosphorothioateanaloguesof ribonucleotideshave been used to increase stability towards enzymes such as nucleases, detailed studies on the relative cleavage rates of the

phosphate and phosphorothioate systems have not been repofled. Almer and Stromberg have measured the difference in rates of cleavage of uridyly1(3'-Y)uridine and the (@)- and (Sp)diastereoisomers of the corresponding phosphorothioateanalogues. lo' The ratios of the rates were found to be K@hosphate)'K(Rpphosphorothioate) - .3; K(phosphte)lK(Sp~ ~1 .7 p and h o were ~ ~ o r ~ i ~ ~ ~ phosphorothioate) - 0'78 and K ( ~ ~ - p h O s p h O ~ O t h ~ ~ t e ) / ~ ~ = shown to be independent of pH in the range 9 - 12.

An oligonucleotide hybrid consisting of a DNA phosphorothioate trimer attached to the 3'-end of the RNA octadecamer has been

synthesised by the combined use of the phosphotriester and phosphoramidite approaches.lo* The 3'-phosphorothioate residues, introduced by the phosphoramidite method, were shown to significantly protect the oligomer from the action of nucleases. This hybrid, in which the ribonucleotide portion is complementary to the leader sequence of phage fl coat protein mRNA, was used to study the formation of the initiation complex in prokaryotic translation. Oligonucleoside phosphorodithioates containing all four nucleobases and up to twenty residues have been prepared using the N,N-dimethylthiophospboraphoramidites (121). lo3

It was

shown to be necessary to sulphurise the internucleoside thiopbosphite (122) rapidly in order to prevent tetrazole-catalysed reactions of the thiophosphite with nucleophiles.

Oligomers

prepared by this procedure generally contained about 8% of phosphorothioate impurities, as determined by

P nmr spectroscopy. The origin of the phosphorothioate linkages was found

to be independent of the reagent used (e.g. anhydrous hi-f-butylamine or aqueous ammonia) to

remove the cyanoethyl group, suggesting that the phosphorothioate does not result from hydrolysis of the phosphorodithioate biester. Thermal melting studies on phosphorodithioatecontaining oligonucleotideshybridised to a complementary DNA sequence revealed a depression of 0.5 - 2.OoC per phosphorodithioate linkage, which is higher than the 0.4 - 0.6OC depression

observed for phosphorothioates. Studies on the formation of O-oxidised products during the formation of phosphorodithioate oligonucleotides by sulphurisation of the H-phosphonothioate

l,ldioxide, (123) have shown that these unwanted diesten with 3H-1,2-benzodithiol-3-one products are due to the generation of the O-oxidising agents ( 124) and ( 125) formed during the

6:

245

Nucleotides and Nucleic Acids 104

course of the reaction (Scheme 20).

To prevent the formation of 0-oxidised products a new

sulphur transfer reagent, 3H- 1,2-benzodithio1-3-one (126)has been developed. Under aqueous reaction conditions that are compatible with both solution and solid-phase synthesis of oligonucleotides, (126)furnished clean and rapid conversion of H-phosphonothioatediesters to the corresponding phosphorodithioates.

N,N-diisopropyl-U-(4-nitrophenyl)-P-methylphosphoramidite (127) has been used to prepare oligonucleotides containing methylphosphonate linkages.lo5 Reaction of (1 27) with a 5’-protected thymidine derivative gave the nucleoside phosphate (128)which could be converted to the dinucleoside methylphosphinate (129)by condensation with a 3’-protected thymidine nucleoside in the presence of sodium hydride. Subsequent oxidation of (129)gave the target dinucleoside methylphosphonate. Bis-(diisopropy1amino)alkylphosphines (e.g. 130), which are readily available from his-(diisopropylamino)chlorophosphine, have been used to prepare nucleoside alkylphosphonamidites(131, Scheme 2 1). O6 In the presence of tetrazole, ( 13 1) reacted rapidly with a 3‘-0-benzoylnucleoside to give the intermediate dinucleoside

methylphosphinate. In situ oxidation of the phosphate with t-hutylhydroperoxideor sulphurisation with phenacetyldisulphidegave the methylphosphonate (132)or methylphosphonothioate ( 133)respectively.

A stereospecific synthesis of dinucleoside methylphosphonates has been

monomer reported which uses a 1,1,1,3,3,3-hexafluoro-2-propanoxymethylphosp~ate

(134).lo7The two diastereoisomers of (134)can be readily resolved by column chromatography and react in THF with a 3’-O-acetylnucleoside in the presence of t-butylmagnesium chloride to give a dinucleoside methylphosphonatein about 65% yield with inversion of configuration (Scheme 22). When the reaction was repeated in pyridine a higher yield (- 80%) was obtained, but a considerable amount of epimerisation was observed. Methylphosphonatelinkages have been incorporated into DNA enzymatically using the triphosphate analogue 2’-deoxythymidine 5’-(a-methylphosphonyl)-B-y-diphosphate (135) (presumed to be a mixture of diastereoisomers) as a substrate. lo8 Avian myeloblastosis virus (AMV) reverse transcriptase was most efficient for this purpose, being able to incorporate 7 -

8 sequential phosphonate linkages. The mechanisms by which oligonucleotidescross biological membranes have been investigated using model phospholipid membranes (liposomes).‘09 The study, which used labelled

oligodeoxyribonucleotidescontainingphosphorothioate,alternatingmethylphosphonate-phosphodiester,and unmodifiedphosphodiesterlinkages, suggeststhat cellular uptake of oligonucleotides by passive diffusion is an unlikely mechanism, even for the more hydrophobic methylphosphon-

Organophosphorus C‘hemistry

246

“\P (Pr’,)d

0

-0

N02

DM DMTo 0 dvB 9P-Me

“P -0 Me/

NO2

N(Pr’), CI--p,

MeMgBr

-

N ‘ (Pri,

/N(P+)2 Me-P, ‘N (Pri)2

(130)

O M T OHO v B a s e collidindHCI I

DMTov DM 9P-N(Pr‘)*

Me/

OBz

(132) X=o (133)X = S Scheme 21

Nucleotides and Nucleic Acids

6:

247 MMTO

MM

OAc

(1 34)

vThy MMT vTh \ 5””. MM

O II t I HO-P-0-P-0-P-0 I

-0

Scheme 22

:

s\

-0

50

p ,\

’

he

(135)

-O

HO

O

V OH T

(136)

s,

,N(Pr‘)*

P I

O-CN

(137)

MMTO

MeO,

s, S

+

(139) OAc

\

Scheme 23

OAc

h

Y

248

0rganop hosphorids C ‘hr m istry

ate-containing oligonucleotides. However, the relatively slow efflux of oligonucleotidesfrom liposomes may be useful for the sustained delivery of these molecules. A 3’-5’-dinucleoside 3’4-phosphorothiolate ( 136) containing 2’-deoxy-3’-thioadeno-

sine has been prepared from the phosphorothioamidite (137) by activation with 5-(4-nitropheny1)tetrazole and oxidation of the resultant thiophosphite with tetra-n-butylammonium periodate. lo The thioamidite (137) is surprisingly unreactive and for this reason it is necessary to use 5-(4-nitrophenyl)tetrazole,which is more acidic than the routinely used tetnuole. Unfortunately the thionucleoside is readily displaced from the phosphorus centre under these conditions and therefore coupling reactions with (137) are accompanied by formation of several side products and give low yields. Dithymidine 3’-S-phosphorothiolate has been prepared in 89% yield by a Michaelis Amusov reaction between 5’-O-monomethoxytntyl-3’-S-(2,4-dinitropheny1dithio)thymidine ( 138) and 3‘-O-acetylthymidine-5‘dimethylphosphite(139) in toluene at room temperature (Scheme 23).l 1

’

The methyl protecting group on phosphorus was cleanly

removed by treatment with thiophenolate with no discernable cleavage of the internucleotide linkage.

The potential utility of phosphotriester chemistry for the preparation of 3’-9phos-

’’’

phorothiolate linkages has also been investigated.

The phosphomthiolatediester (140) was

obtained in 69%yield by phosphorylationof the thionucleosidewith two equivalentsof 2-chlorophenylphosphorodi- 1,2,4-triamlide.

Coupling of ( 140) with 3’-S-benzoyl-3’-thiothymidine

using excess 1-(2-mesitylenesulphonyl)-3-nitro-172,4-triazole,gave the dinucleosidephosphorothiolate (141) in 76% yield. Removal of the aryl protecting group on phosphorus with 0.3 M

N*,N1,I$,I$-tetrarnethyleneguanidinium 2-nitrobenzaldoximate,under anhydrous conditions, was accompanied by about 1% cleavage of the phosphorus-sulphur bond. A dodecadeoxyribonucleotide d(GCACGTSpTGCACG) containing a 3’-thiothymidine

’

analogue of the cis-syn thymidine photodimhas been prepared. l2 he oligomer was synthesised using the phosphorarnidite approach and the presence of the 3’-S-phosphorothiolate linkage established by hydrolytic cleavage in the presence of iodine.

The central d(TSpT) unit was

converted to the photodimer by irradiation with U V light (280 run) and the major cis-syn product isolated by hplc . This photoproduct was annealed to a complementary oligodeoxyribonucleotide sequence and tested for its ability to bind to the DNA repair enzyme T4 enQauclease 4V. The thio-containing duplex was a poorer substrate for this enzyme than the natural photodimer

duplex. Deoxyribonucleoside phosphofo-bis-diethylamidim (142) have been prepared and used for the solid-phase synthesis of digodeoxyribonucleotidescontaking isopropyl phosphotiester

’

linkages at designated positions. l3 The StaMiard coupling of (142) results in an intemucleo-

6: Nuclrotides und Nrrcleic Acids

249

MM b"'

vBa vBase DMTo

DMTo

s,

,NEt2

p\

NEt2

CPG

HovB )-o'p o\ +o

250

Orgunophosphorus Chemistry

side diethylaminophosphmidite linkage (143) which can be converte!d to the product triester (144) by reaction with isopropanol and 5-(4-nitrophenyl)tetrazole and subsequent oxidation.

The diastereoisomers of the modified oligomers were separated by reverse-phase hplc and their absolute configurations determined by chemical correlation with the (@)- and (Sp)phosphothioate analogues of oligodeoxyribonucleotides. 3’-5’-Dinucleoside phosphofluoridates have been prepared starting from the phosphoramidite (145), using sulphuryl chloride fluoride to effect conversion of the dinucleoside silylphosphite to the phosphomfluoridate (Scheme 24). l4

Surprisingly the phosphorus fluorine

bond was shown to be stable to the conditions required for deprotection of the nucleobases. A variety of ingenious isosteric replacements for the intemucleotide phosphate group have

been designed and synthesised and those that contain a sulphur-based group replacing phosphorus are particularly notable.

Starting from a homologated thymidine sulphonic acid monomer

( l a ) , thymidine dimers containing intemucleoside sulphonate or sulphonamide linkages have been prepared.

Triphosgene was used to generate the intermediate sulphonyl chloride (147)

under mild conditions and immediate reaction of (147) with either a 3’-hydroxy-containing or 3’-amino-containing nucleoside gave the sulphonate (148) or sulphonamide (149) dimer respectively (Scheme 25).

The necessary building blocks have been prepared for the synthesis of

sulphide-linked DNA analogues (Scheme 26).

’“

The corresponding RNA dimer (150) has

also been prqami.l17 A stereoselective synthesis of a thymidine dimer containing a non-anionic 3’-CH2-NH-O-

5’-linkage (15 1) has been accomplished via an intermolecular radical reaction.

’’*

In the key

step the radical generated from 5‘-O-trityl-3’-deoxy-3’-iodothymidine, using bis-(trimethylsilyl-

stannyl)benzopinocolate, was reacted with 5 ‘-a( methyleneamino)-3’-(f-butyldiphenylsilyl)thymidine (152) to give the protected derivative of (15 1) in 30% yield. The newly created C-C bond was demonstrated to have an a-configuration at C-3’ by 2-D nmr techniques.

A closely

related methylbydroxylamine-linked nucleoside dimer (153) has been prcpared from 3’-C-formyl-5’-O-tritylthymidine and 5’-0-amino-3’-O-(f-butyldiphenylsilyl)thymI~(Scheme 27).

’

Removal of the 3’-silylprotecting group from (153) enabled it to be incorporated into oligonucleotides using phosphmmidite chemistry.

Hybridisation studies demonstrated that oligo-

nucleotides containing this modified dimer were slightly stabilised in compafison to the natural oligomers and their Watson-Crick base pairing specificity was as good or better than wild type DNA.

This modified linkage also exhibited significant resistance to nucleases. Methylene acetal-linkeddinwleosides have been prepared previously by conde.nsation of

a suitably protected 3‘-O-methylthiomethylenethymidine (154) with tbe 5’-hydroxy group of

vB DMT -

6: Nucleorides and Nucleic Acids

( pr‘)2 N,

+

P-OSiMe, (Pri)*

N’

2s 1

tetrazole DMTo

oYN(Pr‘), OSiMe,

OH

(145) tet razole

HoVB t

OAc

HO

DM vBase ~

o”P\ O, ,F

,OSiMe,

i, S02FCI

P

ii, deprotection

“vBas “Base

OH

OAc

Scheme 24

-03s”/”y’” 1 ‘ ; “ 0 2 ~ T h t riphosgenetDMF m

OAc

OAc

(147)

(146)

x

“=+.V OAc

Scheme 25

(148) X = O (149) X = N H

253

C)r~unc~phosphorus Chemistry

TBDMSO 5'-end unit

H°F

OS02Me

HS

---

central unit

OMe

3'-end unit

OTBDMS

Scheme 26

H°F H-N

/

\

O

OH (150)

V OH T

h

Y

6:

25.3

Nucleorides und Niicleic acid.^

H2N

+

OSiBu'Ph2 I

I i, NaBH,CN/AcOH ii, HCHO/NaBH3CN/AcOH

-

Me-N,

O

V OSiBu'Ph2 T h

1.5% AcOH/CH*CI*

Tro O

Y

V OSiBu'Ph2 T h

Y

(153)

Scheme 27

Levo (0

SMe

0

'"^"VThY """VT *VT H°FTh 0

(155) R = P h (156) R = M e

TMSOTF

.

+

O F O M e 0

O r O M e 0

Scheme 28

thymidine in the presence of N-iodosuccinimide and a catalytic quantity of trifluoromethanesulphonic acid. However, these reaction conditions have proved to be unsatisfactorywhen applied to purine nucleosides.120 A more generally applicable procedure has been developed based on

a h-imethylsilyltrifluoromethanesulphonate-assisted condensation between either 3’-0-benzoyloxymethylthymidine (155) or 3’-O-acetoxymethylthymidine(156) and a suitably 3‘-protected nucleoside (Scheme 28). 121

Oligonucleotidescontaining modifiedsugars - A method has been reported for

4.3.2

the synthesisof 2’-O-methyl and 2’-0-ethyl ribonucleoside-3’-0-phosphoramiQtes( 157) which involves alkylation at an early stage in the synthesis.122 Akylation conditions using either methyl or ethyl iodide and sodium hydride were applied directly to unprotected cytidine and adenosine, or with 0-&protected guanosine and N-3, 0-5‘-proteaed uridine. 2’-Fluorothymidine (Tf) has been incorporated into a number of oligodeoxyribonucleotides viu the phosphoramidite approach.123 Incorporation of two or three Tf residues into one strand of an oligonucleotide duplex caused a significant decrease in duplex stability. In contrast, a considerable increase in both duplex stability and cooperativity of melting was observed for in comparison to d(A12) d(T12). In the latter case it is likely that the d(A12) d(Tfl entire 2‘-fluorothymidine-~ontaining strand may adopt the r i b l i k e 3’-endo conformation and the resulting duplex would therefore be expected to display the higher thermal stability that distinguishes

RNA DNA hybrids from DNA duplexes.

Benmphenone-mediated sensitisation of d(TpG) irradiated at 350 nm in an oxygen1,&lactone Id(TpL)I saturated aqueous solution produces thymidyly1(3’-5’)-2’-deoxy-D-ribono(158). 124 Analysis of the nmr coupling constant data for d(TpG) and d(TpL) indicates that

there are no major conformationaldifferences between the two nucleotides and may suggest why lactone lesions are, in some cases, resistant to repair. An a-anomeric oligoribonucleotidea-[r(UCUUAACCCACA)J has been synthesised using phosphoramidite synthons (e.g. 159). 125

The a-oligoribonucleotides exhibit resistance to

nucleases, including RNase A and anneal in a parallel orientation with complementary DNA sequences. The synthesis and physicochemical properties of oligonucleotidescontaining B-Lr i b (160) or a-L-ribonucleotide (161) units and covalently linked to an acridine intercalating

agent have been studied.126 The acridine conjugate 13-L-d(A4) (160) and a-L-d(A4) (161) formed double and triple helices with poly(U) and polyd(T) respectively. Both the a-L- and B-L-oligomers were highly resistant to nuclease digestion. A conformational study has been conducted on the self-complementary hexanucleotide d(CGCGCG) composed entirely of L-

255

6: Nuclmtides and Nucleic Acids

Hov DMTowB (157) R = Me or Et

CI

(160) R' = Ade, R2 = H (161) R' = H, R2 = Ade

,O ,H O -

Base

2.56

O r g w t o ph osp horus (’hemi.5 tr)!

deoxyribose.’ 27 The data from circular dichroism spectra clearly show that both L-deoxyriboand D-deoxyribo(CGCCCG) possess the same conformational and dynamic properties and the higher order structures of L-DNA are the exact mirror image of those of the natural DNA. Conformational analysis of oligonucleotide single strands containing 2‘ ,3’-dideoxyglucopyranosyl building blocks (162), (the so-called homo-DNA) has been used to address the question as to why nature chose pentose, rather than hexose sugar units for the construction of nucleic acids. 12’

Whilst several factors were found to be important, the analysis revealed that

backbones of single strands are predisposed to generate the helicity of DNA duplexes and that this helicity hinges on the five-memberedness of the sugar ring. Some of the properties of the homo-DNA have been discussed at greater length in a review on the chemistry of potentially prebiotic natural products.129

A less conventional oligonucleotide analogue also based on a

six-membered sugar derivative has been constructed (163) that contains morpholine carbamate linkages. 30 The cytosine-containing hexamer was constructed using the 4-(4’-morpholinomethyl)benzoyl protecting group (163) which confers water solubility to the protected product. The purification and characterisation of these neutrally charged oligonucleotide analogues was greatly assisted by the increase in water solubility. The octameric phosphodiestersof (3,3-bis-(hydroxymethyl)cyclobutyl]-adenine ( 164)and thymine (163, have been prepared together with the pseudo a-oligomers (166) and (167).I3l The oligomers were prepared by a phosphotriester approach using synthons with the general structure (168). 32 The cyclobutyl oligomers formed duplexes with complementary sequences and the thermal melting temperatures (T,)

of the hybrids of ( 164) or (165) with complementary

DNAs were higher than those formed with complementary RNAs.

Most interestingly,

unequivocal interactions between the cyclobutyladenine oligomers (144) and (166) and the cyclobutylthymine oligomers (165) and (167) were observed. Some very exciting results have been obtained from studies on peptide nucleic acids (PNA) which have been designed as oligonucleotide analogues with an achiral peptide backbone consisting of (2-aminoethy1)glycine units with nucleobases attached via methylene carbonyl linkers (169).133 Synthesis of the thymine-containing DNA oligorners was accomplished using monomer (170) in Memfield’s solid-phase approach and lysine was coupled to the C-terminal to enable the overall efficiency of the synthesis to be determined by amino acid analysis.

The

thymine-containing DNA oligomers produced well defined melting curves which hybridised to oligo-(dA) to produce duplexes with Tm values that were much higher than those of the corresponding DNA/DNA duplexes. The affinity of (169, n = 8) for d ( A l d was shown to be so high that it displaces the d(Tlo) strand in a 248 base pair double stranded DNA Fragment with

6:

Niccleorides and Nucleic Acids

OH

(164) Base = Ade (165) Base = Thy

OH

(166) Base = Ade (167) Base = Thy

H

0 -0 7

H

MMTo >Base

?\ P

-".::a /P\

N

0

f NHBOC

Base

258

Organophosphorus Chemistry

a d ( A l d * d ( T l d insert. 134 Molecular modelling techniques have been used to assess the feasibility of replacing the sugar-phosphatebackbone with a polyamide-type backbone.135 Tbe most favourable systems examined were those containing either a-polyamide(171) or urethane (172) backbone. It was predicted that both these arrangements should strongly prefer binding to DNA rather than RNA and show a strong bias for the absolute configuration of the stereogenic centre. The synthesis of the amino acid building blocks (173) and (174) for the amide-type backbone has been achieved by ring opening of the precursor lactone under alkaline conditions.136 Subsequent oligomerisationwas achieved by activation of the carboxyl group as the 4-Ntrophenylester and coupling with the free amino group of another subunit. Using this procedure hexamers derived

from both (173) and (174) were prepared.

Oligonucleotidescontaining modifiedbases - Several studies have appeared on

4.3.3

the synthesis and application of oligonucleotides containing sulphur substituted nucleobases. Oligonucleotides containing 4-thiothymine have been synthesised by the phosphoramidite approach using the 2-cyanoethyl group to protect the sensitive thioamide function.137 Removal of this blocking group from the fully protected oligonucleotide was accomplished in one hour using 0.3M DBU in acetonitrile. This procedure has advantagesover that previously reported

by the same authors, in which 4-(S-4-Ntrophenyl)thymineresidues initially incorporated into oligomers were converted to 4-thiothymine in a post-synthetic treatment with potassium thioacetate in ethanol. 138 clivio er ai have prepared oligomers containing tbe thionucleobases 4thiouracil, Cthiothymine and 6-mercaptopurineusing both tbe phosph~ramidite'~~ and H-phosphonate 140methods. All three thiobases were protected with the pivaloyloxymethyl group (e.g. 175), introduced by alkylation of the thionucleoside with pivaloyloxymethyl chloride in the

presence of potassium carbonate. Although 6-thioguaninehas been used for over h t y years for treatment of human malignancies, the precise molecular basis for its action is still not understood. Recent evidence has accumulated which suggests that incopration of Gthioguanine into DNA is the primary mode of action. 14'

To explore this hypothesis oligonucleotidescontaining this base analogue have

been synthesised using a carefully devised protection and deprotedion strategy. 142 Protection of the thioamide and exocyclic amino functions was achieved with the 2-cyanoethyl and phenoxyacetyl groups respectively. Removal of these groups under carefully chosen conditions (a mixture of sodium hydroxide and sodium hydrogen sulphide)enabled deprotectjon to be achieved without conversion of 6-thioguanine to guanine.

Waters and Connolly have also used the

259

6: Nucleotides and Nucleic Acids

oyYNHC ' fN

(173) n = 1 (174) n = 2

02NJ3N S

"

"

'

O

W

260

0rgar i o ph osph or14s C3i ern istry 143

cyanoethyl group to protect the thioamide function of 6-thioguanine. However, in this study, deprotection under standard ammonolysis conditions resulted in a small, but measurable amount ( - 2%) of

sulphur displacement to give the 2,6-diaminopurine nucleoside. A versatile proce-

dure for the incorporation of guanine derivatives substituted at the 6-position has been reported which uses a 6-(2,Cdinitrophenyl)thioguanine phosphoramidite monomer (176).144

Post-

synthetic displacement of the 2 ,Cdinitrophenylthio group in the fully protected support-bound oligomer provides access to oligonucleotidescontaining 6-thioguanine, 2,6-diaminopurine, 2-

amino-6-methylaminopurine, 0-6-methylguanine or guanine in high yield. The (6-4) pyrimidine-pyrimidonephotoproducts, which are the second most abundant DNA photolesion produced by ultraviolet irradiation, are thought to play a major role in the

induction of human skin cancer. 145 The fvst step in the formation of this lesion is thought to involve a (2+2) cycloaddition between C-5/C-6 double bond of a 5’-pyrimidine and the C-4 carhnyl or imine of a 3’-pyrimidine base to give a four-rnemberedoxetane or azetidine intermediate. To study the formation of the (6-4) adducts a model system has been developed based on the photochemistry of thymidyly1(3’-5’)-4-thiothyrnidine ( 177).146’147 Irradiation of this compound produces a moderately stable thietane (178) whose stereochemistry was determined to he C-5-(R) and C-6-(S) (Scheme 29).

When the irradiation was carried out with the di-

nucleoside phosphate (179) in which the N(3)-position of the 4-thiothymine is methylated, the reaction is essentially stopped at the thietane. In this case two thietane products were isolated. The major product was the expected C-5-(R),and C-6-(S)isomer (180) whilst also a very small amount of the C-5-(S), C-6-(R) isomer (181) was also formed.

The configuration of (181)

established that cycloaddition to give this product proceeds with syn-glycosyl conformation of the 5’-unit and an anti-conformation for the 3’-unit. The photoproducts obtained by irradiation of an aqueous solution of 2’-deoxy-4-thiouridyly1(3’-5‘)thymidinehave also been isolated and their structures determined by 2-D nmr techniques.148 The photochemical reactions of

oligodeoxyribonucleotides containing 4-thiothy mine and 6-thioguanine have been exploited in a useful photo-induced cross-linking reaction between the modified oligonucleotide and DNAbinding enzymes.149 These novel photoaffinity labels have been used to study the EcoRV endonuclease and methyltransferase. Thiolation of the 2-position of uridine has been shown to restrict this nucleoside to a 3’e d o , anti-conformation.150 It has therefore been postulated that for those ~ R N A containing ~

2-thiouridine at the wobble position, the relatively more restricted dynamics and conformation of this analogue are responsible for the preferential recognition of codons ending in adenosine.

HO

I

h v. 360 nrn

OH (177) R = H (179) R = M e

OH

OH (178) R = H (180) R = M e

Scheme 29

0

Me2NCH= N

' I

MMT d'NH'cHMe2

OR

!

(183) R =-P-OI

+

NEt3H

H ,OMe (184) R=-P,

N(W2

262

Organophosphorus Chemistry

Several papers have appeared which describe the synthesis of oligonucleotides containing deazapurine base analogues.

These modified oligonucleotides in which a hydrogen bond

acceptor or donor is removed are useful probes for studying DNA-DNA or DNA-protein interactions.

It has been proposed that tbe curved structures adopted by DNA hgments containing

repeated d(An)-d(T,) (n > 3) tracts, that are in phase with the DNA helical repeat, are caused by a unique mode of hydration.

Ordered water molecules are associated with d(An) d(Tn)

sequences in the form of a spine of hydration which runs along the miwr groove of the helix and involves water molecules hydrogen bonded to the 0-2 atoms of thymine and N-3 atoms of adenine. The role of hydration in DNA bending has been investigated by preparing and studying self-complementary oligodeoxyribonucleotidescontaining 3-deazaadenine (3cA) in place of one of the adenine bases in the parent sequence [d(GAAAATT?TC)],. 15’ After phosphorylation at their Y-ends the decamers were ligated to form multimers and their degree of bending assessed by their mobility on polyacrylamide gel electrophoresis. The multimers of the decamer d(GAA3cAATMTC) showed decreased bending compared to multimers of the parent sequence, whilst the multimers of d(GAAA3cATITTC) did not show any degree of bemding. The results appear to indicate that the degree of connectivity of the hydration along the minor groove may have an effect on bending.

Similar conclusions have been reached by Seela and Grein who

have performed some related studies using d(A6) tracts containing 3-deazaadenineand 7 d m adenine. Oligonucleotides containing 3-deaza-2’deo~yguanosine(~~dG) have been prepared using H-phosphonate monomers (1 82) in which the exacyclic amino function was protected with the

’

(dimethy1amino)methylidenegroup. 53 CD spectra revealed that self-complementary oligomers containing a single 3cdG residue formed B-typehelical structures. Interestingly, the presence of the 3cdG residue did afford the oligonucleotide some degree of protection from the action of non-specific nucleases. The enzymatic synthesis of DNA containing 7-deazaguanine has been performed by polymerase chain reaction (PCR)amplification using Taq. polymerase, pUC18 plasmid DNA as a template and 7-deaza-2’deoxyguanmine 5‘-triphosphate. 154 H-phosphonate and phosphoramidite building blocks for the synthesisof oligoribonucleotides containing 7-deazaguanosine have been prepared. 155 2’-Regioselective protection of 7-

deaza-N-2-isobu~l-5‘-0-monomethoxyttrtylguanosine was investigated using a variety of silyl blocking groups.

Best results were obtained using triisopropylsilyl chloride and silver nitrate

in THF, which gave 63% of the Z’-isomer and 16% of the unwanted 3’-isomer. The 2‘-0protected intermediates were converted into the H-phospbonate ( I 83) or phosphoramidite (1 84) derivatives and successfully used for the synthesis (7cGC)3. Oligonucleotides containing 1,7-

6: Nurleotiries and Nudeic Acids

263

dideaza-2’-deoxyadenosine( lmCdA) (1 85) have been prepared using the H-phosphonate approach and the (dimethy1amino)methylidenegroup for the protection of the amino function. Duplex stability of these modified oligonucleotides was substantially decreased as (1 85) is unable to form either Watson-Crick or Hmgsteen base pairs. Incorporation of (185) into palindromic sequences such as d(CGCG1C7CA1C7CATTCGCG) resulted in the formation of hairpin structures. Attempts have been made to synthesise oligodeoxyribonucleotidescontaining 2-aza-2‘deoxyinosine from a synthon (186) protected with a N,N-diphenylcarbamoyl group. 157 During the deprotection step with aqueous ammonia it was shown that ring opening of the protected 2azapurine occurred to give an oligonucleotide containing the triazene imidazole system (187). On heating and irradiation with ultraviolet light the triazene system was converted in high yield to

5-amino- 1-(R-ribofuranosyl)imidazole-4-carboxamide(dAICA) ( 188).

This conversion

provides an efficient route to oligodeoxyribonucleotides containing dAICA which have not previously been available due to difficulties in obtaining a suitably protected derivative of dAlCA. The large scale synthesis of an oligodeoxyribonucleotidecontaining 5-fluoro-2’-deoxycytidine (FdC) has been achieved using phosphoramidite chemistry.

The FdC residue was

derivative (189) which underintroduced via the 4-0-(2,4,6-trimethylphenyl)-2’-deoxyuridine goes clean conversion to FdC during removal of the oligonucleotide protecting groups with ammonia. An FdC-containing oligodeoxyribonucleotideduplex was shown to form a covalent protein-DNA complex when incubated with DNA (cytosine-5)methyltransferase.159 Selfcomplementarydiribonucleosidemonophosphates containing 2-aminoadenosineand uridine linked through either the 2‘,5’- or 3’,5‘-positions have been prepared.160

Conformational studies

conducted by U V and CD spectrophotometry and nmr spectroscopy have revealed that the 2‘5‘-isomer adopts a stacked conformation which contains a larger base-base overlap and is more stable with respect to thermal denaturation than that of the 3’-5’-isomer. The 0-2-position of thymine is a major site of base alkylation by N-nitroso-akylating agents. To study the effect of alkylation at this site oligodeoxyribonucleotide templates containing 0-2-ethylthymidine have been prepared161 and used to study the in v i m mis-pairing specificity of the lesion.162 The adenine base analogue N-6-hydroxyadenine is of interest since the hydroxyamino group is thought to affect the amino-imino tautomeric equilibrium (Scheme 30) such that it can potentially base pair either with thymine (amino form) or cytosine (imino form).

Oligodeoxyribonucleotides containing N-6-hydroxyadenine were prepared Via the phosphoramidite approach using the r-butyldiphenylsilyl group to protect the exocyclic hydroxyamino

264

Organophosphorus Chemistry

&)

0

0

How OH

MeQMe 0

sugar

sugar

imino form

amino form

Scheme 30

6: Nucleotides and Nucleic Acids

265

function.’63 Duplexes in which Ndhydroxyadenine was complementary to a thymine base were shown to exhibit significantly greater Tm values (- 9OC difference) than those in which it was complementary to cytosine.

Related to this study Nishio et af have prqared several

oligodeoxyribonucleotideduplexescontaining2’-deoxy-N-6-methoxyadenosine ( 190)and studied their thermal stability. 164 Of the duplexes examined the greatest stability (highest Tm) was obtained when (190) was placed opposite dA and the duplex of lowest stability resulted when (190) was paired with dC.

However, DNA replication studies on a template-primer system

containing (190) in the template strand showed that TTP and dCTP were preferentially incorporated into DNA opposite this base analogue. Theoretical techniques have been used to study the non-natural Piccirilli et

I-K

base pair (191) which was originally incorporated into DNA and RNA by

01. 165

Several publications have appeared on the synthesis and properties of oligonucleotides containing 8-substitutedpurine bases. Oligodeoxyribonucleotidescontaining7-hydro-8-oxo-2‘deoxyguanosine have been prepared and characterised.166 The oligomers were assembled by the phosphoramidite approach using monomers in which the two lactam functions were protected with diphenylcarbamoyl groups (192). Nmr studies on a self-complementary oligodeoxyribonucleotide duplex [d(CGC8MoGAATTCCCG)]2 containing 8-methoxy-2’-deoxyguanosine [d(8MoG)] demonstrated that this modified nucleoside and its complementary dC residue both adopt an m‘-conformation about the glycosidic bond and that the duplex is of the B-type

*

structure. 67

The nucleoside analogues 7-hydro-8-0~0-2‘-deoxyadenosine, 8-methoxy-2’-

deoxyadenosine and 8-methoxy-2’-deoxyguanosine have all been incorporated into the oligodeoxyribonucleotidesequence [ d(GGAATTCC)I2 which contains the recognition site for the restriction endonuclease Eco R1.168 All of the modified oligomers were completely resistant to hydrolysis with this enzyme. Polycyclic aromatic hydrocarbons(PAH) are metabolised to bay-region diol epoxides and these electrophilic carcinogens are thought to exert their effects by reaction with the exocyclic

amino groups of DNA bases.

A genedly applicable route to PAH-epoxide adducts has been

developed and applied to the synthesis of the N-&amino adduct of 2‘-deoxyadenosine with tetra-

hydrophenanthrene-3,Cepoxide.169 The adduct was prepared by reaction of the trans-C-4aminolysis product of the epoxide with the 6-fluoro derivative of 2‘-deoxyadenosine (Scheme 31).

The (3S,4S)- and (3R,4R)diastereoisomerswere separated and configuration assigned

through comparison with products derived from optically pure epoxides of known configuration. The (3S,4S)-diastereoisomerwas incorporated into an oligonucleotidepentamer using phosphoramidite chemisby. A post-oligomerisationstrategy for the synthesisof oligonucleotidesbearing

266

Organophosphorits Chemistry

H,"OMe

OH

KN,H-

) , ,.~-~'f~"

N 'N

-0 sugar

K

0

ph2Nyo yANPh2

6:

Nuelcotides and Nuclcic Acids

267

TBDMSO TBDMSO OTBDMS

4 OTBDMS

+ AcO HO

OTBDMS

I

O-CN

Scheme 31

"NJ.

How OH

HO

I

N(Pr')*

(193)

(1 94)

268

0rgan o ph osp horus C’hetnis try

plycyclic aromatic hydrocarbons in the N-ij-position has been developed which is related to that described above in its use of a 6-fluoropurine nucleoside ( 193). 70 The phosphoramidite( 193) was incorporated into oligodeoxynucleotides under standard conditions. After oligomer assembly, but before deprotection the immobilised oligomer was treated with the aminotriol (1%

derived from tetrahydrobenzoIaJpyrene,for five days at room temperature. The resulting

DNA adduct could then be deprotected and purified in the standard manner. A versatile strategy for the selective post-synthetic modification of DNA bases has been

reported that is based on the application of the 3-(4-r-butyl-2,6-dinitrophenyl)-2,2-dimethylpropionyl (BDPDP) base protecting group. 17’

This protecting group, which can be considered

as a phenyl substituted pivaloyl derivative, readily forms amide derivatives with nucleoside bases (e. g. 195) that are resistant to hydrolysis under basic conditions, but are easily cleaved by reduc-

tion at neutral pH liberating (1%) by an internal ring closure. In a demonstrated use of this strategy a 2’deoxyguanosine residue selected for post-synthetic modification was protected using the phenoxyacetyl group whilst the remaining guanine bases were protected with the BDPDP group. The release of the oligomer from the support and removal of the phenoxyacetyl

group was effected using concentrated aqueous a m n i a at room temperature for one hour. Under these conditions

> 8096 of the BDPDP groups were retained such that the guanine base

originally protected with the phenoxyacetyl group could be selectively derivatised with 2-(Nfluorene. ) acetoxy -N-acetyl Oxidative damage to DNA caused by the action of ionising radiation is known to cause pyrimidine degradation to give 2-deoxyribsylformylamineresidues. This degradation product has been prepared by the oxidation of 5’-O-monomethox~tylthymidine using potassium permanganate and lead tetraacetate and then converted to the phosphoramidite derivative ( 197). 72 Oligonucleotidescontaining this lesion were prepared using ( 197) in conjunction with

hyperlabile nucleobase protecting groups so that the final debloclriag step could be perfmed using mildly basic conditions to conserve the integrity of the fragile formylamine residue. When used as templates for in vim replication, oligodeoxyribonuclddes containingthe formylamine residue, were shown either to directthe insertion of guanine or induce a deletion mutation

opposite the lesion. 5.

Oligonucleotidelabelling, Conjogation .ad A W t y Studies The development of efficient and versatile procedures for attaching reporter groups and

other biologically interesting molecules to nucleic acids continues to be an important area of research. Several groups have recently investigated methods that allow reporter molecules to

6: Nucleotides and Nucleic Acids

4

&Xio H

DMToT OH

(195)

H

'

O

w

B

a

s

e

H

270

Organophosphorus C’hemistrv

be attached to the phosphodiester groups of

DNA through an alkyl tether and this strategy has

the advantage that many such groups can be introduced at regular intervals throughout the sequence. Oligodeoxyribonucleotidescontaining alkyl amino groups attached to the phosphates have been prepared by reaction of the internucleotideH-phosphonate linkage with carbon tetrachloride and 1,6-diaminoheXane.173 Prior to the amination step and after a determined number of synthetic cycles were completed, the H-phosphonate linkages were oxidised to phosphodiester groups. lmpomtly it was shown that tbe internucleotide phosphodkster groups do not react with the activated H-phosphonatesand therefore do not interfere with subsequent coupling reactions. Fluorescein isothiocyanate has been used to fluorescently label oligonucleotides containing this internucleotide hexamethylenediaminotether and their hybridisation to a complementary sequence was detected by using a fluorescence polarization microscope to measure an increase in the fluorescence anisotropy. 174 A thiol tether has

been utilised for the site-specific attachment of reporter groups to

synthetic DNA.175 The thiol residue was introduced by the oxidation of an intemucleotide Hphosphonate in the presence of cystamine. After oxidation the terminal amino group was acetylated and the support-boundsequence (198) could then be elongated using standard procedures. The acetamide group at the terminus of the tether was largely resistant to deprotection conditions, but the thiol p u p could be unmasked by treatment with dithiothreitol and derivatised with a variety of thiol-specific reporter groups. Oligonucleotide duplexes containing fluorophores covalently bound through this thiol linker were shown to exhibit thermalstabilities similar to those of the unlabelled duplex. The oxidation of

H-phosphonate linkages has

also been used to introduce the 4-amino-2,2,6,6-tetramethylp~peridine-N-oxyl (TEMPO) spin label at specific internucleotide sites (e.g. 199).176 The resulting phosphoramidite diastereoisomers were separated by hplc and electron paramagnetic resonance was used to study hybridisation of the individual diastereomeric oligomers with the complementary sequence. In contrast with the spectra of the single stranded molecules, line broadening was observed in the presence of the complementary strand. Line broadening was shown to increase with increasing chain length of the target oligomer although the magnitude of this effect varied between the diastereoisomers.

Modified thymidine decamen- covalently linked to 5deazaflavin through an aminoalkyl spacer to a phosphoramidate internucleotide linkage (200) have been prepared and characteri d . 177 T~ values for duplexes formed with poly(d~)were s h ~ to m depend on the position

of attachment of the Sdeazaflavin group.

Oligomers with the flavin derivative at an inter-

nucleotide linkage at the 5 ’ 4 (as in 200) exhibited a higher Tm than the corresponding

6: Niicleotides and Nucleic Acids

27 1

5'

NH,

3'

(CH2)"- 0 - o l i g o m e r - O H

HS

O w G u

272

Organophosp ho riis C’hmii.ylr>i

duplex formed from d(Tlo), whereas positioning of the modified amidate ltnkage centrally in the oligomer lowered the Tm. Several simple and versatile procedures have been developed for derivatising the 5’-end of oligonucleotideswith thiol functions. Attachment of L-cysteine to the 5’-end of a supportbound oligonucleotide was achieved by activation of the 5‘-hydroxy group with carhonyldiimidazole, reaction with S-trityI-L-cysteine and subsequent deprotection gave an oligonucleotide which contained both a thiol and carboxylate function (201) at the 5’-e11d.l~~ Very similar strategieshave been used to prepare oligodeoxyribonucleotidescontaining5’-thioacety1179 (202)

(203)residues. and 5’-horno~ysteinel~ Some potentially exciting studies involving energy transfer from a lumazine chromophore to a 5‘-bathophenantluolineruthenium(l1) complex have been reported.

1-(2-Deoxy-B-D-

~bofuranosyl)-6,7-dimethyllumaZine was incorporated as the S’-terminal residue in an oligodeoxyribonucleotideand the 5’-hydroxy function subsequently derivatised with the ruthenium complex to give an oligomer with the 5’-end structure as shown (204). The lumazine chromophore can transfer light from a N2 laser onto the attached ruthenium complex. Since the efficiency, E, of the energy transfer is highly dependent on the distance between the donor and acceptor, determination of E allows distances to be measured. Incorporation of the lumazine chromophoreand the ruthenium complex at the 3’- and 5’ends respectively of complementary oligonucleotideshas been used to distinguish between the hybridised and non-hybridised state

of the oligomers.182 A model nucleopeptide (205) has been prepared which has a phosphodiesterbond between

the 5’end of a trinucleotide and a serine residue. 183 The oligonucleotide was assembled on a polystyrene support using the fluorenylmethoxycarbonyl p u p to protect the exocyclic amino function of cytosine. The serine residue was introduced from the phospboramidite (206). The synthesis of an antisense oligodeoxyribonucleotide covalently bound to the intercalator fagaronine, which is itself an inhibitor of reverse transcriptaSe, has been accomplished.lU The conjugate (207) was shown to be a more powerful inhibitor of HIV-I reverse transcriptase thao the parent oligonucleotided(TCAGTGGTp); it also was shown to bind more tightly to a complementary RNA sequeoce. Vitamin E is an attractive candidate as a lipophilic carrier of antisense oligonucleotides since it is found mainly in association with subcellular organelles rather than the plasma membrane. Oligonucleotidescontaining vitamin E attached to the 5‘-terminus have been synthesised using the phosphoramidite(208), whilst the use of the vitamin E derivatised support (209) enables attachment at the 3’-positi0n.’~~ The extreme

27 3

!

5

O-(CHZ)G-O-?-O-TCAGTGGTP -0

Me0 Me0

OMe Me

(207)

Organophosphorus Chemistry

274 Me

Me

HN \ CPG

Ade

.U ra

o.,

0

R R !

HO-P-0-P-0-P-O I

I

6: Nrrcleotides and Nuc*lricAcids

275

lipophilicity of the vitamin E moiety greatly facilitates purification of the derivatised oligonucleotides by reverse-phase hplc. A versatile modified solid-supporthas been designed (2 10) which enables oligodeoxyribo-

nucleotides to be prepared substituted at their 3’-ends with phosphate, phosphorothioate, primary amino and thiol

group^.'^

Heterobifunctionaloligonucleotidesderivatised at both the 3’- and

5’-end have been obtained using (210) and a 5’-modifying phosphoramidite. Methods for labelling RNA have been investigated that involve attachment to the 2’position of the ribonucleoside. The phosphoramidite (211) has been used to prepare oligoribonucleotides that contain an amino group tethered to the 2’-position. 187 The amino group can

be specifically conjugated to a variety of reporter molecules such as fluorescein and biotin. A similar strategy has been adopted for the preparation of oligonucleotides containing a pyrene group at a specific sugar residue. 88 The incorporation of the pyrene moiety was accomplished by preparation of 2’-( 1-pyrenylmethy1)uridine(212) which was converted to the protected 3’-

phosphoro-bis-diethylamidite. The oligonucleotide-pyrene conjugates were shown to bind to complementary sequences with cooperative interaction between the pyrene moiety and adjacent base pairs.

The fluorescence intensity of oligonucleotides with a pyrenyl group at a specific

sugar residue was increased on binding to a complementary sequence. 89 DNA labelled through attachment to nucleobases has been prepared using 4-N-I6-(y-

aminopropylamidosuccinylamido)hexyl]-2’-deoxycytidine5’-0-tripl~~phate (213). 190

This

triphosphate derivative is readily modified with biotin or fluorescent labels and can be subsequently incorporated into DNA using DNA polymerase I (Klenow fragment). It has been proposed that the lipophilicity of cholesterol could be used to anchor an oligonucleotide to a cell membrane and might also facilitate cellular uptake and stabilise complexes formed with cellular nucleic acids. An efficient procedure has been developed for the derivatisation of oligonucleotides with cholesterol that starts from the commercially available 6chloropurineribonucleoside.19’

Tritylation of the chloronucleoside and subsequent reaction with

ethylenediamine provides an aliphatic amino group that can be derivatised with cholesteryl chloroformateto give the conjugate (214). By covalently attaching (214) to a CPG solid-phase support, through either the 2‘- or 3’-positions, oligonucleotides were prepared in which the cholesteryl moiety was bound to the 3’-termiaus. This procedure for the prepatationof cholesterol labelled oligonucleotides is r e p o d to have several advantages over previously published procedms.192*193 Some ingenious strategies have been reported for the site-specific cross-linlting of oligonucleotide strands. Oligodeoxyribonuclddes containing thymidine residues in which the N-3-

Organophosphorus Chemistry

276

0

HO (214)

OH

OH

R = cholesteryl

(215)

HS*T 0-GCAATTCCCATITGGAATTGC

I

air oxidation

rTGCAAnCC AT TT

S'TCGTTAAGG

(216)

Scheme 32

..+* (217)

Me

0-Si-t

gJ

/

0I

II

3'

5'

NH-(CH2)6-O-P-O-oligomer-OH

0

-0

(218 )

1

KF/H20

(25'

Ji*

NH-(CH2)6-0-P-O-oligomer-OH

0

(219) Scheme 33

-0

3'

plsition is alkylated with a bemyl-protected mercaptoethyl linker (215) have been prepared.1g4 The benzoyl group can be quantitativelyremoved after solid-phasesynthesis using concentrated ammonia containing dithiothreitol. Aerobic oxidation of an oligonucleotide sequence known to adopt a hairpin structure and containing this thionucleotide at both the 3’- and 5’-ends resulted in the formation of a disulphide bridge between the two stems of the hairpin (216, Scheme 32).

The same method for strand cross-linking has been used to prepare a his-cross-

linked dodecamer (217). 195 The disulphide bridges in both (216) and (217) could be reduced by treatment with dithiothreitol. Oligonucleotides containing a r-butyldimethylsilyl-protectedphenol (2 18) linked to the 5’-terminus have been prepared and evaluated in cross-linking studies. ’%

The silylphenol

function serves as a precursor of a highly reactive o-quinone methide (219) which is released by fluoride-promoted desilylation of (218, Scheme 33).

Thus in the presence of potassium

fluoride (218) was shown to alkylate a complementary DNA single strand. Yields of the crosslinked product, as measured by polyacrylamidegel electrophoresis, were up to 30% and the rate of cross-linking was dependent on the concentration of potassium fluoride. DNA cross-linking using an oligonucleotide probe beiuing 4-(hydroxymethyl)-4,5’,8trimethylpsoralen tethered to the 5‘-terminus has been studied using a complementary single strand target containing six thymidine

Analysis of the photocross-linkingreactions

by polyacrylamidegel electrophoresisdemonstrated that the first extra-helical position to the 3’end of the target sequence was particularly susceptible to the photocross-linking reaction. A single stranded oligonucleotidecontaining an electrophilic nucleobase has been cross-

linked to a duplex to form a triplex in which the third strand is covalently bound. Ethano-5methyl-2’-deoxycytidine (Z) (220) was incorporatedinto a support-boundoligodeoxyribonucleotide by displacementof a precursor 4-triazOlopyrimidine nucleoside with aziridine.19’

The use

of an oxalylester linkage to the solid-support and the 9-fluorenylmethoxycarbonylprotecting

M

group on 5-methyl-2’-deoxycytidine( C) residues enabled aziridine to be used to simultaneously cleave the oligonucleotide from the support, deprotect the exocyclic amino groups and displace the triazole moiety to generate an alkylating oligonucleotide (221). When (221) was incubated with a radiolabelled duplex target (222), under physiological conditions, polyacrylamide gel electrophoresis revealed that a stable cross-link between the single strand (221) and the target duplex was formed. Oligonucleotidesof this type appear to be promising candidates for use as in vim sequence-specific inhibitors of RNA transcription. Recent calculationssuggest that the major and minor grooves of DNA are acidic environments that enhance the reactivity 199

of acid-catalysed elecbophiles, such as epoxides and aziridines towards DNA.

Organophosphorus C'hemistry

278

5'-MCTTITTMCllTTMCTTZ .$Me

(221)

3'-G A A A A A G A A A A G A A A A A 5'-CT T T T T C T T T T C T T T T T Ho+

(222)

OH

(220)= z

NHCOPh

HN-'

Me

Hoyor N*HNH2

0

HO

OR

(226) R = H (227) R = Me

OH

(228)

6: Nrrc*leotide.sund Nucleic Acids

279

Antisense oligodeoxyribonucleotidescontaininga 2-(aminoethyl)thioadenjne residue have been prepared from the phosphoramidite (223).

After deprotection the amino group was

converted to an ablating function by iodoacetylation. On duplex formation the iodoacetamide group is positioned in the minor groove (224) and was shown to cross-link A and G bases in complementary DNA sequences. Cleavage of the target sequences, at the site of alkylation, could subsequently be effected by treatment with piperidine.200

Two oligodeoxyribonucleotidesseparated by a flexible poly(ethyleneglyco1)(225) tether have been prepared for use as an oligonucleotideprobe.201 Studies with LeptomoMs coffosomu SL RNA demonstrated that the two connected oligodeoxyribonuclddes could hybridise to two

complementary single stranded regions of the RNA which are separated by about fifty ribonucleotide units, but are geographically close in the three-dimensional RNA structure. 6.

Nucltic Acid Triple-Hcliccs and Otbcr Unusual Structures The rapid growth in publications on DNA biple helices is largely due to their widely

recognised relevance to the development of therapeutic oligonucleotides. Indeed, triplex formation by site-specific interaction of an oligonucleotide with double helical DNA has been used to

repress transcription in a eukaryotic cell-fiee transcription system.202

he high profile that

studies on DNA triple helices have received also appears to have stimulated a more general interest in structural aspects of DNA chemistry. A major review has been published on singlecrystal X-ray diffraction studies of oligonucleotides and oligonucleotide-drug complexes.203 In triple helix formation the third strand, normally a homopyrimidine strand, is located in the major groove of a duplex consisting of Watson-Crick base pairing. The third strand is orientated parallel to that of the purine strand and the thymine and Cytosine bases form Hoogsteen hydrogen bonds with adenine and guanine respectively. Since protonation of the cytosine

bases is essential in order to provide the hydrogen bond between N-3 of cytosine and N-7 of guanine, the C + G C triad is not very stable at neutral pH. To overcome this problem, 204 oligodeoxyribonucleotides containing pseudoisocytidine (226) have been prepared. Additionally, it was found that methylation of the 2’-hydroxy group to give (227) provided additional stabilisation of triple helical structures. Oligonucleotides unltahhg (227) formed stable triple helices with guanine-containing duplexes at pH values in excess of 7.0.

The

replacement of cytosine by 5-methylc~sinein the pyrimidinecontainingsingle strand has also been shown to increase the stability of triple helices. Studies conducted using the double-helical stem of a DNA hairpin as the duplex showed that cytosine methylation expands the pH range compatible with triplex formation by about one pH unit.2059206

Attempts to understand the

2x0

Organophosphorus C 'hemis try

basis for the increased stability of triple helices that contain 5-methylcytosine have been made through ab inin'o quantum mechanical studies on the equilibrium geometries and proton affinities of cytosine and 5-methylcytosine.207 A non-natural pyrazole deoxyribonucleoside (228)has been designed to participate in

triple helix formation.20* The pyrazole analogue, like (226),mimics a N-3-protonated cytosine base and thus is capable of forming triple helices without the need for protonation. By incorporation into oligodeoxyribonucleotides it was shown that (228)binds to G-Cbase pairs within a pyrimidine triple helix as selectively and as strongly as a cytosine residue, but importantly was

less sensitive to pH. Triple helix formation has also been studied using several other modified oligonucleotides. Single stranded DNA containing a stretch of sixteen purine residues (229)has been used as a target for triple helix formation.209 The complementary duplex (230)was designed to consist of two oligomers, eighteen and sixteen nucleotides in length linked by a hexaethylene glycol bridge that connects the 3'-phosphate of the sixteen-mer to the S'-phosphate of the eighteenmer.

Additionally an acridine moiety was covalently attached to the S-end of (230).

Temperature dependent absorption studies revealed that (230)forms a very stable triple helix with the purine target strand and that the complex shows only a single temperature transition in which both the Watson-Crick and Hoogsteen hydrogen bonds are broken. Very little work has been reportedon the ability of oligodeoxyribonucldes containing neutral replacementsof the phosphodiester linkage to form triple helices with duplex DNA under physiological conditions.

Fwthermore conflicting results have been reported relating to the

ability of methylphosphonatecontahhg oligonucleotidesto form triple helices. Dinucleosides containing 5'-thiOfO-

lhkages (231)have been prepated and incorporated into oligo-

nucleotides containing alternating thioformacetal-phosphodiesterlinkages.21o These alternating oligomers were shown to be capable of sequence-specific triple helix formation. In the same studyoligonucleotidescontainingmethylpbosphonate, (methoxyethy1)idate

(232)and

formacetal linkages (233)were also shown to form triple helical structures with the appropriate duplex. The presence of an abasic site within a pyrimidine strand of a triple helix has been shown to significantly reduce the stability of the triplex.21

A model for a platinawl D N A triplex has been reported in which the normal WatsonCrick hydrogen bonding scheme between 9-methylguanine and 1-methylcytosk is complecomplex bound to the N-7 of guanine in mented by a f~m-(CH~NH~)Pt(II)(l-metbylcytosirse) 212 a Hoogsteen Fashioa.

6:

28 1

Nucleotides and Nuclric Acids

5'-TT AAAAGAAAAGGGGGGAC-3' 3'- A A T T T T C T T T T C C C C C C T\

(229)

I

yH2

(230)

Acridine

DMTov X

v

B a OH

s

Me0

e

(231) X = S (233) X = 0

(232)

3'

5'

H

- - - - - = Hoogsteen bonding

- = Watson-Crick bonding

c A C

AAGAAAAGAAAG TTCTTTTCTTTC A C

C C A

282

Organophosphorus C‘hrmistry

The formation of a triple helix has been enhanced by the addition of discrete binding domains (A and B in 234) which associate through Watson-Crick hydrogen bonding.213 Circular oligonucleotideshave been shown to display very high binding affinities for both complementary D N A and R N A oligomers by forming bimolecular triple-helicalc~rnplexes.~ 14*16

The circular oligonucleotideswere designed to bind strongly to a complementary single-

stranded purine sequence (235), with one side of the circle complementary in the Watson-Crick sense (antiparallel), whilst the other side is complementary in the parallel sense through Hoogsteen base pairing. The sugar conformationsin a 3 1-base D N A oligonucleotidepreviously

* *

shown2 772 to form an intramoleculartriple helix (236)have been investigated by nmr using coupling constants obtained by simulation of phase-sensitive COSY cross peaks.219

The

analysis indicates that all of the thymidine and purine nucleosides adopt a predominantly S-type (near 2’-endo) sugar pucker. Three-dimensional nmr proton-proton connectivities have been used as a general strategy for almost complete proton assignment in a related thirty-one residue intramolecular triplex.220 In another intramolecular triple helix an unusual G T A triplet 221 has been studied by nmr techniques. Triple helix formation has been shown to occur at tandem oligopurine-oligopyrimidine tracts. A single strand of oligopyrimidineblocks binds simultaneously to duplex D N A containing adjacent tracts of oligopurines and oligopyrimidines via both Pu * Pu * Py and

Py Pu Py base triplets as shown in (237).222

This polarity of binding does not require

a special junction such as the 3’-3’ linkage previously used between two oligopyrimidine blocks.223y224 These results indicate that by using both the known types of base triplets in combination with strand switching the requirement of purely homopurine sequences for triplex formation can be relaxed. Free energy calculationshave been used to examine Hmgsteen base-pairing and reversed Hoogsteen base-pairing in D N A triple helices.225 Base-pairings and strand orientations were examined for homogeneous d(T A

T)27 and d(C G G)27 triplexes.

For the T A

T triplexes Hmgsteen base-pairing was preferred with a parallel orientation of the strands. Solvation was found to influence the strand orientation for the C G G triplex with either Hoogsteen or reversed Hoogsteen base-pairing being possible. The thermodynamicsof triple helix formation in octamers of deoxyriboadenylic and deoxyribothymidylic acids have been

226

studied by ultraviolet and CD techniques.

Triple helix formation has been used to direct both cleavage and ligation of DNA. Blunt-end ligation of a 3.7 kilobase pair lioear D N A duplex has been accomplished by juxtaposition of the two D N A termini through triple helix formation with a guide sequence and chemical

6: Nitcleotides and Nucleic Acids

T T

28.3

YYY

?c?c?c??3’ ,

,

,

,

,

,

,

I

i G i G i G i A c c

I I I I I I I l l c

TCTCTCTTG

N = purine or pyrimidine R = purine Y = pyrimidine

(237)

guide sequence

Scheme 34

T CTACG GATGCCCCCCC*-5’ T T

(239) OAc

COOH

Organnphosph orus 'hemisrrj]

284

activation of the terminal phosphates (Scheme 34)227 This non-enzymatic procedure has also been applied to the ligation of a blunt-ended duplex DNA using a guide sequence that crosses between strands at the site of ligation.228 In this case the ligation produced a site for the restriction endonuclease Snc I and the fidelity of the ligation was ascertained by cleavage with this enzyme. Two semi-synthetic nucleases prepared by coupling short oligonucleotides ( I 2 -

13 residues) to a Staphylococcal nuclease have been used to substitute the natural promoter for the ampicillin resistance gene for the lac transcriptional promoter in

The semi-

synthetic nucleases bind to the plasmid by triple helix formation and produce asymmetric cleavage of the two strands. The unusual DNA undecamer [d(ATCAGCGAATA)I2has been shown to form a remarkably stable B-type duplex with four internal G * A mismatches which are proposed to have a novel hydrogen bonding scheme.230 Nmr studies on the duplex demonstrate that the C A mismatched-base pairs have an unusual backbone arrangement (designed BIr) at the phosphodiester linkage.23* This backbone conformation has not previously been observed in solution and when it has been found in DNA crystal structures its presence has been attributed to crystal packing forces.232 Spectroscopic studies have previously shown that d(GGTTTTTGG) forms a tetrameric complex in which self-association results in a planar G-tetrad stabilised by a full

complement of hydrogen bonds.233

* H nmr studies have revealed that the G1 and G8 residues

adopt a syn conformation about the glycosidic bond, whilst G2 and G9 residues have an anti conformation.234 X-ray diffraction and CD studies on short oligodeoxyriboguanylates indicate that a stacked array of Hoogsteen-bonded guanosine tetramers are formed.235 The stacked arrays are able to aggregate to form cholesteric and hexagonal mesophases.

In recent years a number of geomebical objects have been constructed from DNA that have well defined structural properties and are potentially interesting as molecular scaffolding. 236 A new solid-phase procedure has been developed for the synthesis of geometrical structures.

In addition to the usual benefits of solid-supportedsynthesisthe method uses intermediateswhich are covalently-closed and topologically-bonded so that they are able to withstand enzymatic digestion with exonucleases designed to destroy failure products.

The same group has

constructed a trefoil knot (238)from single stranded synthetic DNA.237 The electrophoretic mobility and sedimentation properties of the knot structure differ from those of a circle with the same sequence. Radiolabelled oligodeoxyribonucleotidehairpins (P.g. 239) which function as both primer and template have been used to study template-directed nucleic acid synthesis.238 This system has the advantage that the position of initiation is uniquely defined by the secondary structure

6: Nitclcoticics and Nircleic Acids

285

and interference from products formed off the template is eliminated since they are not radiolabelled. This method has heen applied to the study of non-enzymatic template-directed synthesis using nucleoside 5‘-phosphoro(2-methyl)imidazolides. The folding of RNA into secondary and tertiary

and its possible role in

regulatory processes has been discussed.240 7.

Cleavage of Nuclcic Acids Including Self-Clemring RNA The detailed chemimy of kapurimycin (240)-induced DNA cleavage has been studied

through the reaction of this antibiotic with the self-complementary tetramer Id(CGCG)J2.241

to produce the At neutral pH (240) alkylates the N-7 position of Ci2 and G4 of [~(CGCCI)]~ adducts (241) and (242) in yields of 64% and 7% respectively. Heating at 90°C for five minutes degraded both adducts to (243) with concurrent release of the respective abasic-sitecontaining oligomers. Cationic manganese-porphyrin complexes have been shown to cleave DNA by binding in the minor groove and effecting hydroxylation at either the 1‘- or 5’-carbon atoms of the sugar.242 Novel DNA photocleavers (e.g. 244) which consist of a photoactive 4-nitrobenwyl group, an intercalator and a DNA groove binder, have been designed.243 Compounds of this

type were shown to induce cleavage of DNA upon irradiation (310 nm) which is necessary to activate the triplet state of the Cnitro&enzoyl group. The strand cleavage of DNA induced by has been studied by both the cyclic peroxide 4-ethoxy-I ,4-dihydro-2,3-bedioxin- 1-01 (M)

ethidium bromide fluorescencequenching and agarose gel electrophoresis.244 Results obtained using radical scavengers are consistent with radical induced (possibly hydroxyl radicals) strand scission initiated by the decomposition of Ed. Dimethylsulphoxide has been used as a scavenger

of hydroxyl radicals to prove that DNA cleavage induced by both Fe(II)(haph) and Fe(III)(haph)H202 [haph = N-(2-imidazol-3-ylethyl)-6-((2-imidazo(-3-ylethylamino)methyl]pyridinec~x-

amide] occurs via ferryl(V) intermediates.245 Hydroxyl radicals have been shown to react with adenosine 3’- and 5’-mOnOphOSphatesby addition to the C-4 and C-8 of the purine system.’& The radical (245) formed by addtion of C-4 is a weakly oxidising radical and loses water to give a species that is considerably stronger oxidant due to unpaired spin density at the exocyclic and endocyclic nitrogen atoms. The other adduct (246) undergoes ring opening between N-9 and C-8 in the absence of oxidants.

1 Phage Cro protein has been converted into an operator-specific nuclease by replacing the C-terminal alanine of the wild type protein with ~ y s t e i n e . Alkylation ~~~ of the sulphydryl group with 5-(iodoacetamido)-1,lO-phenanthroline resulted in a semisynthetic nuclease which

Organophosphorus Chen1isrry

2x6

COOH

OAc

0

(241) R = C p O

v

(242) R = CGCpO

OpCG

OH

COOH

OAc

287

6: Nuchrides and Nucleic Acids

HO

(248) R = Et (249) R = H

(247)

o, /o-

-0, 40 /p\

Eto’p\oY7Ade O

w

A

O,, O ,

-OlP\OEt

d OH

e

retains a high affinity for the major groove of the DNA and directs its nucleolybc cleavage to the minor groove. A combination of enzymatic and chemical techniques have been used in a novel procedure for the sequence-specificand strand-specificcleavage of DNA that is based on the incorporation

of a 3‘-S-phosphorothiolate (3’-S-P-0-5’) linkage.248 Oligodeoxyribonucleotidescontaining a 3’-thiothymidine residue at the cleavage site [between the central T and A residues of the sequence d(GATATC)) for the restriction endonuclease Eco RV have been prepared. The selfcomplementary oligomer Id(GACGAT3’SATCGTC)12was shown to be completely resistant to cleavage by the Eco RV enzyme, whilst the heteroduplex composed of 5’-d(TCTGAT3’SATCCTC) and 5’-d(GAGGATATCAGA) was cleaved only in the unmodified strand. In contrast strands containing a 3’-S-phosphorothiolateresidue could be cleaved specificallyat this site with dilute (20 mM) silver nitrate. A number of studies have heen conducted on the hydrolytic cleavage of RNA.

The

hydrolysis of homopolymers of ribonucleotides by oligoamines has been investigated.249 Ethylenediamine was shown to degrade poly(A) to a mixture of short oligomers (mostly five residues or less) over a period of about forty-eight hours and the reaction was observed to be more rapid at pH 7.0 than at pH 8.0.

Ethylenediamine was also an effective catalyst for the

degradation of poly(U) and poly(C), but poly(G) was hydrolysed to only a very small extent. The latter result is probably due to the higher-order four-stranded structures associated with poly(G).

The hydrolysis appears to proceed via the rate determining formation of a 2‘,3’-

cyclic phosphate intermediatesince no catalyk effect is ohserved for the hydrolysis of poly(dA). The regioselective and catalytic cleavage of the P-O(2’) bond of adenosine 2’,3’-cyclic phosphate by 8- and y-cyclodextrins has shown to be significantlypromoted with respect to both selectivity and rate by the addition of alkali metal halides.250 In parWular, a selectivity [for P-O(3’) cleavage as opposed to P-0(2’) cleavage) of 94% was achieved at pH 9.5 and 30°C by the combination of fkyclodextrin and potassium chloride (3.0 M);the values for 6-cyclodextrin alone and potassium chloride alone were 79% and 41 % respectively. The metal salts seem to act by amplifying the difference between the chemical environment of the P-O(2’) and P-O(3’) bonds provided by cyclodextrin complexation. The interconversion and hydrolysis of 2’-5‘- and 3‘-5‘-dinucleoside monophosphates havebeen investigated through a kinetic study.251 Under acidic conditions 2’-5‘- and 3’-5’dinucleoside monophosphates undergo competitive mutual isomerisation and hydrolysis to free the 5’-linked nucleoside and produce a mixture of 2‘- and 3’-monophosphates. The reactions proceed via a common phosphorane intermediate which is formed at high acid concentrations

by an intramolecular attack of the neighbouing hydroxyl group on the monocationic phosphodiester and at low acid concentrations by attack on the neutral phosphodiester. The effect of the nucleobase moiety on the rate of hydrolysis and isomerisation is relatively small. Based on the pentacoordinate trigonal bipyramidal phosphorane transition state proposed in the ribonuclease-mediated hydrolysisof RNA, a pentacoordinate technetium chelate (247) derived from

2’,3‘-diamino-2’,3‘-dideoxyadenosinehas been prepared.252

This transition state analogue

was found to be a potent and competitive (with respect to the substrates ApU and UpU) inhibitor

of ribonuclease U2. The electronic structure of the monoanion phosphorane transition state in ribonuclease A-catalysed RNA hydrolysisand its putative vmdate transition state analogue have

been compared.253 The role of imidaz.de in the catalysis of RNA hydrolysis in both enzymes and enzyme models has been reviewed.254 A number of detailed kinetic studies have been performed on the site-specific endo-

nuclease reaction catalysed by the Tetrahymna ribozyme.

In particular these studies have

examined the fidelity (i.e. the ability to cleave the correct phosphodiester bond within a particular RNA substrate) and the tertiary interactionsof the 2‘-hydroxy groups of the 258 A self-cleaving RNA sequence259 from hepatitis 6 virus has been modified to produce a

ribozyme capable of catalysing the cleavage of RNA in an intermolecular reaction.26o

The

ribozyme cleaved the substrate RNA at a specific sequence and the sequence specificity could be altered by a mutation in the region of the ribozyme which was proposed to base pair with the

substrate. An in vim selection process has been used to isolate specific molecules from RNA pools based on yeast tRNAPhe, that undergo autolytic cleavage with Pb2+ .261 A detailed 500 MHz ‘H and 31P nmr study has been undertaken on branched RNA

structures that model the lariat formed in RNA splicing reactions.

The study was aided by

examining the conformation of the ribonucleotides (248 - 252) which preserve the essential structural elementsof an adenosinebranch point while removing the intramolecularbase stacking interactions.262 Detailed studies on the

decamer263 (253) showed that the uridine at the 5’-

position of the branch point prefers to stack with the 2’-strand of the branch rather than the 3’strand. A branched RNA-DNA conjugate (254) has been prepared and its structure compared to the parent RNA compound (255).264 The intramolecular geometries of both (254) and (255) were shown to be dominated by stacking along the A3’-5’G2’-5’dC(C) axis, although

the RNA-DNA conjugate had a more defined tertiary structure.

The same group hase also

completed the synthesis of a branched cyclic tefraribonucleotide(256) which is a more accurate 265 model of the lariat of pre-mRNA splicing.

200

Or~anophosy horrrs Chemistry

-0,

+o

ccupo

Eto'p'oY7Ade HO

0, 00 EtO/P\ 0-

1252)

O\\

,o

-o/p'o

/O P U C A

O\

P G U G

(253)

OH

WG O\\

,o

0,

//o"a

o / ~ v c y t

HO

OH

42

(254) R = H (255)R = O H 0 HN

0

5L.J

6:

8.

Nttdeotides und NucIeic Acids

29 1

lntmction of Nuclcic Acids witb Small Molecules

Work in this area has been dominated by studies on the enediyne class of anticancer antibiotics which bind to the minor groove and cleave DNA through the generation of a dirad~cal intermediate. A general review on the chemistry and mechanism of action of these antibiotics has appeared266 together with two more focused reviews on n e o c a n i n ~ s t a t i n(257) ~ ~ ~ and the calicheamicins268 (258). Several new members of the calicheamicin family have been isolated and their structures

A large number of synthetic and mechanistic studies have

appeared on the cal~heamicins~~@~~~,dynemicin A273’274 (259), neocaninostatin chromo~ ~ ’ ~detailed ~~ p h ~ r e , ~e~s p’ e r a m i ~ i n (260) s ~ ~ ~and various synthetic e n e d i ~ n e s . ~Several studies have been reported on the activation of the neocaninostatin chromophore. Activation of this antibiotic occurs by nucleophdic attack by a thiol at C( 12), which is then followed by a rearrangement of the ring structure which eventually leads to cycloaromatisation to form the active diradical.

Experiments conducted with non-basic derivatives of the neocaninostatin

chromophore suggest that its activation is dramatically assisted through participation of the carbohydrate amino p u p as an internal base (261).278 The neocaninostatin chromophore causes both single strand and double strand breaks in the DNA.

The strand breaks result

chiefly from hydrogen abstraction from ( 3 5 ’ ) by the diradical species and oxygen transfer from molecular oxygen to the resulting DNA radical. Less than 20% of the strand breaks result from pathways initiated by hydrogen abstraction from C(4‘) and C(1’).

At d(AGC) sequences

double strand cuts result from concomitant l’-oxidation at dC and 5’-oxidation at dT on the complementary strand.279 The extent of this damage is known to be dependent on the structure of the thiol used to activate the drug.

Deuterium isotope effects obtained using sodium 12-

2H2)-thioglycolatesuggest that the dependence on thiol structuremay be due to internal quenching of one radical site of the activated chromopbore by the hydrogen atoms of the thiol side chain. A comparison of DNA damage produced by activation of the -tin

chromo-

phore with several thiol activators revealed that the fragmentation pathway (i.e. the initial site of hydrogen atom abstraction) was also dependent on the thiol activator.28o Both the nucleophilicity and basicity of the thiol have also been shown to affect the activation process.281 A kinetic analysis of the cleavage of covalendy closedcircular DNA by the calcheamicins

and esperamicins has been carried out.282 Analysis of the cleavage experiments by agarose gel electrophoresis showed that espenrmicin A produced mainly single straod cuts resulting in the formation of “nicked” circular DNA.

In contrast calcheamicin was sbown to cause mainly

double strand breaks. This latter behaviour is Unique in that a single activation of the 1,S-diyn3ene ”warhead”produces a double strand break witbout need for further activation. Examination of the structure of the drugs indicates that the location of tbe sugar moiety relative to the

Organophosphorits ('hemistry

NHEt OMe

OH

0

OH

293

6: Nucleolitirs cind Nitcleic Acids

SSSme NHC02Me HO

P

Meorno HA

MeAMe

Me0

o q O M e

(262) n = 0 (263) n = 1 (264) n = 2

0 II

0

9-0

Organophosphorus Chemistry

294

enediyne portion appears to be an important factor influencing single versus double strand cleavage. Studies of the effect of temperature and the concentration of inorganic salts on the rate of cleavage of covalently closedcircular DNA by calcheamicin indicates that hydrophobic interactions are important in the association of this drug with DNA.283 Several dynemicin A analogues have been prepared in which the double bond-containing structure (262) is replaced by a benzene (263) or naphthalene (264) ring.284 The analogues

(263)and (264) undergo the Bergman cycloaromatisationprocess less readily than the parent system and show reduced reactivity towards DNA cleavage.

Addition of thiyl radicals to

a w e s has been shown to produce vinyl radicals that abstract hydrogen atoms from tetrahydro-

furans and tetrahydropyrans mimicking the crucial stages of action of the d y n e antibiotics.285 The mechanism of action of the anti-neoplastic agent mitomycin C is believed to proceed by its initial reductive activation followed by covalent binding of the activated species to DNA. Drug attachment occm sequentially at C( 1) and C( 10) leading to the formation of cross-linked DNA products. A new covalent mitomycin C-DNA adduct (265), in which there is an intra-

strand cross-link,has been isolated from DNA exposed to reductivelyactivated mitomycin C.286 Synthetic oligodeoxyribonucleotideshave been reacted with mitomycin C under coaditions which

restricted this drug to monofunctional alkylating activity.287

Guanine bases in 5'-CG

sequences were shown to be the preferred alkylation sites; the nucleotide at the 3'-position was shown to have relatively little effect in modulating reactivity. The reaction of sodium dithionite-activated mitomycin C with guanine bases at non-cross-linkable sequeoces in both oligonucleotides and DNA was shown to produce a l"deoxyguanosine-lO"-sulpbonatedadduct ( 2 6 6 1 . ~The ~ ~isolation of this adduct suggests that mitomycin c will form cross-linksbetween

DNA and the nucleophilic residues of a DNA binding protein. The formation of these proposed DNA-protein cross-links could be partly responsible for the ability of mitomycin to inhibit DNA

synthesis. Molecular mechanics simulationson covalent complexesbetween left handedhelical DNA and mitomycin C show an interesting network of hydrogen bonding interactions between

the drug and the groove of the left handed

Energy refined models suggest that mito-

mycin C could bind strongly to left handed helices and these results are relevant to earlier studies which suggested that DNA bound by mitomycin C underwent a transition to a non-Z left handed structure. The bleomycin (BLM) antibiotics are a group of glycopept~de-denved anti-tumour agents that

exert their therapeutic effects through the sequence-specific cleavage of DNA that is

dependent on the activation of oxygen by a metal ion.

Two metal complexes of this anti-

tumour agent BLM-Ni2+ and BLM-V03+ have been used to study the interactions between

6:

295

Nucleotides and Nucleic Acids

0/Base H

OH (266)

p$

HO

Me02

L

R (270) R=NH2 (271) R

BLM and a self-complementary dodecanucleotide Id(CCCCAGCTGGGG)]2by nmr spectras c t ~ p y .Although ~~ these BLM complexes do not mediate strand cleavage of DNA under the

usual conditionsthey are thought to bind DNA in the same manner as the active BLM-Fe2+ and BLM-Co3+ complexes. Fluorescence titration and circular dichroism studies showed that the BLM-metal complexes bound specifically to the GpC site. However, nmr experiments did not reveal any significant changes to the imino proton chemical shift values on the addition of either BLM-Ni2 or BLM-V03 . These results are not consistent with the proposed model involv+

+

ing intercalationof BLM and is more indicativeof interaction via minor groove binding. There is still some discussion as to the exact mechanism by which BLMs cleave DNA. The mechanism of interaction of BLM-Fe2+ with DNA to produce the nucleobase propenal (267) and a 3'phosphoglycolate (268) has been investigated.291 Kinetic data obtained using 802,H2 8O and H21802 show that the traditionally accepted mechanism cannot account for all the experimental findings and the authors have proposed an alternative cleavage mechanism. The anti-tumour agent ( + )-CC-1065 (269) acts by selective alkylation of adenine N(3) which lies in the minor groove. It has been demonstrated that critically ordered water molecules are involved in the drug-DNA interactions and phosphate catalysis of the alkylation reac-

tion has also been

In addition to DNA alkylation, this drug also induces local

bending, winding and stiffening of DNA293 that inhibits T4 DNA ligase,294 DNA polymerase295 and helicase II.2%

The preparation and DNA-binding propedes of several simplified

analogues of (+)-CC-1065 have been investigated.297 The indole containing trimer (270) was shown to be an optimal minor groove binding agent with selectivity for AT versus GC rich sequences. Modification of (270) to give a C(5) quaternary amine (271) substantially enhanced DNA binding affinity through the introduction of a stabilising electrostatic interaction.

An

adenine adduct derived from alkylation of calf thymus DNA with duocarmycin C2 an antitumour agent related to (+)-CC-1065, has been isolated and shown to have the structure (272).298

Several DNA binding drugs that act as bifunctional alkylathg agents and are able to cross-link DNA have been prepared and studied. Dimeric DNA alkylating agents containing

two reactive pyrroloindole systems have been prepared and used to cross-link DNA.2w

In

particular the dimer (273) was shown to bind in the minor groove of the helix at AT rich sequences and cross-link the strands through reaction with adenine bases on opposite strands separated by approximately one-half of a helical turn. The pyrrole[2,1-~1(1,4]benzodiazepine bifunctional alkylating agent DSB- 120 (274) has been synthesised and shown to form irreversible interstrand cross-links between two guanine bases.300

Molecular modelling and nmr studies

6:

Nucleotides and Nucleic Acids

OMe

297

v

Me0

HNYo H

(279)

indicate that cross-linking occurs between the NH2 groups in the minor groove with the alkylating agent spanning six base pairs and actively recognising the 5'd(GATC) sequence. The interaction of the anti-tumour antibiotic carcinophilin (275) (the more recently isolated azinomycin B has the identical structure) with double stranded DNA has heen studied.3o1

Bifunctional akylation by this drug affords interstrand cross-links in the major

groove between guanine and purine residues two bases removed. Treatment of the DNA adduct with piperidine at

WOC

results in cleavage of the DNA at the position of amlation.

A previously unrecognised reaction for the reduction of molecular oxygen has been presented that is based on the auteredox disproportionation of the oxazolidine moiety of quinoc a r ~ i (276) n ~ ~and is responsible for the cleavage of single and double stranded DNA.3o3 The interaction of Hoechst 33258 (277) with the minor groove in the duplex Id(GGTAATTACC)]2 has been studied by proton nmr spectrosc0py.304 The data imply that the d(AATT) central core is the preferred binding site even though all six A o T base pairs within the d(TAATTA) tract present the opportunity for similar intermolecular hydrogen bonding interactions. It is likely that the core tetramer binds more tightly at this site where the minor groove is narrowest. Two-dimensional nmr techniques have been used to study the binding of Hoechst 33258 with [d(GTGGAATTCCAC)]2.305

A unique model of the complex was

obtained from molecular mechanics calculations using constraints obtained ftom nOe experiments.

A purine-containing analogue (278) of Hoechst 33258 has been synthesised and its

interaction with DNA i n ~ e s t i g a t e d . ~The ~ analogue (278) was found to have increased affinity for binding to GC sites which has been rationalised through the formation of new hydrogen bonds between guanine NH2(2) in the minor groove and the concave purine N(3) atom of (278). Distamycin A (279) is known to bind in the minor groove of AT rich sequences in a very similar manner to that reported for Hoechst 33258. In the presence of excess drug, complexes can be formed with two distamycin molecules bound side-by-side in the same region of the

minor groove.3m Nmr studies with the duplex (d(CGCATATATGCG)I2 indicate that drug affinity in the 1 :1 binding mode is affected by the width of the minor groove. The groove can expand to accommodate a second drug in the 2:l complex, but it appears to be energetically unfavourable to narrow a wide minor groove even by a small amount.

A phenyl-containing

amidine-linked analogue (280) of distamycin has been synthesiised.308

The amidine group

provides the compound with good water solubility and it also shows specificity for the minor groove of AT rich sequences.

299

6: Nucleotides and Nucleic Acids

qig

H-NMe2.HCI N

0

/

H

H2N +/

H

+

A bis-cationic thiazole analogue (281) of the minor groove binder netropsin has been

shown to interact with the minor groove of AT rich regions despite the availability of thiazole nitrogen atoms capable of hydrogen bonding to GC sequences.309 These results support the view that the bis-cationic nature of the ligand imposes a bias which favours the recognition of AT sites.

The DNA binding properties of a large series of bis-benzamidines related to the

clinically used anti-pneumocystispentamidine (282) have been studied.310 Changes in the Tm point of calf thymus DNA in the presence of these analogues indicates that this class of compound has significant affinity for DNA.

Similar experiments performed with poly(dA)

poly(dA) and the alternating polymer poly(dGdC) poly(dGdC) indicate that the compounds have a moderate selectivity for AT sequences. Results obtained from viscometric titrations and molecular modelling are consistent with interaction in the minor groove. A highly fluorescent derivative of 1,4-6is-2-(4-methyl-5-pknyloxazolyl)benzene (283) obtained by treating a chloroform solution of (283) with dimethylsulphate induces a strong fluorescence in chromatin DNA under UV e ~ c i t a t i o n . ~ ~It is suggested that the fluorescence results from binding of the oxazolium derivative in the minor groove of the DNA. The interaction of 4',6-diamidinc~2-phenylindole(284) with poly(dA) poly(dT) and the corresponding RNA polymer poly(A) poly(U) has been studied by spectroscopic, viscometric, kinetic and molecular modelling methods.312 Interestingly the results show that (284) binds differentially to DNA and RNA showing minor groove binding at AT sites and intercala-

tion of AU sites. Some interesting results have emerged from the study of intercalating agents particularly with regard to their interaction with RNA. The genomic RNA of retroviruses is highly folded with sections of A-form helices containing bulges and loops. Specific RNA conformations such

as the TAR sequence in HIV-I (285) and their interactions with proteins (such as that of HIV-I) are essential for efficient

Disruption of such specific RNA conformations

and/or RNA protein interactions provides a route for retroviral chemotherapy that has not been extensively explored.

Ethidium (286) and an analogue of ethidium containing a 3-carboxy-

phenyl group (287) have been examined for their ability to bind selectively at specific RNA conformationalfeatures such as those that exist in (285).31a Thermal denaturation experiments have shown that (287) binds weakly to both simple DNA and RNA duplexes, as expected from its negatively charged carboxyl group and overall charge neutrality.

However, (287) binds

significantly more strongly to the TAR segment and such binding could critically disrupt the life cycle of HIV-I . Ethidium is also known to bind selectively to some unusual DNA conformations including olig~xyribonucl&&s containingB-Zjunctions.317 Both ethidium bromide

6:

Nucleotides and Nucleic Acids

301

GG U G C A CG GC AU UGC

c ‘AUl

GC AU CG CG

R (286) R = H (287) R = COOH

302

Organo p hospho riis C'hemisrry

(EB) and N,N'-dimethyl-2,7-diazapyrenium dichloride (DAP) intercalate between base pairs in

calf thymus DNA.

Laser flash photolysis techniques have shown that upon illumination of

intercalated EB an electron is transferred to an adjacent intercalated DAP molecule.318 The rate of forward electron transfer decreases with an increasingnumber of interspersed nucleobases and the results are consistent with electron tunnelling through the interspatial base pairs rather than via the phosphate or ribose functions. A series of 2,6aminoalkyl-functionalised 9,IO-anthraquinones (e.g 288) has been

prepared and their interactions with DNA investigated.319 Kinetic studies on both calf thymus DNA and synthetic oligodeoxyribonuclddes indicate that structures of this type intercalate

between base pairs whilst the side chains occupy both the major and minor grooves. DNA Eis-intercalators are of interest since they provide greater opportunity for site-

specific interactions.

A series of DNA bis-intercalators has been prepared in which two

acridine moieties are connected by rigid pyndine-based linkers (e.g. 289).3203321

From

mobility studies on agarose gels it is inferred that DNA cross-linking occurs as shown in (290). Eis-intercalating cyanine dyes (e.g. 291) have been shown to form stable highly fluorescent complexes with double stranded DNA.322

The fluorescence enhancement on intercalation to

DNA is greater than one thousand-fold and enables picogram amounts of DNA to be detected

and quantified. Nmr studies have shown that when DNA is added to an aqueous solution of D-fructose 323 there is a shift in the 6-pyranose/&furanOseequilibrium with the latter form being preferred.

It is thought that this is caused by weak preferential binding of the B-furanose form to DNA. Computer modelling studies support this theory since the pyranose form can make only two hydrogen bonds between the sugar hydroxy groups and the phosphate units, whereas three can be formed for the furanose structure. An in v i m selection procedure has been used to obtain RNA species that bind to D-

tryptophan a g a r ~ s e . ~ The * ~ selected RNA species were shown to be stereoselective in their recognition of D-tryptophan agar-

since the RNA did not bind to the diastereomeric L-trypto-

phan agarose even at a nine-fold higher substrate concentration. This work demonstrates that starting from a large pool of random sequence molecules, RNA species can be isolated that specifically recognise substrates that differ only by a single stereocentre. It has been demonstrated that the stable cross-links formed in calf thymus DNA on exposure to nitrous acid can also be formed in short synthetic oligodeoxyribonucleotides. Using a panel of synthetic oligomers it has been shown that the cross-links are formed most eficiently at sites containing at least two adjacent G G base pairs.325

The nucleotide sequence 5'-

303

6: Nucleotides and Nucleic Acids

Me,+

I

304

0rg an op hospho riis C7i c w 1 i.5 I ry

d(GC) was cross-linked less efficiently than 5’-d(CG) and for the latter sequence it was

conclusively demonstrated that deoxyguanosine residues in opposite strands were cross-linked. 9.

Interaction of nucleic Acids with Metals Traditionally this area has been dominated by studies involving platinum complexes;

although more recently there has been considerableinterest in the use of ruthenium and rhodium complexes as conformation-specificprobes and cleaving agents. The rhodium(111) complexes R h ( ~ h i ) ~ b p yand ~ +R h ( ~ h e n ) ~ p h are i ~ +known to induce efficient nucleic acid strand cleavage in the presence of long wavelength ultraviolet light.

However, the two complexes display For both complexes cleavage is

vastly different shape-selective recognition

initiated by abstraction of a 3’-hydrogen atom, but the partitioning of the resulting C(3’)-radical

between oxygen-dependent and oxygen-independent pathways of decomposition differ for the two complexes.327 R h ( ~ h e n ) ~ p h ihas ~ +also been used as a probe to characterise tertiary structures in tRNA and it appears to be useful for correlating structure and function in RNA.328 The metal complex Ru(phen):+

exists in two enantiomericforms A and A; both enantio-

mers bind DNA although their shuctural binding characteristics have remained unclear. Twodimensional nmr experimentshave demonstrated that both enantiomers bind to the minor groove

of the AT region in the self-complementary duplex [d(CGCGATCGCG)]2.329 An octahedral ruthenium(I1) complex (292) of the alkaloid 2-bromoleptoclinidinonehas been prepared and shown to intercalateinto calf thymus DNA and effect photoactivatedcleavage of double stranded 330 supercoiled DNA under irradiation with visible light.

The adduct formed by platination of d(AGA) with a monodentate platinum complex IR(diethylenetriamine)2+l has been used to simulate the first binding step of cisdiamine-

dichloroplatinum(If).331 Platination occurs at the N(7)-positionof guanine and nmr and X-ray diffraction techniques showed that only the sugar attached to the gUanine base changed its conformation on platination and tbe same residue also exhibited a shift in the synlunti equilibrium towards the syn-conformation. Binuclear platinum(l1) complexes (e.g. 293) have been shown to cross-link oligodeoxyribonucleotide 5‘-phosphorothioates sequence-specifically to complementary single strand targets.332

The most abundant cross-link was formed to the

deoxyguanosine residue complementary to the S-tenninal deoxycytidinein the phosphorothioate strand. The coordination chemistry of the molybdenocene anti-tumour agent Cp2MoC12 (Cp =

q5-CsHs) with DNA constituents has been extensively studied.333 This compound forms

1 : 1 complexes with the 2’deoxyribonucleotide 5’-monophosphates of guanine, adenine, cyto-

sine and thymine. There appears to be little selectivity in the complexation and Watson-Crick hydrogen bonds are not disrupted by the process.

Molecular modelling studies with oligo-

6: Nucleotides and Nucleic Acids

305

306

Organophosphorus C 'hemistry

nucleotide duplexes indicate that complexation is very different from that observed with cisplatin. Metal species have often proved to be essential components in many DNA and RNA cleavage systems. Effective metal ion-centred catalytk systems for the hydrolysis of phosphodiester bonds have been proposed which employ metal ions both to deliver a hydroxide ion in a direct in-line displacement and to complex the incipient alkoxide leaving group. This type of arrangement has been inferred from the study of certain enzyme catalyhc systems.

In

particular both Mg2+ and Zn2+ are directly involved in the 3'-5'-exoouclease activity of the Klenow fragment of DNA polymerase 1 from ~ . c o i iE.coli ; ~ ~alkaline ~ phosphatase is also

reported to use a combination of metal ions in a similar system.335 The role of metal ions in the hydrolysis of phosphodiester bonds has been investigated through model studies on bis-(8-

hydroxyquino1ine)phosphate and bis-(~hydr~xyquinoline)phosphate.~~~ Rare earth metal(111) ions have been shown to accelerate the rate of hydrolysis of RNA dinucleoside monophosphates by a factor of almost

The half-life of UpU at pH 8.0 and 30°C was ten minutes in

the presence of 0.01 M Tm(II1). It is thought that the metal-hydroxo complexes formed at a pH greater than 6.5 are responsible for catalysis, with the hydroxide ion functioning as a general base catalyst by activating the 2'-hydroxy function for intramolecular attack on the phosphorus atom. The uranyl(v~)ion (uo:+)

is known to induce single straad "nicks" in DNA on

irradiation with long wavelength ultraviolet light and it has been used as a sensitive probe for DNA c o n f o r m i ~ t i o n .The ~ ~ ~binding of UO:+

to DNA has been f

d to be a pre-requisite

for photocleavage and the binding constant was estimated to be about 1010M-' at pH 4 . 0 . ~ ~ ~ The angular orientation of the uranyl ion is cmistent with a binding mode which involves the

bridging of phosphate groups on opposite strands of the minor groove. The ability of KHS05 to effect site-specific oxidation of oligonucleotides in the presence of several nickel(l1) complexes has been investigated.24o

In parbcular a Ni(I1) Schiff base complex (294) was

shown to be an excellent promoter of oxidative modification of guanine bases which under alkaline conditions leads to strand cleavage. This reagent bas been shown to be an excellent probe for detecting guanine residues that are not involved in Watson-Crick hydrogen bondingWI

All guanine residues in random coils, mismatches, bulges and loops were oxidised

readily, whilst the other residues remained unchanged.

Sites of d o n were identified by

cleavage of the DNA when subi!ieCted to treatment with piperidhe. A silver(1)complex containingthe model nucleobases 1-me&ylcytosineand 9-methyladen-

ine has been prepared and studied by X-ray diffraction.u2 The cootdination geomeby of silver was shown to be a severely distorted trig&

planar arrangement in which two strong bonds are

6: Nucleotides and Nucleic Acids

307

formed to the N(3) of the pyrimidine and N(7) of the purine and a weaker bond exists to a water molecule. On the basis of this structure an alternative to the existing hypothesis on silver-DNA interactions is proposed which considers the insertion of a silver-aqua entity into an existing base pair. 10.

Analytical and Physical Studies

The dramatic advances that have been made in the study of nucleic acid structure using nmr spectroscopyhave largely been due to the developmentof powerful multi-dimensionaltechniques and the use of isotopically labelled samples. Complete assignment has been made for the proton-linked carbons in the oligoribonucleotide 5’-(GGACUUCGGUCC) using two-dimensional 13C-lH correlated experiments at natural abundance.343 Both the carbon chemical shifts and the 13C- 1H couplings are sensitive to the conformation of the sugar and the phosphodiester backbone. Complete assignment of the phosphorus resonances has been obtained for the same oligomer from a combination of homonuclear and heteronuclear (31P-1H) correlated experiments.3449345 A simple and quantitative procedure has been developed for the refinement of DNA structures using experimental two-dimensional nOe data.346 The procedure calculates

the simulated 2D-nOe spectrum using the full matrix relaxation methad on the basis of a molecular model.

The technique enables the global structure of a DNA double helix to be deter-

mined even when Starting from a grossly different model. A single hetero-TOCSY-NOESY spectrum has been used for the sequential assignment of 31P nmr resonances and for H(l’), H(8) and H(6)resonances in RNA

oligonucleotide^.^^^

The assignment strategy depends on

reasonably efficient transfer from 31P to the 3’- and 2’-protonsand nOe connectivities onward to the anomeric and base protons. This procedure has provided crucial assignment information

for a twenty-nine residue RNA ~ l i g o r n e r . ~ ~

Nmr spectroscopy is particularly useful in studying equilibrium processes such as those ~ ~ ~ nmr studies on [d(CGCGTATATAinvolved in the formation of hairpin s t r u c 3 ~ r e s .Proton

CGCG)], have shown that this self-complementary oligomer forms a hairpin, with a four-

membered ATAT loop, at either low strand or low salt concentrations.350 The protomtion and hydrogen bonding properties of d(TpA) have been studied by nmr.351 Surprisingly, protonation of the N(l) nitrogen of the Y-dAMP moiety in DMSO was found to be competitive with protonation of the phosphate group. In the concentralion range - lo4 M only a small fraction of d(TpA) is self-associated according to the Watson-Crick model. Several studies have been reported which involve nmr studies on isotopically labelled RNA and DNA. Fourdimensional heteronuclear nmr spectroscw has been applied, for the first time, to the sbucture deterrmnation of a uniformly 13c labelled RNA

The

labelled nucleoside 5'-mphosphates were prepared by extracting ribosomal RNA from E. cofi grown in 99% 3C-enriched media, degrading the RNA to nucleoside monophosphates and enzy-

matically converting these to the biphosphates. The RNA duplex was then prepared from the triphosphates by in vim0 transcription with T7 RNA polymerase. 17- 5N1-labelled-2'-deoxyguanosine has been synthesised and incorporated into oligo-

deoxyribonucleotidesto probe Hoogsteen hydrogen bonding in triple helices and guanine tetrads The ~ 9d(A ~ ~ ~C) and d(A G) mis-matches have been using 15N nmr s p e c t r o ~ c o p y . ~ ~ studied by the incorporation of I 1- 15N1-2'deoxyadenosine into oligodeoxyribonucleotides.355 pH dependent 15N nmr studies have provided direct evidence for the protonation of the N( 1 ) nitrogen atom in adenine in these mis-matched base pairs. The synthesis of an oligodeoxyribonucleotide labelled with 13C at the methyl group of thymine and 15N at the exocyclic amino group of cytosine has been described.356 A duplex was prepared in which an isotopically labelled functional group was present in the major groove at every base pair.

The labelled

thymine methyl group facilitates the detection of hydrophobic contacts with aliphatic side chains of proteins.

The utility of the technique was demonstrated in an nmr study of a complex

between the glucocorticoidreceptor DNA-binding domain and a labelled oligodeoxyribonucleotide; a hydrophobic contact was revealed between a thymine methyl group and the methyl groups of a valine residue. The study of DNA structure and dynamics by solid state nmr techniques has been reviewed.357 A prerequisite for gas p

k analysis (for example by mass spectrometry)of large, fragile

molecules is the molecular transfer of these species into the vapour state. Single stranded DNA deposited onto a glass slide in the presence of a large excess of the chromophore rhodamine 6G has been vaporised using an Nd:YAG laser (532 nm, 7 nS pulse). Analysis of the vaporised material by high resolution polyacrylamide gel electrophoresis has shown that with laser pulse energies greater than 85 ml cm-2 the DNA is vaporised without accompanying strand cleavage.358

At lower energies thermal degradation begins before molecular ejection occurs.

Experiments indicate that single strands as long loo0 bases can be vaponsed intact.359 Laser vaporisation has also been achieved for short o l i g ~ n u c l e o t i d e sand ~ ~ duplex DNA.3619362 The ionisation of purine nucleotides by 193 nm laser photolysis in aqueous solution has been studied as a model for oxidative damage of DNA. 363 Fluorescent dideoxynucleotide DNA sequencing has been performed using capillary electrophoresisto separate the DNA fragments and combined with multiwavelength detection of the four different f l ~ o r o p h o m . ~This ~ procedure produces sequence data with accuracy comparable to that obtained with the slab gel method. The stereochemicalm g e m e n t of the

6: Nucleotides and Nucleic Acids

309

four D N A helices that make up a four-way junction that occurs during recombination events has been studied by fluorescence resonance energy transfer (FRET) using many identical D N A fragments possessing dye labels at different positions.365 Molecular dynamics simulations performed on several three-dimensional models of ply(&) .poly(dT) suggest that unusual three-centre hydrogen bonds occur as a result of the high propeller twist at each A T base pair. 366 Reproducible images of D N A molecules in air have been obtained with a scanning force microscope.3''

310

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I54 155 156 157 158 159 160

161 162 163 164 165 166 167 168 169 170

171 172 173 174 175

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640. 338 339 340 34 1 342 343 344 345 346 347 348 349 350 351 352 353 354 355 335 356 357 358 359 360 361 362 363 364 365 366 367

P.E. Nielsen, N.E. Mnllegaard and C. Jeppesen, Ann’ Cancer Drug Design, 1990, 5 , 105. P.E. Nielsen, C. Hiort, S.H. Sonnichsen, 0.Buchardt, 0. Dahl and B. Nordkn, J.Am. Chem.Soc., 1992, 114, 4967. X. Chen, S.E. Rokita and C.J. Burrows, J.Am.Chem.Soc., 1991, 113, 5884. X. Chen, C.J. Burrows and S.E. Rokita, J.Am. Chem.Soc., 1992, 114, 322. S. Menzer, M. Sabat and B. Lippert, J.Am. Chem.Soc., 1992, 114, 4644. G.Varani and I. Tinoco Jr., J.Am.Chem.Soc., 1991, 113, 9349. C. Cheong, G. Varani and I. Tinoco Jr., N m r e , 1990, 346, 680. G. Varani, C. Cheong and I. Tinoco Jr., Biochemistry, 1991, 30, 3280. H. Robinson and A.H.-J. Wang, Biochemistry, 1992, 31, 3524. G.W. Kellogg, A.A. SzewczakandP.B. Moore, J.Am.Chem.Soc., 1992, 114, 2727. A.A. Szewczak, Y .-L. Chan, I.G. Wool and P.B. Moore, Biochemie, 1991, 73, 871. Y. Boulard, J. Gabarro-Arpa, J.A.H. Cognet, M. Le Bret, A. Guy, R. Teoule, W. Guschlbauer and G.V. Fazakerley, Nucleic A c i h Res., 1991, 19, 5159. D.A. Kallick and D.E. Wemmer, Nucleic Acids Res., 1991, 19, 6041. G. Barbarella, L. Tondelli and V. Tugnoli, J. Chem.Res., (S), 1992, 56. E.P. Nikonowicz and A. Pardi, J.Am. chem. Soc., 1992, 114, 1082. J.R. Williamson, M.K. Raghuraman and T.R. Cech, Cell, 1989, 59, 871. I.G. Panyutin, 0.1. Kovalsky, E.I. Budowsky, R.E. Dickerson, M.E. Rikhirev and A.A. Lipanov, Proc.Nal.Acad.Sci., U.S.A., 1990, 87, 867. B.L. Gaffney, C. Wang and R.A. Jones, J.Am.Chem.Soc., 1992, 114, 4047. C. Wang, H. Gao, B.L. Gaffney and R.A. Jones, J.Am.Chem.Soc., 1991, 113, 5486. E.R. Kallenbach, M.L. Remerowski, D. Eib, R. Boelens, G.A. van der Marel, J.H.van Boom and R. Kaptein, Nucleic Acids Res., 1992, 20, 653. T.M.A1amandG.P. Drobny, Chem.Rev., 1991, 91, 1545. R.J. Levis and L.J. Romano, J.Am. Chem.Soc., 1991, 113, 7803. L.J. Romano and R.J. Levis, J.Am.Chem.Soc., 1991, 113, 9665. B. Spengler, Y. Pan, R.J. Cotter and L.S. Kan, Rapid Commun.Mass Spearom., 1990, 4, 99. R.W. Nelson, M.J. Rainbow, D.E. Lob and P. Williams, Science, 1989, 246, 1585. R.W. Nelson, M.J. Thomas and P. Williams, Rapid Commwr.Mass @earom., 1990,4, 348. L.P. Candeias and S. Steenken, J.Am.Chem.Soc., 1992, 114, 699. A.E. Karger, J.M. Harris and R.F. Gesteland, Nucleic Acids Res., 1991, 19, 4955. R.M. Clegg, A.I.H. Murchie, A. Zechel, C. Carlberg, S. Diekmann and D.M.J. Lilley, Biochemistry, 1992, 31, 4846. V. Fritsch and E. Westhof, J.Am.Chem.Soc., 1991, 113, 8271. C. Bustamante, J. Vesenka, C.L. Tang, W. Rees, M. Guthold and R. Keller, BiochemChemistry, 1992, 31, 22.

7

Ylides and Related Compounds BY 6. J. WALKER 1 Introduction The number of publications reporting theoretical studies and those reporting mechanistic studies have increased following the reduction in these numbers last year. One of these reports includes the isolation and separate allowed the first decomposition of certain oxaphosphetanes and this has kinetic study of the second step of the Wittig reaction, albeit for a rather special system. Complex phosphonate carbanions and ylides continue to be widely used in synthesis and the number of reports of the use of the azaWittig and related reactions i n heterocyclic synthesis remain at last year's high level.

2 Methylenephosphoranes Preparation and Structure.- The simplest phosphorus ylide (2) is the most often studied hypothetical molecule in organophosphorus chemistry. It has now been generated in the gas phase from the radical cation ( 1 ) by neutralization-reduction mass spectrometry and the results support many earlier theoretical predictions about the stability of ( 2 ) and the energy barrier to its conversion to the more stable, isomeric rnethylphosphine.1 A large number of bis-ylenephosphoranes (3, X=CR2) have been prepared by a variety of methods2 and bonding in these and related compounds (3) has been studied by a6 initio calculations at the SCF and MCSCF level.3 The results suggest that bis-ylenephosphorane formation becomes more favourable with increasing electronegativity of the X-substituent group. Attempts to generate a mono-ylide by treatment of the bisphosphonium salt (4) with terriarybutyllithium led to the formation of the mono-salt (5).4 Similar attempts to generate the di-ylide ( 6 ) using a range of bases and solvents were unsuccessful. However, good evidence for the intermediate formation of (6) at low temperature was obtained from trapping reactions with 3,4-dichlorobenzaldehyde to give the cummulene ( 7 ) (Scheme 1). The ylide ( 1 0 ) can be generated by treatment of (R)-(3-hydroxy-2,3dimethylbuty1)triphenylphosphonium iodide (8) with two mole equivalents of alkyllithium although the reaction of a second mole of base with the oxaphospholane (9) initially formed is slow.5 31P n.m.r was used to follow the formation of (10) and indicated that the true structure of the ylide was a mixture of interacting aggregates. Wittig reactions of (10) with benzaldehyde

2.1

Ylides and Related Compounds

7:

321

+ -

+ [H3P-C H2]'

HSP-CH2

&;-

(3) X = CH2, NH, 0, SiH2, PH, S

(2)

+ Ph3PL

Ar=

CF3SO3-

7

I

CMe3

CI (5) CI Reagents: i, 2 x Bu"Li, CH2CI2,-78 "C; ii, 2 x ArCHO, CH2CI2,-78 "C; iii, Bu'Li, CH2CI2,-78 "C to 20 "C Scheme 1

(9)

(8) F2C=PCF3 + Me3P

--

-80 "C

to -196

(1 1)

Me

Tr

Me3P=C-P, "C

CF3 (12) X = F, OR

Ph3P

0

322

Organophosphorus Chemistry

under a variety of conditions gave exclusively (E)-alkene. The new ylides (12), which decompose at room temperature, have been prepared by the reaction of fluorophosphaalkenes (11) with t r i m e t h y 1 p h o s p h i n e . 6 Continuing studies of ylides derived from bisphosphinomethanes have provided a variety of 1 x 5 , 3 1 5 - d i p h o s p h o l e derivatives, e.g. (13).7 Conjugated azoalkanes react with triphenylphosphine to give stable 1,4adducts (141.8 The ylides (14) decompose on heating to provide useful syntheses of 5-alkoxypyrazoles (15) and 4-triphenylphosphoranylidene-4,sdihydroxypyrazol-5-ones (la), depending on the solvent used. Full details have appeared of further investigations of the reactions of dialkyl aroylphosphonates (17) with trialkyl phosphites.9 In the absence of added electrophiles the reactions lead to the formation of the quasiphosphonium ylides (19) which, depending on the nature of the alkoxy substituents on the ylide phosphorus atom, rearrange to the bisphosphonate (20). Convincing evidence is presented for formation of the carbene intermediates (18) in these reactions (Scheme 2). The iminophosphoranes (22) and (23) are formed from the reaction of the azide (21) with phosphines depending on the conditions used.10 The structures of a number of stabilized ylides have been studied by 13C, IH, and 31P n.m.r.11 and by X-ray crystallography.12 The X-ray crystal structures of (24) and (27) were compared to those previously determined for (25) and (26) and this data, together with that obtained from Raman and infrared studies on these and related compounds, was used to determine the extent and nature of hydrogen bonding in these systems. Bis(diphenylsily1ated) ylides (28)13 and the borylated phosphonium ylides ( 2 9 ) 14 have been synthesized and their molecular structures determined by X-ray crystallography and, in the case of (29). these structures used to fully interpret I l B , 13C, and I H n.m.r. spectra. The structural parameters determined by X-ray analysis for the P-chloro ylide (30) provide convincing support for negative hyperconjugation in ylides;l5 that is stabilization by the P-Cl (T* orbital accepting electron density from the ylide carbanion. A number of structural studies of iminophosphoranes have been reported. These include the product obtained from the reaction of phosphine (bisphosphine sulphide) (31) with p-tolyl azide which on the basis of its IH and 31P n.m.r. exists i n the C-ylide form (32) rather than as an iminophosphorane.16 Treatment of (32) with base gave the relatively stable iminophosphorane anion (33) which was isolated as a Rh(1) complex. The molecular structures of the iminophosphoranes (34),17 (35),l8 and (36)19 have been determined by X-ray crystallography and their structural parameters compared with those determined for 1,8-bis(dimethylarnino)-

Ylides und Related Compounds

7:

-

? ArCOP(OMe)2

1

i

323

- ? Ary -?( OMe)2

i

0 *

[ A z I ( O M e ) d + (RO),P=O

0

H02C+C02E1

2 x R3P 180 "C

180 "C

PPh3

N=PR3 (24)

N

II

C02Et

R3P

R3P=C( SiH2Ph2)2

(23)

PPh3 (25) n = 1 (26) n = 2 (27) n = 3

(28) R = Me, Ph

/SiMe3

R2N, R2N-7='\

x

a,+

A

But Ph

BR'2

(29) R' = MeS, X = F R' = X = OMe

E

8

Ph2p.clH-PPh2 PPh2

ArN3

E !

LDA

(30)

2 :

PhZP - PPh2

+ Ph2pYPPh2 'r: Ph2P,Ph2P, NHAr

(31)

-,Ph

c,

B"t - --P-

(32)

*

Li+

NAr

(33)

324

(34)

(35) X = Br, BF4, PF6

(39)

(40)

Reagents: i, 2 x BuLi, THF, 0 "C; ii, Ar2C0, 0-50 "C; iii, H30'; iv, 100 "C Scheme 3

-0-C-H ? Ph3F: 3F0f -

R

I ,O-

H,

H C

7Wh3

F3C'

OH (43) Reagents: i, 2 x Bu"Li; ii, RCHO

Scheme 4

7:

Ylides and Related Compounds

325

naphthalene which is known to be a "proton-sponge". 2.2 Reactions of Methy1enephosphoranes.- A recent review of dianion chemistry includes a number of references to P-ketophosphonate 1,3-dianions and their use in synthesis.20 2.2.1 Aldehydes.- A number of reports indicate a renewed interest in the mechanism of the Wittig reaction. The Wittig half reaction, i.e. the formation of oxaphosphetane from ylide and carbonyl, has been the subject of a theoretical study using the MNDO-PM3 method.21 Calculations on the reactions of ethylidenetriphenylphosphorane ( 3 7 ) and the unknown ethylidenephosphorane (38) with a variety of aldehydes provide transition state geometries and enthalpies of activation and reaction. The results suggest that the formation of the oxaphosphetane proceeds by a highly asynchronous (borderline two-step) cyclo addition. A detailed study has been reported of the carbonyl carbon 12C/14C kinetic isotope effect and substituent effects on reactivity and stereochemistry of the benzaldehyde-benzylidenetriphenylphosphorane Wittig reaction.22 The KIE and the Hammett p value were positive under both lithium salt-free (KIE=1.06 and px=2.8) and lithium salt-present (KIE=l.O2 and px=1.4) conditions. These results indicate a polar transition state w i t h substantial nucleophilic character. The isolable ( 4 0 ) have been prepared by the treatment of the oxaphosphetanes phosphine oxide ( 3 9 ) with two equivalents of butyllitium followed by substituted benzophenones (Scheme 3),23 The structures of ( 4 0 ) were X-ray established by 19F, 'H, and 3lP n.m.r. and, in one case, by crystallography. Heating (40) to lOOoC induced decomposition to give quantitatively the Wittig products and offered the opportunity to carry out a kinetic study of the second step of the Wittig reaction at least for this rather special system. The results give a negative p value and only a small solvent effect, suggesting a slightly polar transition state. Treatment of the 2hydroxy-3,3,3-trifluoropropyl-phosphonium salt ( 4 1 ) with one mole equivalent of base does not induce a Wittig reaction but rather leads to the formation of an equimolar mixture of unreacted starting material and the oxaphosphetane-ylide (42).24 The addition of a second mole of base converts (41) into (42) completely and the addition of aldehydes to (42) gives the alkenes ( 4 3 ) with (E)-selectivity and virtually complete retention of configuration at the chiral centre (Scheme 4). The unexpected (E)-selectivity is presumably due to the same reason as the (E)-selectivity observed in reactions of oxaphosphetane anions by Corey, Schlosser, and others.25 A new route to 1,3-dienes is provided by tandem nucleophilic addition to the dienylphosphonium salt (44) followed by reaction with aldehydes.2 6 An attempt to extend the reaction to provide a triene via the vinylogue of

Organop hosp horrts C 'hemistry

326

NHBoc

(44)

i-

+

OH

X- PhA ,s-

NHBoc

Si Me

+

G P P h 3

b

(45)

OH (46)

ArCHo

0

KF, A1203, CH&N

~~ \

(47)

(48)

@%2HCH2SiMePh2

I

,Me CH, NMe2

+

RCHO

TH F -78

c

"C

R (50)

RCH=CC12

(491

RCHO RCHC12

Reagents: i, Ph3P=CHOMe, KOAm'; ii, Hg2Cl2,HCI Scheme 5

OH

7:

Ylides and Related Compounds

327

( 4 4 ) gave only a moderate yield. The reaction of 2-trimethylsilylethylidenetriphenylphosphorane ( 4 5 ) , prepared in situ, with amino aldehydes gives the olefinic 1,2-amino alcohols (46) with syn selectivity via silyl group migration and loss of phosphine from the initially formed Wittig in termediate.27 5-Aryl- and 5-(2-styrenyl)-4,5-epoxy-2(E)-penten-l-ols (48) have been synthesized in one step in moderate to good yields by the reaction of aldehydes with the arsonium salt (47) under mild, phase-transfer conditions.28 The reactions of the individual enantiomers of the ylides (49). prepared from corresponding enantiomerically pure phosphonium salts, with aldehydes gave the vinylation products (50) with enantiomeric excesses ranging from 9% to 92%. It has been reported that by varying the proportions of the reagents, the reaction of triphenylphosphine and carbon tetrachloride in the presence of aldehydes can be directed to give either (51) or (52) as the exclusive product.30 2.2.2 Ketones.- A convenient procedure for the synthesis of 1-formylcyclohexenes by one-carbon homologation of the appropriate a-phenylthioketone, e.g. (53), by phosphorus-based olefination and hydrolysis has been reported (Scheme 5 ) . 3 1 Further investigations of the reaction of ethoxycarbonylmethylenetriphenylphosphorane with o -quinones have been reported.3 Reactions in the presence of triphenylphosphine or alcohols or acetic anhydride led to different products including lactone ylides (54) and furan derivatives ( 5 5 ) . Treatment of (4-bromo-2-butenyl)-triphenylphosphonium bromide (56) consecutively with sodium hydride, dialkyl lithiocuprates and aldehydes or ketones provides a non-stereoselective, one-pot synthesis of 1,3-dienes (57), presumably via the ylide ( 5 8 ) .33 Applications of 1,l -ylide-anions in synthesis have been neglected, indeed the true nature of these compounds has still to be determined. A recent report describes a one-pot synthesis of phydroxy-1,3-dienes via reaction of the allylic 1.1 -ylide-anion (59) with two mole equivalents of carbonyl compound (Scheme 6).34 The quasi-phosphonium ylides (60), which are generally unreactive towards carbonyl compounds, have been shown to undergo the Wittig reaction under photo-irradiation.35 Although acyclic ketones formed normal Wittig products, reactions with cyclohexanones gave allenes (61). 2.2.3 Ylides Coordinated to Metals.- Bisylide-nickel complexes, e.g. (62),

are reported to be excellent catalysts for the formation of novel, soluble matrix polyacetylenes.36 Reports of iron complexes containing bis(methy1ene)phosphoranes include the preparation and X-ray structure determination of (63) .37 The directly coordinated bis(methy1ene)phosphorane-iron complex (64) under-

+

NaH, R12CuLi,

Bu~P Br- -Br

Bu3p-

*

R2&0

R2L

R

R1

1

Reagents: i, Bu"Li, TMEDA, THF; ii, 2 x R1R2CO;iii, H30' Scheme 6 Ph

*

(MeO),P= C,

Me02C,

WR c=c=c,

P i

C02Me

H (611

(60)

B u ~ P30 , "C,

*

PhMe, 1 h

51me3

SiMe3 (64)

(65)

51me3

SiMe3 I

p:;Me3

"-"),

SiMe3

AIBU$

w

Bu"-P

30 "C

\'

SiMe3

H\pGCNSiMe3 SiMea

+ P SiMea

SiMe3

(68)

(66)

(69)

S iMe3

Y

SiMe3

B ~ ' ~ S i ( 0 R e 0+~ ) 2Ph3P=CPh2 ~

1

I,?

-

+

Ph3P-c I W Ph

(67)

7

-

;

(70)

P

t

1 3 Ph ( Re04)2-

7:

Mides and Related Compounds

329

goes rearrangement in the presence of tributylphosphine to give the ( 6 5 ) . 3 8 In a related reaction the I H - h s coordinated heterocycle (methy1ene)phospholane (67), an example of an ylide with a P-H bond, and butylbis(methy1ene)phosphorane (68) are formed on treatment of chlorobis(methy1ene)phosphorane (66) with trisiso-butylaluminium. An X-ray structure of the rhenium ylide complex (70), prepared from (69) and the corresponding ylide, has been reported.39 2.2.4 Miscellaneous Reactions.- A new route to cyclopentenones (72) i n moderate to excellent yields is provided by reaction of the allylic ylide (71) with a-halogenoketones followed by intramolecular Wittig reaction and acid h y d r o l y ~ i s . ~ The o vinylphosphoniurn salt (74), derived from the ylide (73), has now been shown to react with ethoxide ion to give exclusively the phosphine oxide (75)41 and not the ylide (76) as previously reported.42 Kinetic studies of the reaction of cyclopentadienylidenetriphenylphosphorane (77) with chlor0-,~3 bromo- and iodoanil44 to give the ylides (78) have been reported. The rate determining step in the reaction with chloroanil was found to be electrophilic attack of chloroanil on the cyclopentadienyl ring of the ylide (77). 2,2,2-Triphenyl- 1,2h5-oxaphospholanes (79) have been obtained from the reaction of methylenetriphenylphosphorane with epoxides.45 The cyclic form is favoured by non-polar solvents and in one example the structure (79) was confirmed by X-ray crystallography. The amido-stabilized ylide (80) shows higher nucleophilic reactivity than the corresponding ester-stabilized ylide and this allows reaction of (80) with a wide range of Michael acceptors to give both simple adducts, e.g. (81), and a number of useful new products, e.g. (82) and (83), depending on the nature of the solvent and the Michael acceptor.46 Wittig reactions of the new ylides formed provide syntheses of a variety of a,P-unsaturated derivatives. The cyclobutylidene ylide ( 8 6 ) is formed by the reaction of the bis(phosphonat0)ketenimine (84) with ketenylidenetriphenylphosphorane (85).47 Compound (85) has also been used to prepare polycyclic products via addition reactions and intramolecular phosphonate-based olefinations. NMethylnitrilium triflates ( 8 7 ) react with methoxycarbonyltriphenylphosphorane at room temperature to give a mixture of the salt (88) and the novel phosphonium triflates (89).48 On the basis of the relative basicities transylidation should favour the ylide (go), however this is not observed. In an attempt to increase the Wittig-type reactivity of amide derivatives the reaction of phosphonium ylides, e.g. (91), with thioimides, e.g. (92) and (93), has been investigated.49 Although the thio-Wittig reaction takes place, S-alkylation and oxidation-reduction occur in competition and reduce the usefulness of this reaction in synthesis. Further studies of the reactions of a-perfluoroacylalkylphosphonium salt (94) ,50951 generated by

330

OEt

0

-

+

rase

II

NaOEt

(78)X = CI, Br, I

(76)

aprotic solvent

C02Me

Ph3P

n

7:

Ylides and Related Compounds

Ph3P= CHC02Me

+

RC&Me -0Tf

331

-

(87)

Ph3kH2C02Me + Me02:#NHMe -0Tf Ph3P R -0Tf (88) (89)

C02Me ph3p=$NMe

R (90)

Ph3P=CR’ R2

,NASMe

(97) R = n-elkyl, X = 0 (98) R = n-Alkyl, X = S

MeS

I

N=PR3’ (96)

(R = P i , But)

“N*S ’ Me (99)

332

O r ~ u n c ~ ~ h o s p h oC'hrniisrry ric~

acylation of the corresponding alkylidene ylide, have led to new synthesis of perfluoroalkylated derivatives of vinyl esters, P-hydroxyketones, vinylethers, and ketones. The reaction of (94) with Grignard reagents gives the enolates (95) and hence a variety of derivatives.51 (96) react with primary isocyanates (97) or Iminophosphoranes isothiocyanates (98) to give the betaines (99). while similar reaction with isopropyl or tertiarybutyl isocyanate gives the corresponding carbodiimides ( l o o p 2 The reactions of 1,3-ylide-anions (101) with phenylisocyanate and with dicyclohexacarbodiimide have been investigated.53 Both reactions follow a similar path to provide the adducts (102) which are themselves ylideanions. Due to their substantial nucleophilicity, compounds (102) react with ketones as well as aldehydes to give a,P-unsaturated anilines (103) and amidines (104) with good (E)-stereoselectivity. The reaction of the diazomethylenephosphorane (105) with Lewis acids has been investigated.54 Reaction of (105) with boron trifluoride-etherate gave (106). the first example of an a-diazoalkylborate. 1.2.4-Benzotrithins (108) have been synthesized in moderate to good yields by the reaction of alkylidene ylides with benzopentathiepin (1 07) . 5 5 The reaction of phosphonium ylides with phosphorus trichloride has been re-investigated and products characterized for the first time.56 Depending on the molar ratios of ylide to trichloride used the ylides (109) and (110) are formed (Scheme

7).

3 The Structure and Reactions of Phosphonate Anions The factors affecting the competition between transesterification and olefination in reactions of phosphonoalkylcarboxylates (1 11) with aldehydes and potassium carbonate in alcohols under heterogeneous conditions have been investigated.57 The reaction of the carbanion of l - c y a n o - l fluoromethanephosphonate, prepared in siru from diethyl cyanomethanephosphonate (1 12) and N-fluorobis(trifluoromethanesulphonyl)imide, with aldehydes and ketones provides a synthesis of a -fl uoro -a, P - u n s a t u ra ted Wadsworth-Emmons nitriles (1 13) in moderate yield (Scheme 8).58 olefination of 6-methoxytetrahydropyran-3-one (1 14) and 5-arylthio-6m e t h o x y t e t r a p y r a n - 3 - o n e s (115) with ester-stabilized phosphonate carbanions have been investigated.59 In the case of (115) the nature of the solvent and, more surprisingly, the remote arylthio substituent has a significant effect on the (E/Z) ratio of the products (116). The (N-methoxy-Nmethylcarbamoylmethy1)phosphonate (117) has been prepared and used to prepare alkenes with high (E)-selectivity,6* The nature of the amide substituents allow ready reduction of the alkenes to the corresponding aldehydes. Olefination reactions using the N-protected phosphonate (118) have

7:

333

Ylides and Reluted Compounds CH2R

CHR Ph2P{.~ Li' CHR

Ph2<,

R'N=C=X

R: ,C=C,

R2R3C=0

C-CyNR' I 1;R X (102)

R3

P C-NHY

x"

(103) Y = Ph, X = 0 (104) Y = cyclohexyl, X = N-cyclohexyl

CI

?

( Pi2N)2P=C =N2

R'

S

+ Ph3P-CH2R

+

m

Ph3P=CR'R2

s

q

~

+

2

R

R

Br-

i

D

ii

Ph,P=C, PC12

(109) + Reagents: i, PCI3, 2 x Et3N; ii, Ph3PCH2RBr-, 2 x Et3N

[Ph3P]+[S2]

*

Ph3P

R

A

PPh3

CI(1 10)

Scheme 7

0 II

(Et0)2PCH2C02R' + RCHO

K2C03

R~OH

RCH=CHC02R1

0

(111)

Reagents: i, BuLi, THF, -78 "C; ii, [CF3SO2I2NF,THF, -78 "C; iii, BuLi, THF, -78 "C; iv, R1COR2,-78 "C to reflux

Scheme 8

II

+ RCH=CHC02R2 + (Et0)zPOH

334

Reagents: i, Base; ii, 2 x LDA, THF, -78 “C; iii, NH4CI, MeOH

Scheme 9

NHX (1 19)

7:

Ylides and Related Compounds

335

been used to synthesize a range of amino acids (119) bearing an enol ether group (Scheme 9).61 A variety of (E)-alkenes (121) have been prepared in excellent yield and with little or no racemisation from the phosphonate (120).6* Examples of the use of the carbanions of 1,3-dithiolylphosphonates (122) in the synthesis of tetrathiafulvalenes include that of the analogue (123).6 3 The phosphonates ( 124), prepared from diazoalkanephosphonates by rhodium catalysed 0 - H insertion, undergo olefination to provide a synthesis 1 -(Cyclopent-1-enylcarbony1)vinylof cyclic vinyl ethers (125).64 phophonates ( 1 2 6 ) have been used to synthesize fused ring systems containing two or three five-membered rings. The conversion of (126) into the aldehyde ( 127) followed by intramolecular olefinations leads ultimately to tricyclo[6.3.0.0~~~]undecenone derivatives, e.g. (128).65 The steroidal a-(isocyanomethy1)phosphonates (130) and (133) have been synthesized by methylation of the carbanions ( 1 2 9 ) and ( 1 3 2 ) , respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones ( 1 3 1 ) and ( 1 3 4 ) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a -aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 1l ) Y The reactions of the lithium carbanion of diethyl prop-2-enylphosphonate (137) with a,punsaturated ketones and esters have been investigated.68 Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a,p-unsaturated carbonyl is preferred to attack at carbonyl carbon. I n some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate ( 1 4 1 ) , which is a potent inhibitor of m y o - i n o s i t o l monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.69 a -Fluoroalkylphosphonates and their use in synthesis attract increasing interest. The reaction of the carbanion of difluoromethyl-phosphonate ( 142) with di(fert iarybutyl) oxalate provides the unusually stable hemiketal (143); this is a key step in the synthesis of the difluoromethylene analogue (144) of phosphoenolpyruvate (Scheme 13).70 A new, convenient route to 1,ldifluoroalkylphosphonates (146) is provided by the reaction of the carbanion of diethyl difluoromethylphosphonate with aldehydes followed by phenyl chlorothionoformate to give the thionocarbonates (145) which undergo radical-induced deoxygenation to give (146) (Scheme 14).7 1 1.2Difluoroalkylphosphonate derivatives (148) have also been prepared by the reaction of the difluoromethylphosphonate carbanion ( 1 4 7 ) with vinyl k e t o n e s . 7 2 The adducts ( 1 4 8 ) are readily converted, with (E)-

R2 ___)

H

OCHR'(CH2)nC02R2

(124) Z =C02Et, COCHS

Reagents: i, BdOK, THF; ii, Mel; iii, HC104, Dioxan, H20 Scheme 10

7:

337

Ylides und Reluted Cornpounds Ph2C=N

h2c=N) ( Bu'0)2P+

i, ii

FE

*

( Bu'O)2P+

0

0

iii, iv

*

H2N)-E (H0)2p,,0

(1 35)

Reagents: i, KOH, Aliquat 336; ii, E'; iii, HCI, H20; iv,

0

Scheme 11 0

(139)

Reagents: i, BuLi; ii,

0

; iii,

0 Scheme 12

R2

(H0 ) 2

OBn (140)

OBn

OH (141)

338

Organophosphorus Chemistry

0 HO O-Bu'

Na-'O,I

i, ii

8 (Et0)2PCH

F2

F F (143)

(142)

I

HONP O? C02-Na' F F (144)

(EtO)$fiO

____)

OBu'

Reagents: i, LDA, -78 "C; ii, [C02But]2

Scheme 13 0

S (145) Reagents: i, LDA, THF, -78 "C; ii, RCHO, THF, -78 "C; iii, PhOCCl; iv, Bun3SnH,AIBN II

Scheme 14

HO R'

S

0 CH2C'z

__.c

CICH~&~,,O, R'

so2c12

-78 "C

F F (148)

R (Et0)2PCF2Li

F F

~1

(149)

(147)

(150)

(151)

(152)

Reagents: i, 2 x LDA, THF, -78 "C; ii, R1R2CO;iii, H30'; iv, PhCHNH2, xylene, reflux I Me Scheme 15 H

0-yJy Me

Bu

THF, Bu"Li, 0 "C

Me

ay* Bu

(153)

H

O HO

(154)

D

O OH

(1 55)

H

Ph3PZCHPh ec

HO

OH (156)

Me

7:

Ylides and Related Compounds

339

stereoselectivity, into (149) which are useful reagents for the preparation of other functionalized a-fluoroalkylphosphonates. Olefination reactions involving the dianion of p-diethoxyphosphorylpropionic acid ( 1 5 0 ) provide a new synthesis of B,y-unsaturated amides (152) via aminolysis of the initially formed B-phosphoryl-y-lactone (151) (Scheme 15).73 Continuing their studies of carbanion-accelerated Claisen rearrangements Denmark's group have investigated a variety of phosphonamide-stabilized carbanions, e.g. (153) and shown that they react faster than the analogous phosphonate car bani on^.^^ Although internal sidechain 1,3-diastereoseIectivity was high in, for example, (154), asymmetric induction was poor with enantiomeric excesses between 4% and 38%. 4 Selected Applications in Synthesis 4.1 Carbohydrates.. The Wittig reaction of unprotected sugars (155) with benzylidenetriphenylphosphonium ylide leads to open-chain derivatives (156) in good yield.75 2-Deoxy-3,6-anhydrohexano-l,4-lactones, e.g. (157). have been synthesized from aldehydosugars by a Wittig reaction followed by acid-catalyzed methanolysis and rearrangement (Scheme 16),76 The Wittig reactions of 2-thiazolecarbonylmethylene ylide (158) with D-glyceraldehyde and D-arabinose acetonides to give, for example, (159) have been used as key steps in the synthesis of thiazole ketoses, e.g. (160).77 The synthesis of phosphonate analogues of phosphates and carboxylic acids is becoming increasingly important. Intramolecular olefination of the diphosphonate (161). itself prepared by a Knoevenagel condensation of Dlyxose 5-aldehyde with methylene[bis(diethyl phosphonate)], provides a novel synthesis of the phosphonate analogue ( 1 6 2 ) of shikimic acid.7 8 Olefination of the a-D-mannopyranoside (163) with methylene[ bis(diethy1 phosphonate)) has been used as a key step i n the synthesis of the monophosphonate analogue (164) of L-myo -inositol- 1,4,5 - triphosphate.79 Attempts to carry out the olefination reaction directly on the diphosphate (165) failed. 4.2 Carotenoids, Retenoids and Pheromones.- P h o s p h o n a t e - b a s e d 8 0 and phosphonium ylide-based8 1 olefinations continue to be used as major synthetic methods in the preparation of vitamin A derivatives, e.g. (92.1 1Z)vitamin A80 and (72)- and (7Z,llZ)-vitamin A.81 Examples of the use of complex phosphonates in synthesis include an olefination with (166) to provide a route to (-)-citreoviridin (167) ( S c h e m e 17).82 Alternatively the analogous ylides can be used in similar synthetic approaches and olefinations reactions of (168) and (169) have been applied to the synthesis of all (E)-citreomontanin (170),83 (+)-citreoviral,84*85 (+, citreoviridin,84 and the structurally related aurovertins.86

Organophosphorirs Chemistry OHC i, ii

Reagents: i, Ph,P=CHCO2Et;

-

ii, MeOH, H’

Scheme 16

NaOEt EtOH

HO

: 9

(Et0)2PCH2P(OEt)2 CH2C12, NaOH, H20

HO‘*

7:

34 1

Ylides und Related Compounds

II 0

(167)

Reagents: i, Bu"Li, THF; ii, iii, Bu"~NF, THF, 0 "C

Scheme 17

&Aol

PPh3

(168) tJ = 2 (169) tJ = 1

(170)

(172) R = CSHll (1 73) R = (CH2)2COCH2CH3

Ph3P, R'

R2

(175) (176) R' = Me, R2 =R2 Me= H

1 OR'

C5H11

(177)

342

0rganop h osp h orus Chemistry

A new synthesis of three sex pheromones, (171), (172) and (173), of the Winter moth Operophrera brumara involves the use of the ylide (174) which acts as a homologating agent and allows further Wittig reactions of the products after acetal deprotection.87 Standard methods of phosphonate-based olefination have been applied to the synthesis of new retinals, e.g. (175) and (176), with modified methyl substitution patterns.88

4.3 Leukotrienes, Prostaglandins and Related Compounds.- A new convergent synthesis of leukotriene B4 (179) involves a Wittig reaction of the ylide (177) with the aldehyde (178) as a key step.89 Lipoxins A4 (182) and B4 (183) (LXA4 and LXB4) have been synthesized using Wittig reactions of ylides (180) and (181), respectively, as key steps.90 Both LXA4 and LXB4 were obtained as 1:1 mixtures with their all (E)-isomers and these mixtures were separated by HPLC. A total synthesis of (1%)-HETE uses a Wittig reaction of the ylide (184) to construct the eicosane skeleton (185).91 Examples of the use of both phosphonate- and ylide-based olefination in prostaglandin chemistry include the synthesis of the stable prostacyclin analogues (186) containing an azidophenyl group as a photoaffinity labelling functionality.92 4.4 Macrolides and Related Compounds.- Complex phosphonates continue to be used in the construction of the carbon framework in syntheses of macrocyclic compounds, for example (187). (188). and (189) in syntheses of the immunosuppressant FK-506.93 a high affinity ligand for the immunophilin FKBP,94 and the bis-macrolide (-)-colletol,95 respectively. In the case of the immunophilin FKBP intramolecular phosphonate-based olefination is also used as the cyclization step.94 A recently reported asymmetric synthesis of the macrocyclic lactam macebecin uses selective (2)-olefination with the fluoroethyl phosphonate ester (190) to introduce the (E,Z)-dienic amide residue.96 A Wittig reaction of ylides (191) with biphenyl aldehydes (192) has been used to link rings C and D in new convergent synthesis of the macrocyclic bis(biphenyls), plagiochin C and D.97 4.5 Nitrogen Heterocycles.- Intramolecular Wittig reactions have been used to construct heterocyclic rings in, for example, the synthesis of N-alkyl3-pyrrolines (193) (Scheme 18)9* and that of 2-methyl-3-(aryl/alkyl)- 1oxo-l,2-dihydroisoquinolines (195) by a one-pot synthesis from the amides (194) (Scheme 19).99 Recent advances i n the formation of iminophosphoranes by the Staudinger reaction and their reactions have been reviewed 100 and there have been a large number of reports, some of which are minor extensions of

7:

Ylidcs und Related Cornpounds

OH

(CH2)4CH3 ,OMe

-0

0-oc, I

Me

Me

343

HO OH

,OMe

0-0c, I

Me

TBsoQ Me0

COSEt Me

OTBS

Me

344

Organophosphoriis C 'hemistry

?

(CF3CH20)2P~C02Me Me (190)

R

R20

'

q

C H= PPh3

"'0-

\

C02Me

C02Me

i. ii

CCp: N

Reagents: i, NaH, THF; ii, H30'

Me i,ii

(1 94)

Me (193)

Scheme 18

0:

Me

co-( COR CH2PPh3 Br-

iii

d

Reagents: i, Br2, CCI4, hv, reflux; ii, Ph3P, PhMe, reflux; iii, Et3N,toluene, reflux Scheme 19

M

(1 95)

R e

earlier work, of the use of the aza-Wittig reaction in the construction of heterocyclic ring systems. These include the synthesis of indoles, pyrimido[4,5]indoles ( 1 9 6 ) . pyrrolo[2,3-b]indoles ( 1 9 7 ) . and 1.3benzodiazepines (198),101 of pyrazolo[4,3-c]pyridines (199),102 of 3.4dihydroquinazolines and quinazolines,*03 of the methanocyclodeca~b]pyridine ring system ( 2 0 0 ) 1 0 4 and the related pyrrole ( 2 O l ) , l o s of 1,3-benzoxazepines ( 2 0 2 ) and 1,3-benzodiazepines (203).106 and of the phenylsubstituted- (204) and condensed- (205) 5-azaazulenes.107 The reaction of the iminophosphorane (206) with 2-formylpyrrole and 2-formylquinolines has been used to prepare the p-carboline framework of the alkaloids eudistomins A and M and lavendamycin, respectively.108 Treatment of the epoxy-azides (207) with triphenylphosphine gives the azirino[ 1,2-a]indole derivatives ( 2 0 8 ) in surprisingly good yield, presumably via the corresponding iminophosphorane.lo9 The Wittig-type reactions of iminophosphoranes with isocyanates and related compounds have also been extensively used in heterocyclic synthesis. Examples include the preparations of the mesoionic [ 1,3,4]thiadiazolo[2,3c][ 1,2,4]triazines (210) from (209),110 bicyclic guanidines, e.g. (212), from (211),111 naphthypyridines ( 2 1 5 ) , ( 2 1 6 ) , and ( 2 1 7 ) from ( 2 1 3 ) and (214) , I 1 2 pyrido[ 1,2-f]pyrimido-[4,5-d]pyrimidines ( 2 18) , I 13 7H-pyrido[4,3-c]- (219) and 10H-pyrido[3,4-b)- (220) carbazoles,l l 4 tricyclic fused 2,4-diimino- 1.3-diazetidines (222) from the bisiminophosphorane (221),115 benzotriazepines (225) from (223) and (224),1 and mesoionic thiazolo[2,3-b]- 1,3,4-thiadiazoles (227) and N,N-bisheteroarylamines from the iminophosphorane (226), derived from 3-amino-4-phenylthiazole-2( 3H)thione, 1 17 The carbodiimides (229), prepared from the iminophosphorane (228), can be converted into quinolines or a -carboline derivatives depending on the nature of the isocyanate used in the reaction with (228)118 and the reactions of iminophosphoranes ( 2 3 0 ) and ( 2 3 1 ) with aryl and styryl isocyanates provide one-pot syntheses of quinoline, a -carboline, and quinindoline derivatives. 1 4.6 Miscellaneous Reactions.- A full report has appeared of the use of tert-butyl 4-diethylphosphono-3-oxobutanthioates ( 2 3 2 ) in olefination reactions for the preparation of homologated 3-oxobutanthioates and hence of tetramic acid derivatives.120 The reaction of the phosphonate dianion (234) with the aldehyde (233) is a key step in a total synthesis of the tetramic acid antibiotic (&)-tirandamycin B (235). 121 Olefinations involving both ylides and phosphonates have been used to construct the triene (236) en route to the spirotetronate subunit of the aglycone of the antitumour antibiotic kijanimicin.122

346

Organophosphorics C'hemistry

R'

R' Ph3P

R2&o

CHC13 RT *

7:

Ylides und Related C'omporr~rr1.s

347

0 -

pyri dine RNCO

0

Me

702Et 2 x ArNCO

Ph

348

Organophosphorus C’humistry

CHO

Ho%....0

Me

(233) isomerization and deprotection

(235)

OMe

(234)

7:

Ylides und Related C'ompounds

349

A high degree of (E)-selectivity is observed in the synthesis of the vitamin D precursor ( 2 3 7 ) from a Wittig reaction of bromomethylenephosphonium ylide with the corresponding ketone.123 The chiral ylide ( 2 3 8 ) has been used to introduce the side chain in a stereoselective synthesis of the 25-hydroxyergost-22-ene derivative ( 2 3 9 ) which can be converted to various hydroxylated vitamin D2 analogues.124 A new electron donor tetrathiafulvalene vinylogue ( 2 4 0 ) has been synthesized using both phosphonium ylide- and phosphonate-based olefinations (Scheme 2O).I25 Both Wittig reactions and Wadsworth-Emmons reactions have also been applied to the synthesis of new vinylogous tetrathiafulvalenes, e.g. (243). from (241) and (242).126 Complex phosphonates and phosphonium ylides have been used i n a variety of syntheses. For example an olefination reaction of the phosphonate ( 2 4 4 ) has been used to construct the carbon skeleton in a convergent synthesis of the structural fragment ( 2 4 5 ) of the marine metabolite h a l i c h o n d r a m i d e I 2 7 and Wittig reactions with the ylide ( 2 4 6 ) have been used to prepare the polycyclic cervinomycin A1 -trimethyl ether and A2methyl ether.128 Both complex phosphonates (247) and phosphonium ylides (248) have been investigated for use in the synthesis of calyculin A. Use of the phosphonate (247) was not successful due to a competing elimination reaction and the ylide (248) was used in the actual synthesis.129 The Wittig reaction of the o-azidoalkylidene ylides ( 2 4 9 ) with the aldehyde ( 2 5 0 ) has been used in a synthesis of Theonelladins ( 2 5 1 ) and (252). 130 The reaction of allylic azides with triphenylphosphine followed by treatment with the corresponding ketene provides a one-pot synthesis of a allylated nitriles (253) in moderate yield.13 Olefination reactions of the phosphonates ( 2 5 4 ) and ( 2 5 5 ) derived from hydantoin and 1-methylhydantoin, respectively, provide good yields of the expected C-5 unsaturated hydantoin derivatives ( 2 5 6 ) , generally as mixtures of isomers.132 Heterocyclic analogues, e.g. (257), of pulvinones and, e.g. ( 2 5 8 ) , of permethylated pulvinic acids have been synthesized by Wadsworth-Emmons reactions of the phosphonates ( 2 5 9 ) and ( 2 6 0 ) . themselves prepared directly from substituted maleic anhydrides.133 The reaction of ylide (261) with aldehydes to give (262) has been used as a key step in the synthesis of ~-alkyl-a-methylene-y-butyrolactones.1~4 Wittig reactions of the (R)- or (S)-isomers of the aldehyde ( 2 6 3 ) , readily available from serine, provide the alkenes (264) and hence the vinyl glycines ( 2 6 5 ) with defined configuration and double bond geometry (Scheme 2 1). 1 3 5 The reaction of cephalosporin 3'-triphenylphosphorane ( 2 6 6 ) with a-halogenoketones has been used to synthesize new tricyclic cephalosporins (267).*36 One-pot coupling of the phosphonium salt ( 2 6 8 )

*

Organophosphorus Chernisrry

350

' /

CF3S03-

(240) Reagents: i, Ph3P; ii, (Me0)3P; iii, (CH0)2; iv, BuLi, THF, -78 "C Scheme 20

(243) X = Se, S

(242) X = Se, S

(

2 F v

o)

(CH2)30SiMeBu

,CHO

0

OMe

Me

a""" (245)

OMe 0

Me0

Ph3P\

OMe

OMe (246)

Me2N

OTES

t

(247) X = CHZP(OEt)* (248) X = CH=PBU~

X

7:

Ylidcs and Related Compounds

Ph3Pn(CH2)n0N3

+

3s 1

TCH0-

(251) R = Me, H

(252) R = Me, H

OMe

(254) R = H (255) R = M e

OR

Organo p h m p horus Chumi.srry

352

(264)

(263)

Reagents: i, Ph3P=CR'R2; ii, H30+; iii, Jones' Reagent Scheme 21 PhCH2CONH

ws7

\

BU~K,THF

w (274) X = CN, F, Br, CI

Organophosphorus Chemistry

354

and t h e c y c l i c a n h y d r i d e (269) t o give (270) i s a key s t e p in t h e synthesis of (+)-zileuton (271), which is a potent inhibitor of 5-lipoxygenase.137 A new s y n t h e s i s o f p e n t a l e n i c a c i d ( 2 7 3 ) w i t h v i r t u a l l y c o m p l e t e stereo- and r e g i o - c o n t r o l uses Michael addition of t h e carbanion of t h e allylic p h o s p h o n a t e (272). 3 8 P h o s p h o n a t e - b a s e d o l e f i n a t i o n of s u i t a b l y s u b s t i t u t e d cinnamaldehydes has been used t o prepare a number of (E,E)- 1,4-diarylbuta1,3-dienes ( 2 7 4 ) w i t h p r o p e r t i e s s u i t a b l e for use in l i q u i d c r y s t a l display d e v i c e s . 1 3 9 T h e r n e s o - f o r m (276) of a tetrahydrotetrabenzocyclododecene has been s y n t h e s i z e d by b i s - a l k y l a t i o n of t h e b i s - y l i d e ( 2 7 5 ) ; ( 2 7 6 ) isomerizes t o t h e racemic form on heating.140 REFERENCES I.

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1991. 1951.

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Ylides and Related Ccmtpouritls

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440 1 . 102. P. Molina. E. Aller, and A. Lorenzo. Tetrahedron. 1991. 47, 6737. 103. E. Rossi, D. Calabrese, and F. Fanna, Tetrahedron, 1991. 47. 5819.

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Chem. Commun., 1992. 424. 116. P. Molina. A. Arques. A. Alias, M.V. Vinader, M.C. Foces-Foces, and F. Hernandez-Cano, Tetrahedron, 1992, 48. 3091. 117. P. Molina. A. Arques. and A. Alias, Tetrahedron, 1992. 48, 1285. 118. T. Saito, H. Ohmori, E. Furuno. and S . Motoki. J. Chem. Soc., Chem. Commun., 1992. 22. 119. P. Molina, M. Alajarin, A. Vidal, and P. Sanchez-Andrada. J. Org. Chem.. 1992, 57, 929. 120. S.V. Ley, S.C. Smith, and P.R. W d w a r d , Tetrahedron, 1992. 48, 1145. 121. S.J. Shimshock. R.E. Waltermire. and P. DeShong, J. Am. Chem. Soc.. 1991. 113, 8791. 122. J.A. Marshall and S. Xie. J. Org. Chcm., 1992. 57. 2987. 123. B.M. Trost and J. Dumas, J. Am. Chem. SOC.. 1992. 114. 1924.

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Phosphazenes BY C. W. ALLEN

1 Introduction

This chapter covers the literature of phosph(v)azenes with reference to lower valent species when they can be related or transformed to the phosphorus(v) species. Interest at both the fundamental and applied levels continues in this area. Various aspects of phosphazene chemistry were presented at the 6th International Symposium on Inorganic Ring Systems (Berlin, 1991). The invited lectures from the symposium' as well as the submitted papers' have been published. A brief introduction to binary phosphorus nitrides including the diatomic, cyclics and cages has appeared3. A systemization, based on graph theory, for enumerating of skeletal isomers of inorganic heterocycles4 as well as nomenclature proposals for inorganic heterocycles has been presented'. The IUPAC nomenclature recommendations for inorganic rings and chains have been previewed'. Focused reviews will be cited in the appropriate sections below.

New, interesting chemistry involving acyclic phosphazenes (phosphazo derivatives, phosphine imines or more appropriately phosphoranimines) continues to be developed. From the perspective of the synthetic organic chemist, one of the most important recent advances in phosphazene chemistry is the application of the aza-Wittig reaction to organic synthesis in general, and specifically in the synthesis of heterocycles. This interest has been reflected in several recent reviews including an excellent survey of recent advances in the

360

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Staudinger reaction (phosphazene synthesis and reactions with a special focus on the aza-Wittig process)’, and reviews of the applications of the aza-Wittig reaction to heterocyclic synthesis in English’ and Japanese’. The chemistry of new perfluoromethyl silylaminophosphoranimines has been summarized”. Calculations using ab initio methods on HPNS’ suggest that S-H bonds are present and linear isomers are more stable”. Semiempirical MNDO MO calculations on C1,P (E)NPC1, (E=O,S) and Cl,P(O)NPCl,NPCl, give qualitative agreement with the structures observed by x-ray crystallography, vibrational spectra were calculated and normal coordinate analyses performed. MO calculations using AM1 and PM3 methods proved unsuitable12. The structural parameters of the Ph,PNPh- anion suggest some phosphazene ~haracter’~.The measured dipole moments for a series of R’N=P(R)=S derivatives agree well with those calculated from P=S and P=N polarity parameters14. Extensive one and two dimensional NMR studies (13C, ”N, 29Si, 13P) including signs of coupling constants have been reported for (Me,Si),NP(=NSiMe,),”. Stereochemical flexibility about the P=C bond has been shown for the RP[ =NC6H2(CMe,) J =C ( SiMe,) series16. The UV spectra of Me,NC6H,P(=NH)NEt2 in a variety of The use of 1-o-tolyl-2,2solvents have been obtained 17. bis(m-tolu~dino)-2-(N-m-tolylthiourea)monophosphazene in the spectrochemical determination of Mo (V) has been established”. Of the many synthetic routes to acyclic phosphazenes, the Staudinger reaction continues to be the most popular7. Certain examples will be indicated at this point but most are the first step in a synthetic sequence in which the phosphazene is transformed to another chemical entity. The reaction of (E,E)The R2PC1 (R=l) with PhN, gives ( 2 , Z ) -P,P(=NPh)Cl”. azidophosphines C12-, (Et,N) ,PN, (x = 0, 1 , 2) can be converted to phosphinophosphazenes, C12-,(Et,N),PN=PR3, by reactions with R,P. Sequential reaction of Et,NP(N,) with PhN, and PPh, provides the PhN=P( N,) (NEt,)N=PPh,, PhN=P(NEt,) (N=PPh,) mixture2’. The interaction of Ph (RO) P(CR=CF,CH,) with Me,SiN, gives both a poly (phosphazene) and Ph(RO)2P=NSiMe, which is easily hydrolysed to Ph (RO),P (0) NH,“ . The unstable (Me,C),P(=NPh)CrCOEt formed by the appropriate Staudinger reaction undergoes polymerization when left to its own devices but

,

,

8:

Ph osph a zenes

36 1

Ph I

Me3CN NC

CN

(4)

N I

H

(5)

PPh3 I CI RC02CH=C";Pt:

Ph

(7)

CN NCPh MeS

,

Het- NF

9

Het-N

R'

Ph2R

(9)

<

3h2

Organoph osy horus ‘hemistr, 1

can be intercepted by nucleophiles e.g. alcohols give Me,CP (=CHCO,Et) N (Ph)R, diethylamine gives Me,CP(NPh)CH=C(OEt)NEt,, t-butylamine gives Me,CP(NHPh) =CHC (OEt)=NCMe3 and hydrolysis leads to Me3CP(=NPh)CH2C02EtZ2. The synthesis of 2 (R=Ph,P=N , Bu,P=N , (MeO),P=N) from the azide which at high temperature undergo further reaction with phosphines to give the diphosphazenes, 3 , 6-(Ph3P=N) (R,P=N) C,N,H, (R=Ph, Bu) . If the phosphite is used in place of the phosphine the reaction gives another pyridazine 3 ,6- (Ph,P=N) (NEtP(0) (OEt), C,N2H:’. The reaction of chloromethylpoly(styrene) with NaN, and PPh, gives polymer bound CH,N=PPh, units which bind aqueous Fe(II1) with 100% selectively in the presence of numerous other divalent first row transition metal ions2&. The synthesis of 3 from 8 (triphenylphosphorany1)quinoline and Mo(CO),(CH,CN), or in a more complex reaction of Mo(CO),PPh,(CH,CN), with 8 azidoquinoline, presumably through a nitrene intermediate”. The unique diphosphazene (CF,),P=N=PPh, is obtained from (CF,),PN, and Ph,P. Reaction of the diphosphazene(L) with the Fe,(CO), gives Fe(CO),L and Fe(CO),L, in which the (CF,),P center acts as the donor to iron26. The Ph,P[ Ph,P(S) ]2CH/p-tolylazide reaction gives, via C to N proton migration, Ph,P(S)C(PPh,=NHR)=P(S)Ph. The protonated phosphazene can be converted to the monoanion which reacts with [RhLCl], (L=cyclooctadiene) to give LRh (SPPh,),CPPh,=NRZ7. Other reactions of phosphorus (111) derivatives can provide acyclic phosphazenes. N-Chloro compounds can be utilized as a source. The reaction of Y3P (Y=PhO,C1) with ClNS0,Me gives Y,P=NSO,Me‘*. Phosphazenes which are isoelectronic with perchlorosiloxanes such as RN=PCl, (R=Cl,Si , Cl,SiOSiCl,) and C1,P=NSiC120SiC1,N=PC13 are obtained from the reaction of PC1, with precursors such as RN(C1)SiMeT. The boiling points, mass and vibrational spectra of the isoelectric pairs are compared. The phosphites (RO)(R’0)PNR‘SiMe, react at low temperatures with CF,=C (CF,) to give (RO)(R‘0)P (=NSiMe,)CF=C ( CF,) . Higher temperatures are A required to convert RR’ N (SiMe,) to RR’P( =NSiMe,) CF=CFCF,,’.

,

,

novel reaction between Ph,P and tetracyanoethylene leads to Attack of Ph3P on the nitrido nitrogen atom in trans[Os(tpy)Cl,(N)]Cl (tpy=terpyridine) is first order in each

4,’.

8: Phosphazenes

363

reactant and gives trans-[0s(tpy)Cl2(N=PPh3)]+. The phosphoraminato complex undergoes reversible one electron oxidation and reduction. The reduced species is stable in solution but the oxidized material decomposed to the starting nitrido complex32. Photolysis of Ar2P(0)N, (Ar=mesityl) in methanol gives, via a Curtis rearrangement, an unstable ArP(O)=NAr which is captured by the solvent to give ArP (0) OMe (NHAr) Low valent phosphorus compounds also can be transformed to phosph(v)azenes. The reaction of RP=N[2,4,6(Me$) 3C6Hz] with the product of the (Me3Si),CCl,/BuLi reaction gives RP=N[Z 14,6-(Me3C),C,H,]=C(SiMe,)216. The addition of Ph2PC1 to the AdNPNAr- anion (Ad=adamantane, Ar= 2 ,4 ,6-(Me$) ,C,H,) is solvent dependent. In ether, attack on the phosphorus center of the anion gives Ph,P(=NAd)=NAr while in pentane attack on nitrogen gives Ph,PN(Ad) P=NArU. Addition of azobenzene to Phosphorus (v) derivatives can also be Et,CP=NCMe, gives 5 ” . used as starting materials in acyclic phosphazene syntheses. The Kirsanov reaction continues to be useful in this regard. The in situ generation of Ph,PBr, from Ph,P and Br, is an increasingly popular technique for generating the necessary phosphorane. An interesting series of 1,8-disubstituted naphthalenes with “proton sponge” characteristics have been prepared from this Thus the reaction of 1aminonaphthalene gives CloH7N=PPh,which can be protonated with HBF, to C,oH7NHPPh;37. The corresponding reaction with 1,8 diaminonaphthalene gives first the monosubstituted derivative CloH6 (NH,) N=PPh,36 followed by (even with excess Et,N) 6 (R=NPPh,, R’=Ph, X=Br)37. Similarly 1-amino-8-dimethylaminonaphthalene gives 6 (R=NMe,)2 r R’=Ph, X=Br)=. The reaction of MeSO,N(SiMe,), with PC1, gives MeS02N=PC1, in CC1, while in CHC1, a mixture of the above and Me3SiN=S(0)C1(Me) is obtained39. The reaction of chlorophosphoranes with a NSiMe, group bound to a metal atom leads to metal-NPR., systems which have been formulated as MmN-PR, species (i.e. NP single b~nd)~’”’. While the metal-nitrogen bonds are short and the phosphorus-nitrogen bonds are, in some cases, slightly longer than usual (see section 7 ) , this description may be an oversimplification of a more extended electronic system. The reaction of V(NSiMe,)Cl, An extensive study of with PC12MePh2 gives V (NPMePh,) Cl?.

’,.

364

0rgunophosphorus Chemisrry

preparation routes for these complexes has been conducted4'. The reaction of PC1,R3 (R3=Me3,MePh,, Ph,) with W(NSiMe,)Cl,(PMe,) gives [W(NPR3)C1,(PMe,),]C1 while the corresponding Mo species slowly decomposes to [Mo2(N)C1,(PMe3),]+[Me3PNPMe3]-. The direct reaction of excess C1, with M (NSiMe,)Cl, ( PR,) (M=W, Mo) gives M(NPR,) Cl,. The mixture of W(NPMe,)C15 and [W(NPMe,)Cl,(PME,),]+ gives W (NPMe,) Cl,PMe,. Other methodologies such as reactions of W (N)c1, with PCl,R, and W(NPPh,) Cl, with Me,SiNPR, also give phosphoranimido complexes". Attack of a coordinated isonitrile in PtCl,(NCPh), on the phosphorus center in Ph,P=CHCO,R gives 7 (R=Me, Et)&,. Other, less general phosphorus(v) reactions have appeared. The reaction of aminofuroxans with (Me(CH,) 7 ) ,POSO,CF,+ gives the phosphoranimines which under oxidation gives two furoxanes The reaction of (PhNPCl,), with bridged by a -N(O)=N- unit4'. NaOCH,CF, gives the monomeric PhN=P(OCH,CF,) entity4&. Ring opening of (Me3N),b=CHP(NMe,) ,=kH occurs upon reaction with RNH, (R=Ph, p-CNC,F,) to give MeP (NMe,),=CHP ( NMe2)=NR4,. The reaction of Ph,P (S)(NHPh) with bPtC1, (L=Ph,P, Ph,P (CH,) ,PPh,) leads to ring closure and generation of an exocyclic phosphazene in $PkNHP (Ph) (=NPh)k?. The high degree of polarity in the phosphazene bond leads to a wide range of reactions in which the phosphazene is transformed into another functional group. Most of the interest in this area has involved use of the Aza-Wittig rea~tion''~but other transformations, including some discussed above, have been explored. Quinoxalines are available from ortho aryldiamines by sequential reactions with (MeO),PBR, and The reaction of ArN=CC,H,N=PPh, with RCHO PhC (0) C(0) Ph4'. proceeds by formation of the imine from the phosphazene followed by electrocyclic ring closure via interaction with the ArN=C functionally". The reaction of 4iminotripheny1phosphorany1-2,b-dimethy1-5-oxo-3-th~oxo-2,3,4,5tetrahydro-1,2,4-triazines with isothiocyanates gives 1 , 3 , 4 thiadiazo rings fused to the triazine. Corresponding reactions of the 3,tj-dithioxo triazines were also reported49. The

,

,

,

reactions of the hydrazines 8 (G-NH,) with RPh,PBr, (R-Ph, Me) gives 8(L=N=PPh2R) which in turn reacts with isocyanates at

8:

Phosphazenes

365

room temperature to give the carbodiimides 8 (G-N=C=NR’)which continue reaction with the phosphoramines to give betaines 9 (where Het is the heterocyclic ring from 8 ) . If the reaction is conducted at benzene reflux, it gives the diazetidines, HetN=EN(R’ )C(=NHet)hR’5 0 . The transformation of 1,3-b(iminotriphenylphosphoranyl) uracil into pyridino [1,2-f]pyrimido [4,5-d] pyramidines is accomplished by treatment with pyridines and isocyanates5’. The reaction of the platinocyclic species L&NHPPh(=NPh)% with a broad spectrum of carbonyl sources (e.9. PhNCO, CO,, Ph,C=C=O, etc) gives the phosphine oxide L$tNHPPh(O)h. The corresponding phosphine sulfide is obtained from reactions with thiocarbonyl derivative^,^. Allylazides are converted to nitriles by successive reactions with Ph,P and ketenes5,. The reaction of Ph,P with N,CH(Me)C(O)Et and with diphenylketene gives N-pketoketenimine, Ph3C=C=NCH(CH3)C(0)Et which undergoes dimerization. The reaction of N-acylamino iminotriphenylphosphoranes with diphenylketene gives oxadiazolesS3. The interaction of 1-phenylpyrazole with a -CH=C(CO,Et)N=PPh, moiety in the 5 position with isocyanates, ketenes, aldehydes or CS, gives functionalized pyrazolo-[4, 3c] pyridines (10). Use of the 4-isomer gives rise to the corresponding 3 , 4-c isomers of l o 5 & . Treatment of 1,2-C6H,XY [X=OC(O)R, Y=CHC(C)2Et)N3] with triphenylphosphine gives 7membered oxygen heterocycles by attack of the phosphazene on the ester carbonyl. Similar nitrogen heterocycles are available from starting materials with X=NHC (0) R55. (Viny1imino)phosphoranes have proved to be valuable synthetic precursor^^^-^^. The reaction of Ph,P=NCR=CR’ R” with 2-formyl-6dimethylaminofulvene leads to olefin/aminoolefin addition followed by aza-Wittig promoted ring closure to give 5-azaazulene derivative^^^. The addition of Ph3P=NC(R)=CH, with cyclic a , p ketones starts with enamine like alkylation of the phosphoranimine followed by an intramolecular aza-Wittig A similar strategy was process to give ( 2 ,4)-pyridin~phanes~~. followed in the reaction of 2 - and 3-azido-1,6methano[lO]annulenes with tributylphosphine and a,p-unsaturated ketones. The enamine-alkylation of the phosphoranimine and dehydrogenation to give, 7,12 and 5,10-methanocyclodeca[b]

366

Orgu 11 o ph ospho rus C’hemistry

pyridines. The triphenylphosphoranimines were not reactive under similar conditionss8. A molecule composed of fused 1azaazulene and methano[lO] annulene rings can be prepared by the reaction of 3-(iminotriphenylphoshoranyl)-l,6methano[ 10Iannulene and 2-chlorotr0pone~~. The addition of CpZrHCl (Cp=g5-C,H,) to (Me3Si),NP(=NSiMe,) allows for the synthesis of the four- membered metallocycle I (MeSi),N(H)bN(SiMe,)Zr(Cp) (C1)N(SiMe3). Similar species can be prepared using ZrCl, or MeLi/ZrCl, as starting materials or from Ph2P(=NSiMe,)N(SiMe,)2m. The reactions of low valent phosphazenes with main group alkoxides also lead to phosphazene transformations. Thus, E(OR), (E=B, CH, Si; n=3 or 4 ; R=Me or Et) upon reaction with (Me,Si) ,NP(=NSiMe,) give (Me3Si) N(R0) P (=NSiMe3)N- (SiMe,)E (OR)n - 1 6 1 . Reactions in which the phosphazene unit is retained also are of interest. It should also be noted than in the course of these reactions, changes of conditions may lead to phosphazene transformation. Replacement of chlorine atoms in acyclic chlorophosphazenes continues to be explored. Sterically hindered phenolates RONa (R=2,6-C1,C6H,) and R’ONa (R’=2,6Me2C6H3) effect partial substitution OPCl,NPCl, and OPCl,NPCl,NPCl, to give OPC1,NP (OR) and OP (OR’) ClNP (PR’) ClNP (OR’) respectively6,. Primary and secondary amines transform OPC12NPC1, to 0(NRR’) ,PNP(NRR’ ) (NRR’=NHEt, NHiPr, NHtBu, NHPh, pyrrolidino, piperidino and morphol ino) Hydrolysis products (RR’N),P (0) NHP (0)(NRR’) were also obtained6,. The phosphinophosphazene Ph,PNPCl, reacts with ROH (R=Me, Et, Ph, H) and EtSH to give either Ph,PNPX, (X=OPH, SEt) or Ph3PNPH(0)X (X=Cl, OH, OMe, OEt) . Reaction with P (NEt,) gives Ph3PNP(NEt) while fluoride metathesis gives Oxidation of Ph,PNPX, with NO, gives Ph,PNPF, and Ph,PNP(O) F,. Ph,PNP(O)X, (X=OPh, SEt, C1, F ) and with sulfur to give Ph,PNP(S)X, (X=Cl, PPh, F ) b c . A one pot reaction of PCl,, NH,C1 and Me2NH gives (Me,N) ,PNP(NMe,) ,-, via reaction of Cl,PNPCl,+, as a byproduct. Fluoride along with (Me2N)CNP(NMe,) metathesis gives (Me,N),PNP(NMe,),+F- which due to the fact of having the longest F- to cation distance of any salt functions as a very reactive ttnakedlt fluoride source6’. Displacement at

,

,

,

,

.

,

,

32

both sulfur and phosphorus occurs in the reaction of

8: Ph osp haz en es

367

ClSO,NPPh,Cl with NH, to give H,NSO,NPPh,NH, which upon treatment Polyfluorinated with Me,SiNMe, gives Me,SiNHSO,NPPh,NHSiMe,”. aliphatic alcoholates (R‘ONa) transform RR’C (Cl)N=PC13 into RR‘ C (OR‘) and RR‘ C=NP (OR‘) The reaction of (Cl,PNCl,) *X(X=Cl, PCl,-) with HN(POCl,), and ROH (R=Me, Et) in dioxane gives (C1,PNPC1,)’[N(WC1,)2]~ which slowly is transformed to OPCl,NPCl,. The hydrolysis of this product generates HN ( POCl,) Displacement at the nitrogen center of the phosphazene is also a well explored reaction path. The reaction of (EtO),P(O)Cl with (EtO),P(OSiMe,)NSiMe, gives (EtO),P(OSiMe,)NP(O) (OEt),. If acetylchloride is used decomposition to diethyltrimethylsilylphosphate is observed69. Silicon exchange giving Me,SiClNPR, when Me,SiNPR, interacts Me2SiC12 and Me2SiHClm. Trimethylsilyl groups in R,P(=NSiMe,)N(SiMe,), can be selectively or totally exchanged using ArECl ( E = S , se) to give R2P(=NSiMe,)N (SAr)SiMe, or The reaction of PC1, with (R,N) ,P (Cl)=NSiMe, R2P(=NEAr)N ( EAr) (R=iPr) gives (R2N),P(Cl) =NPCl, which interacts with LiNR, to give (R,N),P(Cl)=NP(H)NR, presumably by hydrolysis of the sensitive P(II1)Cl bond. Use of R’,NLi (R’=SiMe,) gives (R2N),PCl=NP (NR‘) and the cyclic species R,N (Me,SiN=) bN (SiMe,) P(NR,) hR’ . Phenyl lithium gives (R,N),PCl=NPPh,. The phosphorous azide, (R2N)P ( N,) =NSiMe,, reacts with PClzX (X=Cl, NMe,) to give (R2N),P(N,) =NPClX which in the case of X=C1 reacts with R,NH to give (R,N),P(N,)=P(NR,)C172. The chlorophosphine azidophosphazenes were explored as potential precursors to cyclodiphosphazenes (see section 3 ) . The mixture of C1C (0) ON-C (R)Cl/Ph,P/Me,SiN, gives Ph,P=NC(O)ON=C(R) Cln. Reactions of the organic substituents in acyclic phosphazenes are also possible. Halogenation of (PhNH),PNPh give (pXC,H,NH) ,PNC,H,-p-X (X=Br, I). Chlorination with C1, gives ortho/para mixtures at both phenyl group^'^. The

,

467.

,“.

ll.

,

distereofacial selectivity in the cycloaddition of 2,2dimethyl-3,4-pyrroline n-oxide to the olefinic center in CH,=CHP(=NPh)R,R, is consistent with a s-cisoid array of the C=C-P=N fragmentT5. Addition of Ph,P=NR (R=Ph, p-FC,H,, CH,Ph) to BF, occurs at the nitrogen center. In cases where the nitrogen substituent is phosphoryl, thiophosphoryl or methanesulfonyl the addition is to the low valent 0 or S

Orpnophosphorus C’hemistry

368

center76. The reactions of [M$C1I2 ( M = R ~ , Ir; $=COD, norbornadiene; L=(O) with the diphosphazene CH,(Ph,P=NR), follow two pathways. The phosphazene acts as a bidentate ligand either through both nitrogens atoms to give M$[ (RN=PPh,)2CH,]i or, as the result of a tautomeric hydrogen shift from carbon to nitrogen, through one nitrogen and one carbon atom to give M$[ (RNHPPh,)CH(Ph,P=NR) 1’. Examples of the reactions of acyclic phosphazenes which lead to cyclic materials containing the phosphazene unit can be found in sections 3 , 4 and 5. Applications other than the use in synthesis also have been noted. Fluorocarbon polymer moldings have improved blocking and friction resistance when the surface is modified by the addition of [ (Ph,PhCH,) ,P],N+X- (X=Cl, OH) Fungicidal activity without concomitant plant damage has been noted for Ph2P(E)N=P(R) Ph2 ( E=OT9,S80) and (XC,H,) ,RP),N+Y- (X=H, halo, alkyl; R=alkyl, substituted benzyl, Y=NO,-, halide, SO,=)”.

”.

3 Cyclophosphasenes

Selected aspects of cyclophosphazene chemistry including aminolysis (by dimethylamine and aziridine), hydrolysis, metal halogen exchange in organometallic reactions and exocyclic reactivity as a route to polymers with cyclophosphazenes as substituents have been revieweds2. Comprehensive reviews of ring opening polymerization and/or equilibration to larger ringsm as well as olefin addition polymerization and copolymerization of cyclophosphazenes with olefin substituents& have appeared. The reactivity of cyclophazenes bound to polymeric chains also has been discussed%. The structure of N,P,Cl, can be reproduced by the molecular mechanics modelling approach with available force field parameters. This methodology was extended to predict the structure of 2 , 2-N3P,C1, (N=PCl,) Semiempirical CNDO/2 calculations using a spd basis set on N,P,Cl,X (X=F, OMe, NH,, Me, Ph) show an increase in negative change on the chlorine atom cis to X. No difference in polarity is obtained when a sp basis set was employedM. A topological analysis to generate

F.

all possible P2N2 rings and calculation of the HOMO/LUMO energies using extended Huckel methods has been reported“.

8: Phosphuzenes

369

,.

Experimental electron densities in the N,P, (NC,H,) C,H, clathrate have been established using low temperature X-ray crystallography coupled with X-X,, and deformation density calculations. Both the aziridine lone pair and the T system restricted to the PNP endocyclic llisland"can be observedM. High pressure Raman and IR spectroscopy on (NPCl,),,, show second order phases transitions at 22 and lOkbar for the trimer and tetramer respectivelya9. In a comparison of the systems, the isoelectronic (C1,SiO) 3 , 4 and (C1,PN) fragmentation patterns in the mass spectra are similar as are the vibrational spectra of the trimers. Differences are observed between tetramers due to the planarity of (C1,SiO) 4 9 0 . The 35Cl NQR frequencies for (NPCl,),,, are smoothly varying in the range 77-293'K. The inverse linewidth parameter shows broadening indicative of a higher order phase transition between 112-142OK for (NPC1,):'. The solution ,'P NMR lines of cyclic phosphazenes bound to Al,O, is broadened while the solid state MAS spectra undergo narrowingp2. The use of cyclophosphazene host clathrates with either aromatic compounds or octahedral metal complexes is reported to lead to secondharmonic generating materials9,. A DTA study shows phase transitions and melting points for N,P,(NH,), and N,P,(N=NC,H,-pOH), with higher values in the latter. Thermodynamic (AH, AS) functions and activation energies are reported for each94. The kinetics under pseudo first order (in N,P,Cl,) conditions of the phase transfer synthesis of N,P,Cl, (OR) from N,P,C16 and Q+RO(Q*=Et,NCH,Ph; R=4-N02C6H4, 2 , 4 - (NO,)2C6H3 and 2 ,5- (NO,) ,C6H,) were followed spectrophotometrically. The rate was enhanced significantly by addition of catalytic amounts of water due to increased degrees of ion pair separation-. The synthesis of cyclophosphazenes by means other than substitution reactions receives sporadic attention. An extensive series of attempts to synthesize cyclodiphosphazenes has been reported',. Internal Staudinger reactions of (R,N),P (N3)=NP (NR,)C1 and (R2N),P ( N,) =NP ( NMe,) C1 (R=iPr) gives rise to oligomers and oligomers plus the desired (R,N),bNP (Cl)(NMe,) k respectivelyn. Based on ,'P NMR

,,,

observations, various azidophosphoranes decomposed to cycloand poly phosphazenes. Specifically, [ PEtC1,-,(N3) ] + goes to

370

Organophosphorus Chemistry

(NP(Et)Cl), and [PMe,C1,~,,(N3),,]+to (NPMe,),,%. The thermolysis of (RO),P( 0)N=PCl, proceeds by loss of POC1, to give [ NP(0R) 2 ] 3 , (R=substituted aryl ;) 97. Exposure of cyclophosphazenes to higher temperatures is a standard route to poly(phosphazenes) (see section 6) however certain systems alternatively undergo ring expansion equilibration reactionsa3. Thus heating of N,P,F,R (R=CMe3, Ph) , N3P3XCR2(X=F, R=CMe,, Ph; X=Cl, R=Me, Et) , N,P3C1,R, (R=Me, Et) leads to tetramers, pentamer s, hexamers and occasionally heptamers, octamers and nonamers. Ring expansion of the tetramers (NPClR),(R=Me, Et) leads to the series of trimers through hexamersm. The halogen free trimer,

,

N,P3(0Ph),[ (CsH4),Fe] undergoes ring expansion to the corresponding hexamerPP. It is proposed that ring expansion occurs via PN cleavage while ring opening polymerization requires cleavage of the P-exocyclic group bond98. Two new anionic binary phosphorus-nitrides having cage structures have been synthesized. The reaction of P3N3 with Li,N or Li,PN, gives The P,N,,'" anion is the isostructural aza analog of Li,,P,N,,. P,OlolOO.Treatment of P3N5 with Zn3N2 and ZnC1, sequentially gives Zn7[P12N2,]C1, which is also directly obtained in the interesting direct reaction of ZnCl,, NH,C1 and N,P3C1,. The P12N,,12' species has a sodalite structure which is built up of P,N, and P,N, fused rings to give the cage compound'". The main route to new cyclophosphazene derivatives continues to be substitution reactions of halocyclophosphazenes. Organocyanamido derivatives are available from the reactions of Me,CFUiNCN and AgPhNCN with N,P3C1,. Both non-geminal, N3P,C1,[ N (CN)CMe, I,, and geminal , N3P,C1,.,[ N (CN)Ph],, (n=2,6) products were obtained'02. The nonequivalence of the OCH, and CCH, protons in the spirocyclic fragment in derivatives of N,P3C1, [ 0 (CH,)30] with primary amines has been used in assignment of structure. The extensive series N3P3Cl,&,[ 0 ( CH,) 30] (n=l, R=NHC,H,, NC,HaO, NCICaO, NC,H,,; ~ 2 , R=NHEt , NHC,H, , NHC,H, , NMe, , NC,H,, NC,HaO , NC,Hl, ; n=4 , R=NHEt , NHC,H,, NMe,, NC,H,O, NC,H80) has been reported. In the disubstituted series, primary amines follow a geminal path and secondary amines favor the non-geminal trans structure. The exception is pyrrolidine in which cis and geminal isomers were also ~btained"~. The reaction of E$N,Me,NH, gives the geminal

8: Phosphazenes

37 1

diamine, 2 ,2-N,P,C1,(NH~N3Me,),, in which the cycloborazine and cyclophosphazene are bridged by a =PNHB= unit'04. Alternative routes to these derivatives involving reactions of chloroborazines with aminophosphazenes are discussed below. Treatment of N,P,Cl, with 4-trimethylsilylethynylaniline gives N,P, (NHC,H,C=CSiMe,) 610'. The reactions of diamines with cyclophazenes continues to be explored. The spirocyclic product 2,2-N3P3C1,[NMe(CH,)NMe] is the exclusive product of the combination of the diamine and N3P3C1,'06. Spirocycle formation is also observed when P(X)OPh(NF2NH2), (X=O, R=H; X=S, R=H, Me) is added to chlorocyclophosphazenes to give 2,2OPh]lo7. N,P,Cl, [ NHNRP (X)OPh] or 2 ,2-N4P,C1,[ NHNRP (0) The reaction of trimer hydrazide (X=S, R=H) with excess ammonia or cyclopropylamine gives N,P,(NHR),[NHNHP(S)OPh]. Two moles of aziride gives both geminal and non-geminal isomers of N,P,Cl, (NC2H,) [ NHNHP (S)OPh] One of the two observed nongeminal (cis or trans) isomers is in excess, while there are two geminal derivatives arising from E and 2 configurations relative to the =P(S)OPh centerlm. Patents for the preparations of spirocycliclW and bridging 'lo oxodiamine derivatives (which have been discussed in previous volumes of this series) of N,P,Cl, are available. A variety of applications were proposed. The role of steric crowding in aryloxy cyclophosphazenes was noted in the synthesis of N,P,Cl,-,(OR) , (R=2,6-C6H,C1,, n=1-4 ,6; R=2 ,6-C6H3Mez, n=2 ,6) The unexpected geminal derivatives are formed for n=2,3. Presumably, the steric crowding favors a dissociate S,l(P) mechanism. The non-geminal product is obtained at n=4. A geminal tetramer 2,2 ,4,4-N,P, (0C6H3-2,6-C1,) ,C1, also has been Selectively in chlorine replacement reactions of reported".

,

.

.

2 ,2-N,P3C1,(N=PC1,), are dramatic in that reactions with NaOR [ R=Ph , p-XC,H, (X=C1, Me , OMe) , OCH,CF, , 0 (CH,) ,O (CH,) OCH,] to give N,P,Cl,[N=P(OR),], occur at 25' while 102' is required to Mixed subst ituent derivatives proceed to N,P, (OR) [ N=P (OR)3] The reactions of oxyanions with have also been obtained".

,

,.

strained transannular ferrocenylcyclophosphazenes have been reported. Treatment of 11 (X=R=R"=R" =F) with NaOR (R=OCH,CF,) ,FeI gives N,P,(OR) ,[ (C5H,),Fe] . Similar N,P,R' (OCH,CF,),[ (CsH4) were obtained from 11 (R' =OPh, Me, Ph; R, R" , X=F) .

The

372

Organoph osp horiis C 'hemistry

,

formation of two regio isomers of N,P,Ph, (OCH2CF3)[ (C,H,) ,Fe]

I

based on gem vs non-gem diphenyl groups, can be accomplished by the reaction of 2,4-N,P,F,Ph, with dilithioferrocene followed by NaOCH2CF3 or in the case of the geminal derivative the reaction of 11 (X=R=Ph; R'=R"=F) with NaOCH,CF,. A cis/trans mixture is obtained from 11 (X=R=R'=R"=F) and NaOPh"'. A series of aryloxy phosphazenes , N3P3(OAr)6 [ Ar=Ph , 3-XC&, (X=CF,, F, C1 , CF,O , Me, MeO) , 4-FC6Hbf 2-FC6H,, 3 , 5-X,C& (X=F, CF,) , 2-F, 5-CF3C6H3/ have been synthesized and C6F5 ] and N3P3 (0-4-FCdHb)2 (OCH,CF,) evaluated as high temperature lubricants for aircraft gas '13 . turbine engines112' The synthesis of cyclophosphazenes with olefin substituents as precursors to vinyl polymers with cyclophosphazene substituents& often utilizes oxyanion reactions e.g. p-vinylphenol with N3P,C16 gives N,P, (OC,H,CH=CH,) C15114' which can be converted to N,P, (OR)50C6H,CH=CH, (R=(OCH,CH,) .OCH, , n=2 ,3 ) '14 and a similar sequence starting with HOC,H,C(O) C(CH,)=CH, followed by NH, (CH,) NMe, gives N,P, [ NH (CH,) 3NMe2] OC6H,C ( 0 )C (CH,) =CH2'16. The related monomers , N,P, (OPh),0C6H,C6H,CH=CH2 and N,PCC170C6H4C6H4CH=CH2, have also been rep~rted''~. Diols or dioxanions also have been used as nucleophiles. Spirocyclic derivatives N,P,Cl,-,,[ (OCH,) ,C(CO,Et) ,In (n=l-3) are available from N,P,Cl, and diethylbis(hydroxymethyl)rnalonate'l8. The spirocyclic tetramers N,P,Cl,-,,[ (OCH,),CMe,], (n=l, 2 (two isomers), 3 ) are prepared from 2,2-dimethylpropane-lr3-diol and N,P,C181'9. Difunctional reagents can also lead to cyclolinear polymer formation. The reactions of N,P,(OPh),Cl, with the disodium salt of 4,4'-sulforylbisphenol have been explored using traditional (condensation) and interfacial methods. Much high yields of modest molecular weight polymers [ N,P, (OPh) (OC,H,SO,H,O) ,], are obtained via the interfacial process. If N3P3C1,-,(OPh), (x<4) is used, a mixture of In a cyclolinear and cyclomatrix materials is obtained','. similar fashion the disodium salt of bis(hydroxybutyramido) butane converts N3P3C16to a cyclolinear material. The product

'"

,-

,

,

may be derivatized with aziridine to provide a water soluble The simplest oxyanion, OH-, continues to attract entity','. attention. A change of system from previous studies (to Et3N/H,0/CDC1,) gives only geminal substitution and oxobridged

8: t'hospharenes

373

dimers',,. In an interesting and significant investigation, it is noted that the reaction of N,P,F, with 2 equivalents of LiBEt,H gives [ N,P,F,BEt,]' which readily reacts with covalent halides or a proton source to give N,P,F5R (R=Me, CH,Ph, Fe(CO),Cp, H) which can be converted to N,P,(OCH,CF,),R. An additional equivalent of LiBEt,H gives [ N,P,F,HBEt,]- while a similar process transforms 11 (X=R=R'=R"=F) to

.

N,P,F,H (BEt,) [ (C,H,) ,Fe] These hydrido phosphazenes appear to be best approximated as having a P(II1) center with negative change on the nitrogen center',,. The two step reactions of N,P,Cl, with RMgC1/ (R3PCuI), followed by HC(0) C,H,CH=CH, gives the vinyl monomers 2 , 2 ' -N3P3C1,(R)CH (OH)C,H,CH=CH,12C. Reactions of exocyclic substituents on the cyclophosphazenes are increasingly explored as routes to phosphazene derivatives which are not available directly from substitution reactions of the halocyclophosphazenes. Treatment of aminophosphazenes, N,P,R,., (NH,) with pentamethyl-Bchloroborazine yields the borazinylphophazenes N,P,R,-, (NHB3N3Me5), (R=Cl, n=2; R=NMe2, n=3; R=NMe,, Ph, n=4). The reaction of N,P,(OPh) ,O' with bN,Me,NH, gives the unstable N,P, (OPh)50bN,Me,'04. Heating of [ NP (NH,),] mixtures with urea gives cyclolinear polymers bridged by NH and NHC (0) NH units',,. Expoxy resins can be cured with a variety of phosphazenes i.e. 2,2-N3P3(OR) ( NH,) (R=Ph, CH2CF,, ClC,H,) 126 and N3P3Cl3R3 The chemistry of the p(R=NHMe12,, NMe2'"). aminophenoxyphosphazenes continues to be exploited as in the (X=H, NH,) with 3 or 4reactions of N3P,(OC,H,X)3(0C,H,NH2)3 nitrophthalimides to give 1212' and of N,P, (OC,H,NH,) with an oligomeric polyimide derived from 3,3' ,4' ,benzophenonetetracarboxylic anhydride and 1,3-bis(3aminophen0xy)benzene and endcapped with 4The ester in N,P, (OC6H,C02Et) is cleaved aminophthal~nitrile'~~. with Me,COK to give N,P3(0C,H,C02H)6130. The reaction of N3P3C1, with NaOCH,CH,OBu gives N,P, (OCH,CH,OBu) while reaction with NH,CH,CO,Et followed by ethanolic KOH gives N,P, (NHCH2C0,K) Another two step sequence involves HOCH,CH(OH)CH,Cl and Ph, gives the spirocycle N3P3[ (OCH,P (0) Ph,) 01,131. The MeP (0) hydroxyphenyl derivative, N,P, (OC,H,OH) can be prepared from N,P, (OC,H,OMe) upon reaction with BBr, or from N,P, (OC,H,OCH,Ph)

,,

,

,

,

,

,

,

,

,.

,

374

Organophosphorus Chemistry

by Pd catalysed hydrogenolysis. The hydroxyl groups can be acetylated using acetic anhydride’,‘. The EtI catalysed phosphazene-phosphazane rearrangement of N3P,(OEt), gives a series of isomers whose ,’P NMR spectra have been obtained’22. The treatment of N3P3R6 (R=OR’, R’ -Ph, C,H,C,HS, Naph, p-CH,C,H,, CH,CH,OPh , (C,H,O) ,CH, , m-EtC,H, ,Ph , NHPh) with the fuming sulfuric acid leads to decomposition of the o-alkyl derivatives but sulfonation occurs for the others. Sulfonation preferentially occurs at the 4-position or the 3-position if the 4 site is blocked’33. The hydrosilation reactions of various phosphazenes containing exocyclic olefins with members of the Me,SiO[ (SiMe,O),(SiMeHO),], SiMe, series have been explored. The use of N,P3X50R (R=o-(CH,CH=CH,) C6H,) with X=C1 gives insoluble cross-linked polymers unless siloxanes with low values of y(di1utedin Si-H) are used. When X=OPh no reaction is observed. The N3P3C1,ECH2CH=CH, proceeds when E=NH but not 0. The best system is N,P,Cl,R where R is the 4-allyl-2methoxyphenolic residue which reacts with all siloxanes including those with x=35, Y=O’~‘. Hydrosilation can be approached from another direction in the reactions of N3P3(OPh),NH (CH,) ,SiMe,X (X=H) which is prepared from X=OEt by LiAlH, reduction. Coupling with olefins gives N3P3( OPh) ,NH (CH,) ,S iMe,CH,CHRR’ (R=H, R’ =CpFeC5H,, S iMe,OSiMe, , S i ( OSiMe,) CH,OEt ; R’ =C (0) OCH2= , R=H ,CH,) and a hydrolysis side product, X=OH, which condenses to form N,P, (OPh),NH (CH,)SiMe,OSiMe, (CH,) ,NHN,P, (OPh),13’. Thermal curing of the alkynes in N,P3(NHC,H,C=CSiMe3), was followed by DSC and Azo derivatives N3P3(NH,) ,-” (N=NR),(R=phenol , catechol , IR’”. resorcinol and quinol; n=6, 4(geminal), Z(gemina1) can be obtained from [NP(NH2)2]3. Thermal decomposition, as monitored by DTA, of the n=6 species occurs in three steps corresponding to reactions of disubstituted azo units. This suggestion is consistent with a two step decomposition for n=4 and one step for n=2lX. Rose Bengal can be bound to cyclophosphazenes by a sequence of react ions in which N,P3 (OPh),OC,H,CH, is allowed to react with NBS followed by Rose Bengal to give 13. The efficiency of 13 as a photosensitizer in singlet oxygen production is equivalent to that of free Rose Ba~gal’,~. Radical addition polymerization of exocyclic vinyl groups to

,,

8:

375

Phosphuzenes

CI

Organophosphorus Chemistry

376

give carbon chain polymers with cyclophosphazenes as substituents continues to attract attention%. Polymers of this type have been prepared from N,P3X,0C6H4CH=CH, ( X=Cl'15; (OCH,CH,) OCH,, n=2,3114) and addition of LiC10, to the oligo(oxyethy1ene) derivatives gives ionic conducting polymer^"^. The homopolymerization as well as copolymerization with styrene and methylmethacrylate of N,P3X50C6H,0C ( 0 )C (CH3)=CH, (X=Cl) has been reported along with the copolymerization reactivity parameters. The monomer with X=NH(CH,),NMe, gives a polymer with a multi-armed on llcascadell substituent116. The homo- and styrene copolymerization of N,P,Cl, (R)CH (OH)C,H,=CH, has been examined. The polymerization kinetics of N3P3C1,(R)CH (Me)OC ( 0 )CR=CH, (R=H, Me) , obtained from reaction of N3P3C1,(R)CH (Me)OH with C1C (0) CR=CH,, have been measured for R=H123. Metal binding to cyclophosphazene derivatives, e g the ionic conductors discussed above, continues to be a subject of interest. The use of N3P3[ OCH,( CH,OCH,) ,CH,OR] (n=2, R=C,H,; n=3, R=CI2Hz5;n=4, R=C,H,-p-C,H,) as phase transfer catalysts shows the expected increase in effectiveness with increase in the number of binding sites. The chemical and physical stability of these materials makes them promising alternatives to crown ethers138. The spirocyclic oxodiamino derivative , (CH,),NH] reacts with A1Me3 to give N3P,C1, [ NH (CH,)3O (CH,)0 (CH,)O N,P3C1, [ N (CH,)3O (CH,),) (CH,) 3N*A1Me]wherein the encapsulated five coordinate aluminum is bound to a methyl group and the four donor (two nitrogen and two oxygen) atoms of the spirocycle. The methyl group on the aluminum can be replaced by chlorine via reaction with Me,Sr~Cll~~.The reaction of 1 4 with M(CO), gives the complexes 1 4 O M(CO) (M=Mo, X=Ph ; M=Mo, W, X,=MeNCH,O) in which the phosphazene acts as a tridentate ligand using an endocyclic nitrogen and a p-nitrogen atom from each of the pyrazole ring^'^^''^'. A palladium chloride adduct 1 4 *PdCl, ( X2=MeNCH,CH30) uses only the two pyrazole centers141. If however, the non-geminal bis pyrazolyl derivative cis2,4,P3N,(OPh) (3, 5-Me2C3HN2) coordinates to the PdCl, center, a five coordinate Pd(I1) moiety is obtained with an endocyclic nitrogen atom providing the additional donor site141. The

..

,

,

,

spirocycle diamino derivatives, (L),N3P3(NMe,) [ NH (CH,),NH] (n=2, 3) form L-M(CO),, (M=Mo, W) and LePdCl, complexes in which one

8: P h osp h a z encs

377

exocyclic NH center and one endocyclic nitrogen are involved in the bidentate binding. With K,PtCl, a PtC1,'- salt of the protonated ligand, LH', is obtained141. The hydrolysis of the bridged species N,P3C1,0C6H,0N3P3C1, with CsOH gives OHI2P(O)OC6H,0P (0)[ P (0)(OH)l 2 (NH) which forms (NH) [ P (0) complexes with transition metals, alkaline metals and lanthanide ions142. Commercial interest in cyclophosphazenes is demonstrated by the large number of patents involving these materials. Due to its facile thermal, electron beam or photochemical crosslinking to cyclomatrix polymers which forms very hard thin films, the hydroxyethylmethacrylato derivative, N3P3[OCH,CH,OC (0) C(CH3)=CH,],, has attracted considerable Patents involving attention for a wide range of end uses143-150. the following applications have appeared: coatings of poly (diallylphthalate) molding^"^ and plywood laminates'44, release sheet coatings having uneven surfaces'45, hard antifogging coating'46, solid-state image pickup element^'^^, matrix for copying photoconductor'", sheets for printing video images'" and thermal recording fi l m ~ ' ~ ~Fire . resistant materials are a reoccurring theme in phosphazene Patents in this area involve alkoxy , appli~ations'~'~'~~. aryloxy or amino derivatives as fire retardant additives in acrylonitrile polymers15', phenoxyphosphazene oligmers as additives to ethylene-methylacrylate-unsaturated ester terpolymers used for coatings on electric wires and cables152, aminophosphazene saltslS3and alkoxyphosphazene 01igomers'~~ for fireproofing cotton. Heat resistant resins155 , thermoplastic moldings156and epoxy resin composition^'^^ are available from functionalized aryloxyphosphazenes such as formyl phenoxy derivatives. Curing of epoxy resins can be effected by . Antistatic film coatings are am inophosphaz enes'26t produced from mixtures of salts and a wide range of alkoxy phosphazene~'~~.An electrical conducting composition for electrochromic display elements include N3P3( CH,C02CH=CH,) [ 0(CH,CH,O) ,Me ] which is cross1inked at the olefin sitela. Fluoroalkoxyphosphazene fluids are under consideration for high temperature lubricant^'^^'^'^, electrical insulating medial6' and electroviscous fluids'". Ammonia

378

Organophosphorus Chemistry

volatilization from nitrogen fertilizers can be controlled with

4

Cyclophospha (thia)senes

This section includes ring systems with both phosphazene and thiazene (or selenazene) components. The decrease in papers in this area noted in last year's survey was apparently temporary with activity returning to the level of recent years. Reviews include a summary of recent chemistry of cyclophosphazenes containing low coordinate (two or three coordinate) sulfur and selenium'6c and selected recent chemistry of four coordinate species including reaction pathways and biological activitys2. Both reviews are by the leading practitioners in the area. The majority of the publications have involved the low coordinate group 6(16) species. The reaction of S,N, with dicyclohexylaminophenyl (2-aminopyridyl) The reactions of phosphine gives (C,H,,)2N(Ph)P"sN'65. RR' P(-NSiMe,)N(SiMe,), with SOC1, leads to fused bicyclic phospha(thia)zenes 15 ( E = S ) . Having structural isomerism based on folding at the nitrogen atoms resulting in the PRR' center All being above or below the directly bonded nitrogens'&. three isomers have been detected. The major isomer has one up and one down thus giving in the isolated example (R=Me, R'=Ph) one endo and one exo methyl group. In the R=Cl, R'=CCl, derivatives both Cls attached to phosphorus are in endo positions. The remaining isomer was observed for the R=R'=Et derivative'&. The selenium analogs 15 (E=Se, R, R'=Me, Et, Ph) are available from the reactions of R,P(=NSiMe,)N(SiMe,), with a SeC14, SeC1, mixture. The 1,3-diphosphazene isomer, R2bNPR2NSeNSek is also obtained. The 1,5 isomer 15 (E=Se, R, R'=Ph) is in equilibrium with the four-membered cyclic radical Reactions of 15 with zerovalent platinum and Ph2P-'67. palladium reagents such as (Ph,P) 2PtC2H, and (RPh2P),Pd give (R"3P)p-l,5- (RR'P),N4E2 (E=S1"' 169,Se"') in which the metal inserts into the E-E bond of 15 giving 16. An alternative route involves reduction of 1, 5-(Ph2P),N,S2 to the dianion with LiBEt,H which in turn adds L$4Cl2 (kphosphines, M=Pt, Ni) to give complexes of the type 16169. Mild heating of 15 ( E = S ) in

8:

Phosphazenes

37’)

the solid state or solution yields, upon loss of a phosphine, the complex dimer 17. Examination of variable temperature 3 1 ~ NMR spectroscopic results shows that the dimer (17) is fluxional involving a 1,3-metallotropic shift of platinum between adjacent nitrogen atoms’”’’70. Other ring systems are available from Ph2P(=NSiMe3)N(SiMe3), reactions. The addition of S,Cl, produces the three coordinate sulfur derivatives Ph,;NS (Cl)NP( Ph),NS (Cl)k and Ph2bNP(Ph),NS (Cl) Addition of RECl to Ph2P(=NSiMe,)N ( SiMe,) gives Ph,P (=NER)N (ER) (see section 2 ) which upon heating eliminate Ar2E2 to form 1,5R,P,(ER),N, 18 (E=S,Se)7’. In a slow solid state reaction, 18 (E=Se; R=Me, Et) isomerizes to the 1,3-Ph,bNP(Ph2)NSe(R)NSe(R)h and decomposes to 1,3-Ph2bNP( Ph2)NSeNSek167. The reactions of (Me,Si)2NPPh,(Me,SiN) CC,H,C(NSiMe,) PPh,N(SiMe,) with SCl, and SeC1, give the arene bridge diheterocycles 19 (E=S, Se) which can be dehalogenated with SbPh, to give the diradicals based on two coordinate E center^'^'. Comparisons to systems related to 19 are a~ailable’~,.The four coordinate sulfur derivative , Na+[ P2N3S02(NH,) (OH),] which contains the O,&NP (OH)(NH,) NP (OH)N anion forms complexes with MC1, (M=Ni, Cd, Hg)lTJ.

,

k.

S n i m l l a n eOU8 Phoa~harenocontaininu Rinu Svstems

Jncludinu M otalla~hor~hasenes A review exploring the relationships in ring systems containing main group and transition elements (including metallaphosphazenes) is available17‘. Calculations at the ab I i initio SCF level on (CF,P),PNP (CF,) ,NVCl,N have reproduced the observed structure to a reasonable degree of accuracy. Delocalization of nitrogen lone pairs to both phosphorus and vanadium centers is indicated but no evidence for aromaticity was obtainedln. Reactions of the nitrilimine R,P(S)C=NNPR, (R=iPr) provide a range of heterocycles, 2 0 , with one phosphazene unit in the ring. Treatment with S , (or se) gives 20 (X=S, Se) with R’C=CR‘ (R’=CO,Me) gives 2 0 (X=-CCR’)=C(R’ ) - ) , with PhN, gives 20 (X=NPh) and with Me,C(O)C(=N,)CH to give 2 0 (X=N-N=CHC(O)CMe,) 176. Photolysis of R,P(S) (C=N,)H gives 20 177

.

(X=-SCH2-) The reactions of Ph,PNHPPh, g i v e rise to single phosphazene heterocycles of the type 21. Treatment with

3x0

Organo phm p h oriis C‘hemistry

PhCECBr gives 21 (R=H, R’=Ph), with Ph,PN=PPh,PPh, gives 21 (R=Ph,P, R’=Ph) and with 2, 3-dichloroquinoxaline to give 21 (R, R’=-NC,H,N-) 178. The Kisanov reaction of H,NCONHCOCl, with PC1, gives C13P=NCC1,CC1, but the 1:3 reaction of the chloromethyl derivative, H2NCONHCOCH2C1, PC1, system gives the phosphazene, C12bNC(C1)NC(C1) kC1ln. The addition of Ph,PCl, to LiCPh (NSiMe,) or p-RC6H,C (=NSiMe,) N ( SiMe,) gives 22 ( R=H , Me, 1 CF,) and Ph,#NP(Ph),NC(Ph)N as a minor product which is also available from PhC [ N (SiMe,) 3 NPPh, and PhSeC1lBO. Another diphosphazene heterocycle i [ R ( Me3Si),N] ,deOP (OPh),NGe [ N (SiMe,) ,R] OP ( OPh),N (R=mesityl) is obtained in the addition of the divalent germanium species. [ R (Me,Si),N] Ge to N,P (0) P (OPh),la’. Novel metallocyclophosphazenes continue to appear. The reaction of Me,Si(H) NSO,NPP,N(H) SiMe, with WOC1, gives C1,lkNP (Ph),NW (Cl),NP (Ph),$Iu. The interaction of R2PC1=NSiMe, (R=C,F,) with C13V=NSiMe, gives R2hNV(C1),NP(R) ,NV(Cl) ,A while R,’PCl=NSiMe, (R’=CF,) and VOCl, or MoO,Cl, and MoOC1, to give R’,bNP (R‘) ,NP (R’) ,NV (C1) ,k or 2 3 and R’ PClMoOCl, respectively. The six-membered ring, Ph,bNP(Ph),NV(Cl),k is obtained from Ph,Cl=NSiMe, and VOC1,’82. The first cyclophosphazene metal oxide, Ph,bNPPh,NRe (0) is available from Me,SiNPPh,NPPh,NSiMe, and Re207. Reactions of this ring system with ArNCO (Ar=2, 6(iPR),C,H,) gives Ph,fiNP (Ph),NRe (=NAr),NP (Ph),NP (Ph),NRe (=NAr),NP (Ph),& and d 3 . The reaction of ReOC1, ( PPh,) with the Ph,P (Se)NP (Se)Ph, anion (L) gives ReOClk which decomposes with loss of Se to 25l”. Main group metals such as tin also form metallocyclophosphazenes. The Ph2P(0)NP(O)Ph, , (L), anion with SnX, (x=Cl, Br, I) gives cis-kSnX, where the phosphazene is bound in a bidentate fashion to tin via the oxygen atoms. The free ligand HL reacts with tin (11) acetate to give SnL, which is fluxional in solution185.

,

,

,k,

This section is devoted to polymers containing open-chain phosphazenes and related cross-linked materials. Cyclolinear and cyclomatrix materials as well as linear polymers with

8:

Ph ospha z enes

38 1

(Me3SiN=PR120)C13Mo-O-MoC13(0PR'2=NSiMe3) I

P

(Me3SiN=PR' 2O)Cl3Mo-0-

P

MoCI,(OPR' 2=NSiMe3)

(23)

Ph2P0N*PPh2 II I

N. ,N ,Re, -0 ArN'lI NAr NAr (24)

3x2

Orgunophosphorits C’hemislry

cyclophosphazenes as substituents are covered in section 3 . Specific aspects of poly(phosphazene) chemistry have been covered in a variey of reviews. Poly(ph0sphazenes) are discussed in a new text on inorganic polymers‘”. Recent advances in poly(phosphazene) chemistry involving synthesis, molecular design to tailor properties and applications have been discussed’87 as has the role of this system in materials science with emphasis on design of polymers by monomer design, materials processing (cross-linking, self assembly, composites, blends, IPN) and surface modif icationlm. The ring-opening polymerization of cyclophosphazenes and heterophosphazenes, with a particular emphasis on the role of ring strain, has been thoroughly discusseda3. Several reviews have focused on new routes to poly(ph0sphazenes) involving condensation polymerization of phosphoranimines with particular emphasis on the use of anionic catalyst in this p r o c e ~ s ’ ~ ~ -The ’ ~ ~ring. opening polymerization of [NS( 0 )XI (NPCl,), (X=Cl,F) and derivatization of the polymers with oxyanions has been summari~ed’~~. The complex mesophase behavior of poly (organooxyphosphazenes) such as fl u o r ~ a l k o x y ’ and ~~ ary10xy’~~ derivatives has been reviewed. The broad spectrum of physical methods used in these studies allow for sorting out issues involving morphology and its relation to backbone Attention has conformation and side chain crystalli~ation’~~. been drawn to the applications potential for poly(phosphazene) elastomers in the oil field’96. The synthesis of poly(phosphazenes) from small molecule precursors continues to attract attention. The heating of substituted cyclophosphazenes can lead to both ring expansion Polymerization was found to accompany and p~lymerization~~. ring expansion for the following organophosphazenes: N3P,F, (R=CMe,, Ph) ; 2 , 4 -N3P3X,R, (X=F, R=CMe3, Ph ; X=Cl, R=Me , Et) : 2 ,4 ,6-N,P,C13R, (R=Me, Et) ; N,P,Cl,R, (R=Me, Et)9 8 . Systems in which the ring is strained, e.g. by a transannular bridge, undergo ring-opening polymerization even if halogen substituents are absent. Thus, heating of 11 (X,R ,R’ ,R”=OCH,CF, : R’=OPh ,Ph ,X ,R,R”=OCH2CF3: X=Me ,Ph ,R ,R’ , R ”= OCH,CF,; R,R’ =Ph,X,R”=OCH2CF3)polymerize in the presence of catalytic amounts of (NPCl,),, or in some cases BCl,, as

8:

Ph osph az enes

383

initiators. Certain of the above will polymerize even in the absence of the intiatorw. The facile ring-opening polymerization of 2,2-N3P3C1,(N=PCl,) has been ascribed to ring strain which was established by molecular mechanics calculationsa5. The solution polymerization of (NPC1,) can be catalysed by sulfamic acid and ammonium ~ulfamate'~'or transition metal and main group metal halides19'. Anionic initiators such as Bu,NF allow direct conversion of ( CF3CH,0),P=SiMe, to [ (CF,CH,O) 'PN], (PBFP)lW. The reaction of Ph ( CF,CH,O) ,P with MeSiN, leads to [ Ph (CF,CH,O) PN] through formation of Ph(CF,CH,O)PN,". The role of POCl, in the control of the molecular weight of (NPCl,), obtained from condensation of Cl,P(O)NPCl, has been explored'". A patent describing the ring-opening polymerization of ClSNPCl,NPCl,N and derivatization of the linear polymer is available'". The ringopening polymerization of [NS(O)X] (NPCl2) (X=FZo2,C1203) and derivatization of the resulting polymers has been described. Phosphorus-nitrides while not strictly phosphazenes, are appropriately covered in this chapter (see also section 3 ) . The preparation of phosphorus imide nitride, HPN,, from P,N, and Mg,N,, NH,C1 has been described. The structure was determined and the IR spectrum assigned2M. The reaction of P,N,, Li,O, P,O, and Li,N gives Li,PN,O which decomposes thermally to LiPO, and Li,PN3205. The other major approach to poly(phosphazenes) involves the reactions of preformed polymers with suitable reagents. The reactions of [NP(NMe,),],[NPX(NMe,) Jb(NPX2)c (X=C1, NH,) with B,N,Me,NH, or E$N3Me,C1, followed by NH, have been utilized to generate poly(phosphazenes) with B-aminoborazine substituents. Pyrolysis of these polymers gave over 50% ceramic yield leading, upon continued pyrolysis at 1300', to crystalline hexagonal BNIM. Poly (dichlorophosphazene) can be converted to [ NP (NHC,H,C=SiMe,) 1' or the trifluoroethoxy copolymer. The trimethylsilyl groups can be removed by aqueous KOH-MeOH. DSC and IR studies show that cross-linked films are formed at and its 180' lo5. The synthesis of [NP(NHC,H,OCO,CMe,),]n methylamino copolymers from (NPCl,), has been reported. Thermal deprotection to the free phenol, [NP(NHC,H,OH) ?I,,, occurs above 165' ' 0 6 . The synthesis of

,

,

0rgan ophosp horids < ’herr1i s try

384

[NP(OR)l~,(NH(CH,)3SiMe20Et)o~,]n has been reported. Reduction of the ethoxy group to the silicon hydride by reaction with LiAlH, was attempted but significant molecular weight l o s s accompanied the reaction’35. Reactions with oxyanions continue to be the most widely explored. The products from the simplestofthese,the hydroxide ion, have been examined by 31PNMR. The hydrolysed, =P(OH)Cl,center and nuclei withas many as eight bonds removed may be observed. It has been proposed that gel formation, which occurs at about 7% =PCl, group hydrolysis, is the result of =P(OH) C1 hydrogen bonding not POP bridge formation207. The reactions of [ (NPC1,),NP(N=PCl,) ,In with alkyl and aryloxides shows regiospecificity occurring first at the PC1, side chains followed by the main chain PC1, centers”. The reactions of NaOCH2CH,0C6H,Cr (CO) with (NPC1,), lead to [NP(OCH2CH2)C,H5Cr(CO)3)2]n, the first poly(ph0sphazene) with a transition metal on each substituent. Mixed substituent (with OCH,CF,) derivatives and the metal free analogs have been also obtained2m. Mixed substituent, [NP(OCH,CF,) .(OC,H,-p-Cl) materials have been synthesized and characterized. Thermal properties are intermediate between the two homopolymers209. High yields of [ NP (OPh),] are obtained when the (NPC1,)JNaOPh reaction is carried out in the presence of a polyether2”. Soluble impurities in the reactions of (NPCl,), can be removed by transport across a semipermeable membrane2l1. The synthetic route to new poly(ph0sphazene) derivatives may contain more than one chemical step. The ester hydrolysis of [NP(OC,H,CO,Et),], with MeCOK gives the free acid (or salt of the acid) which can be cross-linked with di- or trivalent metal ions130. The Ca2+ cross-linked species can encapsulate hybridoma cells without affecting the viability of the cells in their ability to produce antibodies,’,. Poly (phosphazene) microspheres containing the methyl ester of melphalan showed gradual and sustained release of the anticancer agent213. Reactions of (NPCl,), with tetraethylene glycol monododecyl ether or pentaethylene glycol p-(t-octyl) phenoxyether give polymers useful as phase transfer catalysts. The complexing ability of these materials with alkali iodides and bromides was explored214. The use of poly (phosphazenes) containing

,

monosulfoxides and oligo(oxyethy1enes) as polymeric phase

8:

Phosphuzenes

385

transfer agents in the Williamson alkylation of NaOPh has been studied2”. The conversion of [NP(OC,H,OMe) 2 ] , to polymers with predictable amounts of the free phenol can be accomplished by removal of the methyl group with BBr,. The free phenol can be esterified by treatment with acetic anhydride’32. The treatment Of [NP(OC6H,CH3),] with NBS gives [NP(OC6H,CH2Br)o.2(0C6H,CH3)1-8]n which reacts with Rose Bengal to give the polymeric analog of 13’~’. Sulfonation of a wide range of aryloxy and anilino poly(ph0sphazenes) with fuming sulfuric acid leads to polymers sulfonated in the 4-position unless it is blocked and then it occurs in the 3-position. Sulfonation of films, that have been cross-linked by irradiation with 6oCo y radiation, occurs and upon continued exposure causes in depth sulfonation and hydrogel formation. The surface modified materials can be converted to the sulfonyl chloride and amide. The free acid will undergo ion exchange and polypeptide immobilization. The films have improved blood compatibility and serve as sites of cell growth while the soluble polymers exhibit antibiotic behavior’33. The deprotonation of [ NP (Ph)Me] gives an anionic center which can be allowed to react with CO, or fluorinated aldehydes or ketones to give carboxylic acids (and related species) or fluorinated alcohol derivatives216. The exposure of PBFP films to an oxygen plasma causes formation of P-0 and N-0 bonds at the surface2”. Ultraviolet radiation cross-linking of [NP(O(C,H,O),CH,),],, MEEP, has been explored as an alternative to y radiation cross-linking. The use of Benzophenone as a photoinitiator increases the cross-linking density218. The photoinduced grafting of poly(methy1 methacrylate) onto [ NP ( OC6H,-iPr) 2] has been accomplished219. The radiation induced graft copolymerization of dimethylaminomethyl methacrylate onto PBFP and [NP(OPh)2] has been reported. The grafted copolymers were quarterized with methyliodide which gives binding sites for heparin220. The reaction of carbon black with surface sodium phenoxide sites react with (NPCl,), to affect binding of the phosphazene. The grafted phosphazene can be derivatized with phenoxide, aniline, or ethoxide221. The radiation-induced graft copolymerization of N-vinyl-2pyrrolidine and N,N-dimethylaminoethylmethacrylate with PBFP films gives enhanced biocompatibility. Physical studies

386

Organophosphorus Chemistry

(elongation modulus, tensile stress, TEM, etc) were interpreted in terms of interpenetrating polymer networks ( I P N ) ~ ~ ~I.P N ~of MEEP or the bis(propy1oxybenzoate) with poly(styrene), PMMA, poly(acry1onitride) or poly(acry1ic acid) have been prepared and characterized by thermal methods, IR and NMR223. Composite materials are prepared by hydrolysis of Si(OEt), in presence of MEEP o r partially hydrolyzed PBFP. Improved mechanical properties were demonstrated224'225. Several of the unique properties of the poly(phosphazenes) have attracted attention from a physical measurement or calculation perspective. Calculations investigating the potential for, and origin of, non-linear optical properties associated with the phosphorus-nitrogen backbone have been presented226-228.The phosphazenes have calculated hyperpolarizabilities in the range of those reported for organic polymers. These properties are controlled by the difference in n orbital energies between phosphorus and nitrogen which in turn may be related to substituent donor-acceptor effects2',' 227 . Structural and conjugational defects do not appear to play any significant role in phosphazene hyperpolarizability22a. Experimental verification of significant 2nd-harmonic coefficients in thin films of the poly (phosphazenes), [ NP (OCH,CF,) (OR)v] [ R= ( CH2CH,0)kC6H,CH=C,H,N0, k=1-3, CH,CH,N (Et)C,H,N=NC6H,N02] , which have substituents designed to generate non-linear optical properties has been accomplished2a. The plasma stability of [NP(OR),],, (R-CH,CF,, CH,CH, , OPh , OC6H,Cl ) and [ NP (NHC,H,X) 2 3 (X=H,C1) films has been explored by ESCA and ellip~ometry~~'. The eximer behavior, as reflected in fluorescence spectroscopy, of the phenoxy and pcresoxy poly(phosphazene) derivatives has been related directly to morphology hence allowing for use of this spectroscopic probe to study polymer dynamics23'. Phosphazene copolymers containing 4-benzoylphenoxy and P-naphthoxy substituents exhibit interesting photochemical behavior. The light energy absorbed by the benzophenone center is transferred to the naphthalene centers and wasted in photophysics giving rise to photostabilized polymers232. The potential for utilization of phosphazenes in resist applications has been explored by determining the efficiency of radiation induced cross-linking of

8: Phospharenes

387

ally1 s u b ~ t i t u e n t s ~ ~The ~ . value of 31P MAS-NMR spectroscopy took a significant step forward this year with the demonstration of the separate, well defined resonances for crystal1 ine and amorphous phases in a r y l o x y p h o s p h a ~ e n e s ~ ~ ~ ~ ~ ~ . Spin diffusion occurs between phases234-236 and allows for calculation of lamellar thickness2”-2M. Rotation of the aryl group about the PO bond can be examined by ”C M A S - N M R ~ ~ ~ ~ ~ . The hydrolysis chemistry of (NPCl,), can also be examined by solid state 31P NMR methods207‘236 as can be the absorption of poly (Phosphazenes) on colloidal A120, particlesP2. The rate of ring-opening polymerization of 2 , 2-N,P3C1,(N=PC1,) was followed by ,’P NMR spectroscopy. The activation energy for this process is lower than that observed for N3P3C1,. The difference was assigned to ring strain effects”. The solid state radiolysis of [NP(OC,H,R) 2]n has been examined by ESR spectroscopy which demonstrates that radiation damage is localized on the aryl substituent. Non-aromatic substituents e.g. [NP(NEt2)C1],, show involvement of the backbone in radiolytic decay237. Dielectric relaxation behavior of (NPR,), (R=OCH,CF, , 0-nC,H7, NH-nC,Ht” and OCH2C6H,Me , OCH2C,H,ClZ3*) differs above and below Tg. Relaxation below Tg is related to hindered rotation about the side group-phosphazene bond2”. The other relaxation was related to a glass-rubber transition239. Similar behavior was explored for [NP(NR2)2], (R=Me, C6Hp) with activation energies for the processes being determined2“. Single crystal studies of poly(ph0sphazenes) are available and have been the sub] ect of recent structural investigation^^^'-^^^. X-ray and electron diffraction of [NP(OR)2]n (R=C6H,-4-Me2&’, C,H,, 4-MeF2) have been reported with results compared to diffraction of the bulk film in the latter242. The use of cryoprotection in increasing the dose level and hence the resolution obtained for TEM measurements on [NP(OPh),], has been noted243. A thorough examination of the unusual phase transformation behavior of [NP(OC,H,-p-C,H,) 2], Using x-ray diffraction shows a smectic-like side chain The cell structure and novel mesophase behavior of (NPPh2), has been examined2&’. A battery of techniques, including NMR, DSC and x-ray diffraction, allowed for clarification of structureproperty relations in selected poly(phosphazene) thermotropic

Organophosphorus C'hcmistry

3x8

crystal to liquid crystalline phase transition^'^^. X-ray diffraction has been utilized in conjunction with calorimetry and optical microscopy to study phase transitions in [NP(OC,H,P-Rl2] (R=NMe,, CMe,) . The role of R in determining Tg and establishing the temperature range for conformational disorder was explored. The data obtained fit previously established empirical correlations for temperature of phase transitions in this type of polymer2c7. The phase transition behavior of a series of alkoxy phosphazenes , [ NP (OR) J (R=( CH,) ,CH3, n=0-7 ) has been examined and crystallization was observed for n>5,'*. Fiber formation in poly (aryloxyphosphazenes) has been examined in terms of melt viscosity data. The fibers obtained were examined by x-ray diffraction, DSC, SEMI e t ~ . ~ 'The ~ study of salts of poly(phosphazenes) with oxyethylene side chains, e.g. MEEP, as solid electrolytes is an ongoing area of i n v e ~ t i g a t i o n ~ ~Mixed ~ - ~ ~ ~substituent . materials with 0 (C,H,O) 2CH3 or 0(C,H,) ,CH, groups along with sulfonated substituents (OC2H,,SO3Na)can be converted to the magnesium salts by ion exchange. These polymers exhibit low ionic conductivity which, however, can be significantly improved by the addition of cryptand [ 2.1.1 J z S o . Vibrational spectroscopy studies of phosphazene salt systems where cryptands or crown ethers improve conductivity suggests that the origin of this effect is in reduced ion pairingz5'. Complexes of I, and For (PNCl,),, poly (phosphazenes) have been reportedzs2' 253 molecular I, adducts are formed but in the alkoxy systems MEEP, PBFP and [NP(OiPr)2]n polyiodides have been detected by resonance Raman spectroscopy253. The redox reactions involve I, not the polymer and give a polymer stabilized iodonium ion and a polyiodideZs2. High conductivity is observed for MEEP and isopropoxide derivativezs2'253. The addition of I, to MEEP.MI (M=Na, Li) complexes also gives rise polyiodide containing conductors253. Conductivity results for MEEP based ionic conductors have been fit effective by the Bendler-Schesinger form of the Vogel equation which indicates that the defectdiffusion approach is a viable model for the observed conductivity behaviorz5'. MEEP based ionic conductors have been

,

.

included in a microelectrochemical device where all components are confined to a chipz5*. Another area in which poly (phosphazenes)

11:

Phosphuzenes

389

have been demonstrated to be of value is membrane c o n s t r u ~ t i o n ~ ~Some ~ - ~ ~of . this activity has been summarized256. Membranes derived from the three butoxy isomers of [NP(OC4H9)Z], and the dineopentyloxy phosphazene have been evaluated for permeability of 13 gases ranging from Xe to C,H,. Side chain effects are significant with a decrease in permeability but increase in permselectivity with the bulkiness of the side chain being noted'". Gas permeation studies of the diethoxy phosphazene are also available258. Membranes derived from the phenoxy, cumylphenoxy or butylphenoxy derivatives and their copolymers have been examined for liquid-liquid and gas separations. Gas permeability resembles that observed for rubbery polymers and selectivity for glass polymers. Ultrafiltration activity was also examined259. A cyclolinear phosphazene polymer in an inorganic matrix functioned in nanofiltration applications such as removal of dyes from water260. Details of physical and fire resistant properties of a commercial aryloxyphosphazene rigid foam are available26'. Dilute solution characterization of fractionated dihexoxy poly(phosphazene) by light scattering, viscometry and sizeexclusion chromatography has been reported. Parameters such as radius of gyration, Mark-Houwink coefficients and molecular dimensions have been measured or calculated262. The unperturbed dimensions of PBFB and [NP(OPh)2], in dilute solution have been determined. Theta conditions, good and poor solvents and 2nd virial coefficients have been established. The polymers adopt coil like behavior with the size of the coil being dependent on the size of the substituent groupZ6'. Continued commercial interest in poly(phosphazenes) is demonstrated by extensive patent activity and related applications oriented publications (some of which have been noted above). Fire retardency is an ongoing theme in cycloand linear phosphazene applications (see section 3 ) . Aryloxy phosphazenes, including a commercial product, Eypel A , have been utilized for components for fire resistance in foam cushioning2", rocket motor insulation265and electrical wire coating266-268.Alkoxy phosphazene polymers and copolymers impart antistatic properties to silver halide based photographic material^^^^‘^^^. The application of salts of MEEP,

390

Organophosphorus Chemisrry

and related poly(phosphazenes), as polymeric electrolytes when combined with LiAlCl,'" I other 1 ithium lanthanides or Nb cations2" have been investigated. Electrical conductivity was observed in an unspecified polymer derived from heating hexakis (Fe phthalocyaninato) cyclotriphosphazeneZn. Immobilization of biologically active materials such as trypsin inhibitor2m or ovalbumin2m by a sequence of reactions starting by substituent displacement in PBFP with units having active functionalities that couple to materials of interest. Phosphazene moldings from the m-chlorophenoxy derivative are improved by stretching above the phase transition temperature2*'. Fluorophazenes impart heat resistance to Novolak resin moldings282. The use of allylphenoxy substituents as sulfur or radiation cure sites has been further developed2". Oxygen selective isoamylphenoxy phosphazene membranes have been used in gas diffusion anodes284 and [NP(OPh),In membranes have been employed for separation of halogenated hydrocarbons from fl~ids~'~. Processes for improved tensile strength PBFP fibers2&, MEEP metal oxide fibers287 and the use of poly(ph0sphazenes) binders in lowering sintering temperatures for metals I ceramics etc have been established2M. Applications to photoimaging have also been developed. Carbonyl functions in substituents undergo a photocross-linking process useful for ph~toimaging~'~. Photoconducting materials employing poly (phosphazenes) in hole blocking-adhesive layersZPo High light or as resin bindings have been prepareda'. transmittance in the UV region is exhibited by some poly (phosphazene) resins applicable to integrated circuits292. 7 Crvsta 1 Btructuros of Ohomhasones The following compounds have been examined by X-ray diffraction techniques. All distances are in picometers and angles in degrees.

Comnound (Ph,PNPhLiOEt) ( Me2N),PNP ( NMe2);F'

Comments PN 167.2(2) PN 153.6(2) PNMe, 164.4 (5) LNPN 110.8(2)

Ref. 13

65

39 1

8: l’hospha zenes Comments

ComPound

Ph,P (=NS iMe,) N ( S iMe,)

,

,

OPC1,NP (OR) R=2 6-C1,C6H3 O P (OR) C l N P (OR) C l N P (OR) R=2 6-Me2C,H,

,

Ref.

P=N 151.8 ( 1 0 ) ; PN 1 7 0 . 6 ( 9 ) LNPN 1 0 7 . 5

71

PN 1 5 1 . 5 ( 4 ) , LPNP 1 4 2 . 4 ( 4 )

62

156.7(4)

Av. PN 1 5 3 . 5 ( 3 ) 157.6(4) LPNP 1 4 3 . 8 ( 2 ) , 1 3 5 . 3 ( 2 ) LNPN 1 1 4 . 9

293

( M e , S i ) ,C=P ( S M e ) =NR R=2 4 6- (Me,C) C6H, ( M e 3 S i ) ,C=P ( CMe,) =NR

R as above

62

PN 1 5 4 . 9 ( 2 ) LN=P=C 1 3 3 . 2 4 ( 6 )

293

(Me,S i ) ,C=P ( NMe,) =NR R a s above

293

( M e , S i ) 2C=P [ P (CMe,) ,] =NR R a s above

193

(Me,S i ) 2C=P ( P h ) =NR R a s above

PN 1 5 5 . 2 ( 2 ) LN=P=C 1 2 5 . 9 ( 2 )

16

(Me,S i ) ,C=P ( R ) =NR

PN 1 5 4 . 1 ( 2 ) LN=P=C 1 3 5 . 9 4 ( 6 )

16

( P h O ) ,PNSO,Me

PN 1 5 4 . 4 ( 3 ) LPNS 1 2 6 . 2 ( 2 )

28

4

PN 161.8(2) LPNC 1 3 0 . 2 (1)

31

PN 1 5 7 . 5 ( 2 ) LPNC 1 2 8 . 5 ( 2 ) NH---N=P 195(3)

36

R a s above

PN 1 6 3 . 1 ( 7 )

6

X=BF-,;

R=H;

PN 1 5 9 . 8 ( 4 )

6

X = B r - ; R=NPPh,; 6

37

R’ =Ph 163.4 ( 3 )

37

PN 1 5 9 . 8 ( 3 ) , 1 6 1 . 7 ( 3 )

37

PN 160.5(5), 161.0(5)

37

R’ =Ph

-

X=PF, ; R=NPPh3; R’ =Ph 6

X=Br‘ ; R=NPPh,;

R’ = M e

6

X = B r - ; R=NMe,;

R’ =Ph

PN 1 6 0 . 1 ( 2 ) LPNC 1 3 1 . 1 ( 2 )

159.6(5) 161.5(5)

38

392

Organophosphorus C'hernistry Comments

COmDOUnd

Ref.

PN 1 6 0 . 8 ( 3 ) LPNC 1 3 0 . 7 ( 2 )

38

R' =Ph

PN 1 6 1 . 8 ( 5 ) LPNC 1 3 1 . 9 ( 4 )

38

R' =Ph

9 (Het=8-L) R=Ph; R ' = i P r

PN 1 6 3 . 8 ( 4 ) LPNC 1 1 9 . 9 ( 3 )

50

9 (Het=8-L) R=Ph ; R' =CH,Ph

PN 1 6 8 . 1 ( 7 ) LPNC 1 1 6 . 8 ( 5 )

50

[ CF,CFH ( CzNMe,) N=] ,PF,+PF,-

PN 1 5 5 . 5 ( 3 ) , 1 5 4 . 8 ( 3 ) LNPN 1 2 1 . 5 LFPF 9 7 . 4

294

PN 1 6 1 . 2 ( 5 ) , 1 5 7 . 6 ( 5 ) LPNP 1 3 0 . 7 ( 3 )

26

PN 1 5 6 . 8 ( 5 ) , 1 5 6 . 0 ( 6 ) LPNP 1 5 1 . 8 ( 4 )

26

PN 1 5 7 . 6 ( 3 ) , 1 5 6 . 5 ( 3 ) LPNP 1 4 9 . 7 ( 2 )

26

trans-VC1, (NCCH,) NPPh2Me-CH3CN

PN 1 6 6 . 0 ( 3 ) , 1 6 6 . 7 ( 3 ) LVNP 1 7 1 . 8 ( 2 ) , 1 6 4 . 9 ( 2 )

40

WC ls (NPMe,)

PN 1 6 6 . 8 ( 1 9 ) LWPN 1 6 4 . 1 ( 1 2 )

41

[ wcl, (NPMe,) ( PMe,) ,] C 1 2CH,CN

PN 1 6 2 . 8 ( 3 ) LWPN 1 6 4 . 2 ( 2 )

41

[ Wc1, (NPPh,Me) PMe,] C 1 2CH,CN

PN 1 6 3 . 0 ( 4 ) LWPN 1 7 1 . 0 ( 3 )

41

Wcl, (NPMe,)

PN 1 6 2 . 5 ( 1 3 ) LWPN 1 6 3 . 1 ( 1 3 )

41

6

-

6

-

X=BF, ; R=NMe,; X=PF, ; R=NMe,;

Ph,PNP (CF,)

,

Ph,PNP (CF,) ,Fe ( C O )

,

C,H,CH,

2CH3CN

t r a n s - [ 0 s ( t p y ) Cl,NPPh,] PF,*CH,CN

PN 1 6 1 . 8 ( 5 )

32

tpy=terpyridine 7

PN 1 6 4 . 1 ( 4 ) LPtNP 1 1 5 . 1 ( 2 )

42

3

PN 1 6 2 . 6 ( 2 ) LMoNP 1 2 7 . 4 (1)

25

R~NPCPNr i n g d i s t o r t e d boat PN 1 5 9 ( 1 ) , 1 6 1 ( 1 ) LNPC 1 0 7 . 6 ( 8 ) , 1 0 7 . 6 ( 8 )

77

[ Rh ( 4MeC,H,N=PPh,)

CH,. COD] PF,

8:

Phosph ar en es

393 Comments

ComDound

Ref.

P,Nlo'o- h a s P,O,,

L i 1OP,NlO

100

structure PN 158.1(3) LNPN 105.9(1) LNPN 116.0 (2) PlzN2412-s o d a 1 i t e structure PN, Td PN 163.6(7) LPNP 125.8

101

Clathrate structure: 88 electron density distribution 158.3 (1), 159.7 (1) PN, PN,,, 166.5 (1), 167.3 (1) LNPN 116.72 (6) LPNP 123.20(7) PN,, 159 PN,,, 166 PNMe, 165 P,N, kwist b o a t

104

PN 15 7 .l( 4 ) - 159.9 ( 4 ) Cp,Fe b r i d g e d LPNP 112.2(2) P,N, n o n - p l a n a r

111

11 X , R , R ' ,R"=OPh

PN 157.6 (6)-160.1(7) Cp,Fe b r i d g e d LPNP 113.2 ( 3 )

111

11 X ,R=OCH2CF3 R' ,R" =Ph

PN 159.3(12)-163.2(12) Cp2Fe b r i d g e d LPNP 110.4(8)

111

27

P,N, h a l f c h a i r , skew boat PN (mean) 157 9 ( 1)

295

(11)- L i (THF) 3+ R,X=F; R' =BEt,,

122 PN 156.8 (6)-159.2 (6) PN 162.6 (5)-167.4 (6) Li-+NP( B E t , ) H - : n o n - p l a n a r

11 X ,R , R'

,R" =OCH,CF,

-

R"=H

P,N, p l a n a r A l M e c o o r d . to a l l exocyclic N,O PN, 152.7 (9)-165 (1) PN,,, 160.6 (9), 162 (1) exo LNPN 108.8(5)

139

304

Orgunophosphorus C’hemistry

Comments

ComDounri

Ref.

as above with C1 replacing Me; N,P, planar PN, 154 (1)-162 (1) PN,,, 159 (1)-162 (1) exo LNPN 1 0 9 . 7 ( 8 ) f o r Mo coord. see section 3

139

140, 141

PN 1 5 5 . 7 ( 2 ) - 1 5 9 . 8 ( 3 ) PN 1 6 2 . 6 ( 2 ) , 1 6 3 . 7 ( 3 ) LPN (Mo)P 1 2 0 . 1 ( 1) Other LPNP 1 2 6 . 3 (1), 120.1(1)

15 R=endo-Cl; R‘ =exo-CCl,

PN 1 6 0 . 7 ( 7 ) LNPN 1 1 4 . 3 ( 3 ) , 1 1 2 . 0 ( 4 )

166

15 R,R’=Et

PN 1 6 1 . 6 ( 8 ) LNPN 1 1 0 . 6 ( 4 ) , 1 0 9 . 0 ( 3 )

166

16*CHC1 R,R’R’=$h;M=Pt

PN 1 5 9 . 4 ( 1 4 ) - 1 6 2 . 7 ( 1 3 )

168

17 R=Ph

PN 1 5 9 . 1 ( 8 ) , 1 6 0 . 7 ( 8 ) ,

170

163.7 ( 9 )

19-C1 E=Se

Radical dimer linked by Se-N PN 1 5 6 ( 2 ) - 1 6 3 ( 4 ) LNPN 117(1)

171

22

distorted boat-boat PN 1 5 9 . 7 (4)- 1 6 1 . 5 ( 4 ) LNPN 1 2 4 . 9 ( 2 ) - 1 2 7 . 9 ( 3 )

180

RR’deOP ( OPh),NGeRR’ OP (OPh) R=2,4 6-Me3C,H, R’=N (SiMe3)

PN 1 5 0 . 6 ( 3 ) LPNGe 1 5 3 . 7 ( 3 )

181

C1,hNP (Ph),NW (C1) ,NP (Ph),1$ 2THF

PN 1 6 4 . 1 ( 8 ) , 1 5 9 . 6 ( 1 5 ) LNPN 1 1 3 . 5 ( 6 )

66

C~,CNP(R),NV (ci),NP (R),Nr

PN 1 5 8 . 5 (mean) LVNP 1 4 2 . 8 ( 2 ) , 1 6 6 . 3 ( 3 )

182

R=Me

,k

,

R=CH,CF3

1

Cl,+NP (Ph),NP (Ph)*N

PN (mean) 1 6 2 . 3

182

23

PN not given

182

R’=CF,

395

8: Phosphatenes

ComDound

Comments

24

PN 1 5 9 . 5 ( 4 ) -163.8 ( 3 ) LPNP 1 2 0 . 8 ( 2 )

Ar=2 ,6- (iPr),C3H,

Ref.

,.

( A r a ReNP Ph NP (Ph),NRe (=NAr) NP ( P k d

183

1 83

Puckered ring PN 157.7 ( 4 ) - 1 5 9 . 8 LPNP 1 3 9 . 1 ( 5 )

(7)

(Re)PN 1 6 3 . 9 ( 8 ) (Se)PN 1 5 7 . 9 ( 8 ) LPNP 1 2 2 . 0 ( 5 )

184

distorted trig.bipyr PN 1 5 8 . 0 ( 3 ) - 1 5 9 . 6 ( 3 ) LPNP 1 2 5 . 4 ( 2 ) , 1 2 8 . 0 ( 2 )

185

cis-Sn[ OP (Ph),NP (Ph),O],I,

PN 1 5 7 . 2 ( 5 ) - 1 5 9 . 7 ( 5 ) LPNP 1 2 3 . 2 ( 3 ) , 1 2 9 . 5 ( 3 )

185

HPN,

3-D net of corner sharing PN, T,; # N have H PN 1 5 9 . 9 ( 4 ) LPNP 1 3 0 . 1 ( 4 )

2 04

Cell dimensions, space group

241

Cell dimensions, space group

242

Cell dimensions, space group

244

Cell dimensions, space group

245

25

Sn [ OP ( Ph),NP ( Ph)O , J

,

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.

. .

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.

.

.

m,

I

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m,

Author Index

In this index the number given in parenthesis is thr Chapter number of the citation and this is.followrd by tho reference number or numbers of the relevant citations within that Chaprer.

Aagaard, O.M. ( I ) 188 Ahatjoglou, A.G. ( I ) 178 Ahhari, M. (1) 422 Ahdel-Malek, H.A. (5) 59 Ahdel-Megeid, A.E.-S. (6) 21 Ahdou, W.M. ( I ) 240; (2) 22; (5) 165 Ahell, A.D. (7) 12 Ahkowitz, M.A. (8) 290 Ahout-Jaudet, E. ( 5 ) 121, 126, I80 Abraham, K.M. (8) 275 Ahramkin, E.V.(1) 234; (5) 259, 260 Ahramov, A.Yu. (8) 6 7 Ahramyan, T.D. (5) 280 Achari, 9. ( I ) 137 Achiwa, K. ( I ) 5 , 6 , 39, 72 Adam, W . (5) 79 Adamopoulos, S.G. (7) 32 Adams, D.M. (8) 89 Admiraal, G . (6) 331 Advani, S. (6) 178, 180 Afanasov, A.F. (5) 136 Afarinkia, K. (4) 9 ; (5) 98, 194, 223 Afon’kin, A.A. (8) 9 5 Aghack, P. (4) 43; (6) 262-265 Aghandje, M. (6) 319 Agnel, G. (7) 138 Agris, P.F. (6) 150 Aguilar. M.A. (1) 34 Aguilb, A. (5) 35 Ahlgren, M. (5) 154 Ahlrichs, R. (8) 175 Ahmed, S. (8) 102 Ahn, K.D. (8) 206

Ajulu, F.A. ( I ) 391 Akagi, M. (6) 127 Akamatsu, A. ( I ) 86; (5) 110 Akelah, A. ( I ) 270 Akerfeldt, K.S. (6) 59 Akhmetkhanova, 1.Z. (1) 417 Akhtar, M.S. (6) 42, 109, 115 Akiyama, T . (5) 31; (6) 177 Aksinenko, A.Yu. (5) 201 Aksinenko, N.E. ( I ) 353 Aksnes, G. (4) 41 Akutagawa, S. ( I ) 73 Aladzheva, I.M. ( I ) 262-264 Alajarin, M. (3) 13; (7) 17-19, 55, 1 0 9 - 1 1 1 , 119, 131; (8) 36, 38, 49, 50; (8) 52 Alam, T.M. (6) 357 Alamgir, A. (8) 275 Alberda van Ekenstein, G.O.R. (8) 124 Alhericio, F. (6) 75 Albers, W. (2) 26 Albinati, A. ( I ) 93, 423 Alcock, N.W. ( I ) 77, 399 Aldenhoven, H. ( I ) 100 Al-Duayymi, J.R. ( I ) 388 Alekseiko, L.N. ( I ) 288, 289, 316, 318, 323; (8) 86 Aleshkova, M.M. (5) 7 Alewood, P.F. (5) 231 Alexakis, A. (4) 28 Ali, R. (2) 45 Alias, A. (7) 101, 115-117 Alink, M. (6) 331 AI-Jahoori, M.A.H.A. (2) 3 Alkhathlan, H.Z.(8) 47 Alkuhaisi, A.H. (8) 103. 118

Allcock, H.R.(8) 62, 83, 85, 98, 99, 104, 1 1 1 , 123, 130, 133, 135, 186-188, 201, 208, 212, 218, 223, 229, 252 Allen, C.W. (8) 8 4 Allen, D.W. ( I ) 128; (4) 21 Aller, E. (7) 102, 112; (8) 54 Al-Lohedan, H.A. (8) 47 Alloum, A.B. (5) 173 Al-Madfa, H.A. (8) 119 Almendros, P. (7) 114 Almer, H. (6) 18, 101 Alonso, R.A. ( I ) 40 Al-Soudani, A.-R. ( I ) 5 8 Alster, D.K. (6) 91 Althoff. IJ. ( I ) 293, 294; (7) 6 Altmeyer, 0. ( I ) 274; (4) 80 Altona, C. (6) 331 Alunni, S . ( I ) 116 Aly. Y.L. (6) 21 Amatore, C:. ( I ) 396 Amer, M.I.K. (7) 48 Ammon, H.L. (5) 211 Ampe, C. (6) 313 Amrhein, N. (5) 162 An, Y. (5) 76 Anders, E. ( I ) 235 Anderson. A.G. (8) 93 Anderson, D.K. (5) 274 Anderson, G.K. ( I ) 4 Anderson, P. (6) 83 Anderson, W.K. (7) 98 Ando, K. (7) 22 Ando, W. ( I ) 416 Andrews, D.M. (4) 49, 62; (5) 22; (6) 110 Andriamizaka. J.D ( I ) 339

Andrus, A. (6) 74 Ang, H.G.(8) 26 Angelici, R.J. ( I ) 161, 346 Angelova, 0. (5) 307 Anisimova, E.A. (5) 138 Annan, N.K. (6) 320, 321 Antipin, M.Yu. ( 1 ) 218, 290, 345; (4) 39 Aoki, K. (8) 144 Aoyama, K. (8) 150 Aoyama, M. (5) 116 Appel, R. ( I ) 275 Arai, K. (6) 275 Aravanundam, G. (8) 165 Arhuzov, A S . ( I ) 168 Arhuzov, B.A. ( I ) 95, 125, 314, 315, 341 Arce, A.J. (1) 398 Arduengo, A.J. ( I ) 386 Arduengo, J. (2) 44 Arif, A.M. ( I ) 250; (2) 30, 31; (7) 4 Aritien, A.E. (8) 18 Arimura, T. (5) I15 Arkhipov, V.P. (5) 128 Armour, M.-A. ( 1 ) 86; (5) 109, 110

Armstrong, D.R. (3) 1 1 Armstrong, R.W. (6) 301 Armstrong, S.K. (3) 37 Arques, A. (7) 101, 115-117 Arsent’eva, G.B. (2) 9 Arshinova, R.P.(5) 313, 314 Arumagam, S. (3) 12 Asaba, S. (8) 268 Asakawa, S. (8) 278 Ashhy, M.T. ( I ) 352; (8) 13 Ashley, G.W. (6) 279, 291 Ashley, J.A. (5) 241 Asmus, K.-D. ( I ) 189 Asseline, U . (6) 126, 186 Atamas, L.I. ( I ) 224; (5) 140, 141 Atovmyan, L.O. (5) 315 Atrazhev, A.M. (6) 108 Attanasi, O.A. ( I ) 124; (7) 8 Attar, S. (1) 399 Atwood, D. ( I ) 61, 364; (4) 81 Atwood, J.D. ( 1 ) 176 Atwood, J.L. ( I ) 27, 59, 60 Audennec, C.A. (5) 229 Audia, J.F. (1) 146 Audic, A. (6) 139 Austin, E. ( I ) 40 Averkov, A.I. (8) 61 Avila, L.Z. (5) 282 Avino, A. (6) 75 Awano, K. ( I ) 5

Baas, J . (8) 124 Baha. M. (6) 45 Baceiredo, A. ( 1 ) 393; (4) 79; (5) 291; (7) 14, 54; (8) 176. 177 Bachrach, S.M. ( 1 ) 320-322 Bader. A. ( I ) 45 Badesha, S.S. (8) 290. 291 Badet, B. ( 5 ) 113 Badet-Denisot, M. (5) 113 Bahri, H. ( I ) 170 Bai, D. ( I ) 159 Baik, H.G.(8) 209 Bailly, C. (6) 309 Bailly, T. (2) 38; (4) 36 Bain, J.D. (4) 58; (6) 84, 87 Baird, M.C. ( I ) 31 Baird, M.S. ( I ) 388 Baker, M.J. (4) 65 Baker, R. (7) 69 Bakir, M. (8) 32 Bakmutov, V.I. (8) 248 Ball, R.G. ( I ) 283 Ballou, C.E. (5) 41 Balodis, K.A. ( I ) 166 Balueva, A.S. ( I ) 95, 125, 126. I68 Balzarini, J. (5) 153; (6) 10, 48, 66 Bandzouzi, A. ( I ) 136 Banerjee, A.K. ( I ) 137 Banks, M.A. ( I ) 66 Bannwarth, W. (6) 181, 182, 305 Bani), M.C. (8) 212 Bansal, R.K. ( I ) 410. 412-414; (4) 75, 76 Bao, R. (5) 225 Baraniak, J. (5) 94 Barannikova, T.L. (8) 125 Barardini, M.D. (6) 300 Barashenkov, G.G.(5) 184 Barharella, G . (6) 351 Barhe, B. (5) 236 Bardella, F. (6) 157 Bardin, V.V. (4) 22 Baren, B.M. (5) 244 Baron, P. (6) 23 Barr, P.J. (6) 65 Barraclough, P. (5) 243 Barrans, J. ( I ) 415; (4) 74 Barron, A.R. (1) 62 Bartik, B. ( I ) 108 Bartik, T. ( I ) 108 Bartlett, P.A. (6) 59 Barton, D.H.R. (1) 237; (4) 16; ( 5 ) 6, 240; (6) 19

Barton, J.K. (6) 326-328 Bartsch, R . ( I ) 375, 404, 405; ( 5 ) 144 Bbrzu, 0. (6) 61. 62 Basch, H . (6) 253 Baschang, G. (6) 131, 132 B a d e , A. (8) 259 Basso-Bert, M. ( I ) 319; (8) 60 Bastian, H. ( I ) 279, 280 Basu, S. (6) 109 Batail. P. ( I ) I . 2 Bathurst, I.C. (6) 65 Bats, J.W. (5) 73 Battistini, C. (6) 89 Battlaglia, P. (8) 220 Bau, R. (5) 213 Baudler, M. ( I ) 25, 47-51 Bauer, S. ( I ) 291 Bauermeister, S. (5) 95 Baumgartner, G. ( 1 ) 6 7 Bauta, W.E. (6) 270 Bayer, G.M. (7) 36 Beachley, O.T. ( I ) 66 Beagley, B. (3) 40 Beale. J.M. (6) 292 Bearden, W . H . ( I ) 399 Beattie, K.L. (6) 51 Beaucage, S.L. (4) 3; (6) 73 Beaulieu, P.L. (7) 135 Behout, W. ( I ) I08 Becher, J . (7) 125 Becker, G. (1) 302-305 Becker, P. ( I ) 373; (7) 2 Becker, W . ( I ) 302 Beder, S.M. ( I ) 249 Beeley, N.R.A. (5) 197 Been, M.D. (6) 259, 260 Beer, P.D. (4) 15 Beese, L.S. (6) 334 Begley, M.J. (7) 85 Behlan, L.S. (6) 328 Behrens, U . (2) 35 Bekker, A.R. ( I ) 26, 205; (4) 31-33, 35; (5) 106 Belakhov, V.V. (5) 159, 188 Belaya, S.L. (8) 17 Belciug, M.P. (5) 270 Beletskaya, 1.P. ( I ) 151; (4) 85; (5) 143; (8) 22 Beliiin, J.J.A. (4) 46 Beloken, Y.N. (5) 239 Belous, N.N.( I ) 310 Bel’skii, V.K. (5) 224 Belt, H.J. ( I ) 153 Benner, S.A. ( I ) 143 Bennett, F.R. ( I ) 160; (6) 271 Bennett, S. (3) 1 1 Benseler, F. (6) 123

410

Bentrude, W.G. (2) 30, 3 I ; (4) 83; (5) 97, 249; (6) 34, 40, 41 Berdnik, L.V. (5) 139 Beres, J. (6) 40 Berg, R.H. (6) 133. 134 Bergemann, A . (8) 20 Berger, U . (8) 100 B e r g s t r h e r , U. ( I ) 312, 337 Bergstrom, D. (4) 13 Berkman, C.E. (5) 56 Berlin, K . D . (5) 13, 14 Bernadou, J . (6) 242 Bernardinelli, G. ( I ) 297; (4) 66 Bertani, R. (8) 137 Bertrand, G. ( I ) 386, 393; (4) 79; ( 5 ) 291; (7) 14, 54; (8) 72. 176, 177 Beruda, H.(7) 13 Beslan, J . ( I ) 276 Bessard, Y. ( I ) 259 Bestari, K . (8) 171 Bestmann, H.J. ( I ) 252; (2) 17; (3) 3; (5) 131; (7) 42, 45, 47, 140 Betz, P. ( I ) 31 1 Beviere, S.D. (4) 16; (5) 6 Bevierre, M.O. ( I ) 394, 396 Bhanot, O.S. (6) 161. 162 Bhatt, S.D. ( I ) 154 Bickelhaupt, F. ( I ) 298, 420 Bigge, C.F. (5) 237, 245, 246 Billig, E. ( I ) 178 Binger, P. ( I ) 326 Binnewies, M. (1) 377; (4) 67; (5) 215 Biryukov, S.V. (5) 167 Bischofberger, N. (6) 95 Bishop, J.E. (3) 21; (7) 49 Bissinger, P. ( I ) 41 Bitrus, P. (7) 4 8 Bitterer, F. ( I ) 215 Bizanek, R. (6) 286 BjergArde, K. (4) 63; (6) 103 Blackburn, G.M. (5) 257, 302 Blanchard, J.S. (6) 68 Blaschette, A. (8) 2 8 Blinnikov, A.N. (8) 43 Blum, J . ( I ) 9 , 10 Bo, B.I. ( 5 ) 105 Bobbie, B.J. ( I ) 182 Bohkova, R.G. (5) 199 Bock, H. ( I ) 377; (4) 67; (5) 215 Bodalski, R. ( I ) 383; (7) 7 3 Biigge, H.(1) 280 Boelens, R. (6) 356 Boese, R. (1) 279, 281, 313, 407; (7) 14

Boetzel, R. (5) 200 Bofanova, M.E. (5) 232 Bofils, E. (6) 186 Bogedain, G. (8) 90 Boger. D.L. (6) 297. 298 Bohman, 0. ( I ) 266 Boisdon, M.-T. ( I ) 415; (4) 7 4 Boivin, .I.( I ) 237 Bokrnan, F. ( I ) 266 Bolina, R. (8) 66 Bonazzi. S. (6) 235 Bonora. G.M. (6) 7 6 Bonsigmore, L. (8) 214 Bookham, J.L. ( 1 ) 42 Booth, B.L. (7) 48 Borangazieva, A . K . (5) 7 Borch, R.F. (5) 62, 63 Borden, A . (6) 145 Borders, D.B. (6) 268, 269 Borecka, B. (8) 88 Borisenko, A.A. (1) 199, 310 Borovikova, G.S. ( I ) 129 Borowitz, G.B. (4) 2 Borowitz, I.J. (4) 2 Borrmann, H. (5) 305 Bortolus, P. (8) 137, 219, 232 Bos, H.J.T. (7) 5, 124 Bose, D . A . (6) 300 Bossi, M.G.P. (6) 235 Bott, S.G. ( 1 ) 27, 59, 60 bwgeard, D. (8) 12 Boulard, Y. (6) 349 Boulos, L.S. (2) 20 Bounja, Z. (2) 39, 40 Bourdieu, C. (5) 284 Boutin, J.A. ( 5 ) 229 Boutonnet, F. (1) 99; (3) 7; (5) 227 Boutorin, A. (6) 193 Bouyssou, P. (3) 31 Bovey, F . A . (8) 246 &win, A.N. (2) 37 Bowden, M.C. (7) 84, 85 Bowmaker, G . A . ( I ) 399 Bowmer, T.N. (8) 247 Boyce, B.A. (5) 197 Boyd, D.R. (5) 220 Boyd, E.A. (4) 8 Boye, A. (8) 260 Boyer, S.H. (6) 272 b i z , H.J.T. (3) 26 Brahee, L.J. (5) 245 Brandi, A. ( I ) 98; (3) 4, 36, 38; (5) 312; (8) 75 Brando, Y. (6) 277 Brandsma, L. ( I ) 94; (7) 5, 124 Brandt, K . (8) 121, 295 Brasca. M.G. (6) 89

Brauer, D.J. ( 1 ) 215; (8) 90 Braun, H. (6) 16 Braun, J. (3) 42 Bravo, J . (8) 262 Braxton, H.G.. jun. (8) 198 Breit, B. ( 1 ) 31 1-313 Breker, J. (2) 42 Brel, V.K.( I ) 234; (5) 259, 260 Brernand, C . (8) 12 Breslauer, K.J. (6) 233, 234 Breslow, R. (6) 254 Brettle, R. (7) 139 Breuer, E. (5) 205, 279 Bricklebank, N. ( I ) 132; (2) 2 Brinkworth, R.I. (5) 241 Broan, C.J. ( 5 ) 197 Brockrnan, M . (5) 257 Broder, S. (6) 12 Broeders, N.L.H L. (2) 32 Brornhach, H. ( I ) 216, 373; (7) 2 Bronson, J.J. (5) 250, 254, 255 Broom, A . D . (6) 43, 142 Brovarets, V.S. ( I ) 165, 239, 258 Brown, J.M. ( I ) 77; (3) 32; (5) 308 Brown, K . A . (5) 69 Brown, M.L. (5) 9 Brown, S.J ( I ) 31 Brown, T. (4) 53, 54; (6) 185 Brownbridge, P. (7) 59 Browne, K . A . (6) 336 Bruce, A.E. (8) 25 Bruce, M.I. ( 1 ) 177 Bruce, M.R.M. (8) 25 Bruckner, R. (7) 33 Briiger, H. (8) 90 Brugghe, H.F. (6) 166 Bruice, T.C. (5) 69; (6) 247. 3 36 Bruins Slot, H.J.(5) 31 1 Bruix, M. (6) 35 Brun, A.M. (6) 318 Brunar, H. (6) 122 Brunner, H. ( 1 ) 44, 7 0 Brusilouets, A.1. (8) 61 Bruzik, K.S.(5) 30, 36 Bryant, D.R.(1) 178 Bryce, M.R. (7) 63, 126 Brzerifiska, E. (5) 88, 89 Buhlewitz, A. ( 1 ) 4 3 Bubnov, Yu.N. ( 1 ) 242 Buchardt, 0. (6) 133, 134, 339 Buchko, G.W. (6) 124 Buck, H.M. (2) 32 Buczak, H. (6) 312 Budowsky, E.I. (6) 354

41 I

Author Index

Budzelaar, P.H.M. ( I ) 16 Buerger, H. (8) 29 Bujacz, G. (3) 14; (5) 174 Bukharov, S.V. ( 5 ) 55 Bu kowska-St rzyzews ka, M. (5) 303 Bundel, Yu.G. (1) 133 Burgada, R. (2) 38; (4) 36 Burgdorf, D. (8) 29 Burger, K. (4) 7 Burk, M.J. ( I ) 37, 38 Burke, T.R. (5) 235 Burkhartt, W. ( 1 ) 92 Burkhast, B. (1) 416 Burmistrov, S.Y. (4) 39 Burnaeva, L.A. (2) 14; ( 5 ) 135 Burrows, C.J. (6) 340, 341 Burton, S.D.(8) 92 Burzlaff, H. (7) 140 Busch, T. (1) 31 1; (7) 3 Bustamante, C. (6) 367 Butcher, S. (6) 210 Butin, B.M. (5) 164 Butler, I.R. (I) 14 Buttafava, A . (8) 237 Buwalda, P.L. (8) 124 Buzykin, B.1. (5) 300, 301 Bykhovskaya, O.V. (1) 262-264 Cahholet, M.J.T.F. ( I ) 188 Caccarnese, S . (5) 186 Cadet, J. (6) 124 Cadogan, J.I.G. (4) 9; (5) 194. 223 Caellato, U. (8) 184 Cai, B. (1) 418, 419 Cai, Y.M. (8) 26 Calabrese, D. (7) 103; (8) 48 Calahrese, J.C. (2) 44; (4) 42 Caliceti, P. (8) 220 Callegari, R. ( 5 ) 127 Cameron, T.S. (8) 88 Caminade, A.-M. (1) 319; (3) 7; (5) 226, 227; (8) 60 Carnmarata, V. (8) 255 Camp, D. (1) 138; (2) 19 Campbell, G.C. (8) 234 Candeias, L.P. (6) 363 Cano, F.H. (7) 52 Canovas, M. (7) I08 Canute, G.W. (5) 62 Capdevila, J. (1) 149 Capellacci, L. (6) 1 Carenza, M. (8) 220. 222, 237 Carey, J.V. ( 5 ) 308 Carlherg, C. (6) 365 Carlson, D.V. (4) 55; (6) 184

Carmichael. D. ( I ) 391, 421 Carrie, R. ( 1 ) 422; (4) 14 Carroll, M.L. (5) 12 Carter, P. (6) 270 Carty, A.J. ( 1 ) 182 Caruthers, M.H. (6) 72 Casida, J.E. (5) 84 Castan. F. ( I ) 393; (4) 79; (8) I76 Casteel, D.A. (5) 78 Castera, P. (8) 109, 110 Cattani-Lorente, M. ( I ) 285 Cava, M.P. (7) 125 Cavell, R.G. ( 1 ) 283 Cech. T.R. (6) 256-258. 353 Cefelin, P. (8) 215 Cen, W.(5) 150 Cerny, J. (6) 28 Cha, J.K. (7) 82 Chahan, G.M. (8) 1 I Chadha. R.K. ( I ) 68, 127 Chaikovskaya, A . A . (5) 315 Chaires, J.B. (6) 317 Chakrahrty, S.K. (5) 155 Charnherlin, A.R. (4) 58; (6) 84, 87 Charnhrette, J.P. (8) 210, 211 Chan, E.K. (8) 249 Chan, K.L. (6) 241 Chan, Y.-L. (6) 348 Chanda, M. (8) 24 Chandrasekaran, A . (8) 140, 141 Chandrasekhar. V. (8) 106, 117, 180 Chang, C.C. (6) 269 Chang, J.Y. (8) 105 Chang, S.C. (8) 265 Chang, W. (6) 159 Chapleur, Y. ( I ) 135, 136 Charkin, O.P. (8) 1 1 Charrier, C. ( I ) 19, 402, 403, 408 Charuhala, R. (6) 88 Chassignol, M. (6) 209 Chassignol, R. (6) 186 Chatterjee, D. (1) 154 Chattopadhyaya, J. (4) 43; (6) 262-265 Chau, T. (5) 305 Chaudhuri, C. ( 1 ) 137 Chekhlov, A.N. (2) 37; (8) 294 Chen, C.-S. (5) 34 Chen, D. (5) 160, 203 Chen, G. (8) 258 Chen, J. (1) 15; (4) 55; (6) 184; (8) 159 Chen. K. (8) 250. 251 Chen, L. (6) 158, 159

Chen, R. ( 1 ) 418, 419; (5) 225, 3 10 Chen, S. (5) 182, 195, 295 Chen, W.-Y. (5) 233 Chen, X. (6) 340, 341 Chen, Y.-C.J. (6) 252 Chenault, J. (3) 31 Cheng. C.-H. ( 1 ) 175 Cheng, J.-W. (6) 231 Cheng, S.J. (8) 120 Cheng. X . (1) 221 Cheng, Y.-K. (6) 225 Chen-Yang, Y.W. (8) 120 Cheong, C. (6) 344, 345 Cheong, S. (8) 105 Cherches, G.Kh. (8) 125 Cherepanov, I.A. ( I ) 133 Cherkasov, R.A. (5) 91 Chern, R.T. (8) 233 Chernega, A.N. (1) 218, 290, 345, 353, 354; (4) 69; (8) 16. 293 Chernov. P.P. (2) 8 Chernyuk, I.N.( I ) 225 Chiba, M. ( I ) 39 Chichester-Hicks, S . (8) 247 Chicote, M.T. (8) 42 Chiesi-Villa, A. (1) 184 Chimishkyan, A.L. (5) 199 Ching, J. (6) 300 Ching, K.C. ( I ) 223 Chino, K. (7) 55 Chirkova, L.P. (4) 38 Chistokletov, V.N. (5) 135, 136, 26 1 Chivers, T. (8) 7 1 , 164, 166170, 180 Cho, J.E. (5) 53 Chollet-Gravey, A.M. (5) 202 Chopra, G. (5) 308 Chorev, M. (5) 205 Chorlton, A.P. (7) 133 Chou, S.-H. (6) 231 Chou, T.-C. (6) 23 Chow, C.S. (6) 328 Choy, G.S.C. ( 1 ) 273 Chrekasov, R.A. (5) 90 Chrisey, L.A. (6) 97 Christobletov, V . N . (2) 36 Christodoulou, C. (6) 81 Christopherson, M.S. (6) 142 Chudakova, T.I. (5) 87 Chung, B.Y. ( I ) 134 Chung, S.-K. (5) 125; (7) 79 Chuprina, V.P. (6) 231 Churchill, M.R. ( I ) 66, 176 Chuvashev, D.D. ( I ) 200; (2) 7 Cian, A.D (4) 79

412 Cicchi, S . ( I ) 98; (3) 4. 36. 38: (5) 312; (8) 75 Ciosek, C.P. (5)256 Claessen, A.M.E. (8) 213 Claramunt. R.M. (7) 17. 52; (8) 36, 50 Classon, B. (6) 18, 20 Claus, K.-H. (8) 90 Cleary, D.G. (5) 152; (7) 70 Clegg, R.M. (6) 365 Clegg, W. (7) 126 Cleland, W.W. (5) 70 Clive, D.L.J. ( I ) 147 Clivio, P. (6) 139, 140. 146-148 C h a d , S.T. (6) 201 Coe, D.M. (6) 49, 50 Coffin, M.A. (7)63, 126 Coffman, H. (6) 303 Coggio, W.D. (8) 123, 135 Cognet, J.A.H. (6) 349 Cohen, J.S. (6) 94 Cohen, L.H. (5) 123 Cohen, S. (8) 212 Cole, E. (5) 197 Collignon, N. (5) 121, 126, 180 Collington, E.W. (3) 37 Colmenares, L.U. (7) 88 Colocci, N. ( I ) 146 Colombo, D. ( 5 ) 226 Colonna, F.P. (6) 76 Coltrain, B.K. (8) 224, 225, 287 Commenges, G. (1) 393; (4) 79 Connolly, B.A. (6) 137, 138. 143, 149, 248 Contractor, S.R. (8) I03 Cook, P.D. (6) 96, 118, 119. 187 Cook, P.R. (6) 320, 321 Cook, S.D. (5) 220 Coomher, R.N. (6) 17 Cooper, M.K. ( I ) 87 Copohianco, M. (6) 235 Corda, L. (8) 138, 214 C o r d a , A.W. (8) 172 Corizzi, V. (5) 113 Cormier, J.F. (6) 107 Cornet, H. (7) 99 Corrie, J.E.T. (6) 60 Corriu, R. (1) 359 Cory, M. (6) 310 Cosstick, R. (4) 20, 62; (6) 110, 1 1 1, 248 Costisella, B. ( 5 ) 107, 108, 120 Cot, L. (8) 260 Cotten, M. (6) 122 Cotter, R.J (6) 360 Cotterill, 1.C (7) 89 Coughenour, L.L (5) 237

Orgunophosphorus (‘hernistry Coughlin. C S. (8) 254 Couret, C. ( I ) 309. 339. 361 Couture, A. (7) 99 Cowles, J.M. (1) 80; (3) 6 Cowley, A.H. ( I ) 59. 60. 61, 364; (4) 81 Cozine, M.H. (8) 246 Craik, D.J. (6) 304 Cramer. F. (4) 23: (5) 2: (6) 114 Crans, D.C. (6) 68 Cremer, S.E. (1) 80; (3) 6 Crbpon, E. ( I ) 237 Cristalli, G. (6) I Cristau, H.-J. ( I ) 228, 236, 267: (7) 5 3 Criton, M. ( I ) 142 Crooks, P.A. (6) 42, 115 Crooks, R.M. (8) 255 Croshy, R.C. (8) 234, 236 Crothers, D.M. (6) 313 Crowte, R.J. ( I ) 69 Cube, R.V. (5) 244 Cuevas, G. (3) 15 Cui, S. (5) 160 Cullis, P.M. (5) 85. 266 Cummings, D.G. (8) 285 Cunningham, A. (4) 66 Cushman, M. (4) 55; (6) 184 Cyprk, M. (8) 191. 245 Czech, B.P. (5) 144 Czernak. S. (6) 126 Dahkowski, W . (4) 23. 40;(5) 2; (6) 105, 114 Dahrowiak, J.C. (6) 282 Dadger, B.B. (8) 264 Dahan, F. ( I ) 415; (4) 74; (5) 291; (7) 54; (8) 177 Dahl. 0. (4) 63: (5) 48: (6) 103. 339 Dahnke, T. (6) 64 Dai, D. ( I ) 155 Dai, W.-M. (6) 266, 276, 284 Dal Canto, R.A. ( I ) 256 Daly, D.T. (6) 135 Dampeka, R.D. (5) 179 Danchin, A. (6) 62 Danilov, L.L. ( 5 ) 25 Danishevsky, S.J. (6) 272 Dargatz, M. (1 ) 20, 2 I Dartrnann, M. ( I ) 293 Dauhen, W.G. (3) 2 1 . 23 Daumas, M. (7) 61 Dauth. J. (8) 21. 190. 191 David. G.( I ) 373. 424; (4) 73: (7) 2 Davidsnn, M G (3) 1 1

Dawar, H. (6) 180 Day, R.O. (1) 121; (2) 22, 23. 28, 29; (5) 283, 304; (8) 3 1 . 44, 185 Dean, D.W. (5) 149; (7) 71 Dehart, F. (6) 118. I 19. 125 De Bont, H.B.A. (5) 5 De Cian, A. ( I ) 393 Decleercq, J.-P. ( I ) 299 De Clerq, E. ( 5 ) 153: (6) 10, 29, 48, 66 Dedon, P.C. (6) 280, 281 Deeh, A. (7) 10; (8) 23 Deeming, A.J. ( I ) 398 Degols, G. (6) 125 de Graaf, R.A.G. (6) 331 DeGroot, D.G. (8) 253 DeGroot, K. (8) 213 Dehmel, V.C. (5) 256 Dehnicke, K. ( 1 ) 248 De Jaeger, R . (8) 12, 68, 200 De Jongh, C . (5) 2 18 Delmas, M. (7) 57 Delongchamps, C . (6) 35 DeLuca, H.F. (3) 24, 25 Demhek, A.A. (8) 208, 229, 252 de Mendoza, J . (6) 35 Dernik, N . N . (4) 85 De Morais, M.M. (6) 235 Deng, R.M.K. (2) 46; (8) 96 Denik, N.N. (5) 143 Denis, G.V. (5) 41 Denis. J.-M. ( I ) 334 Denmark, S.E. (5) 275; (7) 74 Denney, D.B. (2) 22 Depezay, J.-C. (7) 90 Derouhaix, A. (8) 12 Dervan, P.B. (6) 202, 208, 21 1, 213, 223, 227, 228 De Sanctis, Y. ( 1 ) 398 Deschamps, E. ( I ) 395, 397 DeShong, P. (7) 121 DesMarteau, D.D. (5) 147: (7) 58 Desorcie, J.L. (8) 98 Desper, J.M. (3) 8 Detsch, R. ( I ) 356. 357; (4) 7 I , 72; (8) 34 Dettinger, J . ( I ) 28 de Vaumas, R. ( 1 ) 307, 308 De Vico, A.L. (6) 192 Devine, K G. (6) 5-7, 9 Devine, R.L.S. (8) 229 de Vries, J.G. ( I ) 110 de Vroorn, E. (6) 37 De Waal, B.F.M. ( I ) 188 Dewynter, G.-F. ( I ) 142 Dhawan. H. (5)77

Author Index

Dianova, E.N. ( I ) 411, 417 Dickerson, R.E. (6) 354 Didderding. E. (5) 148 Diefenhach, U. (8) 107, 108 Diekmann, S . (6) 365 Diel, P.J. (5) 181 Dieter-Wurm, I. (6) 212 Dijt, F.J. (6) 331 Dilling, W.L. (8) 112 Dillon, K . B . ( I ) 284; (2) 45, 46: (8) 96, 176 Ding, M. ( I ) 221 Ding. W.-D. (6) 283 Ding, Y. ( 5 ) 160 Dingwall, C . (6) 314, 315 Direktov, D. (5) 156 Distefano, M.D. (6) 213 Dixon, D.A. ( I ) 386 Dmitrichenko, M.Yu. (2) 12; (8) 179 Dmitriev, B . V . (2) 47 Dmitriev. V . K . (2) 12 Doan, K. (8) 251 Dohhs, K.D.( I ) 386 Dohler, M. (6) 128 Dodge, J.A. (8) 99, 1 1 1, 201 Diirr, A. (1) 100 Diirrenhach, F. (8) 90 Diitzer, R. (2) 17 Doherty, N.M. (8) 40,41 Dokuchaeva, I.S. (5) 135 Dolgushin, G . V . (2) 12; (8) 179 Dolgushina, T.S. (5) 224 Dolidze, A . V . (5) 106 Doller, D. (4) 16; (5) 6 Donahue, J.M. (6) 161 Dondoni, A . (7) 77 Donskikh, V.I. ( I ) 200; (2) 7; (5) 137; (8) 17, 179 Dorfman, Y a . A . (5) 7 Dorman, G. (7) 89 Dorow, R.L. (5) 275; (7) 74 Dorrenhach, F. ( I ) 215 Dotzer, R. (7) 45 Dou, D. ( I ) 351 Doveletoglu, A . (8) 32 Downes, J.M. (1) 87 Doxsee, D.D. (8) 164, 167 Doxsee, K.M. (1) 183 Drach, B.S. ( I ) 165, 238, 239. 258 Drapailo, A . B . ( 1 ) 354; (4) 69 Draper, D.E. (6) 239 Draths, K.M. (5) 282 Dreef, C.E. (4) 60;(5) 33. 45; (6) 106 Dreef-Tromp. C.M. (4) 46 Drescher, M. (5) 171

413 Driess, M. ( I ) 23, 24. 349. 350. 360 Drioli, E. (8) 259 Drohny, G.P. (6) 357 Drozdova, T.D. (5) 75 Drummond, J.T. (5) 237. 245, 246 Du. S.M. (6) 237 Duhenko, L.G. (5) 104 Duhourg, A. ( I ) 299 Duhovik, 1.1. (8) 248 Duhreuil, D. (5) 39 Duceppe, J.-S. (7) 135 Duckworth, P.A. ( I ) 87 Duermer, G. (5) 73 Duesler, E.N. ( I ) 351 Dubur, N. ( I ) 99, 319; (8) 60 Duisenherg, A. ( 1 ) 94 Dumas, J . (7) 90, 123 du Mont, W.W. ( 1 ) 210, 21 1 Dunaway-Mariano, D. (5) 21 1 Duncan, L . A . (5) 256 Dunmur, D.A. (7) 139 Dunne, T.S. (6) 269 Duplaa, A.-M. (6) 172 Dupre, C. (4) 66 Dussalt, P. (7) 91 Duthaler, R.O. ( 5 ) I48 Dutta, P.K. ( I ) 137 Dyatkina, N.B. (6) 108 Dyhowski, P. (5) 60 Dyer, G . (3) 40 Dzhiemhaev, B.Zh. (5) 164 Dziemha, P. ( 1 ) I39 Eaton, D.F. (8) 93 Eaton, G . (6) 323 Ehata, T. (6) 160 Ehinger, K. (6) 48 Eckert. J. (6) 306 Eckstein, F. (6) 63. 123 Edwards, M. (8) 164, 166, 168I70 Edwards, P.G. ( I ) 58. 69 Eft'enherger, R. (5) 156 Efremov, Yu.Ya. ( I ) 95, 314. 374; (5) 216 Eggersdorfer, M. (4) 7 Egholm, M. (6) 133, 134 Eguchi, S. (8) 8, 9 Eguren. L. ( I ) 217 Ehrig. M. (8) 175 Eih, D. (6) 356 Eichinger, T. (5) 133 Eikyu, Y. (6) 177 El Adeh. K . (2) 39 Elhaum, N C (8) 234

El-Emadi, 1.M. (8) 94, 136 Elguero, J . (3) 13, (7) 17-19, 52; (8) 36-38. 50 El Hallaoni, A . (5) 208 El Hamad, K ( 1 ) 236 El-Hamshary, H. ( I ) 270 El-Kateh, A . A . (5) 59 El-Khoshnieh, Y.O. (2) 20, (5) 212 Ellestad, G A. (6) 268. 269, 283 Elliot, J. (6) 270 Elliot, R.D. (6) 26 El Manouni, D. (5) 204 Elmasri, M. (5) 13 Elmestour, R. (7) 57 Elms, F.M. ( I ) 160 El-Rahman, N.M.A. ( I ) 240 Elschenhrioch, C. ( I ) 46 Elsevier, C.J. (8) 77 Emhrey, K.J (6) 304 Emi, S. (8) 279. 280, 286 Emmerich, C. ( I ) 371 Endo, T (6) 38 Engel, R. (5) 155 Engel, S. ( I ) 206; (4) 29, 30 Engelhard, H. (8) 151 Engelhardt, U . (8) 107, 108 Enikkev, K.M. (5) 300 Ennis, M.D. (7) 96 Epishina, T.A. ( I ) 152; (8) 73 Erahi, T . ( I ) 229 Erikson, M. (6) 329 Eritja, R. (6) 75, 157 Ernherg, I . (6) 314 Ernst, L. (6) 25 Eschenmoser, A . (6) 128, 129 Escudie, J. ( I ) 309, 339, 361 Etemad-Moghadam, G . ( I ) 276, 299, 379; (3) 10 Ettlinger, M. ( I ) 252; (3) 3: (7) 42 Evans, D.A. (7) 96, 129 Evreinov, V . I . (5) 141 Exarhos, G.J. (8) 92 Ezaz-Nikpay, K. (6) 159 Facchin, G. (8) 137 Fagan, P. (6) 307 Fahmy, A.H. (5) 58 Failla, S. (5) 186 Fairley, T.A. (6) 310 Falck, J.R. ( I ) 149 Fallis, K . A . ( I ) 4 Famhri, L . (8) 219 Famulok, M. (6) 324 Farina. V . ( I ) 179, 180 Farrna, F. (7) 103; (8) 48

414

Farquhar, D. (6) 51 Farr, F.R. ( I ) 80; (3) 6 Farrant, R.D. (5) 243 Fatima, A. (5) 122 Fatou, J.G. (8) 247 Faucher, J.P. (8) 109, 110 Faucitano, A. (8) 237 Faulok, M. (6) 92 Favre, A. (6) 139, 140, 146148 Fawcett, J. (8) 46 Fazakerley, G.V. (6) 349 Fazliakhmetova, Z.M. (2) 27 Feaster, J.E. (1) 38 F d e , A. (6) 305 Fedoroff, O.Y. (6) 231 Fegley, G.J. (7) 62 Feighery, W.G. ( I ) 66 Feigon, J. (6) 217-219, 221 Fell, B. (1) 162 Feng, H. ( 5 ) 160 Feng, K. (5) 310 Fenske, D. (1) 248 Ferguson, G. (8) 171 Fernhdez, A. (6) 240 Fernandez-Baeza, J. (8) 42 Fernandez-Forner, D. (6) 157 Ferrar, W.T.(8) 159, 224, 225, 287 Ferrara, L.M. ( 5 ) 254, 255 Ferrari, M. (5) 206 Ferris, K.F.(8) 226, 227, 228 Feshchenko, N.G.(1) 204, 218; (8) 74 Fettinger, J.C. ( I ) 66 Fewell, L.L. (8) 217 Fiaud, J.-C. ( I ) 82, 169; (3) 33, 39 Ficheux, D. (5) 236 Fidanza, J.A. (6) 175 Fil’chikov, A.A. (1) 151; (8) 22 Filippone, P. ( I ) 124; (7) 8 Filippov, M . V . ( I ) 199 Finch, J.T. (6) 315 Finocchiaro. P. (5) 186 Fiorella, P. (8) 219 Fischer, A. (2) 25, 26 Fischer, J. ( I ) 393; (4) 79 Fisher, H.A. (8) 283 Fitzpatrick, R.J. (8) 133 Flamigni, L. (8) 232, 289 Flanagan, M . E . (6) 303 Fletcher, S.R. (7) 69 Floriani, C. ( I ) 184 Floruss, A. (1) 47, 50 Flory, J.P. (6) 207 Fluck, E. (1) 426; (8) 6, 45 Foces-Foces, C. (3) 13; (7) 17-

Organophosphorus C’hPtn istry 19, 52, 115, 116; (8) 36-38, 50 Foeldesi, A . (6) 263, 264 Folkins, P.L. ( I ) 362; (3) 9; (4) 68 Fontaine, C. (6) 148 Fontanella, J.J. (8) 254 Fontin, G. (8) 132 Forhes, J.E. (7) 86 Formigut!, M. ( I ) I , 2 Forrow, S.M. (6) 308 Forster, A.R. (5) 302 Forsyth. M. (8) 253 Fortier, S. ( I ) 31 Fortt, S. (6) 270 Foss, V.L. ( I ) 199 Foucher, D. (8) 193 FouquC, D. (5) 180 Fourquet, J.L. (8) 25 Fourrey, J.-L. (6) 139, 140, 146-148 Franchetti, P. (6) I Francioni, M. (7) 27 Frank, C.W. (8) 231 Frankhauser, P. ( 1 ) 349, 350 Frehel, M. (1) 281 Freeman, S. (5) 267, 308 Freese, S. (6) 52 Freitag, S. (8) 181 Fresneda, P.M. (7) 108, 114 Friehe, R. (8) 20, 64 Frijns, J.H.G. ( 1 ) 17, 164 Fritsch, V. (6) 366 Fritz, G. ( I ) 52-57, 282 Froehler, B.C. (6) 224 Frost, J.W. (5) 282 Frayen, P. (4) 41; (8) 53 Frye, J.S. ( I ) 399 Fryzuk, M.D. ( I ) 68 Fuchs, E. ( I ) 311. 312 Fuji, K. (6) 177 Fujihara, H. (3) 19 Fujihashi, T . (6) 38 Fujii, A. (7) 29 Fujii, M. ( I ) 187; (4) 82 Fujimoto, K. (7) 65 Fujimoto, T. (3) 30 Fujita, J . (1) 33 Fujiwara, H. (8) 115, 156, 157 Fujiwara, M. ( I ) 229 Fukunda, H. (8) 156 Fukuoka, J. (8) 154 Funhoff, A.S. (3) 21 Furin, G.G. (4) 22 Furmanova, M.V. ( I ) 213 Furukawa, N . (1) 89; (3) 19 Furukawa, S. (5) 172 Furuno, E. (7) 118

Fustinoni, S. (6) 89 Gabarro-Arpa, J . (6) 349 Gahhai, F. ( I ) 364; (4) 81 Gahler, D.G. (8) 207 Gahrielides, C.N. (6) 161 Gadalla, K.Z. (5) 50 Gaertner-Winkhaus, C. ( I ) 358 Gaeta, S.N.(8) 259 Gaffney, B . L . (6) 233, 234. 355 Gage. J.R. (7) 129 Gait, M.J. (6) 81. 314, 315 Gajda, T. ( 1 ) 145 Gakh, A.A. ( I ) 219 Galakhov, M.V. (8) 248 Galan, A. (6) 35 Galenko, T.G.( I ) 224 Galeotti. N. ( I ) 144 Galishev, V . A . (5)224 Gallagher. J F. (8) 171 Gallegos, R. (6) 303 Gallucci, J.C. ( I ) 32 Gamayarova, V.S. (2) 27 Gamper, S. (1) 64, 67, 220, 425 Ganapathiappan, S. (8) 251 Ganouh. N.A.F. ( 1 ) 240 Gao, H. (6) 355 Gao, X. (6) 220 Garbay-Joureguiherry. C. (5) 236 Garhesi, A. (6) 235 Gard, G.L. (5) 158 Gardiner, M.G.( I ) 160 Garner, P. (6) 302 Garot, C. (1) 299 Gasanov, B.R. (4) 24 Gasche, J. (6) 139, 140, 146-148 Gaset, A. (7) 57 Gasparotto, D. (6) 2 M Gates, P.N. (2) 3 Gau, D.-M. (5) 34 Gaulle, V. (6) 330 Gaur, R.K. (6) 44 Gelessus, A . (1) 405 Gellman, S.H.(3) 8 Genet, J.P. (7) 67 Gentles, R.G. (6) 171 Geoffroy, M. ( I ) 285, 297 Gerher, J.P. (5) 269 Gertin, T . (1) 93 Gero, S.D. (5) 240; (6) 19 Gesteland, R.F. (6) 364 Ghazzouli, I. (5) 248 Giannis, A. (7) 75 Gibson, A.W. (5) 118 Gibson, D. (5) 205 Gilbert, D.E. (6) 218

Author lndex

Gilles, A.M. (6) 62 Gillier, H. (5) 204 Gilyarov, V.A. (8) 7 6 Ginieys, J.F.(1) 267 Giovannangeli, C. (6) 209 Giralt, E. (6) 157 Glanzier, A.N. (6) 322 Glaser, P. (6) 62 Glaser, R. ( I ) 273 Glass, T. ( I ) 108 Gleiter, R. ( I ) 293, 326, 426 Glenmarec, C . (6) 264 Gleria, M. (8) 132, 137, 214, 219, 232, 289 Glick, G.D. (6) 194, 195 Glidewell, C. (3) 12 Glinka, T. (6) 303 Glowacki, Z. (5) 316 Gmeiner, W.H.(6) 191 Gnevashev, S.G.(5) 313, 314 Godfrey, S.M. ( I ) 131, 132; (2) I , 2, 1 1 Goehel, M.W. (5) 73 Goebelhecker, S. ( I ) 101 Goede, S.J. ( I ) 298 Goedemoed, J.H.(8) 213 Goerlich, J.R. ( I ) 197 Goesmann, H. ( I ) 53, 55 Goeva, L.V. (8) 173 Goggio, W.D. (8) 218 Gogoi, P.C. (5) 57 Gokota, T. (6) 189 Gol, F. ( I ) 215 Goldherg, I.H. (6) 267, 280, 28 1 Goldman, M.E. (4) 55; (6) 184 Goli, M.B.(1) 81; (3) 28 Gololobov, Y.G. ( I ) 150; (4) 1; (7) 100; (8) 7 Gomelya, N.D. ( I ) 204 Gomez, M.A. (8) 246, 247 Gonbeau, D. (1) 278 Gonce, F. (3) 7; (5) 227 Gong, M.S. (8) 206 Goodisman, J. (6) 282 Goodwin, H.P.( I ) 284 Gordon, E.M. (5) 256 Gorelikova, Yu.Yu. ( I ) 84 Goti, A. ( I ) 98; (3) 4, 36, 38; (5) 312; (8) 75 Gotoh, Y. (1) 231 Gottarelli. G. (6) 235 Goughenour, L.L. (5) 245 Goulet, M.T. (7) 93 Gouygou, M. (1) 278, 309, 379; (3) 10 Grachev, M.K. (4) 31, 32, 34, 35

415

Graczyk, P. ( I ) 104; (3) 14; (5) 174 Grbland, A . (6) 329 Graffeuil, M. (8) 110 Grajkowski, A. (4) 61; (6) 98 Gramlich, V. ( I ) 93 Grandclaudon, P. (7) 99 Grandos, A. (6) 183 Grangeon, A. (8) 260 Granier, M. (8) 176 Grashof. H.R. (8) 159 Gratchev, M.K. ( I ) 205; (4) 33, 39 Gravier-Pelletier, C . (7) 90 Graziani, R. (8) 184 Green, D.L.C. (7) 20 Green, K.E. (5) 12 Green, S.M.(6) 314 Greenbaum, S.G. (8) 254 Greenfield, L.J. (3) 23 Grein, T. (6) 152 Gremler, S. ( I ) 20, 21 Grevatt, P.C. (6) 161, 162 Grifantini, M. (6) 1 Griffiths, D.V. (4) 18; (5) 288; (7) 9 Griffiths, J . (6) 285 Griffiths, P.A. (4) 18; (5) 288; (7) 9 Grigor’eva, A.A. ( I ) 262, 263, 264 Grim, S.O. (1) 81; (3) 28; (7) 16; (8) 27 Grisard, A. (1) 223 Grishun, E.V. (5) 132 Grohe, J . ( I ) 101-103, 292-294, 330, 340, 344; (7) 6 Gross, H. (5) 107, 108 Gross-Berges, V. (7) 72 Grosspietsch, T. ( I ) 330 Grote, C.W. (2) 18; ( 5 ) 157 Groth, U. (5) 207 Griinhagen, U . ( I ) 20 Griitzmacher, H. ( I ) 2%; (7) 15 Gruff, E.S. (6) 332 Grune, G.L. (8) 233 Gryaznov, S.M. (4) 56, 57; (6) 77, 78, 173 Guastini, C. ( I ) 184 Gubnitskaya, E.S. (5) 315 Gudat, D. (1) 275 Gudima, A.O. ( I ) 368 Guervenou, J. ( 5 ) 1 12 Guetard, D. (6) I 1 Gug-Kim, S. (6) 79 Gugliermotte, F. (8) 288 Guha, S.N. ( I ) 189 Guillemin, J.-C. ( 1 ) 334

Guinosso, C.J. (6) 187 Guittet, E. (6) 148 Guizard, C. (8) 260 Gumbiowski, R. (6) 46 GUO,C.-Y. (5) 151 Guo, M. (5) 302 Gupta, A.D. (8) 128 Gupta, N. (1) 410, 412; (4) 75 Gurevich, P.A. (5) 142 Gurskii, M.E. ( I ) 242 Gusarov, A.V. ( I ) 106 Gusarova, N.K.( I ) 105-107 Guschlhauer, W. (6) 349 Guseva, F.F. (5) 297 Gus’kova, L. (6) 193 Guthold, M. (6) 367 Guy, A. (6) 172, 349 Guzhavina, I.G. ( I ) 129 Ha, H.-J. (5) 185 Hahicher, W.D. (4) 25 Hahus, 1. (6) 171 Haddad, M. ( I ) 415; (4) 74 Haddon, R.C. (8) 172, 247 Hadjiarapoglou, L. (5) 79 Haegele, G. (5) 186, 200 Hihner, U . (4) 25 Haenel, J. (I) 198, 209 Haenel, M.W. ( I ) 3 Haeusel, R. (1) 112 Hafez, T.S.(5) 296 Haiduc, I. (8) 4, 5, 87 Hajdu, J . (4) 50 Halazy, S. (6) 22; (7) 72 Halcomb, R.L. (6) 272 Hall, C.D. ( I ) 157, 243-245; (3) 17; (4) 15, 19; (7) 43, 44 Hall, D. (3) 27 Haltiwanger, R.C. ( I ) 207 Hamashima, H. (1) 74 Hamer, T.A. (5) 220. 222 Hammerschmidt, F. (5) 176, 177 Hammoutou, Y. (8) 6 8 Hampell, A. (6) 83 Hanabusa, A. (8) 284 Hanafusa, T. (7) 22 Hanawalt, E.M. (1) 183 Hanaya, T . ( I ) 86; (5) 109-1 I I , 114 Hanchin, C.M. (5) 237 Hanekamp, J.C. (3) 26; (7) 5, 124 Hanna, M.T. ( I ) 249 Hans, C. (8) 253 Hans, G. (8) 182 Hans, J. (2) 29 Hansen, T.K. (7) 125

316 Hanson, B.E. ( I ) I08 Hanssgen, D. ( I ) 100 Harada, J . (8) 233 Harder. S. ( I ) 9 4 Harger, M.J.P. (5) 221, 277. 278, 292; (8) 33 Harling, J . (6) 270 Harlow, R.L. ( I ) 38 H a r d e n , M.R. (5) 251; (6) 31 Harpp, D.N. ( I ) 362; (3) 9; (4) 68 Harriman, A . (6) 318 Harrington, P.M. (6) 278 Harris, B.L. ( I ) 273 Harris, C.M. (6) 170 Harris, J.M. (6) 364 Harris, K.D.M. (3) 12 Harris, T . M . (6) 170 Harrison, B.L. (5) 247 Harrity, T.H. (5) 256 Harrod, W.B. (1) 265 Hartley, J . A . (6) 300, 308 Harusawa, S. (5) 293 Harvey, J . (5) 129; (6) 6 ; (7) 78 Hasenhach, J . ( I ) 49 Hashimoto. H. (7) 92 Hashimoto, T. ( 1 ) 122 Hassanein, M. ( 1 ) 270 Hasselhring. R. (8) 183 Hata, T . (6) 27. 86 Hatanaka, M. (7) 40, 136 Hatfield, G.R.(8) 234 Hatt, K.L. (7) 11 Hattori, T . ( 1 ) 1 I Hatzenhuhler, N.T. (6) 299 (6) 126 H ~ u J.-F. , Hauck, S.I. ( I ) 180 Haughland, R.P. (6) 322 Hausheer. F.H. (6) 207 Hautefaye, P. (5) 229 Haw, J.F. (8) 207, 234, 236 Hay, A.J. (6) 7 Hayashi, A . ( I ) 329 Hayashi, T . (1) 113 Hayashi, Y. ( I ) 268 Haynes, U.J.(5) 250 Hays, S.J. (5) 18 Hayshi, T . ( I ) 13 Healy, P.C. (2) 19 Heaphy, S . (6) 314, 315 Hehel, D. (5) 153; (6) 66 Heckmann, G. (3) 42; (8) 45 Heckmann, M. ( I ) 174 Heesche-Wagner, K. ( I ) 153 Hegdus-Vajda, J . ( I ) 130 Hegemann, M. ( I ) 340. 344 Heidlas. J.E. (6) 57. 58 Heimstracher. E. (4) 7

Hein, J . ( I ) 358 Heinicke, J . ( I ) 409 HClkne, C . (6)93, 209 Helifski, J . (4) 40:(6) 105 Hemling, H. ( 1 ) 9. 10 Henderson, W. (8) 46 Hendrickson, E.K. (5) 46, 47 Hendrickson, H.S. (5) 46. 47 Hengge, A . C . (5) 70 Hhichart, J.-P. (6) 309 Henin, Y. (6) I I Henk, T. (7) 75 Henke, S.L. (5) 67 Henlin, J.-M. (6) 131. 132 Hennawy, I.T. (5) 59 Herhst-lrmer. D. (8) I8 I Hernandez. C . (8) SO Hernandez-Cano, F . (7) 116 Herrrnann. E. ( I ) 20. 21: (5) 305 Herrmann, W . A . ( I ) 163 Herschlag, D. (6) 255, 257, 258 Hertlein, K. ( I ) 235 HervC, M.J. ( I ) 278 Hesse, D. ( I ) 246; (7) 39 Heuhel. J . (8) 6 8 Heuer, L. ( I ) 193 Heydt. H. ( I ) 31 1. 312 Hey-Hawkins. E. ( 1 ) 22 Higashida, S. (8) 235 Hikichi, K. (8) 235 Hill, T.G. (1) 207 Hills, J.M. (5) 257 Hilts, R.W. (8) 164 Himeda, Y. (7) 40 Hindley, N . J . (7) 139 Hiort, C. (6) 329, 339 Hirao, I. (6) 80, 102 Hirao, K. (2) 4 Hiratake. J . (2) 15. 16 Hiroaki, H. (6) 290 Hirose, T. (8) 256, 257 Hirota, K. (6) 45, 90 Hirotsu. K. ( 1 ) 201, 329, 331: (5) 214 Hitchcock, M.J.M. (5) 248 Hitchcock, P.B. ( I ) 342. 343, 375. 391, 405; (3) 41 Ho, J . ( I ) 365 Ho. W.B. (6) 302 Ho, Y.W. (8) 120 Hodkey, D.W. (7) 9 3 Hiinle, W. ( I ) 52, 282 Hoferer, M. ( I ) 30 Hoffmann, A . ( I ) 337 Hoffmann, J . ( I ) 312 Hoffmann, M. (5) 316 Hogg. A.M ( 1 ) 86: (5) 109,

I10 Hoheisel, J . (6) 52 Hoke, G . (6) 192 Holand, S. (3) 34 Holrnes. J.M. (2) 28; (5) 304 Holmes, R.R. ( I ) 121; (2) 22. 23, 28, 29; ( 5 ) 304; (8) 31, 44, 185 Holy, A . (6) 28 Holzer, A . (6) 122 Honert. D. (8) 65 Honeyman. C. (8) 193 Hong, Y.-P. (6) 284 Honza. J . (8) 163 Hooper, D.L. (7) 1 I Hope, H. ( 1 ) 183 Hopkins, P.B. (6) 197. 325 Horan, C.J. ( 1 ) 273 Horiuchi, Y. (8) 153 Horne, D.A. (6) 21 1. 223 Hosaka, H. (6) 79 Hosorni, H. ( 1 ) 331 Hosomi, K. (5) 214 Hosztafi, S. ( I ) 140 Hotei, Y. (3) 30 Hotoda, H. (6) 8 6 Hou, X. (8) 258 Houalla, D. (2) 39. 4 0 Houssin, R. (6) 309 Howard, J . A . K . ( I ) 58 Howe, L. (8) 185 Howson, D. (5) 257 Hozumi, H (8) 241. 242 Hrudkova, H. (8) 215 Hsiao, C.-N. (7) 137 Hu,B.-F. ( 5 ) 233 Hua, D.H. (5) 309 Huang, M. (2) 41 Huang, S.-B. (6) 136 Huang, W . ( I ) 221 Huang, X.-Y. (5) 238 Huang, Y. (2) 30 Huang, Y .-Z. (7) 28 Huffman, J . W . (7) 31 Huh, H. (5) 144 Huh, M.W. (8) 126 Humhlet, C . (5) 246 Humphrey, G.R. (5) I18 Hund, H. (2) 21 Hund, R.-D. (2) 33-35 Hungerhiihler, H. ( I ) 189 Hunter, W.N. (6) 203 Hurley, L.H. (6) 292-296, 300 Hurley, T.B. (6) 53 Hursthouse, M.B. (6) 60;(7) 63 Huszthy, P . ( 1 ) 130 Huy, N.H.T. ( I ) 300. 301 Huyhn-Dinh, T. ( 0 ) 13, 14

417

Hwang, C.-K (6) 276 Hwang, H. ( 1 ) 80; (3) 6 Hyla-Kryspin, I . ( I ) 326 Ihrahim, E.H.M. (8) 94, 136 Ichikawa, A. (6) 39; (7) 92 Ichikawa, J . ( I ) 7 6 Ichikawa, N. (7) 35 Ichikawa, T. (6) 168 Iden, C.R. (6) 171 Igau, A. ( I ) 99, 319; (8) 60 Ignat'eva, S.N. ( I ) 341 Iguchi, Y. (8) 154 lida, A. (6) 160 lida, T . (8) 150 lino, Y. (7) 107; (8) 56 lio, H. (7) 29 Ikehukuro, K. (6) 102 Ikehara, M. (6) 167, 290 Il'yasov, A.V. (2) 27 Imada, T. (6) 27 Imamoto, T. (3) 1 Imhach, J.-L. ( I ) 142; (6) 125 Imhof, W. ( I ) 370 Imhoff, P. (8) 77 Imiolczyk, T . W . ( I ) 207 Inagaki, N. (5) 293 Inamoto, N . ( I ) 85 Indzhikyan, M.G. (5) I19 Ingorokva, K.V. (5) 106 Inoue, H. ( 1 ) 118; (4) 12; (6) 167, 200 Inoue, K. (8) 114, 116 Inoue, Y. (6) 85 Inuhushi, A. (8) 276, 277 Ioannidis, P. (6) 2 0 Ionin, B.I. ( I ) 194, 195; (5) 159, 188 lonkin, A.S. ( I ) 314, 315, 341. 374; (5) 216 lorish, V.Y. (4) 31 Irmer, E. ( I ) 235 Irtuganova, E.A. ( 5 ) 261 Irwin, W.J. ( 5 ) 267 Isakov, V.V. (5) 1 6 6 Ishido, Y. (6) 85 Ishiguro, K. (5) 21 Ishii, M. (7) 29 Ishii, Y. ( I ) 255 Ishikawa. 1. (8) 266, 267 Ishikawa, M. (6) 80, 102 Ishikawa, N. (8) 127 Ishikawa, T . (8) 268 Ishikawa. Y. ( I ) 331; (5) 214 Ishino. Y. (8) 161 Ishizaki, T . (6) 298 Ishizuka, T . (5) 294

Ishmaeva. E . A . ( I ) 384. 385; (8) 14 Ishmuratov, A.S. (5) 81, 82. 83 Islam. S . M . (8) 216 Ismagilov. R.K. (5) 128 Issakides, G. (6) 122 Issleih, K. ( I ) 71 I t o . S . (7) 92 Ito. T . (6) 69 Ito. Y. ( I ) 74, 75, 115 I t o , 2 . (8) 115, 155. 156 Itoh, H. (6) 15 Ivanchenko, V.I. ( I ) 317 Ivanov, A.N. ( I ) 152; (8) 73 Ivanov. Yu.V. (8) 86 Ivanova. E. (6) 193 Ivanova, T.A. ( I ) 224 Ivantsov, A.E. (5) 128 Ivonin, S.P. ( I ) 191. 192, 202; (4) 1 1 ; (8) 17 Iwahuchi, Y. (6) 273 Iwai, S . (6) 112 Iwaoka, T . (5) 258 Iwasaki, H. (6) 69 Iwasaki. S. (6) 274 Iwata, T . (7) 106; (8) 55 Iwatsuki, M. (8) 243 lyengar, B.S. (6) 289 lyer, R.P. (4) 3: ( 6 ) 73 Jachow, H. ( I ) 49 Jackson, J.A. (5) 96 Jackson, W.R. ( I ) 172 Jacobson. R.A. ( I ) 35 Jaeger, L. (8) 102 Jaeger, V . (5) 79 Jaekel, K. (6) 131 JPrvinen. P. (6) 251 Jain, D.V.S. ( I ) 127 Jain, S. (6) 232 Jakuhik, D. ( I ) 3 James. K. (4) 8 Janati, T . ( I ) 334 Janda, K.D. (5) 241; (6) 252 Janecki, T . (7) 73 Jankowski, K.J. (5) 197 Jankowski, S . ( I ) 380. 382, 383; (5) 286 Janout, V. (8) 215 Janssen. R.A.J. ( I ) 188 Jansze, J.P. (5) 45 Jaouhari, R. (7) 89 Jarosinski, M . A . (7) 9 8 Jayasena. S.D. (6) 222 Jeffery. J.C. ( I ) 332 Jeffries. D.J. (6) 6, 8 Jekel. A.P. (8) 124. 134

Jemini. G. ( 5 ) 206 Jenkins, I.D. ( I ) 138; (2) 19 Jenkins. T.C. (6) 300. 319 Jennings. L.J. (5) 251; (6) 31 Jennings, W.B. (5) 219, 220. 222 Jenny, T.F. ( I ) 143 Jensen, M.S. (7) 26 Jeppesen. C. (6) 338 Jerina, D.M. (6) 169 Jiang. J.S. (8) 120 Jiang. R.-T. (6) 64 Jiang, X.-J. (6) 23 Jiang, Y.-P. (6) 282 Jiang, Z.-W. (6) 280 Jiao, X.-Y. (5) 233 Jin. R. (6) 233. 234 Jinkerson, D . L . (8) 10 Jochem, G . ( I ) 367; (4) 78; (7) 56 Johns. R.B. (5) 231 Johnson, C. (7) 135 Johnson, F. (6) 171 Johnson, G. (5) 18, 245, 246 Johnson, J.A. ( I ) 343; (3) 41 Johnson, J.L. (5) 46. 47 Johnstone, B.H. (6) 222 Jones. B.C.N.M. (6) 2, 3, 6. 8, 9 Jones, K. (7) 59 Jones, M.S. (8) 196 Jones, P.G. ( I ) 197, 214; (2) 5 . 25, 26, 42; (8) 28 Jones. R.A. ( I ) 27, 59-61; (6) 233, 234, 355 Jones, T . L . ( 1 ) 83 Joshi, K. ( I ) 6 8 Jouaiti, A. ( I ) 297 Jouin, P. ( I ) 144 Joyner, H.H. (7) 31 Juaristi, E . ( 1 ) 34; (3) 15 Juliano, R.L. (6) 109 Jun, H. ( I ) 346 Jung, K.-H. (6) 16 Jurkschat, K. ( I ) 12 Just, G. (6) 116. 117 Jutland, A. ( I ) 396 Jutzi, P. ( I ) 277 Kahachnik, M.I.( 1 ) 241, 261264; (5) 75, 299; (8) 76 Kahachnik. M.M. (4) 85; (5) 143 Kahra. V. ( I ) 410 Kadyrova. V.Kh. (5) 55 Kafarski, P. (5) 242 Kagan, H.B. ( I ) 169; (3) 39

418

Kageyama, H. ( I ) 269 Kagramanov, N . D . ( I ) 219 Kagukhin, L.F. (8) 7 Kaji, A. (6) 38 Kajihara, K. ( I ) 229 Kajiwara, M . (8) 126, 230, 238. 239, 292 Kajtar-Peredy, M . ( I ) 130; (7) 97 Kakiuchi, H. (5) 298 Kal, V.E. (6) 121 Kal’chenko, V.1. (1) 224; (2) 47; (5) 16, 17, 140, 141 Kalinov, S.M. ( I ) 167 Kallenbach, E . R . (6) 356 Kallick, D . A . (6) 350 Kallrnuenzer, A . (1) 338 Kaltenhach, R.F., 111 (4) 42 Karnaike, K. (6) 85 Kamalov, R . M . ( I ) 125. 126; (4) 37; (5) 91 Kametani, S . (5) 217 Kamiya, N. ( I ) 255; (6) 69 Kan, L . 4 . (6) 204. 360 Kanatzidis, M.G. (6) 333 Kanavarioti, A. (6) 53 Kaneyuki, S . (8) 116 Kannewurf, C.R. (8) 253 Kanornata, N. (7) 104, 105; (8) 57-59 Kansal, V.K. (6) 62 Kanters, J.A. ( I ) 94 Kanzaki, M. ( I ) 229 Kapitonova, T.R. (8) 158 Kapoor, P.N.(8) 169, 170 Kappe, T. (7) 10; (8) 23 Kaptein, R. (6) 356 Kar. K.K. (8) 112, 113 Karaghiosoff, K. ( I ) 222, 410412, 414; (4) 75, 76; (7) 7; (8) 178 Karaki, Y . (8) 273 Karanowsky, D . S . (5) 256 Karara, A. ( I ) 149 Karasik, A.A. (1) 185 Karataeva, F.Kh. (2) 8 Karaulov, A.1. (7) 63 Karger, A . E . (6) 364 Karinskaya, A.S. (5) 7 Karn, J. (6) 314, 315 Karpas, A . (6) 4 Karsch, H . H . (1) 64, 65, 67 Karthikeyan, S . (8) 10 Karytova, V.F. (6) 193 Kasheva, T. (5) 230 Kashin, A.V. (1) 288 Kashiwabara, K. ( 1 ) 33 Kassem, M . E . (8) 94

Orgunophosphorus Chemistry Kasukhin, L.F. ( I ) 150; (4) I ; (7) 100 Kasumov, T . ( I ) 234; (5) 260 Kataeva, O.N. (5) 313, 314 Katagiri, N. (5) 258 Kataky, J.C.S. (5) 57 Kataoke, S . (6) 39 Katayama, K. (8) 243 Kato, H. (5) 298 Kato, K. (3) 18; (7) 23; (8) 162 Kato, R. (5) 21 Kaukorat, T. (2) 5 Kawaguchi, A. (8) 243 Kawai, S.H.(6) 116, 117 Kawaji, H . (7) 104, 105; (8) 58, 59 Kawamoto, H. ( I ) 86; (5) 1 10 Kawano, C. ( I ) 187; (4) 82 Kawase, Y. (6) 167 Kawashima, T. ( I ) 85; (3) 18; (7) 23 Kayamori, N. (6) 244 Kaye, A . D . (5) 266 Kayhanian, R. ( I ) 157; (3) 17; (4) 19 Kayser, M.M. (7) 1 1 Kazanina, T.Yu. (5) 135 Kazankova, M . A . ( I ) 151; (8) 22 Kazantseva, M . V . ( I ) 200; (2) 7; (5) 137 Kazi, A.B. (4) 50 Kazimierz, J. (8) 205 Kearney, A.S. (5) 71 Kehekbaeva, M . M . (5) 7 Keck, G.E. (7) 95 Keck, H. (7) I Kee, T.P. (4) 84 Keglevich, G. ( I ) 295 Kehr, G. (8) 15 Keitel, I . (5) 107, 108, 120 Keller, K. (8) 182 Keller, R. (6) 367 Keller, T . M . (8) 129 Kellner, D. (1) 147 Kellner, K. (5) 187, 234 Kellogg, G.W. (6) 347 Kelly, D.G.(1) 131; (2) 1, 1 1 Kelly, R . C . (6) 299 (8) 46 Kemmitt, R.D.W. Kemp, D . (6) 248 Keneko, C . (5) 258 Kennard, 0. (6) 8 I , 203 Kennedy, D.J. (5) 118 Kenyon, G.L. (6) 65 Kerwar, S.S.(5) 12 Keseru, G.M. (7) 97 Kesselring, R. ( I ) I14

Kettle, D. (5) 243 Kettler, P.B. (7) 16; (8) 27 Khachatryan, R . A . (5) 119 Khadiullin, R.Sh. ( I ) 125 Khailova, N.A. ( I ) 126 Khalil, F.Y. ( I ) 249 Khalitov, F.G. (2) 27 Khamidullin, R.1. ( I ) 26 Khan, M . M . T . (1) 154 Kharchenko, A . V . ( I ) 191. 192, 202; (4) I 1 Kharchenko, V.I. ( I ) 288, 289, 318, 323 Khare, A.B. (5) 210 Khaskin, B . A . (5) 81-83 Khidre, M . D . (5) 165 Khir-el-Din, N. (5) 212 Khmel’nitskii, L.I. (8) 43 Khodorkovskii, V.Yu. ( I ) 166 Khullar, M . (8) 128 Khusainova, N.G. (5) 261 Khusmyatullina, Z.Kh. (8) 158 Kibardina, L.K. (4) 26; (8) 69 Kibbel, H . U . ( I ) 247 Kido, K. (6) 200 Kido, Y. (8) 79, 80, 81 Kiefel, M.J.(7) 127 Kiegiel, J. (3) 22 Kiezek, R. (6) 190 Kilic, A . (8) 63 Kilic, Z. (8) 63 Kim, A S . (7) 129 Kim. C . (8) 229 Kim, C . U . (5) 163, 248, 252, 254; (6) 30 Kim, E.E. (6) 335 Kim, J. (5) 275 Kim, J.-H. (7) 74 Kim, S.J. (6) 170 Kim, T . V . (3) 35 Kim, Y .G. (7) 82 Kimura, Y. ( I ) 269 Kinchington, D. (6) 5, 6, 8. 9 Kinder, F . R . , jun. (7) 98 Kinjo, J . ( 5 ) 153; (6) 66 Kinstler, 0. (6) 192 Kirchhoff, R. ( I ) 378, 407; (7) 37 Kirchner, J.J. (6) 325 Kireev, V.V. (8) 240 Kirk, K.L. (6) 66 Kiselev, A.S. (1) 219 Kiseleva, E.1. (3) 35 Kishikawa, H . (6) 282 Kita, M. ( 1 ) 33 Kitade, Y. (6) 45, 90,91 Kitamura, M . (6) 188 Kitchin, J . (4) 49; (5) 22

Author Index

Kitigawa, T. ( I ) 33 Kizu, R. (6) 293 Kleinpeter, E. ( I ) 2 0 Klepa, T.I. ( 5 ) 99, 100 KliciC, J . ( 5 ) 79 Klimenko, N.M.(8) I 1 Klingenberg, E . H . (8) 208 Kluger, R. ( 5 ) 74, 265 Kmieciak, A . ( I ) 50 Knin, D . S . (6) 195 Knobler, C . B . ( I ) 183 Knollmuller, M. (6) 122 Kniippel, P.C.( I ) 215 Ko, Y.Y.C.Y.L. (1) 422 Kobayashi, H. (6) 274 Kohayashi, T. (5) 298 Kohetz, N . D . (6) 193 Koehler, H . (8) 102 Koenig, M . ( I ) 276, 278, 299. 309, 379; (3) 10 K W g , T. (4) 25 Koepsel, R.R. (6) 245 Koga, Y. (5) 3 8 Koh, J.S. (6) 208 Koh, L.L. (8) 2 6 Kohama, C . (8) 241 Kohler, C . A . (5) 12 Koide, Y. (3) I Kojima, H . ( I ) 118; (4) 12 Kojima, M. (8) 244, 245, 249, 281 Kokzlov, E . S . (8) 19 Kolasa, T. (7) 137 Kolhe, A . ( 1 ) 214 Kolesova, V . A . (5) 199 Kolich, C . H . (8) 198 Kollman, P . A . (6) 165 Kolodyazhnyi. 0.1. (2) 6; (5) 132 Komatsu, H. (6) 168 Kamiyama, M. (6) 249, 250, 337 Komoda, Y. (4) 45; (5) 8 Kondo, Y. (4) 44; ( 5 ) 37 Kondrat’eva, I. (2) 27 Kong, K.-C. ( I ) 175 Konieczko, W .T. (5) 303 Konishi, M . (6) 274 Konishi, T. (6) 244 Konovalova, I.V. (2) 8 , 13, 14; (5) 135 Kool, E.T. (6) 214-216 Kook, L . H . (2) 32; (4) 43; (6) 262 Koomen, G.-J. (7) 46 Kopylov, V . M . (8) 240 Kopylova, L.Yu. (5) 128 Kora, S. (8) 220

419

Korenchenko, O . V . (5) 201 Korkin, A . A . ( I ) 290. 353 Kormachev, V . V . (2) 9; (5) 138 Kormuta, P.P. (1) 129 Koschmieder, S.U. ( I ) 27 Koslov, E . S . (1) 202 Kostina, V.G. (8) 74 Kostka, K. (1) 208 Kostyuk, A.N. (5) 179; (8) 19 Kotsuki, H . ( I ) 158 Koukoulas, A . A . (8) 91 Koutsantonis, G . A . (1) 160 Kovafs, T. ( 5 ) 153; (6) 66 Kovalsky, 0.1.(6) 354 Kovsheva, O.E. ( I ) 241 Kovyazin, V . A . (8) 240 Koyano, H . (7) 92 Koyano, K. ( I ) 73 Kozarich, J.W. (6) 291 Kozima, S. ( I ) 201 Koziol, A.E. (5) 276 Koziolkiewicz, M. (4) 61; (6) 9 8 Kozlov, E.S. ( I ) 191, 192; (4) 10, 11; ( 5 ) 179 Koz’min, A . S . (1) 234; (5) 260 Kraft, D. (2) 24 Krasil’nikova, E . A . (5) 139 Kratky, C. ( 1 ) 36 Kraus, C. ( I ) 248 Krauss, H . (7) 134 Krauss, M. (6) 253 Krautscheid, H . (1) 282 Kravtsov, D . N . ( I ) 84 Krawczyk, E. (5) 60 Krawczyk, S.H.(6) 198 Krawiecka, B. (5) 92 Krayevsky, A . H . (6) 23, 108 Krebs, B. ( I ) 293, 340, 344 Krech, F. (1) 71 Kremer, M. (1) 377; (4) 67; (5) 215

Kremer, P.W. ( I ) 80; (3) 6 Krieger, A . (5) 148 Krill, S. (1) 416 Krishnaiah. M. (5) 14 Krishnamurthy, S.S. (8) 44, 140. 141 Krishnan, B . ( I ) 179 Krishnasn, R. (6) 36 Krivchun, M . N . (1) 194, 195 Kross, M. (8) 139 Kriiger, C . (1) 215, 31 I ; (8) 90 Krummen, A . ( I ) 103 Krupp, G . (6) 44 Krylova, A.I. ( I ) 84 Kryukova, L.Yu. ( 1 ) 190 Kuhota, S. (8) 153 Kuhota, T. ( I ) 119; (7) 24; (8)

27 I , 272 Kuchen, W . (7) 1 Kuchmeier, R.L. (5) 151 Kudrya, T.N. (5) 315 Kudryavtsev, A . A . ( I ) 96; (5) 15

Kuk, K.L. (5) 153 Kukhar, V . P . ( I ) 213; (5) 184, 230, 239 Kukhareva, T.S. (5) 72, 262. 263 Kulagowski, J.J. (7) 64,69 Kuliev, A . B . (4) 2 4 Kumagai, S. (1) 1 1 Kumai, S. ( I ) 268 Kumar, A. (6) 178-180 Kumar, D. (8) 128 Kumar, S. (6) 287 Kumara Swamy, K.C. (2) 28 Kumaravel, S.S. (8) 44, 71, 180 Kumobayashi, H . ( 1 ) 73 Kundig, E.P. (4) 66 Kunieda, T. (5) 294 Kunimoto, K. (2) 48 Kunitake, T. (6) 71 Kunz, H. (5) 209 Kuo, E . E . (6) 87 Kuo, L.Y. (6) 333 Kupce, E. (8) 15 Kurachi, Y. (8) 161 Kuraki, Y. (8) 269-272, 274 Kurfirst, R. (6) 186 Kurg, V . V . (1) 239, 258 Kurihara, K. (6) 71 Kurihara, T. (5) 293 Kurita, J. (1) 79; (3) 5 ; (7) 106 (8) 55 Kurochkina, G.I. (1) 205; (4) 32, 33 Kuroda, R. (6) 243 Kurts, A . L . ( I ) 133 Kuyl-Yeheskiely, E. (6) 12 I Kuzhanova, M.K.(6) 108 Kuzmina, N . A . (5) 239 Kuz’mina, S . N . (5) 138 Kuznetsova, E.K. ( I ) 262, 263 Kvachev, Yu.P. (8) 194 Kvarnstriim, I . (6) 18, 20 Kwik, W.L. (8) 26 Kwon, B.-M. (6) 278 Kwon, S. (8) 130 Labarre, J.F. (8) 109, 110. 13‘) Labhardt. A . (6) 305 Labot, A . (8) 260 Lahruykre. E. (6) 62 Lachmann. J . ( I ) 67

420 La Colla, P. (6) 1 Llge, M. ( I ) 340, 344 Lahoz, F.J. (8) 42 Lahti, P.M. (7) 21 Lahyer, E. ( 1 ) 282 Laitinen, R.S. (8) 6 Lake, C.H. ( I ) 176 Lakhrissi, M. (1) 135, 136 Lakshman, M.K. (6) 169 Lakshmikantham, M.V. (7) 125 Lamhert, J.B. (1) 117 Lamm, G. (6) 199 Lampe, S. (6) 153 Lampeka, R.D. ( I ) 202 Landint, D. (8) 138 Landry, C.J.T. (8) 224, 225, 287 Landry, S.D. (8) 261, 283 Lane, W.S. (6) 159 Lang, H. (1) 370-372 Lange, G. ( I ) 294; (7) 6 Lange, L. (1) 210 Langer, R. (8) 212 Lanneau, G. ( I ) 359 Laportiere, A. (1) 339 Laramay, M.A.H. (2) 43 Larpent, C . ( I ) 109 Laschat, S. ( 5 ) 209 Laszlo, R. (1) 400 LaugAa, P. (6) 148 Lavielle, G. (5) 229 Lawrence, C.W. (6) 145 Layher, E. ( I ) 52 Layrolle, P. ( I ) 276 Lazzari, E. (6) 89 Leach, A.R. (6) 165 Le Bee, C . (6) 14 Lehlanc, M. (8) 25 Le Bret, M. (6) 349 LeClerc, J.E. (6) 145 Le Diguarher, T. (6) 126 Lee, C.-S. (6) 293 Lee, D.C. (8) 263 Lee. H.-C. (6) 171 Lee, I.Q. (7) 91 Lee, K. (4) 27; ( 5 ) 175, 178 Lee, M. (6) 268, 269, 306. 308 Lee, s. ( 5 ) 21 1 Lees, W.J. (6) 57, 58 Lefiaditis, D.A. (7) 32 Le Floch. P. ( I ) 363, 421 Le Goff, P. (1) 19 Le Goftic, F . ( 5 ) 202; (7) 61 Legros, J.-P. ( I ) 415; (4) 74 Legros, J.-Y. ( I ) 82; (3) 33 Lehmann, C. (6) 81 Lehn. J.-M. (6) 330 Lehnen. H. ( 5 ) 131; (7) 47

Lehrach. H. (6) 52 Leighton, J.L. (7) 129 Leijon, M. (6) 329 Leise, M. (1) 370-372 Lejczak, B. (5) 242 Lemaitre, M. (6) 1 1 Le Maux, P. ( I ) 170 Le Merrer, Y . (7) 90 Lemmouchi, Y . (8) 12 Le Moigne, F. (5) 189 Lemos, M.A.N.D.A. (1) 343; (3) 41 Lempert, K. ( I ) 130 Lensink, C. ( I ) 110 Leont’eva, I.V. (1) 262-264 Lequan, M. (1) 223, 257 Lequan, R.-M. ( 1 ) 223, 257 Lermontov, S.A. (8) 30, 294 Lerner, M. (8) 252, 253 Leroux, Y. (5) 204 Lesiak, K. (5) 153; (6) 66 Letsinger, R.L. (4) 56. 57; (6) 77, 78, 192 Leuer, M. ( I ) 373; (7) 2 Leung, P.H. ( I ) 171 Leung, S.S. (3) 21 Leupin, W. (6) 305 Leusen, F.J.J. (5) 31 1 Le Van, D. (1) 292-294, 330, 340,344; (7) 6 Leventis, N. (8) 255 Levis, R.J. (6) 358, 359 Lewis, R. (6) 270, 271 Ley, S.V. (7) 120 Li, C. (5) 160 Li. G. ( I ) 418; (2) 41 Li, S . (5) 264 Li, T . (6) 196 Li, X. (4) 20, 62; (6) 110, 1 1 1 Li, Y. (6) 230 Li, Y.-C. (5) 61 Li. Z. ( I ) 352; (8) 13 Li, Z.-Q. (7) 28 Liakumovich, A G. (5) 55 Liang, M. (8) 193, 202, 203 Lianza, F. ( I ) 9 3 Liao, X . ( 5 ) 264 Lichtenhan, J.P. (8) 41 Liddell, M.J. ( I ) 177 Liehelt, U . ( I ) 247 Lilienherg, I.A. (8) 158 Lilley, D.M.J. (6) 365 Lim, B. ( 5 ) 235 Limhach, H.H. (8) 6 5 Limmer, S. ( I ) 70 Lin, C.H. (6) 292 Lin. J. (5) 146 Lin. K -Y. (6) 210

Lin, X.-F. ( I ) 141 Lindeman, S.V. (5) 167 Lindner, E. ( I ) 28. 29, 174 Linehan. J.C. (8) 92 Ling. Y.-H. (6) 51 Link, M. (8) 35 Link, R. (8) 65 Lipanov, A.A. (6) 354 Lipka, P. (5) 89 Lipman, R. (6) 287. 288 Lippert, B. (6) 212. 342 Liskamp, R.M. (5) 5 Litinas, K.E. (7) 32 Litovchenko. G.F. ( I ) 263, 264 Litvinov, I.A. ( I ) 341, 411; (5) 136, 313, 314 Liu, C. (5) 42 Liu, K. (2) 15, 16 Liu, L. ( I ) 419; (2) 41 Liu, L.K. (1) 15 Liu, M. ( I ) 320-322 Liu, R.S.H. (7) 88 Liu, X. (5) 310 Livantsov, M.V. ( I ) 97. 203; (5) I30 Llamas-Saiz, A.L. (3) 13; (7) 17-19, 52, 115; (8) 36-38, 50 Lloyd, J.R. ( I ) 157; (3) 17; (4) 19 Lohanov, D.I. ( I ) 241 Locquenghien. K . V . (7) 5 4 Liinnherg, H. (6) 251 Loewenthal, E. (6) 129 Loginova, I V. (2) 14 Lohr, D.E. (6) 361 Lomis, T.J. (6) 245 Long, E.C. (6) 327 Lopez, J.A. (8) 42 Lopez. L. ( I ) 415: (4) 74 Lopez-Lazaro, A . (7) 109; (8) 49 Lopez-Lazaro, M. (7) 110 Lopez-Leonardo, C . (7) 52, 131: (8) 50, 52 Lopusinski, A. (5) 1 , 80, 276 Lora, A. (8) 220 Lora, S. (8) 222, 237 Lorenzo, A . (7) 102, 112; (8) 54 Lovan’kov, S.V. (5) 169 Lovely, C.J. (5) 219, 222 Lovinger, A.J. (8) 246 Lowe, A.D. (6) 314 Lowe, G. (6) 320. 321 Lown, J.W. (6) 191 Lown, W.J. (6) 309 Lu, J . (6) 5 3 Lu, X . ( 5 ) 272, 273 Luczak, L. ( 5 ) 276 Ludwig, J . (6) 6 3

Airihor Index Luehke, K.J. (6) 227, 228 Lucke. J . (8) 101, 204 Luh, B.Y. (5) 248, 252; (6) 30 Lukanov, L.K. (5) 192, 193 Lukashev, N.V. (1) 151; (8) 22 Lukes. I. (5) 283 Lukoyanov, N.V. ( I ) 224 Lurnin, S. ( I ) 149 Luo. W . (6) 191 Lur’e. L.F. ( I ) 355; (4) 70 Luzikov, Yu.N. ( I ) 151; (8) 22 Lyashenko, Yu.E. (2) 10 Lyavinets, A.S. ( I ) 105 Lyttle, M.H. (4) 58; (6) 84, 87 Ma, Q.-F. (6) 65 Ma, S. (5) 273 Maack, A. (1) 327 McAfee, S.E. (6) 279 McAuliffe, C.A. ( I ) 131, 132; (2) 1 , 2, 1 1 ; ( 3 ) 4 0 Macaya, R.F. (6) 218, 219 McCaffrey, R.R. (8) 285 Maccioni, A. (8) 138 Maccioni, E. (8) 214 McClure, C.K. (2) 18; (5) 157 McCollum, C. (6) 74, 83 McCort-Tranchepain, I. (5) 236 McCurdy, S.N. (6) 224 McDonald, I.A. (5) 244, 247 McDonnell, G.S. (8) 98 McDougall, M.G. (1) 32 McEwen, W.E. (7) 21 McFarland, J.M. ( I ) 176 McFarlane, W. ( I ) 42 McGahren, W.J. (6) 269 McGall, G.H. (6) 291 McGuigan, C. (4) 51; (5) 24; (6) 2-9 McGuiness, B.F. (6) 286, 288 Macicek, J . (5) 307 McKenna, C.E. (5) 108, 210, 213 McKenna, R. (6) 319 Mackie, A.G. ( I ) 131, 132; (2) I , 2, I I McLaughlin, L.W. (6) 175 McLwd, D.A. ( 5 ) 241 MacMillan, A.M. (6) 158. 159 Macor, J.E. (1) 148 McPhail, A.T. ( I ) 6 3 McQueney, M.S. (5) 21 I MacRory, P.P. (2) 1 I ; (3) 40 Madaule, Y. ( I ) 369 Maddock, J . (7) 127 Maddry, J.A. (6) 42, 115 Madyusinska, L.L. (8) 131

42 I Ma&, H. ( I ) 186 Mading, P. ( 1 ) 227 Maennle, F. (8) 65 Markl, G. (1) 30, 327, 338 Maeta. H . (1) 122 Magati, S. (5) 117 Magdeeva, R.K. ( 5 ) 10, 106 Magill, J.H. (8) 195, 197, 244, 245, 249 Magnus, P. (6) 270, 271 Mah, S.I. (8) 126 Maher, L.J., Ill (6) 202 Mahrnood, N. (6) 7 Mahnot, R. ( I ) 413, 414; (4) 7 6 Mahran, M.R. (5) 165 Maia, A. (8) 138 Maier, L. (5) 160, 181, 182, 190, 196, 198 Maigrot, N. (1) 19, 402. 403. 408 Majoral, J.-P. ( I ) 99, 272; (3) 7; (5) 226, 227; (8) 60.72 Majumdar, A.N. (8) 197, 249 Makarov, G.M. (5) 91 Makhova, N.N. (8) 43 Maki, T . ( I ) 186 Maki, Y. (6) 45, 90 Makino, K. (6) 174. 176 Makleit, S . ( I ) 140 Makovetskii, Y.P. ( I ) 218 Malar, E.J.P. ( I ) 401 Malashonok. I.E. (8) 125 Maleev, V.I. (5) 239 Malek, S. (6) 2 18. 22 1 Malhotra, S. (6) 179 Maligres, P. (6) 276 Malkiewicz, A. (6) 150 Malone, T.C. (5) 18, 246 Malova, E.V. ( I ) 185 Malygin, V.V. ( I ) 224 Malysheva, S.F. ( I ) 105-107 Malyutina, I.V. ( I ) 96 Mamedov, S.A. (4) 24 Mandal, S.B. (1) 137 Mangeney, P. (4) 28 Mann, A . (7) 27 Manners, I. (8) 99, 11 I , 123, 193, 201-203, 223 Manoharan, M. (6) 187 Mansuri, M.M. (5) 255 Manuel, G. (1) 339 Manzini, G. (6) 205, 206 Manzur, J. (1) 398 Marcaux, F.W. (5) 245 Marchi, M. (8) 184 Marco, C. (8) 247 Mardones, M.A. ( I ) 59-61 Mari, F (7) 21

Maria, W.W (8) 75 Mariani, P. (6) 235 Mariano, P.S. (5) 21 1 Marinetti, A. ( I ) 90, 291, 300, 307, 308 Maringgele, W . (8) 181 Marino, J.P.. jun. (6) 195 Mark, J.E. (8) 186 Markharn, G.D. (6) 6 7 Markiewicz, W.T. (6) 190 Markovits, D. ( I ) 223 Markovskii, L.N. ( I ) 290, 316. 317, 354, 355, 368, 384; (4) 69, 70; ( 5 ) 16, 17, 140, 141. 184; (8) 16. 67 Markowska, A . (4) 52; (5) 54 Marks, T.J. (6) 333 Marshall, A.S. (8) 159 Marshall, J.A. (7) 122 Marsrnann, H.C. (8) 90 Marson. C.A. (7) 139 Martens. R. ( I ) 210, 21 1 Martin, G. ( I ) 324 Martin, J.C. (5) 248, 252, 254. 255; (6) 30 Martin, R. (1) 102 Martin, S. ( I ) 292 Martin, S.F. (5) 149; (7) 71 Martin-Lornas, M. (5) 35 Martynov, I.V. ( I ) 152; (5) 201; (8) 30, 73, 294 Maruyarna, I. (8) 115, 155-157 Marvelli, L. (8) 184 Maryanoff, B.E. (7) 25 Masakazu, K. (8) 7 8 Masar, B. (8) 215 Mashirna, K. ( I ) 73; (4) 64 Maskovskii, L.N. ( I ) 129 Maslennikova, V.I. ( I ) 26 Mason, M.R. ( I ) 35 Mason, S. (8) 46 Mastrosov, E.A. ( I ) 263 Mastryukova, T.A. ( I ) 261, 262264; (5) 299 Masuko, T . (8) 241, 242 Mateeva, E.D. ( I ) 133 Mateo, A. (8) 37 Matern, E. ( I ) 53, 54, 56, 282 Mathey, F. (1) 19, 90, 286, 291, 300. 301, 307, 308, 363, 390392, 394-397, 400. 402, 403, 408, 42 I , 423; (3) 34 Mathies, R.A. (6) 322 Matrosov, E.I. ( I ) 241, 262. 264; (5) 72; (8) 7 6 Matso, S . (7) 65 Matsuda, A (6) 151, 163, 164 Matsugo. S. (6) 244

422 Matsukawa, C. ( 5 ) 294 Matsuki, T. (8) 279, 280 Matsumoto, K. ( I ) 158, 201; ( 5 ) 1 I6 Matsumoto, T. (1) 122 Matsumoto, Y. ( I ) 13; (6) 337 Matsumura, K. (3) 19; (6) 337 Matsumura, N. ( I ) 118; (4) 12 Matsuo, Y. (5) 2 I7 Matsura, M. (8) 268 Matsushita, Y. (8) 8 Matsuya. H. (6) 12 Matteucci, M. (6) 95, 198, 210 Matthias, B. (8) 182 Matulic-Adamic-Adamic, J. (6) 23 Matusiak, M. ( I ) 145 Matveeva, A.G. ( I ) 241, 262264 Matyjaszewski, K. (8) 21, 189192, 199, 245 Mautz, D.S. ( 5 ) 8 6 Mavrin, G.V. ( 5 ) 301 Mayer, B. ( I ) 54, 55, 57, 282 Mayer, P. ( I ) 222 Mayr, G.W. ( 5 ) 4 5 Mazand, P. (8) 254 Mazid, M.A. ( 6 ) 6 0 Mazieres, M.-R. ( I ) 333, 368 Meanwell, N.A. ( 5 ) 183; (7) 132 Medici, A. (8) 132 Medvedeva, L.Ya. (8) 173 Meek, D.W. ( I ) 32 Meetsma, A. (8) 165, 168-170, 180, 295 Megati, S. (4) 5 ; (6) 33 Mehrotra, K.N. ( 5 ) 1 I Mehta, G . (7) 128 Mei, A. ( I ) 124; (7) 8 Meidine, M.F. (1) 342, 343, 345, 375, 391; (3) 41 Meier, C. (6) 13 Meijboom, N. ( I ) 16-18, 164 Meisel, M. (4) 6 7 Meller, A. (8) 181 Meltsner. B.R. (8) 198 Memmesheimer, H. (1) 313, 388 Mense, E.H.G. (8) 213 Menzer, S. (6) 342 Merchant, R.R. ( I ) 154 Mercier, A. ( 5 ) 189 Mercier, F. (1) 392 Merino, P. (7) 77 Merker, R.L. (8) 197 Mersmann, K. (6) 155 Merta, A. (6) 28 Metternich, H.-J. ( I ) 306, 373, 375. 376, 389; (7) 2. 38

Organophosphorus Chemistry Metz, B. ( I ) 46 Meunier, B. (6) 242 Meunier-Piret, J. (1) 12 Mewwly, R. ( 5 ) 191 Meyer, B. ( I ) 53 Meyer, T.J. (8) 32 Mezey-Vandor, G. (7) 97 Miao, F. ( 5 ) 310 Michalska, M. ( 5 ) 88, 89 Michalski, J. (4) 23, 40;(5) 1, 2, 80, 276; (6) 105, I14 Miglierini, G. (5) 206 Mikina, M. ( 5 ) 174 Mikdajczyk, M. (1) 104; (3) 14; ( 5 ) 174 Millar, K. ( 5 ) 197 Miller, S.J. (7) 96 Millican, A.T. ( 5 ) 197 Milligan, J.F. (6) 198 Minami, T. ( I ) 76, 78; ( 5 ) 134; (7) 65 Minar, J. (8) 163 Mindlin, Ya.1. (8) I58 Minouni, N. (5) 126 Minto, F. (8) 132, 137, 219, 232, 237, 289 Minuti, L. ( I ) 116 Miranda, R. ( I ) 156 Mirmovsumova, A.M. (4) 24 Mironov, V.F. (2) 13 Mirza, S. (5) 129; (7) 78 Misco, P.F. ( 5 ) 163, 248 Mishima, T. (6) 86 Mishra, G. ( 5 ) I I Mishra, N.C. (6) 43 Misra, R. ( 5 ) 85 Mitchell, A.G. ( 5 ) 267 Mitchell, M.A. (6) 299 Mitchell, T.N. ( I ) 153 Mitrasov, Yu.N. (2) 9; ( 5 ) 138 Mitzel, N.W. (7) 13 Miura, K. (6) 80, 102 Miyahara, 1. ( I ) 201, 329 Miyake, R. ( I ) 13 Miyano, S. (1) 11 Miyata, T. (8) 242 Miyoshi-Saitoh, M. (6) 274 Mizoguchi, K. (8) 257 Mlotkowska, B. (4) 52; ( 5 ) 5 4 Mock, M. (6) 62 Modro, A.M. ( 5 ) 4, 68, 95 Modro, T.A. ( 5 ) 4, 68, 95, 218, 269-27 1 ; (7) 68 Miickel, A. (1) 28, 29 Mohan, T. ( I ) 121; (8) 31, 165 Mohler, E.M. ( 5 ) 67 Moiseev, V.I. (8) 142 Moiz, M.A. ( I ) 154

Molaire, T.R. (8) 224, 225 Molchanova, G.N. (5) 75 Molina, P. (3) 13; (7) 17-19, 52, 101, 102, 108-112, 114-1 17, 119, 131; (8) 36-38, 49, 50, 52, 5 4 Msllegaard, N.E. (6) 338 Momchilova, S. ( 5 ) 307 Mondragon, J. ( I ) 156 Montagne, C. ( I ) 144 Montagnier, L. (6) 1 1 Montague, R. (8) 21, 190, 191, I99 Monternay-Garestier, T. (6) 209 Montero, J.-L. ( I ) 142 Montgomery, J.A. (6) 17, 26, 42, 115 Moody, C.J. (7) 6 4 Moon, S.-H. ( 5 ) 125; (7) 7 9 Moor, M. (6) 25 Moore, M. (6) 81 Moore, M.R.(8) 46 Moore, P.B. (6) 347, 348 Morgan, L. (5) 67 Morgan, T.A. (8) I12 Mori, R. (1) 7 8 Mori, S. (7) 107; (8) 56, 144 Moriarty, R.M. (2) 15, 16 Morimoto, T. ( I ) 5 , 6, 39, 72 Morin, D. (8) 211 Morishita, K. (8) 149 Moriya, K. (8) 239 Moronov, V.F. (2) 8 Morozov, V.I. (2) 27 Morozova, L.N. ( 5 ) 179 Morris, K.B. (7) 12 Morton, G.O. (6) 269 Moser, P. (6) 131 Moskva, V.V. ( 5 ) 128, 300 Motoki, S. ( 5 ) 217; (7) 118 Motoyoshiya, J. (5) 134 Moulds, C. (6) 210 Mouloungui, Z. (7) 57 Moulton, R.D. (8) 275 Mozzherin, D.J. (6) 108 Muller, A. ( I ) 280 Miiller, F. (6) 181, 182 Muller, G. ( I ) 64,65, 67, 425 Mueller, J.E. (6) 237 Mueller, W.B.(8) 261 Muench, D. ( 5 ) 244 Muir, A.S. (2) 3 Mukhametov, F.S. (4) 4 Mukmenova, N . A . ( 5 ) 55 Mullah, K.B. (4) 83; ( 5 ) 249; (6) 3 4 Mullen, K. (7) 63 Mullins, S.T. (6) 320, 321

423 Mumhauer, S. (6) 192 Munier, H. (6) 61, 62 Munier, P. (7) 87 Murakami, A. (6) 174. 176 Murakami, I. (8) 238 Murakami, K. (8) 162 Muralidhara, M.G.K. (8) 106 Muraoka, M. (6) 160 Murashov, D.A. (8) 86, 131 Murata, H. (7) 35 Murata, M. ( I ) 5 , 6, 72 Murata, T. (6) 112 Murchie, A.I.H. (6) 365 Murphy, J.A. (6) 285 Murray, M. (8) 122 Murry, J.A. (7) 95 Murshov, D.A. (8) 142 Musin, R.Z. ( I ) 95 Muth, H.-P.(6) 47 Mutti, S. (4) 28 Muzyka, P.V.(8) 16 Myers, A.G. (6) 278 Myers, C.B. (6) 67 Myers, J. (5) 36 Nadet, B.S. (8) 112 Nadler, E.B.(5) 93 Naeveke, M. (8) 28 Nagahara, S. (6) 174, 176 Nagareda, K. (7) 22 Nagasaki, T. (5) 115 Nagata, H. ( I ) 115 Nagel, U. ( I ) 43 Naguchi, A. (5) 109 Nah, C.S. ( I ) 134 Nahorski, S.R.(5) 26, 42 Nakae, H. (8) 292 Nakagami, K. (6) 15 Nakai, M. (6) 168 Nakamoto, A. (2) 48 Nakamura, Y. (6) 177 Nakanaga, T. (8) 276, 277 Nakane, H. (6) 45 Nakanishi, K. (6) 286, 288 Nakanishi, T. (6) 82 Nakano, H.(4) 59; (6) 113, 188, 189 Nakata, Y. (6) 90 Nakatini, K. (6) 275 Nakatsuji, Y. (6) 174 Nakaura, M. (6) 174 Nakayama, M. (7) 65 Nakayama, T. (6) 290 Nakayama, Y. ( I ) 78 Nam, G.-S. (5) 185 Namane, A. (6) 61 Naomoto, K. (8) 127

Naw, A . (6) 39 Naumov, V.A. ( I ) 341: (5) 136, 313, 314 Nawrot, B. (6) 150 Naylor, A. (3) 37 Nazmutdinova, V.N. (4) 38 Neganova, E.G. (1) 199 Negishi, E. (7) 138 Negishi. K. (4) 59; (6) 113 Negishi, M. (7) 92 Negrebetskii, V.V.( I ) 205, 317; (4) 33, 34; (5) 199; (8) 16 Neidle, S. (6) 300, 319 Neidlein, R. (5) 133 Neiland, O.Ya.( I ) 166 Neilson, C.J. (8) 135, 218 Neilson, R.H. (8) 10 Nekhoroshkov, V.M. ( I ) 314, 374; (5) 216 Nelson. J.A. (6) 51, 141 Nelson, J.H. ( I ) 399 Nelson, J.R. ( I ) 178 Nelson, J.S. (6) 136 Nelson, R.W. (6) 361, 362 Nelson, T.D. (3) 20 Nethaji, M. (8) 140, 141 Netz, D.F. (7) 60 Neuman, A. (5) 204 Neumann, B. ( I ) 378; (7) 37 Ngo, D.C. (8) 62, 85 Nguyen, D.L.(4) 48 Nguyen, M. (6) 301 Nguyen, M.T. ( I ) 387 Nguyen, T. (5) 305 Nichiogi, K. (8) 278 Nicholaides, D.N. (7) 32 Nichalls, D. (5) 267 Nicholls, S.R. (6) 9 Nickson, C. (6) 4 Nicolaou, K.C. (6) 266, 273, 276, 284 Niecke, E. ( I ) 216, 274, 275, 306, 356-358, 366, 373, 375, 376, 389, 406,424; (4) 71-73, 77, 80; (7) 2, 38; (8) 34, 35 Nief, F. ( I ) 390, 400 Nieger, M. ( I ) 212, 216, 274, 275, 356-358, 424; (4) 71-73, 80; (7) 113; (8) 34, 35, 51 Nielsen, C. (6) 21 Nielsen, P.E. (6) 133, 134, 338, 339 Nielsen-Marsh, S. ( I ) 69 Niemann, J. ( I ) 366; (4) 77 Niant'ev, E.E. ( I ) 26, 205; (4) 31-35, 39; (5) 10, 72. 106, 262, 263 Nikiforov, T.T. (6) 137. 138,

149 Nikoforev, N.G. ( 5 ) 138 Nikolaeva, N.V. ( 1 ) 314, 315 Nikonov, G.N. ( I ) 95. 125, 126, 168, 185 Nikonowicz, E.P. (6) 352 Nishijima, Y. (4) 59; (6) I13 Nishikawa, S. ( I ) 78 Nishikawa, Y. (8) 114 Nishimoto, T. (8) 292 Nishimura, H. ( 1 ) 13 Nishimura, Y. (1) 187; (4) 82 Nishio, H. (6) 163, 164 Nishio, K. (4) 59; (6) 113 Nishizawa, H. ( I ) 158 Nitta, M. (7) 104, 105, 107; (8) 56-59 Niwas, S. (6) 26 Nixon, J.F. ( I ) 306, 335, 342, 343, 345, 375, 376, 391, 404, 405; (3) 41; (7) 38 Niyazymbetov, M.E. (5) 120 No, B.1. ( I ) 196 Nohle, N.J. (5) 39 Nobles, J.A. (6) 306, 308 Nocentini, G. (6) I Noe, C.R. (6) 122 Nogradi, N. (7) 97 Noltemeyer, M. ( I ) 246; (7) 39; (8) 66, 181-183 Nomura, N. (5) 64,65, 66 Nordkn, B. (6) 329, 339 Noritake, Y. (5) 64,65 Norman, A.D. ( I ) 207 Norman, A.W. (3) 21 Norwood, B.K. ( I ) 251; (3) 2; (7) 41 Noth, H. ( I ) 338, 351 Novak, L. (7) 30 Novikova, Z.S. ( I ) 310; (4) 85; (5) 143 Nowick. J.S. (6) 92 Noya, S. (8) 284 Noyori, R. (7) 92 Nozaki, K. (4) 64 Nunota, K. (6) 188 Nupponen, H. (5) 154 Nuretdinova, O.N. ( 5 ) 297 Nuyken, 0. (8) 2 I , 201 Nyburg, S.C. ( I ) 243 Nyce, P.L. (5) 244 Nyulaszi, L. ( I ) 400 Oakley. R.T.(8) 171, 172 Obara, T. (6) 15 Oherhauser, B. (6) 122 O'Brien, J.A. (4) 55; (5) 256;

424 (6) 184 Ocando-Mavarez, E. ( I ) 324; (8) 72 Ochiani, H. (8) 238 Ochocki, J . ( I ) 208 O’Connell, J . F . (7) 49 O’Connor, T.J. (6) 5-9 Oda, Y. (6) 167 Oehler, E. (5) 161, 171 Oehlert, W. ( I ) 25, 48, 50 Oehme, H. ( I ) 287 h v o s , L. (6) 48 Otitserov, E.N. (2) 8 Ogasawara, T. (4) 44; ( 5 ) 37. 38 Ogata, M. (8) 148 Ogata, T. ( 5 ) 116; (6) 38 Ogawa, S. ( I ) 89; (3) 19 Ogawa, T. (6) 85 Ogura, E. (6) 127 Oh, D.Y. ( 5 ) 53, 175 Ohashi, Y. (6) 188 Ohdoi, C. (6) 151 Ohkuma, T. (6) 38 Ohmori, H. (1) 186; (7) 118 Ohms, G. ( I ) 209 Ohno, A. ( I ) 187; (4) 82 Ohta, K . (3) 30 Ohtsuka. E. (6) 112, 167, 200 Ohuchi, S. (6) 27 Oivanen, M. (6) 251 Oka, A. (5) 38 Okada, K. (1) 331; (5) 214 Okada, Y . ( 1 ) 76, 78 Okamoto, R. ( 5 ) 114 Okamoto, Y. ( 5 ) 289, 290 Okano, T. (8) 9 Okano, Y. ( I ) 416 Okazaki, R. (3) 18; (7) 23 Okhota, B.V. ( I ) 316 Oki, T. (6) 274 Ollmann, R.R., jun. (3) 21 Olms, P. (8) 182 Olsen, W.K. (6) 135 Ono, A . (6) 151, 163, 164, 204 Ono, K. (6) 45 Onoe, Z. (8) 144 Onys’ko, P.P. (3) 35; (5) 87 a w i n g , G.E. (8) 124 Ootani, K . (8) 292 Opiela. S . ( I ) 277 Orduna, J. (7) 77 Orgel, L . E . (6) 238, 332 Orita, M. (6) 167 Ornstein, P.L. (7) 96 Oronzo, J.L. (8) 21 1 Orr. D.C. (6) 49 Ortwine. D.F. ( 5 ) 245, 246 Oshorne, S.E. (6) 195

0rgano p hospho rus Chemistry Ossig, G . (8) I81 Otmar, M. (6) 28 Otsuho, T. (5) 294 Otto, C. (3) 29 Ouazzani, F. (5) 208 Ovahloc, E.B.V. (8) 213 Ovakimyan, M.Zh. (5) 280 Ovsepyan, S . A . (5) 119 Oyama, H. (8) 79- 81 Ozaki, H. (6) 189 Ozaki, K. ( I ) 118; (4) 12 Ozaki, S. (4) 44, 45; ( 5 ) 8, 31, 37, 38

Paaren, H.E. (3) 24 Pahuccuoglu, A . (6) 90, 91 Pacheva, L.M. ( I ) 224 Pack, G . (6) 199 Padtare, S. (6) 33 Pagliarin, R. ( 5 ) 206 Pagniez, G.P. (8) 200, 210 Pai. D. (8) 290 Paik, K.C. ( 1 ) 134 Paine, R.T. ( 1 ) 351 Pakrashi, S.C. ( I ) 137 Pale, P. (6) 57 Palma, G . (8) 220, 222, 237 Palou, J . ( I ) 244, 245: (7) 43. 44 Pan, B.F. (6) 141 Pan, T. (6) 261 Pan, Y. (6) 360 Pani, A. (6) 1 Pannunzio, T. (6) 107 Panosyan, G . A . ( 5 ) 1 19 Panyutin, I.G. (6) 354 Papadogianakis, G. ( I ) 162 Papkov, V.S. (8) 194, 248 Pardi, A. (6) 352 Park, Y.C. (8) 206 Parker, D. ( 5 ) 197 Parks, H.G.(8) 103 Parkhomenko, N . A . ( I ) 224; (5) 17, 140, 141 Parkin, A. (5) 25 I , 253; (6) 3 1 , 32 Parkins, A . W . ( 1 ) 243 Parry, D.M. (6) 50 Parry, J.S. ( I ) 58 Parvez, M. (8) 62, 71, 104. 1 1 I , 123, 166 Paschalidis, C. ( 1 ) 425 Pastor, S.D. ( I ) 114; (2) 22; (5) 191 Patel, D. (6) 220 Patel. M.T. (4) 84 Patel, P. (7) 83-85

Pathak, D.D. ( 1 ) 45 Pathirana. R.N. (6) 7 Patin, H. ( I ) 109 Patois, C. ( 5 ) 12 I Patsanovskii, 1.1. ( I ) 384. 385; (8) 14 Pattenden, G. (7) 83-86, 127, 133 Pavlenko, S . A . ( I ) 289 Pavlov, V . A . (5) 300 Pawelke, G. (8) 29, 90 Pawloski, C.E. (8) 112, 113 Payrstre, C. ( I ) 369 Pearson, M. ( I ) 77 Pedersen, E.B. (6) 21 Pdrini, P. (8) 132 Pedroso, E. (6) 75, 157, 183 Pei, D. (6) 229, 303 Pelmore, H. (6) 323 Penades, S. (5) 35 Peng, J . ( I ) IS5 Peng. S. ( I ) 155 Pen’kovskii, V.V. ( I ) 288, 289. 318, 323 Penner, G.H. (3) 16 Percival, M.D. (5) 3 Peregudov, A . S . ( I ) 84 Perella, F . W . (4) 42 Perera. S.D. ( I ) 7, 8 Peresypkina, L.P. ( 5 ) 103, 104 Peri, S.P. (5) 78 Perich, J.W. (4) 47, 48; (5) 19, 20, 23, 231 Perlat, M.-C. (6) 126 Perlman, K.L. (3) 24, 25 Perlmutter, P. ( I ) 172 Perraud-Darcy, A . (7) 53 Perrin, C. (6) 139 Perrotta, A . T . (6) 259, 260 Pershin, D.G. ( 1 ) 242 Peruzzini, M . (8) 184 Pestana, D.C. ( I ) 347, 348 Peterson, A . C . ( I ) 80; (3) 6 Petrik, J . (6) 4 Petrosyan, V.S. ( I ) 97, 203; (5) 130 Petrov, A . A . ( I ) 194, 195; (5) 224 Petrov, E.S. ( I ) 241 Petrov, K.A. ( I ) 190; (5) 5 I Petrova, 1. ( 5 ) 307 Petrovskii, P.V. ( I ) 241; ( 5 ) 75 Petruneva, R.M. ( I ) 196; (5) 105 Pettitt, B.M (6) 225 Petzold, G.L. (6) 299 Pezzin, G. (8) 220, 222 Pfister-Guillouz(t, G. ( I ) 278

Author Index Ptlaum. S. ( I ) 327 Ptleiderer, W . (6) 88, 181 Phadtare, S. (4) 5; (5) I17 Phillion, D.P. (5) 152; (7) 70 Phillips, A . M . M . M . (5) 271; (7) 68 Phillips, I.G. (1) 283 Piccirrilli, J . A . (6) 258 Pickett, W.C. (5) 12 Pienta, N.J. ( I ) 265 Pierre, A . (5) 229 Pietrusiewicz. K . M . (1) 98; (3) 4, 36; (5) 29, 30, 32. 312; (8) 75 Pinchuk, A . M . (4) 10; (5) 15, 99, 100, 179, 315 Pindur, U. (3) 29 Pinter, G.W. (5) 246 Pionteck, J. (4) 25 Pisarnitskii, D . A . ( I ) 97 Piskunova, Zh.P. (8) 95 Pitie, M . (6) 242 Pitterna, T . (6) 270 PI& F.P. (1) 244, 245; (7) 43.

44 Plass, W . (8) 45 Plotnikov, V.F. (5) 224 Plotnikova, O . M . (5) 10 Plouvier, B. (6) 309 Plusec, J . (5) 256 Plyamovatyi, A.Kh. ( I ) 125; (5) 300 Podda, G. (8) 138, 214 Podgornyi, A . V . (5) 15, 101, 102 Podsiadio, S . (8) 205 Pohjala, E. (5) 154 Pohlmann, K. ( I ) 338 Polsky, B. (6) 23 Polyakov, A . V . ( I ) 242 Pomheiro, A . J . L . ( I ) 342, 343; (3) 41 Pon, R.T. (6) 191 Poncet, J . ( I ) 144 Popov, A . F . (8) 95 Popov, A . V . (8) 294 Porz, C. (1) 275 Porzel, A . (5) 281 Posner, G . H . (3) 20 Potapov, V . K . (6) 173 Potekhin, K . A . ( I ) 234; (5) 260 Potikha, L . M . (4) 10 Potin, P . (8) 72, 200, 210, 21 I Potrzehowski, M.J. (5) 80 Potter, B . V . L . (5) 26, 27, 39. 42 -44 Poulter, C.D. (5) 86 Povolotskii, M.I. ( I ) 317, 354.

425 355; (4) 70; (8) 16 Powell, N.I. ( I ) 398 Power, M.B. ( I ) 62 Power, P.P. (1) 347, 348 Prakash, G . (6) 216 Prakash, K.R.C. (7) 76 Pratt, R.F. (5) 268 Praviel, G. (6) 242 Pressman, L.S. (4) 22 Preussler, C. (5) 234 Previsani, N. ( I ) 143 Prichard, R.G. (2) I , 2. 1 1 Priehe, T.S. (6) 141 Prikhtd’ko, Yu.V. (5) 114, 168 Principato, G . (5) 186 Pringle, P . G . (4) 65 Priou, C. ( 1 ) 359 Prishchenko. A . A . ( 1 ) 97, 203; (5) 130 Pritchard, C.E. (4) 53 Pritchard, R.G. ( I ) 131, 132; (3) 40 Pritzkow, H . ( I ) 23, 24, 296, 349, 350; (7) 15 Procopio, A . (5) 49 Prousek, 3 . ( I ) 226 Prout, T.R. ( I ) 207 Provotorova, N.P. (8) 248 Prukasha, T.K. (2) 22. 23 Prytkov, S.E. (8) 131, 142 Puhert, A . W . (5) 245 Pudovik, A . N . (2) 8, 13. 14, 36; (4) 26, 37, 38; (5) 91, 135. 261; (8) 69 Pudovik, M . A . ( I ) 125. 126; (4) 26, 37; (5) 91; (8) 69 Pulukkody, K. (5) 197 Puyenhroek, P. (8) 134 Pyle, A . M . (6) 256, 326, 327

Rahil, J . (5) 268 Rainbow, M.J. (6) 361 Raj, I.I.S. (8) 117 Rajan, N.I. ( 5 ) 67 Raju, C.N. (5) 13, 145 Rakesh, S. (8) 182 Rakhmatulina, T.N. ( I ) 105-107 Rakitin, O . A . (8) 43 Ramy, R . (8) 10 Ranaivonjatovo, H . ( 1 ) 36 I Randjit, P. (6) 192 Rao, A . V . (7) 130 Rao. B.D.N. (6) 70 Rao, B . V . (7) 130 Rao, K.E. (6) 309 Rao, M . N . S . (8) 71 Rao, S . M . (6) 289 Rao, S.P. (7) 76 Rapoport, H. (7) 49 Rappoport, Z. ( 5 ) 93 Rasika Dias, H . V . (2) 44 Raston, C.L. (1) 160 Rath, N . P . ( I ) 4 Rathore, A . (6) 42 Ratmeyer, L . S . (6) 312, 316 Ratner, M . (8) 251, 253 Ratovskii, G.V.( I ) 200; (2) 7. 47; (8) 17, 179 Rauhold, T . (8) 66 Ravichandran, R. (5) 191 Ravindar, V . ( I ) 9, 10 Ray, B . D . (6) 70 Rayner, B . (6) 125 Razumov, A . I . (5) 142 RChek, J . , jun. (6) 35, 92 Rddick, C. (8) 190 Reddy, C.D. (5) 13, 14, 145 Reddy, G.R. (7) 130 Reddy, G.S. ( I ) 120 Reddy, M . S . (5) 14 Reddy, N.S. (8) 106 Qian. Z. ( I ) 230 Reddy, R.S. (5) 13. 14, 145 Redmore, D. (5) 77 Qiu, W . ( I ) 254; (7) 50 Reedijk, J . (6) 331 Quadrifoglio, F. (6) 205, 206 Rees, C.W. (4) 9; (5) 194. 2 2 4 Quaedflieg, P . J . L . M . (6) 120, Rees, W . (6) 367 12 I Reeves, K . A . (5) 222 Quesada, M . A . (6) 322 Reffy, J . ( I ) 409 Quiclet-Sire, B . (5) 240; (6) 19 Regan. A.C. (4) 8 Quin, G.S. ( I ) 380, 383; (5) 284 Quin, L . D . ( 1 ) 295, 380-383; (5) Regitz, M . ( 1 ) 311-313, 326. 336, 337, 339, 388, 392. 41( 283-287 Reichert, F. ( 1 ) 356; (4) 72 Reid, B.R. (6) 231 Reid, G.P. (6) 60 Rahow. L . E . (6) 291 Rzisch, J . ( I ) 139 Rachon, J . (5) 316 Reisgys, M . ( I ) 23, 24 Radhakrishnan, I. (6) 220 Reitel. G . V . ( I ) 354 Raghuraman, M.K. (6) 353 Reitz. A . B . (7) 25 Ragulin. V . V . (5) 232

426 Remerowski, M . L . (6) 356 Remers, W.A. (6) 289 Rempel, G.L. (8) 24 Renaud, E. ( I ) 31 Renner, G. (8) 201 Reszka, A.P. (6) 319 Rettig, S.J. ( I ) 68 Retz, D.M. ( 5 ) 245 Revel, M. (2) 40 Reynolds, E.C. (4) 47, 48; (5) 23 Reynolds, R.C. (6) 42, 115 Rhee, S.B.(8) 105 Riheill, Y. (7) 53 Ricard, L. ( I ) 19, 90. 300, 301, 308, 391, 392, 394, 395, 402, 403, 408; (3) 34 Rice, B.L. ( 5 ) 151 Rich, L.C. ( 5 ) 256 Richter, L. (5) 207 Richter, R. (5) 305 Riding, G.H. (8) 99, 1 I 1 Rieger, R. (6) 171 Riemer, C. (2) 17; (7) 45 Riesel, L. ( I ) 198, 209; (8) 20,

64 Rifqui, M. (1) 276 Riggs, R.M. (6) 17 Rikhirev, M.E. (6) 354 Riley, M.L. ( I ) 391 Riley, P.A. (6) 2, 3 Rillie, I.M. (8) 122 Rink, H. (6) 131, 132 Riordan, J.M.(6) 26 Risser, S . M . (8) 226-228 Rohert, F. ( I ) 257 Roherts, K.A. ( I ) 222 Roherts, N.K. ( I ) 160 Roherts, S . M . (6) 49, 50; (7) 89 Robinson. H. (6) 346 Rohinson, P.D. ( 5 ) 309 Rohl, J.A. ( 5 ) 256 Rohles, J. (6) 75, 183 Roche, D. ( 5 ) 309 Roder, E. (7) 134 Rodevald, L. (5) 187 Roelen, H.C.P.F. (4) 60;(5) 45; (6) 37, 106, 166 Riiling, A . (6) 154 Riischenthaler, G.-V. (2) 21, 3335; (5) 158 Roesky, H.W. ( I ) 246; (7) 39; (8)66, 174, 182, 183 Rogoza, L . N . (4) 22 Rohwer, E.R. ( 5 ) 270 Roig. U. (6) 186 Rokita. S.E. (6) 196, 340, 341 Roland, S. (7) 67

Rolland, H . (8) 72 Romanenko, V.D. ( I ) 290, 316. 317, 333, 353-355, 368, 384, 385; (4) 69, 70; (8) 14. 16, 293 Romano, L.J. (6) 358, 359 Rookhuizen. R.B. (3) 26; (7) 5. 124 Roques, B.P. (5) 236 Rosenbach, M . T . (6) 53 Rosenherg, I. (6) 23, 28 Roskamp, E.J. ( I ) 256 Rosowsky, A. (6) 24 Rosser, D . S . E . (6) 247 Rossi, E. (7) 103; (8) 48 Rossi, R. ( I ) 40; (8) 184 Rostovskaya, M.F. ( I ) 167; (5) 166-168 Roth, H.R. (5) 183; (7) 132 Roth, K. ( I ) 252; (3) 3; (7) 42 Rothenberger, E. ( I ) 3 Rothmann, H . ( 1 ) 56 Rothwell, 1.P. ( I ) 88 Rotter, H. (8) 65 Rougee, M. (6) 209 Roumestant, M.-L. (5) 208 Roush, W.R. ( I ) 141 Roy, A.K. (8) 39 Rozanov. I.A. (8) 86, 131, 142, 173 Rozhenko, A.B. (5) 184 Rozinov, V.G. (8) 179 Ruhan, A.V. ( I ) 290, 316, 353355, 368, 384, 385; (4) 70; (8) 14, 16, 293 Ruchkina, N.G. (5) 10 Ruder, S . M . ( 1 ) 251; (3) 2; (7) 41 Rudji, R.B. (5) 141 Rudkevich, D . M . (5) 16 Rudnev, G.V. (5) 51 Riiger, C. (4) 25 Ruegg, G.M. (5) 148 Ruiz-Perez, C. (6) 157 Ruppert, D. (7) 140 Ruprecht, R.M.(6) 24 Rusanov, E.B. (8) 293 Russ, P. (5) 235 Russell, D.R. (8) 46 Russell, R.B. ( I ) 31 Rutkovskii, E.K. (8) 74 Rye, H.S. (6) 322 Ryte, A.S. (6) 193 Ryu, S. (5) 96 Ryzhikov, D.V. (4) 37 Sahat, M. (6) 212, 333, 342

Sadanani, N.D.( I ) 383 Safadi, M. (5) 205 Safsaf, A. ( 5 ) 204 Sagi, J. (6) 48 Saha, J. (6) 24 Saiki, N. (8) 279. 280 Saito, I. (6) 241 Saito, M. (6) 39 Saito, T. (5) 217; (6) 15; (7) 118; (8) 161 Saito, Y . (8) 278 Saiz, E. (8) 262 Sakagami, K. (7) 136 Sakai, N. (4) 64 Sakai, T. (5) 217 Sakai, Y. (6) 277 Sakakura, T. (5) 238 Sakamoto, A. (3) 1 Sakamoto, H. (1) 115 Sakatsurne, 0. (6) 80 Sakharov. S.G. ( I ) 205; (4) 32, 33 Sakuta, N . (8) 160 Sakya, S . M . (6) 297 Salamohczyk, G.M. (5) 29, 30, 32 Salamonczyk, I. ( I ) 98; (3) 4; ( 5 ) 312 Salas, I . ( I ) 156 Salvati, L. (8) 133 Salvati, M.E. (6) 301 Samadi, M. (5) 240; (6) 19 Samkhavadze, L.O. (5) 106 Sams, D.W.I. ( I ) 332 Samuels, W.D. (8) 92 Samuelsson, B. (6) 18, 20 Samuilov, Y.D. ( I ) 417 Sanchez, M. ( I ) 333, 368 Sanchez-Andrada, P. (7) 119 Sandhoff, K. (7) 75 SandstrBm, A. (4) 43; (6) 262 Sangen, 0. (4) 59; (6) 113, 188, 189 Sanghvi, Y.S.(6) 118, 119 Santelli, M. (7) 87 Saravanamuthu, A . (8) 25 Sarfati, R.S. (6) 61, 62 Sarina, T . V . ( I ) 317, 333, 355, 368; (4) 70 Saris, C.P. (6) 166 Sarma, J. ( I ) 237 Sarngadharan, M.G.(6) 192 Sarvarova, N.N. ( I ) 168 Sasagawa, Y. (8) 97 Sasaki, D.Y. (6) 71 SatgC, J . ( I ) 361 Satishchandran, C . (6) 67 Sato, H . (6) 79

Author Index

Sato. K. ( 5 ) 21 Sato, R. (7) 55 Satow, Y. (6) 69 Sattler, E. (1) 22 Savage. P.B. (3) 8 Savignac, P . (5) 121, 126, 180 Sawai, H . (6) 54, 55 Sawai, K. (8) 282 Sawamura, M. ( I ) 74. 75, 115 Sawata. S . (6) 250 Sawyer, D . A . (5) 43. 44 Saxe, J . D . (6) 207 Saywl, M.B. (8) 94, 136 Sayer, J.M.(6) 169 Sayo, N . ( I ) 73 Schaeffer, C. (5) 229 Schaffner, G.(6) 122 Schaper, W . (7) 140 Schauh, R.E. (5) 12 Scheer, M. ( I ) 20, 21 Scheich, H . (7) 63 Scheinmann, F. (7) 89 Scheinplein, S.W. (7) 33 Schepartz, A . (6) 201 Scheper, R.J. (8) 213 Scherer, O.J. (3) 42; (8) 3 Schervan, A . (8) 90 Schiehler, W . (5) 33 Schier, A . (7) 13 Schiller, J . (8) 15 Schilling, F.C. (8) 246 Schlageter, M. (7) 80 Schlewer, G. (5) 40 Schloh, M.O. (8) 255 Schlosser, M. ( I ) 259 Schluter, R. ( I ) 364; (4) 81 Schlutz, S.C. (6) 313 Schlutze, P . (6) 219 Schmaltz, T. (4) 13 Schmidbaur, H. ( I ) 41, 220, 425; (7) 13 Schmidpeter, A . ( I ) 222, 367, 41 I ; (4) 78; (7) 7, 56; (8) 178, 185 Schmidt, A . (7) 113; (8) 51 Schmidt, D . ( 1 ) 406 Schmidt, M. ( I ) 302-304 Schmidt, R.R. (6) 16 Schmit, G . (5) 148 Schmitt, L. (5) 40 Schmitz, F.J. (6) 330 Schmutzler, R . ( I ) 193, 197, 213, 214; (2) 5, 25, 26, 42 Schneider, B. (5) 281 Schnepp, K. (5) 234 Schnick, W . (8) 100, 101, 204 Schnid, B. (1) 423 Schnoes, H.K. (3) 24

427 Schoeller, W.W. (1) 311, 357, 366; (4) 71, 77; (7) 3; (8) 34 Schoellkopf, U. ( 5 ) 207 Schoentjes, B. (6) 330 Schomher, B.M. (8) 40 Schomhurg, D. ( I ) 193; (6) 25 Schreiher, S.L. (7) 94 Schreiner, E . P . (6) 273 Schroth, G. ( 1 ) 3 Schuette. H.R. (5) 281 Schulte-Koerne, E. (8) 28 Schultz, P.G. (6) 229 Schumann. H. (1) 9, 10, 217 Schwalhe, C . H . (5) 308 Schwaftz, K.H. (5) 120 Schwarz, W . ( I ) 302, 303, 305 Schwesinger, R , (8) 65 Schwetlick, K. (4) 25 Scoponi, M. (8) 219 Scremin, C.L. (6) 76 Seale, P . W . (4) 49; (5) 22 Searle, M.S. (6) 304 Sehhach, J . ( I ) 46 Secrist. J . A . , 111 (6) 17, 26, 42, 115 Sediva, K. (6) 28 See, R.F. ( I ) 176 Seela, F. (6) 46, 47, 152-156 Seeman, N.C. (6) 236, 237 Segawa, H . (2) 48 Seidel, B. (5) 79 Seidel, J.L. (7) 60 Seidler, N . (1) 305 Seitz, S.P. (4) 42 Sekine, M. (6) 82 Self, M.F. ( I ) 63 Selirn, A. ( I ) 270 Semenov, V . V . ( I ) 219 Sendyurev, M.V. ( I ) 194, 195 Sentemov, V.V. ( 5 ) 139 Sergienko, L.M.(2) 47 Seshadri, T . P . (6) 36 Seto, H. (1) 230 Setzer, W . N . (5) 9; (6) 41 Sevin, A.F. (3) 27 Shahana, R. (5) 59 Shagidullin, R.R. ( I ) 125; (5) 300 Shagi-Mukhametova, N.M. ( 5 ) 130 Shah, S . R . (7) 128 Shamsevaleev, F.M. (5) 90 Sharma, D . C . ( I ) 413, 414; (4) 76 Shaw, A . C . (8) 89 Shaw, B.L. ( I ) 7, 8, 173 Shaw, J.-P. (6) 198, 224 Shaw, L.S. (8) 103

Shaw, R . A . (8) 63, 103, 118, 1 I9 Sheardy, R . D . (6) 317 Sheldrick, G.M.(8) 181 Shen, G.S.( I ) 183 Shen, Y. ( I ) 253, 254; ( 5 ) 150; (7) 34, 50, 51 Sheo, D.C. (8) 263 Sheppard, R . E . (6) 245 Sherman, A S . (1) 384, 385; (8) 14 Shermolovich, Yu.G. ( I ) 129; (5) 184; (8) 67 Shevchenko, I.V. ( I ) 213 Shevchuk, M.I. ( I ) 225 Shi, L.-L. (7) 28 Shi, M. (5) 289, 290 Shi, Y. ( I ) 159; (8) 229 Shihaev, V . N . (5) 25 Shibata, T . (8) 79-81 Shihutani, S. (6) 171 Shihuya, S. (4) 6; (5) 170 Shigematsu, H . (8) 115, 157 Shigeta, S. (6) 45 Shijo, M. ( I ) I I Shilin, S.V. (8) 179 Shimazu, M. (6) 54, 55 Shimidzu, T. (2) 48; (6) 188, 1 89 Shimizu, S.I. (6) 10 Shimmin, P . A . (5) 221, 292; (8) 33 Shimshock, S . J . (7) 121 Shin, H . (6) 302 Shin, J . A . (6) 213 Shin, W . S . (5) 175 Shinkai, S. (5) 115 Shinohara, H . (8) 160 Shinohara, K. (6) 127 Shinohara, Y. ( 5 ) 38 Shinomiya, M. (6) 243 Shinozuka, K. (6) 55 Shintani, Y. (6) 226 Shiota, K. (5) 31 Shiotani, N . (4) 4 4 Shiratori, S . ( I ) 79; (3) 5 Shirota, I. (6) 244 Shishido, K. (6) 277 Shneider, M . A . ( 5 ) 188 Shriver, D.F. (8) 250-253 Shtepanek, A . S . (5) 15 Shu, D . (6) 317 Shumeiko, A . E . (8) 95 Shuto, S. (6) 15 Shvetsov-Shilovskii, N . I . (5) 199 Sihuya, M. (6) 277 Sie, E.-R.H.B. (7) 64 Siehert, W . (1) 349, 350

428 Sieghahn, H . O . G . ( I ) 266 Siegel, M . M . (6) 269 Sieler, J . (5) 305 Siemieniak, D . R . (6) 299 Sierra, M . L . ( I ) 402, 403, 408 Sierzputowska-Gracz. H . (6) 150 Sigman, D.S. (6) 247 Sigurdsson, S . T . (6) 325 Sikorski, J . A . (5) 274 Silaghi-Durnitrescu, 1. (8) 87 Simmerl, R. (4) 7 Simmoneaux, G. ( I ) 170 Simon, A . (5) 305 Simon, C . ( I ) 140 Simon, E.S. (6) 56 Simone, C . M . (6) 68 Sindona, G.(5) 49 Singh, M. (6) 314 Singh, M.S.(5) 1 1 Singh, U . C . (6) 207 Sinha, N . D . (4) 58; (6) 84 Sinitsa, A . D . (3) 35 Sinsheimer, J.S. (6) 218 Sinyashina, T . N . (2) 8 Sisti, M. (5) 206 Sitlani, A . (6) 327 Skelton, B . W . ( I ) 177; (2) 19 Skinner, M. (6) 314 SklenAr, V. (6) 217 Skohun, A . S . (5) 168 Skoweranda, J . (5) 303 Skowrofiska, A . (5) I , 60 Skripskaya, O.V. ( I ) 225 Slahko, M . G . (5) 166 Slighton, J.L. (6) 299 Slusarchyk, D . A . (5) 256 Smith, A . (5) 277 Smith, A . L . (6) 276 Smith, E . C . R . (5) 183; (7) 132 Smith, J.G. (5) 67 Smith, S. (5) 243 Smith, S . C . (7) 120 Smith, W . (6) 150 Smolii, O.B. ( I ) 238 Snaith, R. (3) 1 1 SO, J.-H. (1) 117 Sochacka, E. (6) 150 Siinnichsen, S . H . (6) 339 Sohn, Y.S. (8) 209 Sokolov, M . P . (5) 300, 301 Sokolov, V.B. ( I ) 152; (2) 10; (5) 201; (8) 73 Sokolov, V.V. ( 5 ) 224 Sokol’skaya, 1.B. (8) 240 Solans, X. (6) 157 Soldatova, I . A . (5) 72, 262, 263 Soleilhavoup, M . (5) 291; (8) 177

Organophosphorus < ‘hemistry Solodenko. V . A . (5) 230, 239 Solomon, J . J . (6) 161 Soloshonok, V . A . (5) 184, 239 Solouki, B. ( I ) 377; (4) 67; (5) 215 Somers, P.K. (7) 94 Sommese, A . ( I ) 380 Sopchik, A . E . (6) 40 Sorina, T.G. (8) 158 Sorokin, V . D . ( I ) 234; (5) 5 1 , 260 Sotiropoulos, J.-M. (7) 54 Soukup, M. (7) 81 Sournies, F . (8) 109, 110 Sowa, J.R. ( I ) 161 Spada, G.P. (6) 235 Spangler, C . W . (8) 229 Speers, P. ( I ) 244, 245; (7) 43, 44 Spengler, B. (6) 360 Spieser, E. (6) 131. 132 Spiess, B. (5) 40 Spilgies, G. (8) 151 Spotts, P.H. (6) 306 Sproat, B.S. (6) 44 Sreenivasa Reddy, V . (8) 141 Stadler, H. (5) 275; (7) 74 Stahlhut, E. ( I ) 100 Stalke, D . (3) I I ; (8) 181, 182 Stam, C . H . (8) 77 Stammler, H.-G. (1) 279, 378, 407; (7) 37 Stang, P.J. ( I ) 222, 232-234, 250; (7) 4 Stankowiak, A . ( I ) 235 Stannett, V.T. (8) 233 Starzewski, K . A . O . (7) 36 Stawihski, J . (6) 99, 100, 104 Stec, W.J. (4) 61; (5) 94; (6) 98 Steenken, S . (6) 246, 363 Steier, W . H . (8) 229 Steigelmann, 0. ( I ) 425 Stein, C . A . (6) 192 Steitz, T . A . (6) 313, 334 Stella, V.J. (5) 71 Stelzer, 0. ( I ) 215 Stepanov, G.S. (4) 37 Stepanov, P . A . (5) 142 Stephan, D . W . ( I ) 365 Sterk, H . (7) 10; (8) 23 Stocker, J . ( I ) 222; (7) 7; (8) 178 Stockert, J.C. (6) 31 I Stoelwinder, J . (7) 66 Stolka, M. (8) 290 Stnll, K. (8) 185 Stone, M.P. (6) 170 Storer, R. (6) 49. 50

Straw, T. ( I ) 99; (8) 176 Striimberg, R . (6) 100, I01 Struchkov, Y u . T . ( I ) 218, 234, 242, 290. 345; (4) 39; (5) 167. 260 Stuhhe, J . (6) 291 Stuetzer, A . ( I ) 41 Sturm, D . (8) 20 Sturtz, G. (5) 112 Stussi. D. (4) 66 Su, B. (8) 258 su, Y . ( I ) 35 Subrarnanian, S. (5) 13 Sudheendra Rao, M . N . (8) 165 Sugawara, Y . (6) 69 Sugimoto, N . (6) 226 Sugiyarna. H. (6) 241 Sugiyama, M . (8) 81 Suh. G . - H . ( I ) 172 Sukhozhenko, 1.1. (8) 294 Summerton, J.E. (6) 135 Sun, D. (6) 293-296 Sun, M. (5) 310 Sun, X. (5) 272 Sunaga, R. (6) 274 Sunatsuka, H . (8) 266-268 Sund, C . (4) 43; (6) 262, 263, 265 Sundaralingham, M . (6) 232 Sung, Y . K . (8) 209 Sunitsa, A . D . (5) 87 Sunthankar, P . (5) 14 Suvalova, E . A . (5) 87 Suzuki, A . (6) 45 Suzuki, H . (1) 269 Suzuki, K. (1) 122 Suzuki, M . (7) 92; (8) 150 Suzuki, T. (6) 273 Suzuki, Y . (6) 79 Suzura, Y . (8) 145 Svisunova, N . Y u . (5) 239 Swann, P.F. (6) 144 Swartz, W . H . (5) 211 Swenson, R. (3) 24 Swigor, J . E . (5) 250 Swords, 8 . (4) 51; (5) 24 Symons, M . C . R . (6) 323 Syndikus, D . ( I ) 101 Szabolcs, A . (6) 48 Szameitat, U . ( I ) 292 Szantay, C . (7) 30 Szewczak, A . A . (6) 347, 348 Szewczyk, J . (5) 285 Szewczyk, K . M . (5) 285 Szostak, J . W . (6) 324 Sztruhar, S. (7) 30 Tachon, C . ( 1 ) 278, 379; (3) 10

Author Index

Tada, Y. (8) 276, 277 Taddei, M. (7) 27 Tahar, M . (1) 169; (3) 39 Taieh, M. (2) 40 Tajiri, Y. ( I ) 89 Takahashi, K. (8) 126, 127 Takahashi, S. (6) 160 Takaku, H. (6) 79. 80, 168 Takamuku, S. ( 5 ) 289, 290 Takano, K. (8) 152 Takano, Y. (8) 144 Takaya, H. ( I ) 73; (4) 64 Takechi, N. ( 5 ) 31 Takegawa, T. (1) 75 Takegoshi, K. (8) 235 Takeshige, Y . (6) 250 Takeuchi, H. (3) 30 Takeuchi, Y. (7) 136 Takita, S. (8) 79, 81 Talanova, G.G.(5) 102 Talham, D.R. (8) 255 Talwar, G.P.(6) 180 Tamm, L.A. (5) 261 Tanaka, A . (6) 226 Tanaka, H.(8) 246 Tanaka, I . (8) 235 Tanaka, K. (6) 177 Tanaka, M. (5) 238; (8) 161 Tanaka, S. (3) 30 Tang, C.-C. (5) 52 Tang, C . L . (6) 367 Tang, J.S. (1) 295, 380 Tanida, M. (8) 266, 267 Tanier, S. (7) 67 Tanigaki, T. (8) 114, 116 Tanious, F . A . (6) 312 Tanmatu, H. (1) 255 Tao, X. (5) 272 Taornoto. A . (8) 278 Tarantili, P . V . (7) 32 Tarazona, M.P.(8) 262 Tarussova, N.B. (6) 23 Tasdelen, E.E. ( I ) 172 Tashiro, K. ( I ) 325 Tashiro, M. (7) 136 Tashma, Z. ( 5 ) 279 Taylor, G.E. ( 5 ) 302 Taylor, N.J. ( I ) 182 Taylor, S.A. (8) 234 Taylor, S.D. (5) 74, 265 Taylor-Robinson, D. (6) 6 Tehhe, K.F. (I) 48 Tehhutt, A . A . (5) 220 Tehhy, J.C. (4) 18; (5) 288; (7) 9 Tegge, W.( 5 ) 41 Tbule, R. (6) 172, 349 Terekhova, M.I. ( I ) 241

429 Tereshima, S . (6) 275 Terhorst, T. (6) 224 Terlouw, J.K. (7) 1 Terron, G. ( 1 ) 297 Teunissen, H.T. ( I ) 420 Thelin, M. (6) 99, 104 Thihault-Starzyk. F. (5) 173 Thiele, G . (8) 65 Thiele, M. (8) 178 Thilmont, N. (1) 109 Thomas, C.J. (8) 165 Thomas, M.J. (6) 362 Thompson, A . S . (6) 300 Thompson, C.M. (5) 56, 96; (7) 20 Thompson, M.A. (5) 9 Thorimbert, S . (7) 67 Thornton-Pen. M. (1) 7. 8 Thuong, N.T. (6) 126, 186, 209 Thurston, D.E. (6) 300 Tidwell, R . R . (6) 310 Tiekink, E.R.T. (1) 87 Tilika, V . Z . (1) 166 Tillmanns, B. ( I ) 25 Timmers, C.M.(6) 121 Timokhin, B.V. ( I ) 200; (2) 7. 12, 47; ( 5 ) 137 Tinoco, I.,jun. (6) 343-345 Tipton, A.L. (6) 333; (8) 252, 253 Tishler, M. (5) 228 Tkachev, V.V. (5) 306, 315 Tkatchenko, I. ( I ) 181 Toda, M. ( I ) 201 Togni, A . (1) 112, 114 Togo, H. ( I ) 237 Toia, R.F. (5) 84 Toiron, C . (6) 35 Tokiwa, Y. (6) 274 Tokoroyama, T. (7) 29 Tolkunova, V . S . (1) 84 Tollerfield, S.M. (6) 2 Tolmachev, A . A . ( I ) 191, 192, 202; (4) 10, I I ; (5) 15; (8) 17, 19 Tomasz, J . (6) 40 Tomasz, M. (6) 286-288 Tomho, G.M.R.(1) 93 Tomii, K. (8) 239 Tominaga, K. (8) 238 Tomioka, H. (7) 35 Tommes, P. (7) 1 Tondelli, L. (6) 235, 351 Tonelli, A . (8) 246 Tong, G. (5) 231 Toone, E.J. (6) 56 Top, M. (I) 139 Topolski. M. ( 5 ) 316

Tordo, P. (5) 189 Torgasheva, N . A . (5) 81-83 Torgemyan, A . M . (5) 280 Torisawa, Y . (6) 276, 284 Torley, L.W. (5) 12 Torreilles, E. ( I ) 236, 267 Torrence, P . F . (5) 153; (6) 66. 90, 91 Tosaka, M. (8) 243 Toshio, Y. (8) 127 Toulhaut, C . ( I ) 260 Toulmk, J.J. (6) 93 Touzin, A . M . (7) 67 Toyota, K. (1) 325, 328, 331 Toyota, T. (5) 214 Tran-Cong, Q. (6) 174 Trent, 1.0. (7) 12 Trentham, D.R. (6) 60 Treshchalina. L . V . ( I ) 190 Trishin, Yu.G. (5) 135, 136, 261 Troepol’skaya, T.V.( I ) 185 Trofimov, B.A. ( I ) 105-107 Trost, B . M . ( I ) 1 1 1 ; (7) 123 Troy, L. (8) 283 Tsai, M.-D. ( 5 ) 36; (6) 64 Tsay, S . - C . (6) 284 Tsay, Y.-H. ( I ) 215 Ts’o, P.O.P. (6) 204 Tsuhokawa, N. (8) 221 Tsuchida, H.(8) 22 1 Tsuchiya, T. (1) 79; (3) 5 ; (7) 106; (8) 55 Tsuji, M. (8) 243 Tsujino, M. (6) 15 Tsukamoto, K. (8) 148 Tsukamoto, M. (5) 21 Tsvankin, D.Ya. (8) 248 Tsvetkov, E.N. ( I ) 84; (2) 37; ( 5 ) 232 Tudanca, P . L . L . (7) 59 Tuerck, G. (8) 151 Tufto, K.B. (6) 207 Tugnoli, V . (6) 351 Tukanova, S.K. (5) 164 Tulmachev, A . A . (5) 179 Tur, D.R. (8) 215, 248 Turvill, M.W. (7) 133 Tuzhikov, 0.1.( I ) 96 Tweedy, B.R. ( I ) 157; (3) 17: (4) 19 Tyka, R. ( 5 ) 200 Tykwinski, R. ( I ) 232 Uccella, N . ( 5 ) 49 Uchihori, Y. ( I ) 230 Uchida, T. ( 5 ) 21 U d a , 1. (7) 40

430 Ueda, T. (6) 151, 163, 164 U d a , Y. (6) 127 Uemura, M. ( I ) 13 Ueno, Y. (6) 8 6 Uesugi, S. (6) 160, 167, 290 Uesugi, T. ( I ) 328 Ugi, I. (4) 17 Uhlenbeck, O.C. (6) 261, 328 Uhlig, F. ( I ) 2 1 Ulach, J. (6) 28 Ullmann, J. ( I ) 233 Ulrich, J. (6) 172 Umemoto, T. ( I ) 2 3 I Umeno, M. (1) 230; (8) 80, 81 Umezu, Y. ( I ) 7 8 Umond, M. (8) 7 9 Urata, H. (6) 127 Uskokovic, M.R. (3) 22 Ustenko, S.N.(2) 6; (5) 132 Utsumi, F. ( 5 ) 116 Uziel, J. (7) 67 Uznanski, B. (4) 61; (6) 9 8 Vainiotalo, P. (5) 154 Valdor, J.F. ( I ) 109 Valente, R.R. (5) 63 Valentijn, A.R.P.M. ( 5 ) 123 Valerio, R.M. ( 5 ) 231 Valero, R. (1) 244, 245; (7) 43,

44 Valery, J.-M. (6) I26 Valter, B. (8) 215 Van Asselt, R. (8) 77 Van Bolhuis, F. (5) 31 I ; (8) 295 van Boom, J.H. (4) 46,60;(5) 5, 33, 45, 123; (6)37, 106, 120, 121, 166, 205, 206, 356 van de Grampel, J.C. (8) 82, 124, 134, 165, 168-170, 180, 295 van den Elst, H. (4) 60; (6) 106, 120, 166 van den Heuvel, H.L.A. (7) 124 van der Haest, A.D. ( 5 ) 31 1 van der Lee, A. (8) 168, 169, I70 van der Marel, G.A. (4) 46, 60; (5) 33, 45, 123; (6) 37, 106, 120, 121, 166, 205, 206, 356 Van Doom, J.A. (1) 16, 17, 18, 164

Van Dranken, D.L. ( I ) 1 1 1 van Garderen, C.J. (6) 331 Van’kin, G.I. (1) 224 van Lenthe, J.H. ( I ) 9 4 van Leusen, A. M. (7) 66 Van Meervelt, L. (6) 81

Orgun oph osph orus C ’hemistry

Van Oijen, A.H. (5) 5 Vanquickenhorne, L.G. ( I ) 387 Vansweevelt, H . ( I ) 387 van Zoest, W.J. (7) 66 Varani, G. (6) 343-345 Vasil’ev, B.K. ( 5 ) 167 Vasilev, N. (5) 307 Vasseur, J.-J. (6) 118, 119 Vasyanina, L.K. ( I ) 26, 205; (4) 33, 39; (5) 106, 263 Vaultier, M. (4) 14 Veal, J.M. (6) 312 Veeneman, G.H. (5) 124 Veith, M. (8) 139 Veits, Yu.A. (1) 199 Velasco, L. ( I ) 156 Velikokhat’ko, T.N. (8) 30 Venanzi, L.M. ( I ) 93, 423 Venkataraman, H. (7) 82 Venkov, A.P. ( 5 ) 192, 193 Venturini, L. ( I ) 116 Vepsailginen, J. ( 5 ) 154 Verdine, G. (6) 158, 159 Verduyn, R. (4) 46 Verfiirth, U. (4) 17 Verkade, J.G. ( I ) 35; (2) 43 Vermes, B. (7) 97 Veronese, A.C. ( 5 ) 127 Vesely, J. (6) 28 Vesenka, J. (6) 367 Vessey, J.D. ( I ) 173 Veszpremi, T. ( I ) 409, 426 Veya, P. (1) 184 Viala, J. (7) 87 Viallefont, P. (5) 208 Victorova, L.S. (6) 108 Vidal, A. (3) 13; (7) 17-19, 1 I I , 119; (8) 36-38 Vidal, M. (1) 260 Vidal, P. (6) 23 Vieira, A.J.S.C. (6) 246 Vil’chevskaya, V.D. ( I ) 84 Villemin, D. ( 5 ) 173 Vinader, M.V. (7) 101, 116 Vinayak, R. (6) 83, 316 Vincens, M. ( I ) 260 Vincent, B.R. ( I ) 362; (3) 9 ; (4) 68 Vincente, 1. (8) 42 Vincer, P. (7) 30 Vinindra, K.D.V. ( I ) 332 Vinogradova, S.V. (8) 215, 248 Visscher, K.B. (8) 62, I 1 1, 212, 223 Vitovskii, V.Yu. (8) 179 Vlasova, O.G. (8) 43 Vlassov, U.V. (6) 193 Voelter, W. ( 5 ) 122

Voertse, A.A.W. ( I ) 139 Vogt, P. (7) 8 0 Vogt, R . ( I ) 214 von der Giinna, V. ( I ) 366; (4) 77 von Locquenghien, K.H. (7) 14 von Schnering, H.G. ( I ) 52, 282 Vo-Quang, L. ( 5 ) 202; (7) 61 Vo-Quang, Y. (5) 202 Voronkov. M.G.( I ) 105 Vostrokmutova, Z.N. ( 5 ) 141 Vostsekhovskaya, O.M. (5) 104 Votruha, 1. (6) 2 8 Vovna, V.I. ( I ) 316 Vreekamp, R.H. (4) 42 Vul’fson, S.G. ( I ) 168 Vydzhak, R.N. ( I ) 165, 238 Vyle, J.S. (4) 20; (6) 1 1 1, 248 Vysotskii, V.I. ( I ) 167; (5) 166169 Wacker, D.A. (6) 87 Wada, A. ( I ) 268 Wada, M. ( I ) 229 Wada, T. (8) 81 Waddling, C. (8) 193, 203 Wagener, C.C.P. (5) 68, 269 Wagman, A.S. (5) 149; (7) 71 Wagner, E. (6) 122 Wakabayashi, A. (8) 81 Wakabayashi, H. (6) 55 Wakai, H. (6) 54, 55 Wakefield, B.J. (7) 89 Walker, C. (6) 306 Walker, I. (5) 267 Walker, R.T. (6) 10 Waltermire, R.E. (7) 121 Walther, P. (3) 42 Wamhoff, H. (7) 113; (8) 51 Wandless, T.J. (7) 9 4 Wang, A.H.-J. (6) 37, 346 Wang, C . (6) 355 Wang, D. (6) 116 Wang, E. (6) 221 Wang, G. (5) 160, 182, 195 Wang, H. (6) 130 Wang, M. ( I ) 163 Wang, R. ( 5 ) 225 Wang, T. (7) 34; (8) 216 Wang, W.-B. (7) 28 Wang, X. ( 5 ) 79 Wang, Y. (6) 234; (8) 93 Wannagat, U. (8) 29 Wannagay. U. (8) 90 Wanner, M.J. (7) 46 Waratani, K. (8) 278 Ward, T.R. ( I ) 93

Author Index

Waring, M.J. (6) 309 Warren, S. (3) 27, 37 Wasada, A . (2) 4 Watanabe, K.A. (6) 2 3 Watanabe, M . (5) 172 Watanabe, Y. (4) 44,45; (5) 8, 37, 38 Watanuki, T. (8) 148 Waters, T . R . (6) 143 Watson, S.M. ( I ) 131; (2) I , I I Watson, S . P . (5) 220 Weakley, T.J.R. ( I ) 183 Weher, J. (4) 66 Weher, L. ( I ) 279-281, 378, 407; (7) 37 Weding, D . L . (5) 183; (7) 132 Weeks, K.M. (6) 313 Wehmer, J.M. ( I ) 148 Weidhase, R. (5) 281 Weintraub, H.J.R. (5) 247 Weiss, C.D. ( I ) 120 Weiss, J.-V. (1) 197 Weiss, R. (1) 206; (4) 29, 30 Weith, H.L. (4) 55; (6) 184 Welker, M.F. (8) 104 Well, M. (2) 25, 2 6 Weller, D.D. (6) 130, 135, 136 Wells, R.L. ( I ) 63 Wemmer, D.E. (6) 307, 322, 350 Wen, T. (5) 213 Wendeborn, S . V . (6) 276 Wenzel, T . (6) 156 Werner, H . ( 1 ) 9 2 Wessolowski, H. (5) 158 West, R. (8) 186 Westerduin, P. (5) 124 Westerhausen, M. ( I ) 302-305 Westermann, H . (1) 212, 275 Westhof, E. (6) 366 Westra, J.G. (6) 166 W a l i n g , T . ( I ) 388 Whang, K. (7) 82 Whitaker, K.W. (5) 9 White, A.H. (I) 177; (2) 19 White, J.D. (7) 2 6 White, J.L. (8) 234 White, L.A. (6) 308 White, M. (8) 191 White, P.S. (8) 32 White, W . (8) 190 Whitehead, B.J. (4) 18; (5) 288; (7) 9 Whitehead, M . A . (8) 91 Whitesides, G.M.(6) 56-58 Whitten, J.P. (5) 244, 247 Wiaterek, C. (1) 47 Wickstrom, E . (6) 109

43 I Wicnienski, N.A. (6) 299 Widhalm, M. (1) 36 Widmer, E. (7) 80, 81 Wieber, M. (2) 24 Wieczorek, M.W.(3) 14; (5) I74 Wiecwrek, W . (1) 98; (3) 4; (5) 3 12 Wiemer, D.F. (4) 27; (5) 76, 178 Wilbrandt, D. ( I ) 12 Wild, B. ( I ) 45 Wild, S.B. ( I ) 83, I71 Will, D.W. (4) 53, 54; (6) 185 Williams, D.M.(6) 123 Williams, H . A . M . (5) 124 Williams, M.G. (6) 299 Williams, P. (6) 361, 362 Williams, R . M . (6) 303; (7) 62 Williamson, J.R. (6) 353 Willis, A.C. ( I ) 45, 83. 171 Wilson, T. (8) 93 Wilson, W.D. (6) 230, 312, 316 Wingen, B. ( I ) 51 Winkler, T. (5) 196 Winter, R. (5) 158 Wintersgill, M.C. (8) 254 Winching, P. (5) 241 Wise, J.G. (6) 247 Wisian-Neilson, P. (8) 216 Wissner, A . (5) 12 Withers, S.G. (5) 3 Witt, M. (8) 66 Woisard, A . (6) 139 Wold, B. (6) 202 Wolf, J,-G. ( I ) 369 Wolf, R. ( I ) 333, 368; (2) 39 Wolf-Kugel, D. (6) 22 Wolfsberger, W. ( I ) 91, 92, 123; (8) 7 0 Wolmershauses, G. (3) 42 Won, Y.M.(8) 126 Wong, T. (7) 1 Woo, J . (6) 197 Wood, C.E. (8) 10 Wood, G . L . (1) 351 Woodward, G. (8) 122 Woodward, P.R. (7) 120 Woodward, S. (1) 77; (3) 32 Wool, I.G. (6) 348 Wovkulich, P.M. (3) 22 Wrackmeyer, B. (8) 15 Wrenn, S. ( 5 ) 12 Wright, D.S. (3) I I Wright, G. (6) 52 Wright, J.J.K. (5) 183; (7) 132 Wright, P.B. (4) 58; (6) 84 Wright, S . H . B . (5) I18

Wrighton, M . S . (8) 255 Wr6blewski, A . E . (5) 303, 316 Wu, G. (1) 155 WU, G.-P. (5) 52 WU, J.-P. (5) 237 WU, M.-J. (7) 31 WU, S.-Y. (5) 84 Wu, S.H. (6) 291 Wu, T. (6) 238 Wu, X.P. (1) 380. 381, 383; (5) 283, 287 Wu. Y.L. (5) 228 Wunz, T.P. (6) 289 Wyckoff, H.W. (6) 335 Xiang, Y. ( I ) 253, 254; (7) 50, 51 Xiao, W . ( I ) 221 Xie, S. (7) 122 Xodo, L . E . (6) 205, 206 Xu, J . (5) 295 XU, Y.-Z. (6) 81, 144 XU, Z.-Q. (5) 147; (7) 58 Yaginuma, S. (6) 15 Yagodinets, P.I. ( I ) 225 Yaguchi, A . (8) 143, 146, 147 Yaloyskaya, A.I. ( I ) 133 Yal’tseva, N.S. (5) 138 Yamaguchi, R. (1) 201 Yamaguchi, T. (6) 80 Yamaji, M . (6) 39 Yamakage, S. (6) 263 Yamamoto, H . ( 1 ) 86; (5) 64-60, 109-111, 114 Yamamoto, I. (3) 30 Yamamoto, K. (5) 289 Yamamoto, M. ( I ) 119; (5) 258. (7) 24 Yamamoto, N. ( I ) 5, 6 Yamamoto, T. ( I ) 76 Yamana, K. (4) 59; (6) 113, 188, 189 Yamashita, K. (8) 8 Yamashita, Y. (8) 230 Yamataka, H . (7) 22 Yamauchi, A . (1) 75 Yamazaki, A . (1) 113 Yamwdki, K. (6) 249 Yanagihara, N. (8) 284 Yanagisawa, A . (5) 64, 65, 66 Yang, X. (5) 9 Yano, S. (8) 239 Yanovskii, A.I. ( I ) 242 Yao, X. (5) 225 Yarchoan, R. (6) 12

432 Yashiki, T . (4) 59; (6) 113 Yaw, M. (6) 15 Yassin, S.M. ( 5 ) 50 Yasui, S. (1) 187; (4) 82 Yasuike, S. (1) 79; (3) 5 ; (7) 106; (8) 55 Yasunami, S. (8) 269, 270, 273, 274 Yatsimirskii, K.B. (5) 102 Yeung, A.S. (8) 231 Yokomatsu, T. (4) 6; (5) 170 Yoneda, F. (6) 177 Yoneda, R. ( 5 ) 293 Yonemori, S. (1) 268 Yonetake, K. (8) 241, 242 Yoon, H.S. (8) 126. 127 Yoon, M. (8) 105 Yoshida, H . ( 5 ) 116 Yoshida, Y. (1) 269; (5) 304 Yoshifuji, M. (1) 325, 328, 331; (5) 214 Yoshikawa, K. (1) 5 Yoshimura, H. (1) 328 Yoshinari, K. (6) 249 Yoshino, M. (8) 284 Yoshioka, H. (1) 230 Young, B. (6) 257 Young, S.G.(8) 197, 249 Young, V.G. (1) 346 Yousif, N.M.( 5 ) 50 Yu, H. (2) 31

Orgunophosphorus Chemistry Yu, J.S. ( I ) 88 Yu, R.C.U. (8) 291 Yuan, C. (5) 160, 182, 195. 203, 264 Yudelevich, V.I. ( 5 ) 188 Yue, S . (6) 322 Yurchenko, A . A . (4) 10 Yurchenko. L.V. (6) 193 Yurchenko, R.I. (1) 96; (5) 99101, 103, 104 Yurchenko, V.G. ( 5 ) 100, 101 Yuzawa, Y. (1) 85 Zahirov, N.G. ( 5 ) 90 Zahotina, E.Ya. ( I ) 41 I , 417 Zaher, H. ( 5 ) 279 Zain, R. (6) 100 Zakharov, L.S. ( 5 ) 75 Zaman, F. (5) 122 Zang, H. (8) 259 Zard, S.Z. ( I ) 237 Zarrinmayeh, H. (6) 298 Zasorina, V.A. (5) 102 Zavadskii, K.S. (1) 310 Zayed, M.F.(2) 20; (5) 212 Zhiral, E. (5) 161, 171 Zechel, A. (6) 365 Zefirov, N.S.(1) 234; (5) 260 Zellner, K. ( I ) 64, 65 Zemlicka, I . (4) 5 ; ( 5 ) 117; (6) 33

Zerial, A. (6) 1 I Zettlmeier, W . ( I ) 44 Zhang, G.-Z. ( 5 ) 52 Zhang, H. (1) 155 Zhang, X . ( I ) 73 Zhang, Y. (6) 236 Zhao, Y.-F. (5) 61 Zhdankin, V.V. ( I ) 232, 234, 250; (5)260; (7) 4 Zheng, Q. (6) 144 Zhichkin, P.E.( I ) 151; (8) 22 Zhu. G. (1) 155 Zhu. J . ( 1 ) 221; (5) 272 Zhu, Q.-Y. (6) 23 Zhukov, V.P. (8) 248 Zidani, A . (4) 14 Ziller, J.W. (8) 40, 41 Zimmermann, R. (7) 140 Zipory, E.S. ( 5 ) 93 Zon, G. (6) 230, 316 Zon, J . (5) 162 Zotov, Yu.L. ( I ) 196; (5) 105 Zoutherg, M.C. (8) 77 Zschunke, A . ( 1 ) 71 Zsolnai, L. (1) 372 Zumhulyadis, N. (8) 224 Zur, L. (8) 253 Zwierzak, A. (5) 95, 218, 269, 270 Zykova, T . V . (5) 142 Zyner, E. (1) 208