Organophosphorus Chemistry

Organophosphorus Chemistry

Volume 23

A Specialist Periodical Report

Organophosphorus Chemistry Volume 23 A Review of the Recent Literature Published between July 1990 and June 1991 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 CHEMISTRY

ISBN 0-85186-216-0 ISSN 0306-0713 Copyright 0The Royal Society of Chemistry 1992 All Rights Reserved N o part of this book may be reproduced or transmitted in any form or by any means -graphic, electronic, including photocopying, recording, taping, or information storage and retrieval systems - 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 Bookcraft (Bath) Ltd.

In trod uction

The "Physical Methods" chapter has not appeared in Organophosphorus Chemistry since volume 19 and our difficulty in finding an author to replace John Tebby is a measure of the wide knowledge and volume of work required. We are delighted that Declan Gilheany from University College, Dublin has now agreed to take on the task from volume 24 and, in his first contribution, to cover the major points from the appropriate literature of the last few years. Interest in the synthesis and chemistry of phosphines and phosphonium salts continues at a high level. Reports include one describing a sterically protected triarylphosphine which survives heating in peracetic acid for 24 hours! Compounds containing p,-bonded phosphorus continue to be the subject of major interest. The phospha-alkyne ClCP has been characterised and it has been shown that simple phospha-alkynes RCP, including that with R=H, can persist in solution for several days. Further evidence is available that, for p,-bonded compounds, the structural effects of hybridisation changes at phosphorus are much more significant than for nitrogen; x - b o n d ing interactions may account for only half of the observed bond shortening. There have been relatively few truly novel developments in pentaand hexaco-ordinated phosphorus compounds. The emphasis continues to be on cyclic phosphoranes and structural aspects of pentaco-ordinated compounds and a useful review covering X-ray and 1H n.m.r. investigations of the latter area has appeared. It has been shown that phosphoranes containing five-, six-, and seven-membered rings retain their solid state structures in solution and that the boat conformation is preferred for saturated six-membered rings in apical-equatorial orientations of trigonal bipyramids. T h e importance of apical-equatorial ring orientations for intermediates in enzymatic reactions of phosphorinanes appearing as tbp cyclic AMP analogues has been emphasised. New developments in phosphine oxide chemistry have been largely confined to the continuing use of stabilised carbanions in synthesis. In view of this we intend to stop covering the area in a separate chapter from Volume 25. With the exception of the phosphine oxide-stabilised carbanion chemistry, which will be reported in "Ylides and Related Compounds", the material now covered in the chapter will be incorporated in chapter 1 together with phosphines and phosphonium salts. V

vi

Introduction

With the notable exception of nucleotide chemistry, highlights in the trivalent- and pentavalent-phosphorus acid areas have not been numerous in the period covered. Olah's demonstration that triisopropyl phosphite can be used as a substitute for Clemmenson/Wolf-Kishner techniques for the reduction of ketones to hydrocarbons is noteworthy, as is the remarkable structure of P 2 S e 5 . As noted in the Introduction to Volume 22, the pentavalent phosphorus acid area remains to a large extent in the doldrums. T h e exceptions to this are in the myo-inositol phosphate and aminophosphonic acid areas, with a rapidly growing interest in the synthesis of peptide-like compounds based on the latter. There has been substantially more activity in phosphonic/phosphinic acid chemistry than in that of phosphoric acids. Hammerschmidt's work on the biosynthesis of natural products having the P-C link, e.g. the role of hydroxyalkylphosphonic acids in fosfomycin and also the biosynthetic pathways to 2-aminoethylphosphonic acid, is worthy of special mention. Nucleotide chemistry continues to be dominated by the potential use of analogues as chemotherapeutic agents, particularly as anti-HIV drugs. In spite of many problems the anti-sense approach to viral chemotherapy continues to make steady progress and it is likely that anti-viral oligodeoxynucleotides will enter phase-one clinical trials in the near future. Interest in the interaction of nucleic acids with many diverse ligands which bind and cleave DNA has been maintained by the world-wide initiatives in molecular recognition and numerous elegant studies have appeared on this subject. Reports of theoretical and, especially, mechanistic studies on ylides and phosphonate-stabilised carbanions and their reactions are much reduced this year although these reactions continue to be very extensively used in synthesis. Developments include the increased range of heterocyclic systems synthesised by aza-Wittig reactions, the increased number and complexity of phosphonates used in natural product synthesis and the variety of new methods of introducing fluorinated-alkyl functions. Activity continues to increase in both basic and applied areas of phosphazene chemistry. Exciting advances in (po1y)phosphazene chemistry include anionic initiation of condensation polymerisation of phosphoranamines at modest temperatures, new heterophosphazene polymers and the first interpenetrating network polymer containing a poly(ph0sphazene) hydrogel which can encapsulate living cells while allowing them to retain biological activity. Finally, an overview of the regio- and stereochemical pathways followed in the reactions of cyclophosphazenes and principles for predicting these pathways has become available.

D W Allen and B J Walker

Contents

CHAPTER

1

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

1

Introduction

1

2

Phosphines

1

2.1 Preparation

1

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

2.1.1 2.1.2 2.1.3 2.1.4

2.1.5

2.2 Reactions of Phosphines 2.2.1 2.2.2 2.2.3 2.2.4 3

4

5

6

CHAPTER

2

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

1 4

7 9 9

12 12 12 13 15

Halogenophosphines

17

3.1 Preparation 3.2 Reactions of Halogenophines

17 17

Phosphonium Salts

19

4.1 Preparation 4.2 Reactions of Phosphonium Salts

19 22

p,-Bonded

23

Phosphorus Compounds

Phosphirenes, Phospholes and Phosphinines

31

References

36

Pentaco-ordinated and Hexaco-ordinated

Compounds By C.D. Hall

1

Introduction

48

2

Structure, Bonding and Ligand Reorganization

48

vii

...

Contents

Vlll

3

Acyclic Phosphoranes

49

4

Ring Containing Phosphoranes

52

4.1 Monocyclic Phosphoranes

52 55

Hexaco-ordinated Phosphorus Compounds

58

References

64

4.2

5

CHAPTER

CHAPTER

3

Bicyclic and Tricyclic Phosphoranes

Phosphine Oxide and Related Compounds

By B .J. Walker

Preparation of Phosphine Oxides

66

Structure and Physical Aspects

68

Reactions at Phosphorus

68

4

Reactions at the Side-Chain

68

5

Phosphine Oxide Complexes

71

References

75

4

Tervalent Phosphorus Acids By 0. Dahl

1

Introduction

77

2

Nucleophilic Reactions

77

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

77 79 79

Electrophilic Reactions

82

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

a2

3

3.4 Miscellaneous

a7 91

4

Reactions involving Two-co-ordinate Phosphorus

93

5

Miscellaneous Reactions

93

References

97

Phospholipid or Phosphoprotein Synthesis

CHAPTER

a4

5

Quinquevalent Phosphorus Acids By R.S. Edmundson

1

Phosphoric Acids and their Derivatives 1.1 Synthesis of Phosphoric Acids and their

102

Derivatives

102

Derivatives

119

1.2 Reactions of Phosphoric Acids and their

ix

Contents 1.3 Uses of Phosphoric Acids and their

Derivatives

2

Phosphonic and Phosphinic Acids and their Derivatives

2.1 Synthesis of Phosphonic and Phosphinic

CHAPTER

132

Acids and their Derivatives

132

and Phosphinic Acids and their Derivatives

169

2.2 Reactions and Properties of Phosphonic 3

132

Structures of Quinquevalent Phosphorus Acid Derivatives

18 3

References

184

6

Nucleotides and Nucleic Acids By R. C o s s t i c k

I

Introduction

196

2

Mononucleotides

196

2.1 Nucleoside Acyclic Phosphates 2.2 Nucleoside Cyclic Phosphates

196 206

3

Nucleoside Polyphosphates

206

4

Oligo- and Poly-nucleotides

2 13

4.1 DNA Synthesis

2 13

4.1.1 Chemical Synthesis 4.1.2 Enzymatic Synthesis 4.2 RNA Synthesis

2 13 2 16 2 17

4.2.1 Chemical Synthesis 4.2.2 Enzymatic Synthesis

2 17 220

4.3 Modified Oligonucleotides

220

4.3.1 Oligonucleotides Containing Modified

Phosphodiester Linkages

220

Sugars Oligonucleotides Containing Modified Bases

229

4.3.2 Oligonucleotides Containing Modified 4.3.3

232

Oligonucleotide Labelling, Conjugation and Affinity Studies

241

Nucleic Acid Triple-Helices and Other Unusual Structures

247

Cleavage of Nucleic Acids Including SelfCleaving RNA

250

Interaction of Nucleic Acids with Small Molecules

255

Contents

X

9 10

CHAPTER

7

Interaction of Metals with Nucleic Acids

262

Analytical and Physical Studies

265

References

268

Ylides and Related Compounds

By B.J.

Walker

I

Introduction

277

2

Methylenephosphoranes

277

2.1 Preparation and Structure 2.2 Reactions of Methylenephosphoranes

277 279

2.2.1 Aldehydes 2.2.2 Ketones 2.2.3 Ylides Co-ordinated to Metals 2.2.4 Miscellaneous Reactions

CHAPTER

279 283 283 283

3

The Structure and Reactions of Phosphonate Anions

289

4

Selected Applications in Synthesis

295

4.1 4.2 4.3 4.4

Carbohydrates Carotenoids, Retenoids and Pheromones P-Lactams Leukotrienes, Prostaglandins and Related Compounds 4.5 Macrolides and Related Compounds 4.6 Nitrogen Heterocycles 4.7 Miscellaneous Reactions

295 295 295

References

306

Introduction

313

Acyclic Phosphazenes

313

Cyclophosphazenes

323

Cyclophospha (thia)zenes

334

Miscellaneous Phosphazene Containing Ring Systems Including Metallophosphazenes

334

6

Poly(phosphazenes)

336

7

Molecular Structure of Phosphazenes

344

References

348

8

AUTHOR INDEX

297 297 301 301

Phosphazenes B y C.W. Allen

360

1

Phosphines and Phosphonium Salts BY D. W. ALLEN

1

Introduction

The past year has seen the appearance of the first volume of a major new work in the Saul Patai series on "The Chemistry of Functional Groups", concerned with the chemistry of organophosphorus compounds. This volume contains much of interest to readers of this chapter, reviewing the chemistry of primary, secondary, and tertiary phosphines, polyphosphines, and heterocyclic organophosphorus(II1) compounds. The Proceedings of the International Conference on Phosphorus Chemistry, held in Tallinn, USSR, in July 1989, have now been published, a significant amount of the work reported being relevant to the sections below, but which has not been reviewed further herein.2 Also of note are a number of reviews covering the generation and use of diorganophosphide reagents in the synthesis of phosphines , new methods of preparation of optically active phosphines for enantioselective transition metal catalyst systems, the application of the diphosphine BINAP(1) as a chiral element in asymmetric catalysis, and the chemistry of stable Mathey has reviewed three areas in which his phosphinocarbenes the chemistry of group has made significant contributions &y phospholes and related rr-complexes , the chemistry of 3-membered carbon-phosphorus heterocycles, and the reactions of coordinated phospha-alkenes.

.

2

PhosDhines

2.1 PreDaration 2.1.1 From HaloaenophosDhines and Oraanometallic Reaaents.A Grignard procedure has been described which enables the synthesis of large quantities (g1 mole) of trimethylphosphine from the reaction of methylmagnesium bromide with triphenylphosphite.l o High yields of tertiary alkylphosphines have been obtained from the reactions of Grignard reagents with the phosphorochloridite (2).l1 1

2

Organophosphorus Chemistry

Q

PPh,

~

p

p

n PR2

R2P (5)

h

Me

z

(3)

BuP ‘ , /c C ‘C iC HH

R = Menthyl

& c

PPh2

gPCH2CH2P@

(6)

A

/

&PPh2

0-

(9) R = Me, Et, Pr’, But, or Ph

v

(10)

4-1;. “-6””’ -1

NHMe

(14)

PPh2

R = H or PPh2

Me (17)n = 1 o r 2

n

1: Phosphines and Phosphonium Salts

3

Grignard procedures have also been employed in the synthesis of a range of hindered triarylphosphines, e.g. , ( 3 ) ,l2 and the chelating diphosphines ( 4 ) l3 and (5). l4 The reaction of f-butyldichlorophosphine with ethynylmagnesium bromide has given the dialkynylphosphine (6) from which macroheterocyclic polyphosphine systems involving alkynyl units have been prepared.l 5 An alternative route to the chelating diphosphole ligand ( 7 ) is provided by the reaction of 2,2'-dilithiobiphenyl with 1,2-bis(dich1orophosphino)ethane. Lithiation of chlorophenyl precursors with lithium metal, followed by treatment with chlorodiphenylphosphine, has been used in the synthesis of the new chiral diphosphines ( 8 ) .l 7 The "phospha[ 3 3 radialene" system ( 9 ) is formed in the reactions of 3,4-dilithio-2,5-dimethyl-2,4-hexadiene with organodichlorophosphines.l8 Two reports have appeared of the reaction of 3-lithiated D-camphor with chlorodiphenylphosphine. Treatment of the lithium reagent with 0.5 mole of the halogenophosphine results in the formation of the phosphino-enolate (10) as the only product. However, when 1.0 mole of the halogenophosphine is used, the main product is the 3-exo-phosphine (11) together with some of the 3-endo-isomer (12).19 On standing in solution the latter becomes the main product, and, indeed, is the only product reported by a second group.20 The generation of organolithium reagents by the direct metallation of acidic carbon substrates continues to be widely employed in the synthesis of phosphines. Direct o-metallation of methoxybenzene by butyllithium in the presence of tetramethylethylenediamine has been used in an improved route to tris-(o-methoxypheny1)phosphine (13).21 The o-phosphino-N-alkylanilines (14) have been prepared by the reactions of chlorodiphenylphosphine with the products of ortholithiation of the lithium salts of N-methyl-N-phenyfcarbamates, followed by acid decomposition of the intermediate phosphinocarbamates.22 A range of phosphines, e.g. , (15), has been prepared by the reactions of halogenophosphines with the product of ortho-metallation of N,N,N',N'-tetramethyl-P-phenylphosphonothioic diamide.23 Metallation of ferrocene with an excess of butyl-lithium, followed by treatment with dichloro(phenyl)phosphine, has led to the isolation of the chiral (but unresolved) phosphine (16).24 Lithium reagents derived from tetramethylcyclopentadiene have been employed in the synthesis of the unsaturated phosphines (17), whose coordination chemistry has also attracted some attention.25 The new chiral phosphine ligand

Organophosphorus Chemistry

4

(18) has been synthesised in the coordination sphere of iron by the reaction of a lithium enolate precursor with chlorodiphenylphosphine.26 The synthesis of the first closo-phosphacarborane system has been reported, utilising the reaction between a diorganometallic derivative of a dicarborane, with 2,4,6-tris-tbutylphenyldichlorophosphine 27 Other monophosphino derivatives of dicarboranes have also been prepared.28

.

2.1.2 Preoaration of PhosDhines from Metallated Phosphine6.- The past year has seen a significant increase in the number of papers describing the generation of metallophosphide reagents, and their use in synthesis. A range of new diphenylphosphido-metal derivatives has been prepared by the electrochemical oxidation of metals in acetonitrile solutions of diphenylphosphine 29 Treatment of the secondary phosphine ( But2SiF)2PH with butyllithium yields the cyclic zwitterionic phosphide (19) which does not involve a lithium-phosphorus interaction.30 A procedure for the synthesis of tris(trimethylsily1)phosphine and its conversion to lithium bis( trimethylsily1)phosphide has been published.31 This, and related silylphosphide reagents, have found extensive use in the synthesis of new polyphosphorus systems.32-39 Simple binary inorganic phosphide reagents have also continued to find application for the synthesis of novel cyclopolyphosphines, the contributions of Fritz et a1,40-43 and Baudler g& .144-51 being especially notable. Interest is growing in the synthesis and structural characterisation of phosphido-derivatives of aluminium,52 gallium,53-57 and indium,5 8 , 5 9 since thermal decomposition of such compounds may offer novel routes for the preparation of metallophosphide electronic devices. Metallophosphide reagents have also found use in the synthesis of cyclic stannylphosphine systems, e.g. , ( 2 0 ) .60t61 Applications of phosphinomethanide anions in synthesis continue to appear.6 2 Substitution reactions of neopentyl and cyclohexyl halides with the diphenylphosphide ion in liquid ammonia appear to proceed via the SRNl m e ~ h a n i s m . ~ The ~ , ~reactions ~ of ally1 halides with lithium diphenylphosphide have given the allylphosphines ( 2 1 ) 65 As expected, phosphide reagents attack the carbon atom of imines derived from aromatic amines, and, after protonation, N- (phosphinomethy1)arylamines (22) can be isolated.66 The reactions with epoxides of dilithium mono-organophosphides derived from primary phosphines proceed as would be predicted with ringopening to form the bis (hydroxyethy1)phosphines (23) 67

.

.

.

5

1: Phosphines and Phosphoniurn Salts

Ar NHC H2P(

Ph,PCH2CH=CR1 R2 (21) R'R2 = H or Me

R'COP<

,CH2CH(OH)But R1P , CH~CH(OH)BU'

R'

(22) R' = Me or Ph

But

ButP,

,COR'

PR2,

(24) R' = Pr' or But R2 = Et, Pr', or But

Ph

(23) R' = But or Ph

( BU~M~,S~)~P-P(S~M~,BU'),

M R ~ ~

(25) R' = But or Pr'; R2 = Me, Pr', or But; M = Ge or Sn

H2NCH2CHzP-PCH2CH2NH2

P+zPCH&H2Y (27) Y = OM@or NMe2

(26)

I

Ph

I

Ph

(28)

(34)R = Me or OMe

HN(C H ~ C H Z P R ~ ) ~

OMe (38) R = Me, Et, or Pr' (37)

(39)

Organophosphorus Chemistry

6

Phosphide reagents derived from the acylphosphines, RCOPHBut (R = But or Pri), react with halogenophosphines to form the acyltrialkyldiphosphines (24),68 and with triorgano-tin or -germanium halides to form the acylphosphines (25).69 Nucleophilic attack at halogen appears to be involved in the reaction of lithium bis(t-butyldimethylsily1)phosphide with 1,2dibromoethane, the diphosphine (26) being isolated.7 0 The normal substitution pathway is followed in the reaction of lithium di-isopropylphosphide with P-chloroethyl-esters or -amines, to give the functionalised phosphines ( 27 ) 71 The reactions of phosphide reagents with alkyl halides or sulphonate esters have continued to be a favourite route for the synthesis of new phosphine ligands, many of which are chiral, and of interest in the area of homogeneous catalysis. Among new chiral ligands reported are the diphosphine (28),72 the polydentate bis(aminoalkylphosphine) (29),73 and a series of chiral poly(phospholanyl) systems, e.g. , (30).74,75 A new approach to chiral diphosphines of the DIOP variety is afforded by the ringopening, using lithium diphenylphosphide, of a chiral diepoxybutane derived from tartaric acid to give the diphosphine (31), ketalisation of which occurs readily to form the familiar DIOP system.76 Michael addition of lithium diphenylphosphide to y alkoxybutenolides is the key step in a new approach to the synthesis of (S,S)-chiraphos (32). In related work, the reaction of lithium diphenylphosphide with 2-methoxyfuranone has given the novel, chiral, functionalised phosphine (33). 7 7 The dilithiophosphide reagent derived from l12-bis(phenylphosphino)benzene has been employed in the synthesis of the axial-chiral macrocyclic diphosphines (34).78 The lithiophosphide route has also been applied to the synthesis a number of "wide-span" chelating ligands, e.g., (35),79 (36)*' and (37).81 Protection at nitrogen using the trimethylsilyl group has considerable advantages in the reactions of bis(2-chloroethy1)amine with lithium diorganophosphide reagents, the protecting group being easily removed with water during work-up to give the phosphines (38).82 Selective displacement of a mesylate group has been utilised in the synthesis of the tripodal O,S,P-ligand (39).83 Although much less popular than lithiophosphide reagents, sodio- and potassio-phosphide reagents continue to be employed in phosphine synthesis. Cleavage of phenyl groups from phenylphosphines using sodium in liquid ammonia has been used to generate phosphide reagents in the synthesis of the trimethylsilylmethyl-

.

1:

Phosphines and Phosphoniurn Salts

7

.

phosphines ( 40) 84 An improved route to the bis (phosphino)pyridine (41) is afforded by the reaction of the readily available 2,6-difluoropyridine with sodium diphenylphosphide in liquid ammonia.8 5 The latter reagent, on treatment with carbon dioxide, yields the phosphinocarboxylate, Ph2PCOONa. With alkyl halides, this yields the alkyldiphenylphosphine with loss of C 0 2 , but alkylation using dimethyl sulphate gives the ester, Ph2PCOOMe.86 Potassio-phosphide reagents have been employed in the synthesis of further gallium-phosphorus systems,87 the diphosphine (42),88 and a range of chiral, chelating diphosphines bearing p-dimethylOther related p-dimethylaminophenyl substituents, e.g. , (43) aminophenylphosphine systems have also been reported. Generation of monophenylphosphide reagents by treatment of phenylphosphine with potassium hydroxide in DMSO has been used in a synthesis of the chiral phospholane (44).9 1 Further reports have appeared of the synthesis of the phosphine (45) by the alkenylation of elemental phosphorus in superbase media. 9 2 f 9 3 Superbase media have also been employed in the reactions of diphenylphosphine with allylic and propargyl halides.94

.*’

2.1.3 PreDaration of Phosphines by Addition of P-H to Unsaturated Compounds.- The products of base-catalysed addition of diphenylphosphine to diphenylacetylene depend on the conditions used; in addition to the Cis- and trans-isomers, (46) and (47) respectively, the meso- and racemic forms of the diphosphine (48) have also been isolated.95 Under free radical conditions, diphenylphosphine adds to terminal alkynes to give E-vinylphosphines as the primary kinetic product, but the 2-vinylphosphines ( 4 9 ) are the main products isolated. On the other hand, addition to allenes usually gives complex mixtures of products, in which the predominant components are vinylphosphines formed by addition of the diphenylphosphino radical to the central carbon of the allene.96 The diphosphinomethanes (50) undergo intramolecular P-H addition to form the 1 ,5-diphosphabicyclo[ 3,3,1]nonane system ( 5 1 ) 97 The hydrophosphination of acrylonitrile has been shown to be catalysed by a platinum (0) complex of tris-( 2 - c y a n o e t h y l ) p h o ~ p h i n e . ~The ~ alkylphenylphosphinopropionitriles ( 5 2 ) have been obtained by the radical addition of the secondary phosphines, PhPHR, to acrylonitrile.9 9 Further examples of the base-catalysed addition of diphenylphosphine to up-unsaturated-nitriles and -esters have been reported, the use of cyclic acceptors enabling the synthesis of the chiral functionalised systems (53). l o o Photochemical addition of

.

8

Organophosphorus Chemistry

Ph2P PhP(R)CH2SiMe3 (40) R = Et,CH2CHMe2,or Ph

Ph2Po

P

lo"""

P

h

2

(41)

(42)

[ PhCH=CH] 3P

Me---QMe

2

H

ph2Ph px:h

PhZP, PPh2 CH-CH Ph' Ph

Ph

HLpCH2=CHCH,/

n

H p\

(49)

(48)

(47)

(46)

CH2CH=CH2

PhPRCHzCH2CN (52) R = n-alkyl, Pr', Bus, or cycloalkyl

>c..2h

~3

Ph2P

NC

(53)n = 3 or 4

Me2PCH2CH2SiX3

(54) X = hal, Me, or OMe

R1@0Me

MeO@ R2

\ / Ph2.P

Ph P ~ Z P ( C HhRMe2 ~)~ (56)n = 2 o r 3 R=HorMe

X=CIorI

X-

LTJ Ph

(58) X = 0 or S

(57)

BH3

t p\ Ph'= 1 R'

(59) X = CH2 or S

PPh2 (55)

(60) R',R2 = H or Me

OMenthyl

(61) R' = Me or o -MeOCsH4

1: Phosphines and Phosphonium Salts

9

dimethylphosphine to vinylsilanes has given a range of new silylalkylphosphines (54).lo’ Further reports have appeared of the synthesis of phosphorinanones by the addition of phenylphosphine to divinylketones,lo2 I lo3 and also of the reactions of 1,5-diketones with phenylphosphine, which lead to phosphorinane derivatives.l o 4 Addition of either P-H or P-Si to the C=N bond can occur in the reactions of phenyltrimethylsilylphosphine with benzaldimines.lo5 Whereas secondary phosphine oxides add cleanly to the N=N double bond of dialkylazodicarboxylates, the related reactions with diphenylphosphine proceed only slowly to give a complex mixture of products. 2.1.4 PreDaration of PhosDhines by Reduction.- A new route to chiral diphosphines in the biphenyl series (55) is afforded by Ullmann coupling of 2-iodophenylphosphine oxides, followed by reduction of the biphenyldiphosphine dioxide with trichloroThis reagent has also been used in the final step of si1ane.l” a route to the chiral diphosphine BINAP( 1) , and in the preparation of a series of cationic, water soluble phosphines (56) from the corresponding phosphine oxides. l o g Surprisingly, lithium aluminium hydride has proved to be a far superior reagent compared with halogenosilanes for the reduction of oxides of medium size cyclic diphosphines, e.g. , (57).‘lo Lithium aluminium hydride has also been employed in the reduction of phosphinyl chlorides to give secondary phosphines bearing adamantyl substituents, and for the reduction of acylphosphonates to primary phosphines, RCH2PH2, (R=l-adamantyl or 1-adamantylmethyl). ‘12 Similarly, the bis( primary)phosphines (58) have been obtained by reduction of related bisphosphonate esters with lithium aluminium hydride.’13 In related work, cyclic diphosphines (59) have been obtained by the reduction of corresponding cyclic diphosphinate esters using diphenylsilane, whereas open-chain phosphines, MePHCH2XCH2PH2 (X = CH2 or S), were obtained using lithium aluminium hydride as the reducing agent. Dichloroalane in tetraglyme has been employed in the reduction of alkynyl- and allenyl-phosphonates, enabling the synthesis of gram quantities of the related primary phosphines, e.g. , (60).’15 2.1.5 Miscellaneous Methods of Preparina Ph0sDhines.- A new route to triphenylphosphine (and its oxide) is provided by the arylation of red phosphorus using iodobenzene in the presence of nickel(I1) bromide at >200’C. Phosphines bearing a chiral substituent

10

Organophosphorus Chemistry

have been prepared from chiral alcohols conversion to the alkyldiphenylphosphine oxide, and subsequent reduction using The reactions of organolithium reagents with trichlorosilane.'17 chiral trivalent phosphorus esters and amides, whose configuration at phosphorus is protected by conversion to the related borane adduct, have been employed in new approaches for the synthesis of The menthyloxyphosphine-boranes ( 61) chiral phosphines 11*, 11' undergo stereospecific cleavage of the alkoxy group on treatment with one-electron reducing agents, to form the intermediates (62) which can be protonated or alkylated to form the chiral phosphineboranes (63). The borane group is easily removed on treatment with triethylamine.1 2 0 The cyclophane system ( 64 ) has been isolated in 12% yield from the reaction of tris(2-mercaptopheny1)phosphine with 1,3,5-tris(bromomethyl)benzene under basic conditions. The phosphorus atom is poised above the basal aromatic ring, and is remarkably unreactive, surviving heating in peracetic acid for twenty-four hours!121, 122 Alkylation of the copper( I) complex of lI2-bis(phosphino)benzene, using lI3-dibromopropane in the presence of base, has given the tetraphosphorus cage system (65).123 A route to the dihydrodibenzophosphorins (66) is afforded by the acid-catalysed reactions of bis(3-dimethylaminopheny1)arylphosphines with aromatic aldehydes.124 Hydrolysis of tris(2-cyanoethy1)phosphine in refluxing concentrated hydrochloric acid affords the air-stable, water-soluble phosphine (67), which has been used for the selective reduction of disulphides in aqueous solution.125 The phosphino-alkenylborane (68), which has a large molecular polarisability, has been obtained by hydroboration of Routes for ethynyldiphenylphosphine using dimesitylborane 12' the synthesis of amidoarylphosphines, e.g., (69), have been developed.127 A range of new 2-aminoethylphosphine ligands (70) has been obtained by the base-catalysed addition of primary- and secondary-amines to vinyldiphenylphosphine.128 A new route to methylenebis(diary1phosphine) monoxides (71) is afforded by the reaction of diarylphosphines with formic acid in the presence of concentrated hydrochloric acid. The phosphino-indole ( 72 ) is formed in the reaction of 1,2-dimethylindole with chlorodiphenylphosphine in the presence of a base.130 A new route to the cyclic silaphosphine (73) is provided by the reaction of a dimethylsilyltriflate with phenylphosphine.13' Phosphinoacetic esters, e.g., (74), accessible y & the reactions of the related alkyl chloroacetates with trimethylsilyldiorganophosphines,132,133 undergo silylation at oxygen to form the 2-

.

.

I:

Phosphines and Phosphonium Salts

Ph2P'

CH=CH

11

RZ= aryl

,BMes2

Ph2PCH2CH2NR1R2 (70) R' = H or alkyl R2 = alkyl

(68)

F? Ar2PCH2PAr2 (71) Ar = Ph or

p -tolyl

Ph

(69)

aTi

PPh2

I

(72)

. ,

(82) R = C13C; Z = 0 R = S-; Z = S

'\ I

Me2Si

I

SiMe,

Ph2PCH2C02R

I

Me2Si Lp/SiMe2

Me

I

Ph

Me

(73)

(74) R = Me or But i-

OPR3

I

(76)

(83)R = Et or Me

(84)

12

Organophosphorus Chemistry

diphenylphosphino-substituted silyl enol ethers (75). 133

Side-chain elaboration of phosphinoferrocenes has given new chiral ligand systems.134 Cyclopolyphosphines bearing pentamethylcyclopentadienyl substituents have been prepared.135 2.2 Reactions of PhosDhines 2.2.1 Nucleophilic Attack at Carbon. The initial product of the reaction between a tertiary phosphine and tetrakis(trif1uoromethy1)cyclopentadienone is the adduct (76), which on heating The phosphonium salts transforms to the ylidic system (77).13' (78), formed in the reactions of tropylium tetrafluoroborate with phosphines, exist in solution in equilibrium with the isomeric norcaradienyl form (79). 137 The phosphacyclobutene ( 8 0 ) undergoes a series of [4+2] cycloaddition reactions with Michael acceptors, e.g., dimethyl maleate, to form e.g., the six-membered & the intermediacy of zwitterionic adducts ring system (Sl), y arising from nucleophilic attack by phosphorus at the double bond of the acceptor.138 Adducts of 2-phosphino-alkenylboranes with carbon disulphide or chloral have been shown to adopt the cyclic structure (82).13' Further studies have been reported of the reactions of tertiary phosphines with phenylacetylene in protic The ylides ( 8 3 ) are formed in the reactions of solvents.14' tributylphosphine with methoxyallene.14' Addition of P-H to the carbonyl group of l,l,l-trifluoropropanone occurs in its reactions with phosphine and primary and secondary phosphines, with the formation of new, chiral phosphines, e.g. , (84).142 Various products arising from insertion of reactive phosphines into either the C=C or the C=O bonds of carbon suboxide, C3O2, have been characterised.143 A spectroscopic study of the interaction between triphenylphosphine and various unsaturated cyclic anhydrides has also been reported.144 2.2.2 NucleoDhilic Attack at Ha1oaen.- Diorganotrichloromethylphosphines, accessible via the reactions of secondary phosphines with tetrachloromethane in the presence of triethylamine, can be used as convenient reagents for the preparation of new, reactive phosphonium salts, and also to promote chlorination, dehydration, and condensation reactions under mild conditions.145 Further examples of synthetic applications of triphenylphosphine-tetrahalomethane combined reagents have appeared. The use of acetonitrile as a cosolvent with the triphenylphosphine-tetrachloromethane system allows the dehydration of aldoximes to nitriles under mild

13

1: Phosphines and Phosphonium Sults

Deuterium isotope studies of the dehydration of conditions.14' alcohols by the triphenylphosphine-tetrachloromethane system have been reported,147 and an example given of a synthetically useful rearrangement of an alcohol in the presence of this reagent to give chiral products.148 A convenient route to N-methoxyamides is provided by the reactions of carboxylic acids with N,O-dimethylhydroxylamine hydrochloride in the presence of triphenylphosphine Combinations of triphenylphosphine and tetrabromomethane 14' with trihaloacetic acid derivatives have been employed in a study of the halogenation of optically active octan-2-01s. 150

.

2.2.3 NucleoDhilic Attack at Other Atoms.- A reinvestigation of the course of the reaction of triphenylphosphine with o-azidobenzaldehyde has revealed a marked temperature dependence. In ether at -20°C, the phosphatriazene (85) is formed, whereas at room temperature, in dichloromethane, the products are the phosphazenes (86) and (87).15' The Mitsunobu procedure continues to attract attention. The use of p-dimethylaminophenyldiphenylphosphine instead of triphenylphosphine aids separation of the phosphine oxide by acid e ~ t r a c t i 0 n . l ~The ~ use of p-nitrobenzoic acid as the nucleophilic partner in the synthesis of hindered esters results in a significantly improved yield, proceeding with inversion of configuration at the alcohol carbon.153 The stereochemical course of Mitsunobu reactions of urethane derivatives is anomalous.154 Applications of the triphenylphosphine-diethyl azodicarboxylate reagent have been described for the synthesis of phenolic ethers from indan aminoalcohols and phenols ,155 cyclodehydration of a,w-aminoalcohols to form azacycles ,156 and the regiospecific O-alkylation of p-tetronic acids.157 This reagent system has also been applied to the regioselective and stereospecific substitution of unsymmetrical 1 ,2-diols, 31P n .m.r. studies revealing the intermediacy of both phosphorane and oxyphosphonium species.15' The reactions of the phosphine ( 4 5 ) with chalcogens proceed normally.15' Ring-opening of cyclic disulphides16' and polysulphides161 occurs on treatment with triphenylphosphine Combinations of tertiary phosphines with di(2-pyridy1)disulphide have been used in the synthesis of 2-oxazolidones from 2-amino-lphenylethanol and carbon dioxide.162 The tributylphosphine diphenyldiselenide combination has been used as a coupling reagent in peptide synthesis.163 Various borane adducts of polydentate phosphines have been prepared,164, 165 and a polyborane adduct of

.

14

Organophosphorus Chemistry

/

c 7 phpP12 c, P

N-CH2PPh2

PhZPCH2-N

OJ

W

Ph2PC(SiMe&

Ph2PCH2C>P Phh OSiMe3

(90)

O

(92)

(EtO),Si

app (93)

PPh2

1: Phosphines and Phosphonium Salts

15

trimethylphosphine has been characterised.166 The reaction of tris(trimethylsily1)phosphine with borane has been reinvestigated. The initial phosphine-borane adduct decomposes above 1OO'C to form phosphinoborane ring systems.167

..

iscellaneous Reactions of Phosghines.- A number of triheteroarylphosphines have been shown to undergo substituent group exchange or biaryl coupling on treatment with aryl- or heteroaryllithium reagents. Thus, e.g., treatment of tris(2-benzothiazoly1)phosphine (88) with phenyl-lithium leads to the formation of 2,2'bibenzothiazolyl (66%). Similarly, tris(2-pyridy1)phosphine gives rise to 2,2'-bipyridyl (81%). In contrast, treatment of tri(2thieny1)phosphine with 2-pyridyl-lithium, followed by quenching with water, results in the formation of thiophen (El%), together with 2,2'-bipyridyl (23%). These reactions are believed to involve the formation of hypervalent phosphoranide intermediates, and explain some of the earlier difficulties experienced in attempts to synthesise heteroarylphosphines such as ( 8 8 ) from the reactions of the heteroaryl-lithium reagent and phosphorus trichloride. Cyclisation of the phosphine ( 8 9 ) to the bridged system (90) occurs on treatment with acid. The phosphorus atom of ( 9 0 ) appears to react normally with o-chloranil to form a phosphorane. Various macrocyclic systems have been obtained from condensation reactions of the phosphino-dialdehyde (91) with hydrazine derivatives.17' The diphosphine (92), of interest as a new hybrid ligand system for linking main group and transition metal ions, has been prepared by the reaction of diaza-18-crown-6 with diphenylphosphine and paraformaldehyde.17' Attention has been drawn to the virtues of tri(2-fury1)phosphine (93) as a ligand in organometallic catalytic systems involving palladium. Its reduced donor power relative to triphenylphosphine has a beneficial effect on the rates of reactions catalysed by palladium complexes.172 Examples of the cleavage of phosphorus-carbon bonds of phosphines coordinated to transition metals continue to appear.173-177 Perhaps the most surprising reaction of this type reported recently is the conversion of triethylphosphine to diethylfluorophosphine in the coordination sphere of iridium in the reaction of an iridium triethylphosphine complex with hexafluorobenzene .17* The crowded phosphine, diphenyltris(trimethylsi1yl)methylphosphine ( 9 4 ) , has been shown to undergo desilylation and cyclometallation reactions on coordination to platinum( 11) .I7' The reaction of diphenyl(trimethylsilylmethy1)phosphine with

16

Organophosphorus Chemistry

benzophenone in the presence of caesium fluoride results mainly in the formation of the phosphine (95).180 Addition reactions of alkynylphosphines continue to be explored. I 182 Treatment of tris(trimethylsily1)phosphine with bis(dimethylamino)methane, and related aminomethylethers, in the presence of zinc chloride, results in the formation of tris(dialkylaminomethy1)phosphines and tris (alkoxymethy1)phosphines.183 Constant current electrolysis of triphenylphosphine in the presence of a carboxylic acid in dichloromethane leads to the formation of acyloxytriphenylphosphonium salts, which are subsequently capable of in-situ conversion to esters, amides, and p-lactams under mild conditions.184 Phosphino-stabilised ally1 anions are formed on deprotonation of phosphinopropenes with alkyl-lithium reagents. 85 The kinetics of sulphonation of a range of bis(dipheny1phosphino)alkanes have been reported.186 Photolysis of 2-mercaptoethyl(methy1)phenylphosphine results in its conversion to ethyl(methy1)phenylphosphine sulphide.187 Photoreduction of the 10-methylacridinium ion occurs in the presence of triphenylphosphine in methanol, the phosphine being oxidised.188 In the presence of an electron acceptor, triphenylphosphine undergoes photo-oxidation to form a radical cation, which can be trapped by nucleophilic reagents.18' Dicyclohexylphosphine acts as a single electron donor towards triphenylmethyl bromide, generating the triphenylmethyl radical. The reactions of water-soluble sulphonated triarylphosphines with a-bromoketones in aqueous solution proceed via attack at halogen, with the formation of the phosphine oxide and the debrominated ketone. In other solvent systems, e.g., aqueous triethylamine, phosphonium salts are formed.l g l The reactions of phosphinocarbeneslg2 l9 and phosphino-substituted nitrilimineslg4 (and related salts)l g 5 have received further study. Kinetic isotope effects have been measured for proton exchange between diphenylphosphine and alcohols and thiols.l g 6 A further report of the chemistry of phosphorus-oxygen-boron heterocycles has appeared.lg7 The reactions of X ,A 3-P ,Pdiphosphines, and related X 3 ,X '-systems , with o-quinones involve not only oxidative addition to X3-phosphorus, but also insertion of a further quinone moiety into the phosphorus-phosphorus bond. The diphosphine (96) can be anchored to silica gel y & the siloxy group, and used to form recyclable catalyst systems.lg9

1:

Phosphines and Phosphonium Salts

3

17

Haloaenophosphines

3.1 PreDaration.- Very little has been published in this area in the past year. Procedures have been presented for the synthesis the of sterically crowded halogenophosphines, e.g., ( 9 7 ) , reactions of organolithium reagents with phosphorus trichloride.2 o o Regioselective metallation of N,N-dimethyl-3,5-bis(trifluoromethy1)aniline with butyl-lithium/hexane or methyl-lithium/ether, followed by phosphorus trichloride, provides routes to the aryldichlorophosphines (98) and (99), respectively.201 Metallation of 1,3-bis(trifluoromethyl)benzene with butyl-lithium, followed by treatment with chlorodifluorophosphine, results in the formation of a mixture of the fluorophosphines (100) and (101).202 The reactions of trimethylsilylphosphines with bromodifluorophosphine provide a route to fluorinated and silylated di- and triphosphines, e.g. , (102).203 Treatment of the zirconium complex (103), derived from t-butylphospha-ethyne, with either phosphorus pentachloride or phosphorus tribromi.de u phosphorus tri-iodide, results in the formation of the trihalogenotriphosphabicyclo[ 1,1,llpentane system (104).204 The synthesis, physical properties, and general reactivity of cyanodiorganophosphines has been reviewed.205

3.2 Reactions of Ha1oaenoDhosDhines.- The bicyclic phospholenium salt (105) is formed in the cycloaddition of dichlorophenylphosphine with 3,4-bis(methylene)-thiolane.206 Cycloaddition reactions of trimethylsilyl(organo)chlorophosphines with a dipolar boron-nitrogen reagent, and an iminophosphine, respectively, have given the heterocyclic systems (106) and (107).207 Bis(ha1ogenophosphin0)methanes undergo dehalogenation on treatment with Fe2(C0)9 to give either complexes of diphosphiranes (108) methylenebis(phosphido) complexes. At higher temperatures, clusters containing phospha-alkene ligands are formed by metalpromoted cleavage of P-C-P skeletons.208 A tricoordinate phosphorus cationic intermediate appears to be involved in the reactions of chlorodiphenylphosphine with t-butanol in the presence of various heterocyclic bases.209 The selenium ester (109) is formed in the reaction of chlorodi-t-butylphosphine with the lithium selenophenolate.210 Tricyclic phosphoranes are formed in the reactions of dichloro(organo)phosphines with the enol form of 1,1 ,1,5 ,5 ,5-hexafluoropentan-2,4-dione . l1 Pentacovalent species (110) arise in the reactions of dichloro(organo)phosphines with

18

Organophosphorus Chemistry

R I

A

I

R-P-N-Bu' IP\

/p\ BU'B=NBU~

R-P-P-R

(106) R = (Me3Si)2CH, Me5C5,

PrLN, or But

R -P-,

x' x

=C:

ON

R

,CC'3

R-P,

cc13

CI

(1 11) R = Me, Pr', or Ph

(1 10)

R - ; w C H 2 ]

X-

3 (113) R = Me or PhCH2 X=BrorI

+

,-PPh3

4x-

Meo$+popri

Br

OPri

3

PPh3 B r

(1 15)

Y+ PPh3 I-

+

g s S~ & h 3CI-

Me3PCH2CH(OMe)Ph BPh4(1 19)

,$ I

Ph2P(CH2) Ph2 Me

X-

+

Ph3P(CH2JnCH(OH)CH3 X(120)

NHPh

+

+

B u ~ P C H ~ C E C C H ~ P B2CIU~

+PPh3 B r

1: Phosphines and Phosphoniurn Salts

19

.

a-dichloronitrosoalkanes l2 In the presence of appropriate nucleophilic reagents, these go on to give products derived from the related quasi-phosphonium ions.213 The reactions of bis(dich1orophosphino)methanes with alkoxylating agents have been studied.214 Vicinal diols are converted to alkenes in high yield in the presence of a reagent system consisting of chlorodiphenylphosphine, imidazole, and iodine, in an inert solvent.215 Treatment of organo(trichloromethy1)chlorophosphines with tris(diethy1amino)phosphine and carbon tetrachloride results in the formation of the phosphines (111).216 The formation of labile P-P bonded compounds in the reactions of halogenophosphines with aluminium trihalides has been studied by n.m.r. 217 Halogenophosphines coordinated to osmium(I1) undergo nucleophilic substitution reactions relatively slowly.218 Mono-organomonochlorophosphines, RPHC1, have been prepared and stabilised within the coordination sphere of a metal. 219 The halophosphonium salts RPC13+ PC16- are reduced to the organodichlorophosphine on treatment with diethylamidodifluorophosphites.220 The reactions of cyano(pentafluoropheny1)phosphines with stable nitroxyl radicals have been studied.221 4

PhosDhonium Salts

4.1 PreDaration.- Primary alkyltriphenylphosphonium salts are accessible from the reactions of alcohols or lactones with triphenylphosphine hydrobromide.222 Quaternization of the phosphine (112) with an alkyl or benzyl halide, followed by demethylation of the ether function using iodotrimethylsilane provides the phosphonium salt (113), which, in the presence of further phosphine, undergoes quaternization to form the tetraphosphonium salts (114). Repetition of this methodology enables the synthesis of polyphosphonium cascade systems.223,224 Conventional quaternization procedures have also been used in the synthesis of the salts (115),225 (116),226 and (117).227 In the latter, the bulky triphenylphosphonium group has only a slight preference for the equatorial position of the dithiacyclohexane ring system, perhaps as a result of competition between repulsive 1,3-interactions in the axial conformers and a possible sQp-P3d anomeric interaction. Quaternization of 1,3-bis(diphenylphosphino)propane with a,w-bisphosphinylalkanes bearing P-bromoethyl substituents at phosphorus is a key step in the synthesis of tetraphosphorus macrocyclic systems.2 2 8 Monomethyl-

20

Organophosphorus Chemistry

phosphonium salts (118) of a,w-bis(dipheny1phosphino)alkanes have been obtained using haloacetic acids or esters, the intermediate carboxyalkylphosphonium salts suffering decarboxylation in situ.2 2 9 The reactions of water-soluble, sulphonated triarylphosphines with activated alkynes under acidic or neutral conditions have given a range of vinylphosphonium salts.230 Improved yields of such salts from the related reactions of triphenylphosphine are obtained if the reactions are conducted in reverse (water-hydrocarbon) report has been published by the m i c r o e m ~ l s i o n s . ~A~second ~ same group of the formation of the salt (119) in the reaction of phenylacetylene with trimethylphosphine coordinated to cobalt(1) in methanol solution.232 The chiral 2-hydroxyalkylphosphon~umsalt (120, n=l) has been obtained from the reaction of triphenylphosphine with epoxypropane in the presence of either dibenzoyltartaric or camphorsulphonic acid. The corresponding reaction of the epoxide with methylenetriphenylphosphorane yields the 3-hydroxyalkylphosphonium salt (120, n=2), again in chiral form.233 A wide variety of vinylphosphonium salts has been obtained the stereospecific reactions of triphenylphosphine with vinyl triflates in the presence of a zerovalent palladium-phosphine complex.234 The bis (phosphonium) salt ( 121) is formed in the reaction of tributylphosphine with 2,3-dichlorobutadiene.235 Synthetic routes have been developed to the salts (122), which undergo conversions to enol lactones and allene~, and ~ ~also ~ to the P-enaminophosphonium salts (123), which are precursors of Wittig reagents employed in the synthesis of 2-vinyl-1-aza-1,3-dienes and penta-1 ,4-dien-3-ones.237 Polymer-bound tetraarylphosphonium salts have been prepared via the Horner reaction of appropriate ring-halogenated polystyrenes with triphenylphosphine in the presence of nickel ( I1 ) bromide.238 2 3 9 Electrochemical oxidation of triphenylphosphine in the presence of cyclic enol silyl ethers (or esters) gives the salts (124);240 in the presence of allylsilanes, allyltriphenylphosphonium salts are formed. This procedure has been adapted for the preparation of the salts (125) bearing P---methylene functionality.241 The distannetane-bisphosphonium salt (126) has been isolated from the reactions of a stannyl-substituted phosphorus-ylide with borontrifluoride.242 The salt Ph4P+ AsC16- has been characterised.243 Addition of iodine to methyltriphenylphosphonium iodide gives the related triiodide salt, Ph3P+Me 13-. 2 4 4 Treatment of polymer-bound benzyltriphenylphosphonium bromide with chromium

21

1: Phosphinesand Phosphonium Salts

0

But2

+

!ySyPPh3 'H

Ph3P'

Sn But2

2BF4-

(124) R = Me; n = 1-3

,C02Me

X-

Yr R3

? ,P )h 3 6 ,

I

-

Ph I-

I

Ph3P+

(130)

dPPh3 +

+

Ph3P-GPPh3

(132) Ar = Ph or p -tolyl

+

Ph2P-CH-PPhs

II I

20Tf -

X-

0 COR

-+ (134)

(133)

CI-

NHCOAr

Ph B r

(131)

+ S*N Ar

+

CICH=CHCH--PPh,

(135)

F3C [C5Me5(CO),Fe]P=P

ArP=PNHAr

[ArP-Prr-NArILi

(137) Ar = Mes

F3C

(138) Ar=Mes

(136) R = H or CF3 ArP-CECTMS I

ArP-CECTMS

ArP

SiMe,

ArP

SiMe,

)(

(141) R = H or Me

(139) Ar = 2,4,6-Bu'3C6H2

Bu'P=C:

But

OR

(143) R = PPr'2 or GePr'3

C ' k0 Bu'

[)But

R o

+

(EtzN)2C=P-PNRz (144)

X-

(142)

E 2*? f!

f,$C-P=P-NR2 Et2N (145)

X-

22

Organophosphorus Chemistry

trioxide provides the related dichromate salt, useful as an easily recoverable oxidising agent.245 Organotellurenyl cationsI RTe+ , can be stabilised by the addition of triphenylphosphine, forming the salts Ph3P+TeR X-.246 New routes to nitrogen-bridged bis (phosphonium) salts have been described.247,248 4.2 Reactions of Phosphonium Salts.- Another survey has appeared of the consequences of through-space NZP-P(IV) interactions in the chemistry of o-dimethylaminophenylphosphonium salts.249 Full details have been given of the formation of bipyridyls in the decomposition of alkyltri-(2- or 4-pyridy1)phosphonium salts under neutral, or mildly acidic, aqueous conditions, providing further examples of ligand coupling arising from hypervalent intermediates.2 5 0 Further reports have been published of solvent effects on the rate of alkaline hydrolysis of phosphonium salts,251 and also of the alkoxide-promoted decomposition reaction.252 Unsymmetrically substituted hydrazines have been obtained by the alkaline hydrolysis of related hydrazinylphosphonium salts prepared by alkylation of N-phenylaminophosphazenes 253 Dithiole-containing ylides, e.g . I (127), are formed in the reactions of the tributylphosphine-carbon disulphide zwitterion with electron-withdrawing alkynes 254 The alkylthio(triary1)phosphonium salts (128), obtained by alkylation at sulphur of tris(2,6-dimethoxyphenyl)phosphine sulphide, are thermally stable, but react with thiols in methanol to form unsymmetrical disulphides, together with the phosphine hydrobromide (129), enabling a facile regeneration of the phosphine and its sulphide.255 Treatment of phenacyltriphenylphosphonium bromide with iodine in the presence of potassium carbonate gives the benzoyliodomethylphosphonium salt (130), a convenient reagent for the direct synthesis of arylethynyl phenyl ketones by chain extension of aldehydes.256 Fluorinated p-ketophosphonium salts have been used in routes to fluorinated b r o r n o a l l e n e ~and ~ ~ ~for the fluoroalkylvinylation of thiophens.258 The first successful 1,3-dipolar cycloaddition reactions of nitrones with ap-unsaturated phosphonium salts have been reported, leading to the formation of phosphonium salts bearing heterocyclic substituents, e.g., (131).259 Cyclocondensation of the vinylphosphonium salts (132) with sodium thiocyanate gives the thiazolylphosphonium salts ( 133). 260 Further synthetic applications of the phosphonium anhydride (134) have been reported.261f262 Examples of phase-transfer catalysis involving phosphonium salts also continue

.

.

1: Phosphinesand Phosphonium Salts

23

to be reported.263,264 Studies of the phosphoryl-hydroxy ylide tautomerism of the salts (135) have also continued.265 5

p,-Bonded

PhosDhorus Compounds

Activity in this area has continued at about the same level as last year. Structural evidence has been presented for the characterisation of phosphorus and arsenic analogues of organic azides in the coordination sphere of a A theoretical comparison of potential rr-bonding in distibene, HSb=SbH, and dibismuthene, HBi=BiH, with that in related diphosphenes and diarsenes, suggests that such p,-bonded antimony and bismuth systems should be isolable, given suitable steric protection.267 Standard procedures for the synthesis of sterically crowded diphosphenes have appeared.268 Weber ' s group has continued to develop the chemistry of diphosphenes bearing complexed transition metal species as substituents at phosphorus. The diphosphenes (136) are reported to be thermally labile, but can be trapped as o-complexes with a chromium carbonyl acceptor.269 Further studies of the coordination chemistry of such diphosphenes have been described. 70 Trapping of P-metallodiphosphenes in cycloaddition reactions has also been achieved.271 272 Treatment of the aminodiphosphene (137) with butyl-lithium has given the l-aza-2,3-diphospha-allyl system (138), from which metal complexes have been isolated.273 Information of relevance to the gas-phase formation of P=C and PrC systems has been obtained from an analysis of the molecular states of phosphorus compounds.274 Theoretical studies of substituent effects on P=C and P=N bond properties have been reviewed.275 Solid state 13C and 31P n.m.r. studies of P=C and PzC systems have been reported.276 The diphosphine (139) rearranges at room temperature to form isomers of the bis(phosphinidene)cyclobutene system ( 140).277 Condensation of primary phosphines bearing 2- or 3-hydroxyalkyl substituents with N-arylpivalimidoyl chlorides provides a route to the thermally stable, cyclic non-conjugated phospha-alkene ethers, (141) and (142), respectively. Both systems undergo ring-opening on oxidation in air, or on treatment with water.278 A phospha-alkene stabilised by a C-carboranyl group has been prepared.279 Organothallium derivatives of acylphosphines have been employed in the synthesis of the thermally unstable phospha-alkenes ( 143). 280 The phospha-alkene-phosphenium ion (144) undergoes fast valence

24

Organophosphorus Chemistry

isomerism towards the diphosphene system (145), which subsequently suffers dimerisation to form the cyclotetraphosphine system (146).281 The reactions of the "phospha-Wittig" reagents (147) with aldehydes have given thermally unstable phospha-alkene complexes which can be trapped with methanol to give complexed phosphinites.282 The complexed cyclic phospha-alkene ( 148) has been prepared by a related intramolecular reaction.283 X-ray studies have confirmed the structures of the functionalised diphosphiranes (149) obtained from the reactions of -. diphosphenes with carbenes. Photolysis of the diphosphiranes leads to geometrical isomers of the lI3-diphosphapropenes (150), which have also been shown to exhibit r ~ t a m e r i s m . ~ A~ theoretical ~,~~~ study has appeared of the formation of diphospha-allenes by the ring-opening of diphosphiranes using methyl-lithium.286 A route to the C- (dialky1amino)phoepha-alkene (151) has been described,287 and its reactions with C,N-diphenylnitrone,288 sulphur,289 and dimethyldisulphide2 studied . The structure of the stable P-(aminoalky1)phospha-alkene (152) has been determined by X-ray techniques, stabilisation of the double bond being attributed to steric shielding, the bond length falling in the usual range for phospha-alkenes.291 A rotational mechanism for the E-2 isomerisation of the P-(aminoalky1)phosphaalkenes (153) has been derived from a multinuclear n.m.r. study of their dynamic stereochemistry.292 A theoretical study has been reported of the structure and reactivity of 2,3-diphospha-1,3butadienes 293 An electrochemical study of phospha-alkenes has shown that they undergo irreversible oxidation and reduction processes.294 A theoretical study of the methylenephosphonium ion (154) reveals the presence of a twisted double bond.295 Treatment of the methylenephosphonium salt (155, R=Me3Si) with 2,3-dimethylbutadiene yields the ene product (156), whereas the related reaction of (155, R=H) results in the formation of the [ 2 + 4 ] cycloadduct (157).296 Full details have now appeared of [2+4] cycloadditions of the P-halophospha-alkene (158) with dienes.297 Several reports have appeared of the hydroboration of phospha-alkenes 298-300 The reactions of phospha-alkenes with chlorodiphenylb~ron 302 ~~~ and ~ sulphuryl chloride303 have also been investigated. Protection of the phosphorus lone pair of a phosphaalkene by coordination to a metal has enabled a study of the epoxidation of the P=C bond, resulting in the formation of the coordinated oxaphosphirane (159).304 Mathey's group has explored the reactivity of metal-complexed phosphabutadienes,305 and Weber ' s

.

.

1 : Phosphines and Phosphonium Salts

25

PJEf2

Ar,

+ :I

Et2NLC,

NR2 P-P' 2(I I P-P, R~N' C-N ;, E2 t

+

I:

NEt2 (146) Ar,

@

+ ,c,

X'

Bu3P=P' R \

(148)

[MI

(149) X' = CI,Br, Me, or Ph (147) R = Ph, But, or Et2N; X2 = CI or Br [MI = Fe(C0)4, Cr(CO)5, or W(CO)5

Ar0'\X2 (150)

PhP=CHNMe, (Me3Si),C=PNR2

(151)

+

R2P=CR2

x' qSi

Me3 A1C14-

>

(

R

(' 52)

(153) R = e.g. Me, Pr', But , or MeaSi

B u t 2 k H(SiMe,),

Al C14-

/

(154)

(163)

(164) R = But, Ph, or 2,4,6-But3CsH2

26

Organophosphorus Chemistry

group has continued to study the chemistry of phospha-alkenes bearing complexed metallo-substituents at the double bond.306 The general coordination chemistry of phospha-alkenes has also continued to attract interest.307,308 The reaction of the phospha-alkene (160, R=H) with dichlorocarbene results in the formation of the phosphirane (161), which, on treatment with t-butyl-lithium, undergoes conversion to the phospha-allene (162, R=H). In contrast, the reaction of dichlorocarbene with (160, R=Ph) gives the phospha-indane system ( 163). 309 The coordination chemistry of phospha-allenes has received attention,310 and the reactions of phospha-ally1 complexes with chalcogens occurs with oxidation at phosphorus.311 Full details have now appeared of the synthesis of the sterically protected 1-aza-3-phospha-allenes (164), together with a study of their hydrolysis reactions, which proceed via nucleophilic attack at phosphorus, with subsequent cleavage of the P=C bond.312 The hindered phospha-allene (162, R=Ph) is converted to the phosphirane (165) on treatment with dichlorocarbene. Subsequent reaction of the latter with butyllithium affords the phospha-butatriene (166). With dichlorocarbene, the diphospha-allene (167) affords the di-phosphirane (168).313 On treatment with naphthyl-lithium, this is converted into the 1,4-diphosphabutatriene (169), which, in the presence of t-butyl-lithium, is transformed into the diphosphinoalkyne ( 170) 314 The reactions of diphospha-allenes with sulphur have also been studied.315 Phosphabutatrienes of type (166), but which bear m- or g-halophenyl substituents at the terminal carbon atom dimerise at the P=C bond in a head to tail manner to give the 1 ,3-diphosphetanes ( 171). 316 A theoretical study of the electronic structure of phospha-butatriene and related phospha-cumulenes has appeared.317 Oxidative coupling of a C-lithiated phospha-allene has given the lr6-diphosphahexatetraene system (172), in several isomeric forms, some of which subsequently undergo conrotatory ring closure to form various isomers of the bis(phosphinidene)cyclobutene system (140).318 The first azatriphosphapentadiene system (173) has been prepared, but requires stabilisation by coordination.31 Linear phosphinidene complexes have been prepared by metal-induced cleavage of the P=C bond of the phospha-ketene (174).320 Studies of the reactivity of various l-metalla-2-phospha-1,3-diene systems (e.g., 175) have also been reported.321,322 There have been a number of interesting developments in the

.

I:

Phosphines and Phosphonium Salts

27

CI\ /CI

/"\

Ar\

c\\CPh2

PA :

P=C=PAr

(167) Ar = 2,4,6-BUt3C6H2

X'

Ar-P-P-Ar

Ar2 Ar

-

P=C =C' Me,Si/

F P t ArP \p-Fe(C0)3

SiMe, 'C=C=P-Ar

//

ArN

(173)

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

4 \ /

P=C=O

RC12CPH2 OAr Ph

or Me3Si

(CO), H

R-C=P

(175)

(174)

HP=C,

(1 76) R = H, Me, Et, But,

(177) R = H, Me, Et, or Bun

/'

NR2 (178) R = Me, Et, or Pr

+ (Me2N)3py/p\NMes N=N (1811

I

BPh4-

R2

R'-

/"\

C=P

(1 82) R' = 2,4,6-But3C6H2, But,

CMe2Et, or 1-adarnantyl R2 = H, Me, But, PhCH2, or Ph X = CI, Br, or OR

R'-C-

Apx

(183) X = CI, Br, or F

28

Organophosphorus Chemistry

area of phospha-alkyne chemistry. Two groups have reported the synthesis and spectroscopic characterisation of C1-CmP.323, 324 Spectroscopic evidence of the transient existence of the bisphospha-alkyne p=C-C=P has also been presented.325 Elimination of hydrogen chloride at the surface of hot potassium carbonate from the phosphines (176) has given a series of simple phospha-alkynes (177). Surprisingly, these compounds persist in solution in THF under nitrogen for periods of up to several days.326 The phospha-alkyne (177, R=NPri2) is formed in the reaction of trifluoromethylphosphine with di-isopropylamine. With less crowded secondary amines , this reaction gives the phospha-alkenes ( 178). 327 Treatment of the dichlorophosphino-substituted phosphonium salt (179) with an excess of DABCO results in the formation of the phosphonio-phospha-alkyne (180), which can be trapped in the usual way with various reagents. Thus, e.g., with mesityl azide, the phosphatriazole (181) is formed.328 A theoretical consideration of the stereochemistry and regiochemistry of anionic addition to phospha-ethyne, PnCH, has shown that the course of the reaction is dependent on the nature of the nucleophile. Whereas H- prefers to attack at carbon, Fpreferentially attacks at phosphorus.329 Two groups have reported studies of the addition of halocarbenes to phosphaalkynes. Although both agree on the initial, transient formation of the 2H-phosphirenes (182), one reports the subsequent formation of acetylenes,330 and the other the 1-halogeno-1H-phosphirenes (183), which exhibit normal halogenophosphine reactivity.331 The first example of the transformation of an ql-coordinated phosphaalkyne into an ql-coordinated phospha-alkene has been reported.332 Interest in the reactions of the phospha-alkene ButC=P (for which a standard synthesis is now available)333 in the coordination sphere of a metal has continued, with studies of the formation of diphosphacyclobutadiene complexes,334,335 and of cyclo-oligomerisation with alkynes to form a monophosphacyclobutadiene complex.336 The chemistry of compounds involving p,-bonds between phosphorus and elements other than carbon also continues to develop. An improved route to the sterically crowded phosphasilene (184) is afforded by the reaction of mesitylphosphine and a sterically crowded dichlorosilane in the presence of butyllithium.337 The phospha-silene (185) has been trapped with 1 , 3 - d i e n e ~ .The ~ ~ ~chemistry of P=N systems has been reviewed.339 A theoretical study of the electronic effects of

I: Phosphines and Phosphonium Salts

4

29

SiMe,

(Me2N)3P

P=N,

Mey-f' HN,p-/N

SiMe,

(Me3Si),N -P=N-SiMe,

(189)

+ CI-

(193)

7

Si (SiMe3),

Ph

R'.

PSiMe, R

30

Organophosphorus Chemistry

substituents at the P=N bond indicates that the presence of a uelectron-withdrawing group at phosphorus results in a shortening of the bond, whereas an electron-donating group produces the opposite effect. Surprisingly, the effects of substituents at nitrogen are the reverse of those at phosphorus. There is now adequate structural data to lend general support to these conclusions.340 The iminophosphene (186) possesses an unusually long P=N bond, in accord with quantum chemical calculations.341 Dipole moment studies of N-phosphino-substituted - iminophosphenes support the presence of a localised P=N bond, indicating that their stability in solution and in the solid state is due to steric screening of the double bond. 342 The iminophosphene (187) , obtained from the reaction of the salt (179) with sodium bis(trimethylsilyl)amide, has a delocalised structure, and is best viewed as involving a heteroallyl anion system.3 4 3 A range of new stable heterocyclic two-coordinate P=N systems, e.g., (188), has been prepared from the reactions of thiosemicarbazides with phosphorus trihalides in the presence of a base, or of semicarbazides with tris(dimethy1amino)phosphine in xylene.3 4 4 Various substitution reactions of P-halo iminophosphenes have been reported,345-347 and the first ucoordination complexes of such systems prepared.348 An X-ray study has confirmed the structure of the adduct of the iminophosphene (189) with chloro(dicyclopentadieny1)zirconium hydri.de to be the zircona-azaphosphirane (190).349 Solid-state n.m.r. characterisation of the N=P bond in (191) has been reported.350 Thioxaphosphene, HP=S, and selenoxaphosphene, HP=Se, have been characterised as complexes with osmium(0),351 and the related (organothio)thioxaphosphene MeSP=S, has been generated in the gas phase.352 Interest in n-interactions between phosphorus and boron has also continued. Some aspects of the chemistry of quasiaromatic phosphorus-boron cyclic systems have been reviewed,353 and Cowley has reviewed the work of his group on p,-bonded systems.354 The existence of multiple bonding between boron and phosphorus in phosphinoboranes has also been reviewed.355 Further studies of the structures of sterically crowded P,Pdiphosphino-diorganoboranes have shown a remarkable variation in the phosphorus-phosphorus bond length, leading to the conclusion that n-bonding interactions in diphosphenes account for only half of the bond-shortening observed, significantly less than that in diarylazo compounds. This work therefore provides further evidence that the structural effects of hybridisation changes are significantly greater for phosphorus than for nitrogen.356

1:

Phosphines and Phosphonium Salts

31

Cleavage of the B2P2-ring system of (192) with a chromium carbonyl complex has given the heteroallene (193), which has a very short boron-phosphorus bond, (1.743 f l ) and in which there is the expected orthogonal arrangement of the substituents at nitrogen and phosphorus.357 Interest has continued to grow in the chemistry of 0 3 - A 5 systems, and several new species, e.g., (194),358 have been characterised, and their reactions studied.358-363 Similarly, further development of the chemistry of phosphenium ions, R2P+, has occurred. In addition to the synthesis of new e.g., (195),367 these species have found application for the synthesis of new heterocyclic systems via cycloaddition reactions.368-370 The chemistry of phosphinidenes, RP: , has also received further study.371 6

PhosDhirenes, PhosDholes and PhosDhinines

A theoretical study of 1H- and 2H- phosphirenes has enabled the calculation of inversion barriers at phosphorus, and leads to the

conclusion that the 1H-phosphirene system (196) is not antiaromatic, the bonding of phosphorus atom being pyramidal.372 The coordination chemistry of 1,2,3-triphenylphosphirene (197) has been explored.373 Photolysis of the phosphirene (198) leads to the formation of the dihydrophosphasilete system (199), which, on treatment with an acid chloride, is converted to the heterocyclic system (200) .374 A theoretical consideration of the status of phosphorus and arsenic as heteroatoms in potentially aromatic five- and sixmembered ring systems has concluded that the "aromaticity indices" for phosphorus in phosphorin systems are similar to those for nitrogen in the related pyridines. The situation is less favourable for arsenic. The study has also concluded that 1Hphospholes are less aromatic than the corresponding oxygen heterocycles.375 A dipole moment study of arylphosphines and phospholes supports the view that phospholes are weakly aromatic compared with related pyrroles.376 The reactivity and stability of 1,3-benzazaphospholes, 1,3-benzodiphospholes, and their anions have been investigated by quantum-chemical calculations. The results are consistent with the qualitative chemical behaviour of such systems, and suggest that the extraordinary stability of the 1,3-benzodiphosphole anion (201) may be due to its electronic structure which corresponds to that of a benzo-bridged heteroallyl

32

Organophosphorus Chemistry

anion.377 On prolonged heating at 170"C, the phosphole (202) is converted to the tetrameric system (203) which, on treatment with sodium naphthalenide in THF, is converted into the diphosphole dianion (204), which is iso-electronic with a-sexithienyl. This sequence represents a first step towards the synthesis of phosphorus analogues of the polythiophenes.378 The reaction of o-xylylenebis(tripheny1phoephonium) dibromide with phosphorus trichloride in the presence of triethylamine gives the diphosphonio-isophosphindole system (205) for which various canonical forms may be written. In some respects, this has phosphenium ion reactivity, but with reduced Lewis acidity. It is also more basic than is usually found for phosphenium ions, and can be protonated to form (206), which has been described as the first stable P-H unsubstituted phosphole, n.m.r. studies indicating a planar sp2-hybridised phosphorus atom. 379 Thermal rearrangement of the bisphosphole (207) occurs on heating above 150'C with the formation of the isomeric bis(2H-phosphole) system (208), which can be trapped with various reagents.380 Further examples of the formation of bicyclic adducts of simple phosphole oxides with dienophiles have been reported.381,382 Metal complexes of phospholyl anions have received further study, a paramagnetic uranium complex now having been described.383 The chemistry of polyphosphacyclopentadienyl anions has also continued to develop. The reaction of red phosphorus with potassium dihydrophosphide in boiling DMF provides a simple preparation of the pentaphosphacyclopentadienyl anion384 which has enabled further studies of its coordination chemistry.385 The product of the reaction of white phosphorus and sodium in diglyme has been reinvestigated and found to be the hitherto unknown 1,2,3-triphosphacyclopentadienyl anion (209) ,386 and not the triphosphacyclobutenide anion previously assumed.387 Protonation of an equimolar mixture of the anions [ P2C3But3]- and [ P3C2But2]affords the corresponding di- and tri-phosphacyclopentadienes which undergo a [4+2] cycloaddition to form the tricyclic system (210).388 Considerable interest continues to be shown in the chemistry of heterophospholes, and several new systems have been described. The insertion of sulphur and selenium into the 1,2-dihydrophosphete system (protected at phosphorus by coordination) gives the 2,5dihydro-lt2-thia-and -8elena-phospholes (211), again as the respective P-complexes.389 The reactions of quaternary salts of 2-alkylpyridines with phosphorus trichloride in the presence of

1: Phosphines and Phosphonium Salts

33

-

Na+

-

Na’

RPP

Ph3P--- ‘**P*’

(204) R = 5-(2,2’-bithienyl) (203) R = 5-(2,2’-bithienyl)

EtO,

(21 1) X = S or Se

kj

s’/

\

(212) R’ = Me or Ph R2 = PhCO, CN, COZEt, or p -NO&H4 C02Et

Me&

s”

SMe

(213)

\

SMe

MewMe Me

Me

34

Organophosphorus Chemistry

triethylamine have given the air-stable 2-phosphaindolizines (212), a previously unknown system.390 The first 1 ,2 ,3-benzazadiphosphole (213), having a stable P=P link, has been prepared from the reaction of 2-aminophenylphosphine with tris(dimethy1amino)The ph~sphine.~ ~ ~ synthesis and the study of the reactivity of diaza- and triaza-phospholes have also continued to be productive areas.392-398 Treatment of the phosphole sulphide (214) with a diazoalkane initially yields the carbene adduct (215), which, on treatment with triphenylphosphite, is converted into the functionalised phosphinine (216) .399 Carbene-induced ringexpansion reactions of phospholene oxides to give six-membered ring phosphorus compounds have also received further study.400 A route to the first 2,2'-biphosphinine (217) has been described, and this system chracterised by X-ray diffraction as a metal complex.401 A vanadium n-sandwich complex of phosphinine has been prepared by a new metal-ligand co-condensation approach.402 Two groups have reported studies of the reactions of phosphinines with sulphur. The initial product of the reaction of the phosphinine (218) with sulphur is the transient P-sulphide (219) which reacts with further sulphur to give (220).403 In contrast, the diphosphinophosphinine (221) reacts with sulphur to form the isolable trisulphide (222) 404 Various ring-transformation products have been obtained from the reactions of simple phosphinines with carbenes 405 The 1I 3,5- A3-diaza-phosphinine (223) is formed in the reaction of a related diazapyrylium salt with tris(trimethylsily1)phosphine. With acetylenic dienophiles, (223) is converted via heterobarralene intermediates in sequential addition-elimination steps to the phosphinines (224).406 Similar addition-elimination reactions have also been reported for the 1 , 3 , A3-azaphosphinine (225).407 With diazomethane, (225) is converted into the diazadiphosphachiropteradiene system (226) 408 Methods for the synthesis of 1 2-dihydro-1,2 X3-azaphosphinines (227) have also been developed,409-411 and such compounds have been transformed to related A5-systems, e.g. , (228).412 Interest in the synthesis of new ~~-phosphinine and -azaphosphinine systems has also developed,413-420 and a number of new examples described, e.g., (229),413 (230),414 and (231).420

. .

.

I:

Ms$e

35

Phosphines and Phosphonium Salts

‘

Me

F S

Ph

P h a p p PPh, h 2

Me

(221)

ArR& r: (224) R = Ph, SiMe3, H or C02Et

R’ N R3

d

2 ~2

(227) R’, R2 = alkyl R3 = alkyl or aryl

(2311

36

Organophosphorus Chemistry

References 1 2

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31 32 33 34 35 36 37

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1990, 3,291. R. men, B. Cai, L. Liu, G. Li, L. He, PhosDhorus, Sulfur, Silicon, Related E l m . , 1991, 3,129. R. Chen and B. Cai, PhosDhorus. Sulfur, Silicon. Related E l m . , 1991, 57, 83. 0. S. Diallo, L. L q e z , Y. K. Rodi, and J. Barrans, Phosphorus. Sulfur, Silicon, Related E l a n . , 1991, 3,17. 0. S. Diallo, L. Lcpez, and J. Barrans, Tetrahedron Lett., 1991, 32, 501. S. Holand, L. &card, and F. Mathey, J. Ora. Chem., 1991, 56, 4031. G. Keglevich, A. Szollosy, L. Eke, V. F’ulop, and A. Kalman, J. Ora. Chem., 1990, 55, 6361. P. Le Floch, D. Carmichael, L. Ricard, and F. Mathey, J. Am. Chem. Soc., 1991, 113, 667. C. Elschenbroich, M. m t n y , B. Metz, W. Maasa, J. Graulich, K. Biehler, and W. Sauer, Angew. Chm.. Int. Ed. Enal., 1991, 30, 547. S. Holand, J. M. Alcaraz, L. Ricard, and F. Mathey, Heteroat. Chm., 1990, 1, 37. A. N. Hughes and K. L. Knudsen, Heterocycles, 1990, 2,543. G. W k l , K. Hohenwarter, M. L. Ziegler, and B. Nuber, Tetrahedron Lett., 1990, 3l, 4849. G. W k l and C. Doerges, Anaew. Chem., Int. Ed. Enal., 1991, 3, 106. G. Wkl, C. mrges, T. R i d , F . 4 . Kliirner, and C. Ldwig, Tetrahedron Lett., 1990, 3 l , 4589. G. MSrkl, C. mrges, H. S t h , and K. Polborn, Tetrahedron Lett., 1990, 31, 6999. H.-L. WaiTan, C. Bordieu, and A. Foucaud, Tetrahedron, 1990, 46, 6715. W. H.-L. WaiTan and A. Foucaud, J. Chm. Res.! (S), 1991, 52. E. Ya Levha, A. N. Pudovik, and A. M. Kibardm, Zh. obshch. Khim., 1990, 60, 759 (Chem. Abstr., 1990, 113, 172 179). C. Bedel and A. Foucaud, Tetrahedron Lett., 1991, 32, 2619. L. D. Win, J. C. Kisalus, J. J. Skolimwski, and N. S. Rao, PhosDhorus. Sulfur, Silicon. Related E l m . , 1990, 54, 1. Y. Van den Winkel, J. Van der Laarse, F. J. J. De Kanter, T. Van der Does, F. Bickelhaupt, W. J. J. Smeets, and A. L. Spek, Heteroat. Chem., 1991, 2, 17. W. &ed, M. Fulde, and J. W. Bats, Helv. Chim A c t a , 1990, 73, 1888. E. Fluck, G. Heckmann, W. Plass, H. Bijsse, and A. Miller, PhosDhorus. Sulfur, Silicon. Related E l m . , 1991, 3,49. E. Fluck, M. spahn, and G. Heckmann, LNaturforsch., B, 1991, 46, 762. W. Plass, G. Heclunann, and E. Fluck, PhosDhorus. Sulfur, Silicon, Related Elem., 1991, 55, 19. E. Fluck, W. Plass, and G. Heckmann, Z. Anoru. Alla. Chem., 1990, 588, 181. E. Fluck, W. Plass, G. Heckmann, H. EGgge, and A. Miller, Z. Naturforsch.. B, 1991, 46, 202.

2

Pentaco-ordinated and Hexaco-ordinated Compounds

BY C.D. HALL

1. Introduction - The year has again seen a diminution in research activity in this area with the emphasis on cyclic phosphoranes and structural aspects of pentaco-ordinate phosphorus chemistry. With reference' to the latter, a useful review has appeared covering X-ray structures and variable temperature l H n.m.r. investigations of cyclic pentaoxyphosphoranes. The studies include five-, six-, and seven-membered rings and show that the solid state structures are retained in solution. They also reveal that for saturated, six-membered rings in apical-equatorial orientations of trigonal bipyramids, the boat conformation is preferred. The importance of apical-equatorial ring orientations for phosphorinanes appearing as tbp intermediates in enzymatic reactions of cyclic AMP analogues is also emphasised.

2. Structure. BondinP and Lipand ReorpanizatiQn - Several theoretical papers dealing with bonding, ligand reorganization and apicophilicity in hypercoordinate molecules have appeared. In the first of these a new analysis of the dfunction contributions to the ab initio wave functions of hyperco-ordinate and normal valency compounds is reported for molecules of first- and second-row elemenW2 Energy minimization calculations show that the optimum d-function exponent for any element changes very little from one compound to another, even those differing as much as H2S and SF6. The paper also provides no support for the view that diffuse d orbitals on the central atom take part in bonding after being contracted in the field of electronegative oxygen o r fluorine atoms around the periphery. The hydroxyphosphoranyl radical, H3:OH has been studied computationally and shown to have two local minimum equilibrium structure^.^ Each is characterised by a t b p geometry in which the unpaired electron is localized equatorially but they differ in the disposition of the OH group which may be axial (preferred) or equatorial. Interconversion of the two local minima was found t o be accomplished more efficiently by a pseudo inversion process (62kJmol-l) rather than a pseudorotation (71kJ mol-l). Pentaco-ordinated phosphoranes, PH4X, substituted with a full range of first- and second-row groups have been studied using ab initio ca1cu1ations.* Calculations with zero-point energy corrections provided relative energies of the 48

2: Pentnco-orclinated and HexLico-ordinated Compounds

49

various isomers thus enabling the intrinsic apicophilicities of the first- and second-row groups to be derived and compared with the available experimental data. The calculated apicophilicities (in kJ mol-l) are OH (+1.7)> SH (-0.4) > CH3 (-3.7) > PH2 (-14) > NH2 (-30) > SiH3 (-36). Compounds such as PH4F and PHqCl were regarded as unsuitable models for energy comparisons due to their high degree of ion-pair character. Structural studies in this area have been dominated by the contributions of Holmes and his collaborators. New monocyclic penta-oxyphosphoranes (2-6) were synthesised from the reaction of tris-(2,6-dimethylphenyl)phosphite (1)with a diol or a quinone. The pentaco-ordinated derivatives (2-5) were studied by X-ray analysis and represent the first structurally characterised monocyclic oxyphosphoranes having six-, seven- and eight-membered rings.5 All possess t bp geometries with the rings spanning apical-equatorial positions and retention of these structures in solution is indicated by lH, 13C and 31P n.m.r. Twist-boat, rowboat and distorted-tub conformations are found for the six-(2), seven43) and eight451 membered ring derivatives respectively. Phosphorane (4) has a more planar phosphorinane ring as a consequence of ring unsaturation. Variable temperature IH and 13C n.m.r. studies established non-rigid behaviour supporting a simple Berry pseudorotation in which the rings exchanged apicalequatorial positions. New bicyclic pentaoxyphosphoranes (7-9) containing five- t o sevenmembered rings were also synthesised by oxidative addition of a diol or a quinone to a cyclic phosphite. Variable temperature l H and 13C n.m.r. studies in solution revealed intramolecular ligand exchange processes in which apicalequatorial interchange occurred between tbp ground states plus a higher temperature process consistent with an exchange intermediate with the ring located diequatorially in a tbp.6 The activation energy for the latter process for (9) is 48kJmol-1 whereas the n.m.r. spectra of (7) and (8) do not coalesce up t o 90°C presumably due t o the strain associated with placing the unsaturated fivemembered rings of (7) and (8) in a di-equatorial position. X-ray analysis supported the interpretation of the solution state behaviour and again showed that six-membered rings prefer a boat conformation occupying apical-equatorial positions in a tbp. 3. Acvclic Phosphoranea - The tetrachlorophosphorane (11)synthesised by the reaction of (10)with chlorine, is covalent in the liquid phase (g31P= -39) but was shown by solid state MAS 31Pn.m.r. t o have the structure [P(CH2Cl)Cl# [P(CH2CI)C151-with g31P=lll.l and -206.1 in the crystalline state.7 This is the first example of an organophosphorane having a structure like that of solid [Pc14]+ [pc16]-. The reaction of dibromo-2,2,3,3-tetrafluoropropoxydifluorophosphorane (13) obtained from (12) and bromine, adds two moles of chloral (14a) or bromal (14b) to give both diastereomeric forms of the stable difluorophosphoranes (15abI.The reaction of a series of tetrafluorophosphoranes (16) with the trimethylsilylethylenediamine (17) yields the corresponding

Organophosphorus Chemistry

50

0 ArO.. ArO.

I

P-0

I

OAr

(3)

0 ArO.. I

ArO.. I

(4)

,P-0

AAr

OAr

OAr X=Y=H X=Y=CI X = H; Y = CI

(5)

F (CHF2CF2CH20)PF2B1-2 (13)

+

Br

I

2 CX3CH0

I

( CHF~CF~CHZO) P(OCHCX3)2

I

(14a, b)

F a; X = CI b; X = Br

b)

2: Pentaco-ordinated and Hexaco-ordinated Compounds

51

(16a-e) a; R = Me (1 7) b; R = Me3SiCH2 C; R = P h d; R=C6F5 e; R = 2, 5-Me2C6H3

RR’PF3

+

(1 8a-e)

( + Me3SiF)

-

Me@N(Me)CH2CH2NMe2

RR’PF2N(Me)CHzCH2SiNMe2 (19) R = R = P h (20) R = Ph; R ’ =

3(Me3SiCH2)3As+ 2AsC13 (22)

-

0-

3(Me3SiCH2)3AsC12+ 2As (23)

52

Organophosphorus Chemistry

trifluorophosphoranes (18a-e). The difluorophosphoranes (19) and (20) were formed in a n analogous reaction and some of these di- and trifluorophosphoranes react with PF5 t o form the corresponding azonium hexafluorophosphates (e.g.21).9 An X-ray structural analysis of these latter compounds reveals the expected t b p geometry a t the pentaco-ordinate phosphorus. Finally in this section, although not strictly relevant t o phosphorus, the reaction of the arsine (22) with AsC13 produced the crystalline arsorane (23) which was characterised by elemental analysis, l H and 13C n.m.r. and mass spectrometry,10

..

4. R n ip ~ o n t a n ln l~ Pho4.1 Monocvclic Phosnhoranes - The unsymmetrical methylphosphoranes (26a-e) were obtained in isolated yields of 88-100% by the reaction of the phosphonamidite (24) with 3,5-di-t-butyl-orthobenzoquinone and a series of alcohols (ROH) via the intermediate (25).11 These compounds hydrolyse rapidly in aqueous acid t o a diastereomeric mixture of (27) and the work represents a first step towards the development of stable transition state analogues for phosphoryl transfer reactions. Thermochemical studies in solution and in the gas phase of the reactions of phosphites (28a-e) with benzil (29) to form the monocyclic or bicyclic phosphoranes (30a-c) have shown that the reactivities of the phospholane derivatives (e.g. 28c) are considerably lower than those of the acyclic (28a) and six-membered ring analogues (28b). This is considered to be a consequence of the higher intraring strain energies developing in the phospholanes during nucleophilic attack on the carbonyl carbon of benzil.12 The fluorophosphite (31) has been shown to react with chloral (32) in a sealed tube t o form the crystalline 1,4,2-dioxaphospholene(33, ti31P= -44) with a high degree of ~ t e r e o s e l e c t i v i t y . In ~ ~ contrast, bromal gave only the corresponding vinyl phosphate. By comparison, the reaction of di-and trihalophosphoranes (e.g. 34) with chloral or bromal (35ab) gave the unusual (l-haloalkoxy) phosphoranes (36ab).14ab Another interesting reaction of halophosphoranes (e.g.37) involves addition to the triple bond to give functionally substituted, crystalline phosphonium ylids (e.g.38) whose structures were assigned by IH, 13C and 31P n.m.r.15 Pentaco-ordinate oxaphosphoranes are finding further prominence as reagents in organic ~ y n t h e s i s . ~An~ interesting ,~~ example of this is found in the synthesis of (+/-I truns- and (+/-) ~is-neocnidilides~~ in which a crucial step is the condensation of the 1,2,h5-oxaphospholene(39) with valeraldehyde (40) t o produce the highly substituted phosphonates (41,syn) and (41,anti) in a ratio of 1.8 : 1. These diastereomers were then transformed uia an intramolecular Wadsworth-Horner-Emmons olefination to the target molecules. The reactions of hexachlorodiazaphosphetidine (42, R=Me) with NaOR (R = C H ~ C F Q or Ph) give the hexaalkoxy derivatives (43). The reaction of the N-phenyl derivative (42,

2: Pentaco-ordinated and Hexaco-ordinated Compounds NPri2

53

v + 0

Me-P-0

8

(24)

I

!+ ROH

Me-

(26a-e) a; R = Me b; R = Et C; R = Cyclo-C~H11 d; R = EtNHCO(CH2)3C02Me e; R = CH2CH2SS

R’O, P - 0 ~ 3

+

PhCO.COPh

R20‘ (28a-c)a; R’ = R2 = R3 = Et b; R’-R2 = MeCHCH2CH2,R3 = Et c; R’-R2 = MeCHCHMe, R3 = Et

Ph (29)

(30a-c)

54

Organophosphorus Chemistry

(CF3CH20)3P

+

2C13C.CHO

(31)

(32)

CCI, (33)

(34)

(38)

(37) X, Y = CI or Br

?'

Me

(42)

(43) R = CH2CF3 or Ph; R' = Me I

R'= Ph NaOCH2CF3, Et20, -78

OC

110 OC, R

7

PhN=P(OCH,CF,),

(44)

MeN=P( OCH,CF,),

(45)

=

CH2CF3

2: Pentaco-ordinated and Hexaco-ordinated Compounds

55

R=Ph) with NaOCH2CF3, however, afforded the monophosphazene (44).l8 The structure of (43, R= CH2CF3, R'=Me) was confirmed by a single crystal X-ray diffraction study and its transformation into its monomer (45) at llO°C followed by its redistribution reaction with (MeNPF3)z were both investigated by n.m.r. spectroscopy. The crystal structures of (46a, R=Me) and (46b, R=Ph) have been determined a t -95OC. Both molecules are associated with crystallographic inversion centres and the P2N2 rings are therefore exactly planar with bond lengths which are consistent with trigonal bipyramidal phosphorus. l9 4.2 Bicvclic and Tricyclic Phosphoraneg - Oxidative addition of phenanthraquinone (48) to the dithiaphosphorinane (47) gave a new thiophosphorane (49) containing a sulphur-bonded, six-membered ring. An Xray analysis (of both the monoclinic and triclinic modifications) revealed a tbp structure with the ring sulphur atoms located, unexpectedly, in apicalequatorial sites and with the more electronegative xylyloxy oxygen atom relegated t o an equatorial position.20A twisted boat conformation exists for the dithiaphosphorinane ring and l H n.m.r. spectroscopy is consistent with the retention of the solid state structure in solution with rapid intramolecular ligand exchange. Several pentaco-ordinate phosphorus compounds containing sixmembered rings (50-53)have been synthesised from the corresponding phosphite and either (CF3)2CO or (CF3)2CO.CO(CF3)2as models of P(V)H20 o r enzyme -

CAMP adducts.21 The X-ray structure of (53) showed it to be close to tbp with the six-membered 1,3,2-dioxaphosphorinanering disposed in apical-equatorial positions and with the oxygen equivalent to 05' of CAMP in the apical position. The dioxaphosphorinane ring is in a twist conformation in the crystal and l H n.m.r. studies show the six-membered rings of (50-53) to be in non-chair (probably twist) conformations as well. In consequence, it is suggested that the likely role of phosphodiesterase in the catalyzed hydrolysis of CAMP is probably to ensure the formation of a cAMP-H20 adduct with the water and P-03' bonds coapical. The hydrido spirophosphorane (54) reacts smoothly with the amines (55) to form the spirophosphoranes (58) via (56) and (57).221nan analogous reaction, the phosphonate (60) - prepared from (59) and dimethylformamide dimethyl acetal, reacts with (54 R=H) t o form the spirophosphorane (61) which contains four- and five-coordinate phosphorus. A new series of dibenzophosphoranes (62a-d), (63) and (64) containing uncommon functional groups such as hydroxy, 0x0, and dihydrido, attached to the phosphorus atom, have been prepared and characterised by lH, 13C and 31P n.m.r. The structure of (63) was also established by single-crystal X-ray analysis which revealed a molecule approximately half way between t b p and r p configurations. The key synthesis for many of these compounds is the condensation of (65) with diphenolamine (66) to produce (62b).23

56

Organophosphorus Chemistry

rirB

0 I

0-p ---0 F3c+ O J’!cH

(cF3)2

CF3 (50) B = H ; Y = O (51) B = thymin-l-yl; Y = 0 (52) B = H;Y = CH2

x ?<

O H 0

R

O

0

R R

-

R

~

)

R

(55) R’= Me, Et, or Bu’ R X= ~ MeO, REtO, orMe2N

~ HO

o R

(54) R = H o r M e

I

CH2NR’z

CH2NR,’ (58)

2:

Pentaco-ordinated and Hexaco-ordinated Compounds

(EtO),P(O)H

-

+ Me2NCH(OMe)2

(59)

(62a-d)a; X = OMe

b; X = NMe2

o N+HR~

c; x = d; X = H

0 NMe, II

I

(EtO),P-CHOMe

57

-

(54) R = H

0 II

NMe,

I

(Et0)2P-CH-P

1

\

0,

o ,

0'

'0

58

Organophosphorus Chemistry

Another displacement on the P-N bond produces a spirophosphorane (71) from the reaction of (67) with ethylene glycol (68) via trico-ordinate (69) and tetraco-ordinate (70) intermediates. The conversion of (69) t o (70) involves an unusual 1,2-migration of an alkyl group from N t o P and the resultant phosphonimidate (70) isomerises rapidly to (71).24 There was no evidence for the formation of the dimer of (70). In a similar reaction, 1,3-propane diol (72) gave the spirophosphorane (73). The synthesis of new tricyclic phosphoranes containing a P-H bond (75a-d) has been achieved through the reaction of diaminodiols (74a-d) with (65)25 and characterised by lH,13C and 31P n.m.r. These hydridophosphoranes react readily with ketopantolactone (76) to form phosphoranes (77 a-d) and in the cases of chiral phosphoranes (75b-d) the resultant diastereoselectivity is in the range of 92-95%. These phosphorane alcohols are transformed quantitatively into alkoxyphosphoranes (e.g. 78a-d) when they are kept at room temperature for 10h. The reaction of diazaspirophosphoranes (e.g.79) with alcohols, however, leads t o a simple ring opening to amino phosphites The reaction of tetraazamacrocycles with trico-ordinate phosphorus has been shown to afford a good route to mono-substituted azamacrocycles thus using the phosphoryl entity as a valuable protective group. This is represented schematically by (81-87) which depicts t w o possible routes t o the monofunctionalized tetrazamacrocycle (87).27 Tetrazaspirobicyclic phosphoranes (88a-c) also feature in the synthesis of a new class of spirobicyclic transition-metal substituted phosphoranes (89a-c) with the five-co-ordinated phosphorus bound to manganese. The compounds were characterised by l H and 31P n.m.r. spectroscopy and by thermal analysis.28 To conclude the section, an unusual iodophosphorane (91) prepared by the reaction of (90) with iodine has been shown to involve a h5P-I bond by solid state I3C, 15N and 31P n.m.r. spectros~opy.~~

5. Pexaco -ordinate PhosDhorus ComDoun&- The reaction of trianilidophosphaazobenzene (92) with dipyrocatecholphosphorane (93) in the presence of triethylamine proceeds t o give a diazadiphosphetidine (94) containing both tetraco-ordinate and hexaco-ordinate p h o s p h o r ~ s .Similar ~~ betaine-type structures (96) were synthesised by the analogous reaction between (95) and the chlorophosphorane (93)31,the product being characterised by m.s., l H and 31P n.m.r. The synthesis and characterisation of neutral hexaco-ordinate phosphorus compounds has been described in consecutive papers from Cave11 et al. 32,33 In the first of these, substituted bidentate amido ligands derived from carbodimides gave a series of compounds (1OOab-103ab) from the generic reaction of (97) with (98). The compounds were characterised by m.s., i.r., and multinuclear n.m.r. and in the case of (102a) by a single crystal X-ray diffraction study. In the second report, the reaction of the silylated form of substituted

2: Pentaco-ordinated and Hexaco-ordinated Compounds CH2NEt2 I

+ Ho) HO

59

Organophosphorus Chemistry

60

(74a-d)a; R = H b; R = Me C; R=Pr‘ d; R=CH*Ph

1

+/

(75a-d)

(77a-d)

R.T., 10 h

R.T., 10 h

1

(78a-d)

H

H

2: Pentaco-ordinated and Hexaco-ordinated Compounds

'H

61

62

Organophosphorus Chemistry

‘5

kNR‘

Ir““

0

0

( 8 8 a s ) a; R = R’= Me b; R = R’= Ph c; R = Me, R’= Ph

(89ax)

(91)631P= - 109

(PhNH),P=NPh

t

(92)

X = CI or CF3

R = cycIo-C6Hll or Pr‘

(99)

2: Pentaco-ordinated and Hexaco-ordinated Compounds R CI I CI\L,N P +>Cl CI -"1 CI I R

63

'

R (101a, b)

(1OOa, b)a; R = cyclo-C6H11

b; R = P r '

(1 02a, b)

(103a, b)

'

a E S i M e 3

PX5

L

(104a-d) a; E = NMe b; E = O

(105a-c) a; X = F

E=S d; E = N - p y C;

(py = 2-pyridyl

b; X =CI

C;

X=CF3

(106a-h) a; X = CI; E = NMe b; X = F ; E = N M e C ; 3X = CI; X = CF3; E = NMe d; X = C I ; E = G e; X = F ; E = O f; X = F ; E = S 9; X = CI; E = N-py h ; X = F; E = N-py

07a, b)a; R = b; R =

c > N -COCH3 I

R (108a, b) a; R = CI b; R = O E t

7

64

Organophosphorus Chemistry

pyridine ligands (104a-d) with 5-halogenophosphoranes (105a-c) also yields a series of neutral hexaco-ordinate phosphorus compounds (106a-h)by elimination of trimethylsilyl halide. The structures were evidenced by the high field of 31P n.m.r. (6,-135 to -202)and by the single crystal X-ray structure of (106a). Saturation transfer n.m.r. experiments indicate that the fluorine exchange in (106b) involves two competitive processes of the opened ring intermediate, both of which had similar energy barriers of 57.8kJ mo1-l for pseudorotation and 56.1kJ mol-l for ligand rotation. Both two co-ordinated phosphorus compounds (107ab) and trico-ordinated phosphorus compounds (108ab) have been shown t o react with catechol (109) in the presence of triethylamine to form the hexacoordinate structure (110).34 In conclusion, therefore, one can see that, although interesting chemistry is still emerging from the field of hypervalent phosphorus , the excitement generated in the early stages of the study of these compounds is beginning to subside. One of the most gratifying features of the work to date, however, has been the application of principles established in the phosphorus arena to the chemistry of elements other than phosphorus in and beyond the third row of the Periodic Table.

REFERENCES 1. K.C.K.Swamy, S.D.Burton, J.M.Holmes, R.O.Day and R.R.Holmes, Phosphorus, Sulfur and Silicon, 1990,53,437. 2. E.Magnusson, J.Am.Chem.Soc., 1990, 112, 7940. 3. C.J.Cramer, J.Arn.Chern.Soc., 1990,112, 7965. 4. P.Wang, Y.Zhang, R.Glaser, A.E.Reed, P.von R. Schleyer, and AStreitwieser, J.Am.Chem.Soc., 1991,113, 55. 5. S.D.Barton, K.C.K.Swamy, J.M.Holmes, R.O.Day a n d R.R.Holmes, J.Am.Chern.Soc., 1990,112, 6104. 6 . K.C.K.Swamy, R.O.Day, J.M.Holmes and R.R.Holmes, J.Am.Chem.Soc., 1990,112, 6095. 7 . K.B.Dillon and T.A.Straw, J.C.S.Chem.Commun., 1991, 234. 8 . V.F.Mironov, E.N.Ofitserov, I.V.Konovalova, P.P.Chernov, and A.N.Pudovik, Bull.Acad.Sci. USSR, (EngLtransl.) 1991, 40, 1929. 9. T. Kaukorat, P.G.Jones and R. Schmutzler, Chem.Ber., 1991,124,1335. 10. R.L.Wells, A.P.Purdy and C.G.Pitt, Phosphorus, Sulfur and Silicon, 1991,, 67,l. 11. R.M.Moriarty, J. Hiratake and KLiu, J.Am.Chem.Soc., 1990,112, 8575. 12. V.V. Ovchinnikov, Yu.G. Safina and R.A. Cherkasov, J.Gen.Chern. USSR, (Engl. transl) 1990,60,878. 13. I.V.Konovalova, L.A. Burnaeva, V.F. Mironov, I.V.Loginova, a n d A.N.Pudovik, Bull Acad.Sci. USSR,(Englhansl.) 1991, 40, 2612. 14a. V.F.Mironov, T.N.Sinyashina, E.M.Ofitserov, E.I.Gol'dfarb, I.V.Konovalova, a n d A.N.Pudovik, J.Gen.Chem.USSR (EngLtransl) 1990, 60, 846. 14b. E.N.Ofitserov,V.F.Mironov,T.N.Sinyashina,T.V.Konovalova, J.Gen.Chem. USSR (Engl. transl), 1990, 60, 33. 15. V.F. Mironov, E.I.Gol'dfarb, P.P.Chernov, I.V. Konovalova, and A.N.Pudovik, Bull. Acad Sci. USSR (Engl.transl), 1990, 39,1319. 16. C.K.McClure and K.-Y.Jung, J.Org.Chem., 1991,66, 867.

2:

Penraco-ordinated and Hexaco-ordinated Compounds

65

17. C.K.McClure and K-Y. Jung, J.Org.Chem., 1991,66, 2326. 18. S.S.Kumarave1, S.S.Krishnamurthy, R.O.Day and R.R.Holmes, Phosphorus, Sulfur and Silicon, 1991,67, 163. 19. P.G.Jones and R. Schmutzler,Phosphorus, Sulfur a n d Silicon, 1991,66,173. 20. K.C.K.Swamy, J.M.Holmes, R.O.Day and R.R.Holmes, J.Am.Chem.Soc., 1990,112,6092. 21. J.H.Yu, A.M.Arif, and W.G. BentrudeJ.Am.Chem.Soc., 1990,ll2,7451. 22. A.A.Prishchenko, M.V.Livantsov, P.V.Zhut-skii, D.A.Pisamitskii, N.M.Shagi-Mukhametova and V.S.Petrosyan,J.Gen.Chem.,USSR (EngLtransl) 1990, 60, 398. 23. A.Murillo, L.M.Chiquete, P.Joseph-Nathan and R.Contreras, Phosphorus, Sulfur and Silicon, 1990,53,87. 24. S.A. Terent'eva, N.A.Pudovik, and A.N.Pudovik, J.Gen. Chem.USSR, 1990, 60, 397. 25. Y. Vannoorenberghe and G.Buono, J.Am.Chem.Soc., 1990,112, 6142. 26. L.I.Mizakh, L.Yu Polonskaya, A.N.Gvozdetskii, and L.B.Karpunina, J.Gen.Chem. USSR,1990,60,1274. 27. A.Filali, J.-J.Yaouanc, and H. Handel, Angew. Chem.Znt.Ed.Engl., 1991, 30, 560. 28. B.N.Anand, R.Bains and Km. Usha, J.Chem.Soc., Dalton Trans., 1990, 2315. 29. D.C.Apperley and R.K.Hams, Phosphorus, Sulfur and Silicon,1990,54,227 30. E.K.Rutkovskii, I.S.Zal'tsman, N.G.Feshchenko and A.M.Pinchkuk, J.G'en.Chem. USSR,1990,60,1491. 31. I.S.Zal'tsman, G.K.Bespal'ko, A.P.Marchenko, A.M.Pinchuk, A.D.Sinitsa, a n d S.K.Tupchienko, J.Gen.Chem. USSR,1990,60, 1942. 32. DKKennepohl, B.D.Santarsiero,and R.G.CavellJnorg.Chem., 1990,29,5081. 33. D.K. Kennepohl, A.A.Pinkerton, Y.F.Lee and R.G. Cavell, Znorg.Chem., 1990, 29, 5088. 34. R.Chen and B.Cai, Phosphorus, Sulfur and Silicon, 1991,67,83.

3

Phosphine Oxides and Related Compounds BY B. J. WALKER

1 Preparation of Phosphine Oxides Nickel bromide is reported to catalyse the arylation of amorphous red phosphorus with iodobenzene to give a temperature dependent mixture of triphenylphosphine oxide and tetraphenylphosphonium iodide.] Since the latter compound can be hydrolysed to the former the method provides a synthesis of triphenylphosphine oxide in almost quantitative yield. Monoand tri-3-sulphonate-substituted triphenylphosphines' react with activated alkynes in water to give new hydrophilic phosphine oxides (1) or vinylphosphonium salts or alkenes depending on the pH and the nature of the acetylene.2 Chiral di- and tri-arylphosphine oxides have been prepared in 9 5 % enantiomeric excess by sequential nucleophilic displacement reactions on the phosphorus oxide (2) derived from ( l R , 2S)-ephedrine.3 Xray analysis was used to determine the absolute configuration at phosphorus for both (2) and a further reaction intermediate. The phosphine oxide (3)4 and difluoromethyldiphenylphosphine oxide (4)5 have been prepared, the l a t t e r by the reaction of chlorodifluoromethane with diphenylphosphine oxide, for use in the synthesis of fatty acids and difluoroalkenes, respectively. However reactions of (3), and the corresponding phosphonium salt, with carbonyl compounds gave only poor yields of alkenes. Olefination reactions with ( 4 ) gave moderate yields of difluoroalkenes but attempts at extension to the synthesis of monofluoroalkenes by the use of monofluoromethyldiphenylphosphine oxide were unsuccessful.^ The yneeneallenylphosphine oxides ( 6 ) have been synthesized, as potential DNA cleaving and anti-tumour agents, from the alcohols ( 5 ) . 6 In solution compounds (6) readily cyclise to aromatic structures (7). A variety of phosphine oxides (9) have been prepared from vinylphosphonium salts (8) for use in the synthesis of chiral phosphinocarboxylic acid ligands.7 The cycloaddition of alkynyldiphenylphosphine oxides to 1,3h3-azaphosphinines (10) provides a route to 2-diphenylphosphinoxido-h~-phosphinines(11) - 8 Phosphine radical cations, generated by one-electron oxidation of phosphines with excited singlet 1,4-dicyanonaphthalene, form phosphine oxides on reaction with water.9 Alkyldiphenylphosphine oxides (12) and sulphides (13) have been conveniently prepared in moderate yield by the 66

3: Phosphine Oxides and Related Compounds

67

0

0

II

II

Ar2-" PhPCH=CHR

4s03Na

n-cll

(1) A r =

(2)

F2CHPPh2 H23

(3)

(4)

n = 1,2

(8) n = 2, 3

(9) x =

'-' U'

CHO, C02Me, C02H

n =2,3

Ph

0

II

RCECPPh2 Ph

X

II

PhZPCI

Sm12

+

RX'

'

r. t.

*

X

II

Ph2PR (12) x = o (13) X = S

68

Organophosphorus Chemistry

reaction of chlorodiphenylphosphine oxide or sulphide, respectively, with alkyl halides in the presence of samarium diiodide.10 Macrocyclic phosphine oxides ( 1 6 ) have been synthesized by the reaction of halogenated diphosphine dioxides (14) with the diphosphine (15) followed by alkaline hydrolysis of the phosphonium salt formed.11

2 Structure and Physical Aspects The structural parameters of the 1:l crystalline adducts (17) formed from diphenylphosphine oxide and azodicarboxylates have been determined by X-ray analysis.12 X-ray methods have also been used to show that the structure of the product from the reaction of 1H-phosphole l-oxide (18) with dichlorocarbene is (19 ) , a 1,4-dihydrophosphinine rather than the phosphepine structure previously reported.13 The X-ray crystal structure of tris(chloromethy1)phosphine oxide has been reported. 1 4 Substitution effects on 31P and 13C n.m.r. spectra of a number of tris(4substitutedpheny1)phosphine oxides have been investigated. 15 A variety of studies, including ones of surface modification and thermal stability, on poly(ary1ene ether phosphine oxides) have been reported.16 3 Reactions at Phosphorus Phosphine-boranes (20) have been synthesized directly from phosphine oxides without isolation of the intermediate phosphine.17 The thermal elimination of water from phosphorus-oxygen compounds, including phosphine oxides, in the gas phase has been investigated.18 4 Reactions at the Side-Chain Phosphine oxide-based olefin synthesis continues to be used although rather less than might be expected in view of the opportunities for controlling stereochemistry that the method offers. Both (Z)-penta-2,4-dien-l-01 ( 2 2 ) and substituted (E)-penta-2,4-dien-l-ols (24) have been synthesized by this method.19 Synthesis of the (2)-isomer (22) involves the use of the furan Diels-Alder adduct (21) to establish the (Z)-stereochemistry (Scheme 1). The (E)-isomers (24) are available by a more general route via (23). The Diels/Alder-active (E,E)- 1-methoxy-4-trimethylsilyl-l,3-butadiene (26) has been prepared by the reaction of methoxymethyldiphenylphosphine oxide anion with trans-trimethylsilylpropenal followed by separation and decomposition of the (RS.SR)-2-hydroxyalkylphosphine oxide adduct (25).20 Sequential reaction of the carbanions of a-methoxyallyl(dipheny1)phosphine oxides with alkyl chloroformates and aldehydes provides a general, convenient, one-pot route to 4-methoxyalka-2,4-dienoates (27) (Scheme 2).2 1 High diastereofacial selectivity is observed in the intermolecular

3: Phosphine Oxides and Related Compounds

69

Ph2P(CH2)3PPh2

(16) n =2,3

Me

Me

M

PO h '/

PTC NaOH, HzO, CHC13

-

-d-.; o"

\ Ph

70

Organophosphorus Chemistry

@FPh2

i

H

w

ii

i

P

h

2

*

H

OH iii, iv

/

OH

H

OCOAr

R2

01

R3

? I +

vi, vii

Ph2P R2

0

R3 OH

+

OH

R4

(23)

(24)

II

Reagents: i, Ph2PCH2Li;ii, NaBH4;iii, NaH; iv, ArCOCI, DMAP, CH2CI2;v, 170 "C, 8 mins; vi, 2 x BuLi; vii, R42C0

Scheme 1 OMe

Reagents: i, 2.2 x LDA; ii, CIC02R3;iii, R4CH0

Scheme 2

3: Phosphine Oxides and Related Compounds

71

pinacol cross-coupling of a,a-disu bsti tuted a - ( d i p h e n y l p h o s p h i n o y 1 ) acetaldehydes to give ( 2 8 ) . 2 2 On treatment with base the diols (28) provide a stereospecific synthesis of 3,3-disubstituted allylic alcohols (Scheme 3). Phosphine oxide-based olefinations of allenyldiphenylphosphine oxides ( 2 9 ) have been used to provide a short synthesis of [3]-cumulenes ( 3 0 ) (Scheme 4)?3 Olefination reactions with the phosphine oxide (31, X=H) have been used to synthesize a variety of vitamin D analogues including the first example ( 3 2 ) of a (7Z)-isomerz4 and the key step in a short, flexible synthesis of 25-functionalised vitamin D3 analogues (33).*5 The individual enantiomers of (E)-but-2-enyl-t-butylphenylphosphine oxide ( 3 6 ) have been prepared from the corresponding (+)-( 3 4 ) - and (-)-(3 5 ) - t b u t y l m e t h y l p h e n y l p h o s p h i n e oxides.26 Under basic conditions each of the enantiomers of (36) react 100% stereoselectively with 2-methylcyclopent2-enone to generate enolates (37), which in turn react with 4-chlorobut-3en-2-one to give ( 3 8 ) . Compound ( 3 8 ) can be converted into the hydrindenone ( 3 9 ) which is suitable for conversion into vitamin D analogues. Both phosphine o x i d e - ( 4 2 ) and phosphonate-(43) c a r b a n i o n s , prepared from the corresponding allenes ( 4 0 ) and ( 4 1), undergo carbanion-accelerated Claisen rearrangement at room temperature with complete regioselectivity to give ( 4 4 ) .27 Kinetic and stereochemical studies of the intramolecular Diels-Alder reactions of cycloalkenylallenylphosphine oxides ( 4 5 ) have been reported.28 G ern -dialkyl effect accelerations and differences in rate due to the allene-ene tether length were observed and measured. The thermal 1,3-dipolar cycloaddition of N-benzylidene-a (dipheny1phosphinoyl)glycine esters (46) to N-phenyl maleimide has been investigated.29 The reaction involves rate-determining dipole formation and gives good yields of two diastereomeric endo adducts ( 4 7 ) and ( 4 8 ) . With less reactive dipolarophiles the dipolar cycloaddition reaction is the ratedetermining step.30 The reaction has been used to provide a route to polyfunctionalised 2-(diphenylphosphinoy1)pyrrolidines with generally good P-syn 4-endo selectivity. A study of the cycloaddition of nitrones to vinylphosphine oxides, sulphides and selenides to give (49) and (SO) shows that the regio- and diastereo-selectivity of the reactions varied widely depending on the substituents and the conditions used.3 1 Both diazo derivatives ( 5 1) and nitrilimines (52) have been synthesized by the reaction of the lithium salts of phosphorus-substituted diazomethanes with chlorophosphi nes .3 2 5 Phosphine O x i d e Complexes The bimetallic, bis(phosphine oxide) complex (53) has been prepared by the

Organophosphorus Chemistry

72

Reagents: i, [V2C13(THF)6]2[Zn2CIe]; ii, excess NaH

R2F OH

Scheme 3 0 I1

Rbc+pph2

i, ii

H

R2

5

(29) Reagents: i, KN(SiMe3)2,THF, -78 “C; ii, R2R3C0

Scheme 4

Ph,P=O I

+

X = Li ___)

R’O’.’ 0

R2 =

TBSO-.’

.‘-Y

HO’

Me OH

(32) R’ = R2 = H

73

3: Phosphine Oxides and Related Compounds 0

0 II

(34)

(35) 0-

c"('".."'t 0 II

Ph

0

(39)

? (40)2 = Ph2P(O-)

,

R4

R4 R3

(42)Z = Ph,P(O) (43)2 = (Bu'O),P(O)

(41) Z = (Bu'O),P(O)

(44)

74

Organophosphorus Chemistry

Ph

3:

Phosphine Oxides and Related Compounds

75

reaction of the corresponding biphosphine with Co(I1) chloride followed by treatment

with

hydrogen

peroxide.33

determined by X-ray crystallography.

T h e structure of ( 5 3 )

has been

Reports of examples of the synthesis

of phosphine oxides incorporated in metallocyclic rings include the platinum complex (54);34 the structure (54) has been confirmed by X-ray diffraction studies.

Structural

studies

of

phosphine

oxide-uranium

complexes,35~36

including an X-ray structure of tetrabromobis-[tris(pyrrolidinyl)phosphine oxide] uranium(IV),36 have been reported. REFERENCES 1.

H-J. Cnstau, J. Pascal, and F. Plenat, Tetrahedron Letters, 1990, 31,

2.

C. Larpent, G. Meignan, and H. Patin, Tetrahedron, 1990, 46, 6381.

3.

J.M. Brown, J.V. Carey, and M.J.H. Russell, Tetrahedron, 1990, 46, 4877.

4.

A. Stoller, C. Mioskowski, C. Sepulchre, and F. Bellamy, Tetrahedron Letters, 199 1 ,

5463.

32, 495. 5.

M.L. Edwards, D.M. Stemerick, E.T. Jarvi, D.P. Matthews, and J.R. McCarthy,

6.

K.C. Nicolaou, P. Maligres, J. Shin, E. de Leon, and D. Rideout, J. Am. Chem. SOC., 1990, 112, 7825.

7.

Y. Okada, T. Minami, Y. Sasaki, Y. Umezu, and M. Yamaguchi, Tetrahedron Letters,

8.

G. Markl, F.G. Klarner, and C. Lodwig, Tetrahedron Letters, 1990, 31, 4589.

Tetrahedron Letters, 1990, 31, 5571.

1990, 31, 3905. 9.

G. Pandey, D. Pooranchand, and U.T. Bhalerao, Tetrahedron, 1991, 47. 1745.

10.

M. Sasaki, J. Collin, and H.B. Kagan, Tetrahedron Letters, 1991, 32, 2493.

11.

M. Vincens, J.T. Grimaldo-Moron, and M. Vidal, Tetrahedron, 1991, 37, 403.

12.

D. Camp, P.C. Healy, I.D. Jenkins, B.W. Skelton, and A.H. White, J . Chem. SOC., Perkin Trans.1, 1991, 1323.

13.

G. Keglevich, A. Szollosy, L. Toke, V. Fulop, and A. Kalman, J. Org. Chem., 1990, 55,

6361. 14.

A.N. Chekhlov, Y.G. Kulishov, S.E. Tkachenko, and E.N. Tsvetkov, Bull. Acad. SC.

USSR, 1990, 39, 1406.

15. 16.

W-N. Chou and M. Pornerantz, J. Org. Chem., 1991, 56, 2762. H.F. Webster, C.D. Smith, J.E. McGrath, and J.P. Wightman, Abstracrs of American Chemical Society, 1991, 202, Aug. p.52; ibid, p. 53; ibid, p. 54.

17.

T. Irnamoto, T. Oshiki, T. Onozawa, T. Kusumoto, and K. Soto, J . Am. Chem. SOC.,

18.

H. Bock and M. Bankmann, Z. Anorg. Allg. Chem., 1991, 606, 17.

19.

P.S. Brown, N. Greeves, A.B. McElroy, and S. Warren, J. Chem. SOC., Perkin

20.

J.T. Pegram and C.B. Anderson, Tetrahedron Letters, 1991, 32, 2197.

21.

E.F. Birse, M.D. Ironside, L. McQuire. and A.W. Murray, J. Chem. S O C . , Perkin

1990, 112, 5244.

Trans.1, 1991, 1485.

Trans.], 1990, 2811.

Organophosphorus Chemistry

76 22.

J. Park and S.F. Pederson, J. Org. Chem., 1990, 55, 5924.

23.

I. Saito, K. Yamaguchi, R. Nagata, and E. Murahashi, Tetrahedron Letters, 1990, 31, 7469. M.M. Maestro, F.J. Sardina, L. Castedo, and A. Mourino, J. Org. Chem., 1991, 5 6 .

24.

3582. 25.

J.L. Mascerenas, J. Perez-Sestelo, L. Castedo. and A. Mourino, Tetrahedron Letters,

26.

1991. 32, 2813. R.K. Haynes, J.P. Stokes, and T.W. Hambley, J. Chem. Soc., Chem. Commun., 1991, 58.

27. 28. 29. 30.

S.E. Denmark and J.E. Marlin, J. Org. Chem., 1991, 56, 1003.

M.L. Curtin and W.H. Okamura, J. Org. Chem., 1990, 55, 5278.

J.J.G.S. van Es, K. Jaarsveld, and A. van der Gen, J . Org. Chem., 1990, 55, 4063.

J.J.G.S. van Es, A. ten Wolde, and A. van der Gen, J. Org. Chem., 1990, 55, 4069.

31.

A. Brandi, S. Cicchi, A. Goti, K.M. Pietrusiewicz, and W. Wisniewski, T e t r a h e d r o n ,

32.

M. Granier, A. Baceiredo, Y. Dartiguenave. M. Dartiguenave, H-J. Menu, and G.

33.

S.I. Al-Resayes. P.B. Hitchcock, and J.F. Nixon. J. Chem. SOC., Chem. Commun.,

34.

R.D.W. Kemmitt, S. Mason, M.R. Moore, J. Fawcett, and D.R. Russell, J. Chem. Soc.,

35.

Chem. Commun., 1990, 1535. G.S. Conary, R.L. Meline, L.J. Candle, E.N. Duesler, and R.T. Paine, Inorg. Chem.

1990. 46, 7093.

Bertrand, J. Am. Chem. SOC.,1990. 112. 6277.

1991, 78.

Acta, 1991, 189, 59.

36.

J. G. H. Dupreez, H. E. Rohwer, B. J. A. M. Vanbrecht, B. Zeelie, U. Castellato, and R. Graziani, Inorg. Chem. Acta, 1991, 189, 67.

4

Tervalent Phosphorus Acids

BY 0.DAHL

1 Introduction

The title of this chapter has been changed from Tervalent Phosphorus Acids because tervalent phosphorus acids don't exist! Derivatives of tervalent phosphorus acids, however, are abundant, and it is these, e.g. (RO)3P, RP(NR'2)2, and similar compounds with at least one P-N, P-0, or P-Sbond, the chapter is about. A comprehensive review has appeared on the synthesis, structure, bonding, and reactivity of acyclic iminophosphines, R-P=N-R'.' Proceedings of the 9th International Round Table on Nucleosides, Nucleotides, and their Biological Applications, Uppsala, 1990, which contain many papers of relevance for this chapter, have been published.2

2 Nucleophilic Reactions 2.1 Attack on Saturated Carbon.- A modified Arbuzov procedure to prepare galactose-6-phosphatehas been p ~ b l i s h e dIt. ~involves an Arbuzov reaction of diphenyl isopropyl phosphite (1) with a protected 6-iodogalactoside(2); the merits of the phosphite (1) is that the isopropyl iodide formed does not compete with (2),and that the diphenyl phosphonate product can be easily converted to a dibenzyl phosphonate by base catalysed ester exchange and the latter reduced cleanly to the free phosphonic acid. Alkylation of the 1,3,2-oxazaphospholan (3) is the first step in a stereoselective synthesis of phosphinates and tertiary phosphine oxides. The phosphonium intermediates (4) are relatively stable when RX is reactive (methyl iodide, benzyl chloride) and have now been observed by n.m.r. to decompose to the Arbuzov products (5) with full r e t e n t i ~ n .Less ~ than full retention in the overall reaction is due to formation of both (4a) and (4b) from pure (3), probably because (4a) isomerises to (4b) via a phosphorane mechanism.

77

Organophosphorus Chemistry

78

R' = alkyl, aryl R2 = COOMe, CN

0' Ph2PCI

-

R2

-?% - 78 "C

PPh,

4:

Tervulent Phosphorus Acids

79

2.2 Attack on Unsaturated Carbon.- The well-known 2,3-sigmatropic rearrangement of ally1 phosphites to allylphosphonates has been used to obtain a series of substituted allylphosphonates ( 6 ) for use in Horner-Emmons reaction^.^ Surprisingly the products were pure Z-isomers for R 2 = COOMe but mainly Eisomers for R2 = CN. A similar rearrangement served to prepare some allenic phosphine oxides, e.g. (7),designed as DNA-cleaving molecules.6A full paper has appeared on the reactions of benzothiete (8) with trialkyl phosphites or dialkyl phenylphosphonites, e.g. (9);7the mechanism proposed is nucleophilic attack on the exocyclic carbon of ( 8 ) followed by an Arbuzov-type dealkylation. Tris(dimethy1amino)phosphine reacts at room temperature with arylaldehydes bearing electron-donating groups, or benzaldehyde, to give a-aminophosphonic diamides (10) which are useful for Horner-Emmons-type condensations.8 The addition reactions of in situ generated trimethylsilyl phosphites, phosphonites, or phosphinites (1 1) with imines, e.g. (12), have been ~ t u d i e dThe . ~ reactions are much faster than similar additions to aldehydes, and most substituents X are tolerated, although surprisingly the rate is decreased by electron-withdrawing groups; other C=N compounds like isocyanates and diarylcarbodiimides react similarly, but no reaction occurred with dicyclohexylcarbodiimide, hydrazones, or oxime ethers. Phosphites, and other tervalent phosphorus compounds, are effective reagents for the reduction of oxidatively damaged thymidine derivatives, e.g. (13);1° the reaction is thought to begin with attack at the carbonyl carbon as shown. Triethyl phosphite is unreactive towards phenyl isothiocyanate below 150 OC and removes sulphur to give phenyl isocyanide at higher temperatures; addition of acetic acid, however, results in the formation of a thiocarbamoylphosphonate (1 4) at room temperature.ll The same product is obtained from (15) and other tert.-butoxy compounds at room temperature without the addition of acid; obviously the addition product (16) must be trapped by protonation from an acid or a tert.-butyl carbocation in order for the reaction to proceed. Several thio analogues of phosphoenolpyruvate (17) have been prepared from ethyl bromopyruvate and the thio- or dithiophosphites

(18).12

2.3 Attack on Nitrogen, Chalcogen, or Halogen.- Azides react with phosphites to give phosphazides, e.g. (19), which normally undergo the Staudinger reaction to give phosphazenes,e.g. (20). In thecase of (20),a Wittig-type reaction with the carbonyl group then occurs to give (21).13The phosphazide intermediate (19, R = H),

Organophosphorus Chemistry

80

Ph

ArCHO

+

P(NMe2)3

d y\N l

R1R2P-OSiMe3 +

-

Me,? ArCH-P(NMe,), (1 0)

--x&

“NH P(O)R’R~

X (12)

(11)

R‘,R2 = OEt, OSiMe3, Ph

0 M e N y i e

0A N

A

OH

+(Ph0)3P

-

+

HO

P(OPh)3

MZ? ):

0

- (Ph0)3P =O ~

Me I

R

M e N p e OAN

A

OH

J- H*O

0

4:

Tervalent Phosphorus Acids

81

(18) R' = Me, Et, Pr' R2 = Pr', Bu, Ph n = 1,2

OCOMe Phk

'

-

(Pri2N)2P-P (NP$ 2 ) ~

(26)

X

N*P(OEt)3

(Pr'2N)2P-X-P(NPri2)2

(27)X

-

= S , Se, Te

Me Ph

?

(Et2Nc-S-12

(28)

82

Organophosphorus Chemistry

however, gave the triazole (22), probably via a 1,5-electrocyclisation to (23), instead of the usual Staudinger 1 ,4-cyclisation.14 Acylphosphonites (24) with one equivalent of hexafluoroacetone gave the phosphites (25), probably via attack of phosphorus on the oxygen of hexafluoroa ~ e t 0 n e . lThe ~ reactions of a-halogenated phenylnitromethanes with triethyl phosphite have been studied, and the different products rationalised by a mechanism which begin with attack of phosphorus on oxygen.16 Oxidation of tetrakis(diisopropy1amino)diphosphine(26) with elemental sulphur, selenium, or tellurium gave mostly the symmetrical diphosphinochalcogenides(27);” the crystal structures of (27, X = S , Te) were determined. Tetraethylthiuram disulphide (28) has been introduced as a reagent which can replace elemental sulphur for oxidation of oligonucleoside phosphites to phosphorothioates;18 the rate of oxidation is rather low (15 min on solid support), but the less hindered tetramethyl analogue gave mostly dealkylation of the phosphite instead of oxidation. The reactions of alkylbis(diisopropylamino)phosphines (29) with tetrachloromethane or bromotrichloromethane to give P-halogenoylides (30) which rearrange to halomethylphosphines (31) continue to attract interest. A kinetic study of the rearrangement of (30, X = CI, R = H)19 and further studies of the reactions of the bromo compounds20 have appeared.

3 Electrophilic Reactions 3.1 Preparation.- Several new chelating diphosphite ligands (32)21 and (33)22

have been prepared from phosphorus trichloride and the appropriate phenols or alcohols. The methylenebisphosphonites (34)23 and analogous bisphosphoramidites (35)23 and (36)24325 have also been made for studies of their chelating properties. Some thio- (37) and dithiophosphites (38) have been prepared from a thiol and the corresponding phosphorochloridite or -dichloridite.12 They are very sensitive towards oxidation and hydrolysis, and the thiophosphites (37) in particular rearrange easily to thiophosphonates (39); they could be used quickly, however, to prepare thio analogues of phosphoenol pyruvate (17). The first aminophosphines with two trichloromethyl substituents on phosphorus, (40), have been prepared as shown;26they are not easily hydrolysed and do not react with hydrogen chloride! Recent work on the reaction of phosphorus trichloride with aldehydes has resulted in the isolation of the primary products (41) and

4:

Tervalent Phosphorus Acids

83

R

(33) R = Ph, COOEt, COOP6

P(OR2)2 R~N’ \

(34) X = 0,s; Y = CH2 (35) X = 0,s;Y = MeN

RS-P (0Et)2

e

P(OR2)2

(36) R’ = Me, Ph R2 = CH2CF3,Pr’, Ph

E

R-P(OEt),

(RS),P-OMe

r.t.

(37) R = Pr’, But, 2-pyridyl

PC13 + RCHO

(39)

__

R3N

(38) R = Pr’, Bu

CI 1 RCH-O-PC12 (41) R = Pr, Pr‘

84

Organophosphorus Chemistry

the importance of acid and base catalysis has been realised; very pure phosphorus trichloride (distilled from N,N-diethylaniline) did not react at all with aldehydes! A series of polycyclic phosphites (42)were prepared from the corresponding tetrol and tris(dimethylamin~)phosphine.~~ There was no tendency of (42)to form the square-pyramidal H-phosphorane (43)but instead an internal dealkylation occurred to give the H-phosphonate (44). Exchange of amino groups in tris(dialky1amino)phosphineshas been used to prepare several new cyclic aminophosphines, e.g. (45)which is an efficient reagent for the determination of enantiomeric purity of alcohols,28 (46)which could not be obtained pure due to further condensation reactions,29 and (47)and (48).30 The 1,3,2-benzothIazaphospholen (49)was made from the phosphorodiamidite (50),31 and the 1,3,2-thiazaphospholan (51) from methyl phosphor~dichloridite,~~ in a search for new phosphorylating agents. Diethyl phosphorochloridite and N-acetonyiacetamide (52) gave the phosphite (53) which upon heating was converted to the isomeric phosphite (54) and subsequently to the 1,3,2-oxazaphospholen (55).33A similar initial attack on the amide group of (56) by ethyl phosphorodichloridite gave the 1,4,2-0xazaphospholen (57) which rearranged upon heating to (58).34The enimine (59) with phosphorus trichloride did not give the expected 1,2-azaphospholen (60),but the dihydro-l,2azaphosphorin (61).35

3.2 Mechanistic Studies.- Nucleophilic substitution reactions at tervalent

phosphorus centres are very often not stereoselective, but when the nucleophile is RLi the stereochemical result has usually been clean inversion. In a recent report, aimed at asymmetric synthesis of phosphines, the first substitution reaction on the borane adduct (62)gave mostly retention, while the next two steps both occurred with a high degree of i n ~ e r s i o nA. ~series ~ of tervalent phosphorus acid imidazolides, e.g. the phosphorimidazolide (63), has been prepared and the uncatalysed substitution of the imidazole group with methanol or diethylamine studied.37 In the case of (63),the primary product with methanol was the inverted phosphite, but with diethylamine the reaction was not stereoselective. Two salts of tris(dialky1amino)phosphines with tetrafluoroboric acid, (64)and (65),have been isolated.38According to 31P n.m.r. the proton is located on phosphorus, and the salts are extremely susceptible to alcoholysis.

4:

Tervalent Phosphorus Acids

x

A

\ (42) n

Me

+

(Me2N),P-OMe

NHMe

*

= 0-4

a s ) - o M e N Me

(50)

(49)

ASH

+MeOPCI2

0

NHMe

lB A>P-OMe Me

(51)

86

Organophosphorus Chemistry

J

0

EtOPC12

EtOJy

+

EtO' (56)

Et

)-+ 4 I

-1y-

+ PC13

Et

Pr

-D A

'?PAR 0-P,

0

OEt

(55) X, R = Me (58) X = OEt R = CF3, Ph

(57)

Bu

Bu

CI

N y R P-0

- EtOH

-

Pr

Bu I

Et

+

(Et2N)3P-H BF4-

(R0)2P-NEt2 (66) R = Me, Et, But, PhCH2, 4-BrC6H4CH2, Ph

(

X

o CH2C$)1-NPri2

(67)X = F, CI

PhCH20-P (NEt2)2

(68)

4:

Tervalent Phosphorus Acids

87

3.3 Use for Nucleotide, Sugar Phosphate, Phospholipid, or Phosphoprotein Synthesis.- A series of phosphoramidites (66) and (67) has been evaluated for use to prepare O-phosphorylserine and O-serine phosphorylated p e p t i d e ~ . ~The ~ - ~best l compromise between stability to the usual deblocking

reagents in the Boc peptide synthesis and ease of cleavage of the phosphorus protecting groups was found for (66, R = phenyl or 4-bromobentyl). The phosphoramidite (66, R = benzyl) has been used in an improved synthesis of dihydroxyacetone phosphate,42and the phosphoramidite (67, X = H) in the syntheses of some hexosamine-inositol phosphate^.^^ The phosphorodiamidite (68) was used to prepare a cyclic inositol phosphite which gave inositol phosphate diesters after oxidation and transesterification.44A guanosine 5'-diphosphate mannose analogue containing a hexadecyl phosphate group was obtained from the phosphorodiamidite (69).45 The 1,3,2-0xazaphospholan(70) undergo hydrolysis with opening of the ring under very mild conditions to give after oxidation the phospholipid (71).46Another approach to similar phospholipids involves the phosphoramidite (72), which is transformed to (73) under conditions that avoid base-catalysed acyl migrations and therefore give very pure products.47 Phosphoramidites containing reporter groups, e.g. biotin, are not new, but several improved reagents for labelling of oligonucleotides have been reported this year. These include the biotin reagents (74),48(75),49and (76),50all of which allow for multiple labelling with biotin, the protected biotin reagent (77)51which likewise allows multiple labelling, and (78)52which contains a dimethoxytrityl group on biotin for easy quantisation of the coupling efficiency. A reagent (79) containing a phosphotyrosine group makes possible the detection of oligonucleotides by antibodies specific for p h o s p h ~ t y r o s i n e .Some ~~ phosphoramidites (80) containing 2,2'bipyridyl groups were used to prepare nucleoside-bipyridine conjugates which cleaved RNA in the presence of copper(l1) ions.53 A previously reviewed method to prepare oligodeoxyribonucleotides or their phosphorothioate analogues has been further d e v e l ~ p e d . ~ The ~ , ~phosphite ~ monomers (81) are coupled to support-bound nucleoside using N-methylimidazole as catalyst and the products are hydrolysed to H-phosphonates (82) with water; capping with the phosphite (83) and hydrolysis after each coupling cycle was found necessary in order to obtain products of a reasonable purity. A full paper has appeared on the use of nucleoside alkyl phosphorochloridites (84), prepared in situ from the H-phosphonate diesters (85)and the dichlorophosphorane (86), for the

88

Organophosphorus Chemistry

J

Me3N

NPri, DMT -0-P' Biotin-NH-0 1 \O -cN +

(74)

(73) 0

(75)

MMTrO Biotin-NH

Biotin

4:

Tervalent Phosphorus Acids

89

(77)

(78)

NHFmoc (80) n = 4,11

(79)

DMTroY + - DMTro i, NMI

ii, H20

o@

PriO-P(OCH(CF3)2)2 (83)

Organophosphorus Chemistry

90

DMTrO

3” H ‘

RO’.

Br

(86)

(85) R = Me, CH2CH2CN

(84)

-rfzDMTro-vbz dT

(86)

DMTro

DM ,o,y

Br

0. Pri2N

’\ 50

0.

,P-CI Pri2N

H

OMTr0Y

R’ R ~ P -N ,

::

O ,

OSiButMe2

I PN -nO

O%CN (91) R1R2N= MezN, MeEtN,

n

Et2N, Pri2N, 0

uN

(92)

4:

Tervalent Phosphorus Acids

91

preparation of nucleotide dimers in solution and oligomers on solid support.56The yields were about 99% per step for the solid support synthesis of a Tle-mer which compare well with the phosphoramidite method. An in situ prepared phosphorochloridite (84, 6 = Tbz, R = Me) has further been used to obtain a H-phosphonothioate (87) which gave a phosphorodithioate (88) after oxidation with sulphur.57The reagent (86) could also be used to convert a H-phosphonamidate (89) to a dinucleoside phosphoramidite Preparation of RNA fragments by the phosphoramidite method has been . ~ ~the five uridine phosphoroptimised with regard to the amino s ~ b s t i t u e n t s Of amidites (91) tested, the ethylmethylamino compound was preferred. The dimethylamino compound decomposed by attempted column chromatography on silica, but the other phosphoramidites could be purified in this way. Of these (91, NR1R2 = NMeEt) gave the fastest couplings, 96-97% yield on solid support after 4 min, with tetrazole as the catalyst. The neopentyl phosphoramidite (92)has been prepared and used to make TT-dimers containing a neopentyl phosphorothioate linkage;60 the separated diastereomers were coupled to give oligomers with alternating phosphate and neopentyl phosphorothioate linkages. Two symposia-in-print papers have appeared on the preparation of oligonucleoside phosphorodithioates.61s62The paper by Caruthers et aL61 describes some improvements in the preparation of the preferred monomers, the nucleoside thiophosphoramidites (93); with these improvements, oligonucleoside phosphorodithioates could be obtained in good yields (96-98% per step) with a low amount of impurities (2-3% of monothioate linkages). The same nucleoside thiophosphoramidites (93, R = Me) were used by Gorenstein et al.62, and one of them (B = T) could be obtained pure by flash chromatography on silica under an inert gas. A 12-mer DNA fragment containing one 5'-S-phosphorothioatelinkage has been prepared by tetrazole-catalysed coupling of a standard nucleoside phosphoramidite (94) with a 5'-mercaptooligonucleotide (95).63 3.4 Miscellaneous.- A series of new 2-aminoalkyl diphenylphosphinites (96) has

been prepared and used as catalysts for linear dimerisation of b ~ t a d i e n e sSeveral .~~ phosphinites, e.g (97) and (98), and phosphites (99) were prepared as precursors for chiral phosphine oxides;65the phosphine oxides were made by catalysed Arbuzov rearrangements.

Organophosphorus Chemistry

92

DMTroY (93) NR2 = NMe2,

R

*I

+ HOCH2CHNH2

Ph2P-NMe2

(97) R = Ph,

[

R-S-P+

PhzP-OCH2CHNH2

(99) R = H, Me

(98)

S t

*s

R = Me

-

R

*I

7 [R-S-P=S

.t-

R-P'

S

R = Me, Ph

4:

Tervalent Phosphorus Acids

93

4 Reactions involving Two-co-ordinate Phosphorus The first examples of a two-co-ordinated tervalent organothiothioxophosphine ( 100) have been observed in the gas phase by neutralisation-reionisation mass spectrometry.66 The compounds are formed by the two routes shown from dithioxophosphoranes which are again the primary products of thermal decompositions of Lawesson-type reagents. The haiogenoiminophosphines (101 ) have been prepared from the known chloro compounds by exchange with AgF, MegSiBr, or Me3Sil.67 The crystal structures of (101, X = CI, Br) show that they exist as the Z-isomers.68 A series of aminoiminophosphines (102) were studied with respect to their E/Z geometry.69 The Z-isomer was the thermodynamically stable isomer for .the dimethylamino, diethylamino, and pyrrolidino compound, but (102) with larger N-substituents had the E geometry. Phosphenium ions (103) and 1,2-diimines gave in a facile (1+4) cycloaddition reaction the 1,3,2-diazaphosphoIenium cations (104).70 With two equivalents of imines (105), however, phosphenium ions gave 1,4,2-diazaphosphoIanium cations (106), probably via a stabilised carbocation as shown.71 The 1,3,2-benzazathiaphospholium ion (107) has been prepared as the tetrachloroaluminate, and its crystal structure determined.72 Attempts to prepare the phosphenium phosphaalkenes (108) gave the arnino. ~ ~ stable, diphosphene carbocations (109) which dimerised at room t e m p e r a t ~ r eThe cyclic aminodiphosphene (1 10) was readily formed from 2-phosphinoaniline and tris(dimethylamin~)phosphine.~~ The aminodiphosphene (1 11) formed spontaneously from the phosphinoiminophosphine (1 12) when the latter was prepared as shown.75 The first, stable two-co-ordinated phosphorus heterocycles with only one double bond in the ring, (1 13), were prepared by the simple route shown.76

5 Miscellaneous Reactions Triisopropyl phosphite (114) has been shown to be an effective reagent to convert aldehydes or ketones to hydrocarbons (1 15).77 The mechanism proposed is reminiscent of the Meerwein-Ponndorf reduction of ketones to alcohols. Aminophosphines (1 16) and Lawesson reagents (1 17) gave products (118) at room

94

Organophosphorus Chemistry

' \

(101) X = F, Br, I

(102) NR2 = NMe2, NEt2, NPi2, NBut2, N(SiMe3)2,

+

(Me2N)sP

-

H

4:

Tervalent Phosphorus Acids

R’\

x=c;

95

R2

R’

X

/

N-NH

+

(Me2N)3P

N

+P

NH2

,N-W

(1 13) X = 0, R’ = H, R2 = Ph

X E S , R’ =Me, R2= H

c,

R1, C ,H R2

Me

C :

bJp%

R1\ Me

R2‘

CH,

+

[ O=P-OPri]

Organophosphorus Chemistry

96

S

/

P~'~NH

Ar

-

E

R', P(S-P-NR22)3-, I

Ar

4:

Tervalent Phosphorus Acids

97

temperature where ArPS2 was inserted into one or two P-N bonds.78 The phosphono phosphaalkyne (119) gave an 1,2-addition compound (120) with diisopropylamine and a 1,2,3,44riazaphosphole(121) with mesityl a ~ i d e . ~ ~ Two new cage compounds containing tervalent phosphorus have been prepared. The trithiadiphosphabicyclo(2,2,1)heptanes (122) were obtained by reduction of the corresponding P,P-disulphides with triphenylphosphine,80 and monomeric P2Se5, which has the remarkable structure (123), by CS2 extraction of an annealed amorphous P2Se5 glass.81

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

E. Niecke and D. Gudat, Angew. Chem. lnt. Ed. Engl., 1991, 30, 217. J. Chattopadhyaya (ed.), Nucleosides Nucleotides, 1991, 10, 1. M. F. Wang, M. M. L. Crilley, B. T. Golding, T. Mclnally, D. H. Robinson, and A. Tinker, J. Chem. SOC., Chem. Commun., 1991, 667. S. Jug& M. Wakselman, M. Stephan, and J. P. Genet, Tetrahedron Lett., 1990, 31, 4443. T. Janecki and R. Bodalski, Synthesis, 1990, 799. K. C. Nicolaou, P. Maligres,J. Shin, E. d. Leon, and D. Rideout, J. Am. Chem. SOC., 1990, 112, 7825. H.-L. Eckes, H.-P. Niedermann, and H. Meier, Chem. Ber., 1991, 124, 377. F. Babudri, V. Fiandanese, R. Musio, F. Naso, 0. Sciavovelli, and A. Scilimati, Synthesis, 1991, 225. K. Afarinkia, C. W. Rees, and J. I. G. Cadogan, Tetrahedron, 1990, 46, 7175. R. Yanada, K. Bessho, T. Harayama, and F. Yoneda, Chem. Pharm. Bull. Tokyo, 1991, 39, 1333. T. K. Gazizov, Y. V. Chugunov, and L. K. Sal'keeva, J. Gen. Chem. USSR, 1990, 60, 491. C. Despax and J. Navech, Phosphorus, Sulfur and Silicon, 1991, 56, 105. H. Takeuchi, S. Yanagida, T. Ozaki, S. Hagiwara, and S. Eguchi, J. Org. Chem., 1989, 54, 431. S. V. DAndrea, A. Ghosh, W. Wang, J. P. Freeman, and J. Szmuszkovicz, J. Org. Chem., 1991, 56, 2680. A. A. Prishchenko, M. V. Livantsov, N. V. Boganova, and I. F. Lutsenko, J.

98

16 17 18 19 20 21 22 23 24 25 26

27

28 29 30 31 32 33

34 35

36 37

Organophosphorus Chemistry Gen. Chem. USSR, 1989, 59, 2485. H. Burgess and J. A. Donnely, Tetrahedron, 1991, 47, 111. H. Westermann, M. Nieger, and E. Niecke, Chem. Ber., 1991, 124, 13. H. Vu and B. L. Hirschbein, Tetrahedron Lett., 1991, 32, 3005. 0. I. Kolodyazhnyi, J. Gen. Chem. USSR, 1990, 60, 1541. 0. I. Kolodyazhnyi, 0.B. Golokhov, and S. N. Ustenko, J. Gen. Chem. USSR, 1990, 60, 1536. M.J. Baker, K. N. Harrison, A. G. Orpen, P. G. Pringle, and G. Shaw, J. Chem. SOC., Chem. Commun., 1991, 803. D. J. Wink, T. J. Kwok, and A. Yee, Inorg. Chem., 1990, 29, 5006. S. Kim, M. P. Johnson, and D. M. Roundhill, Inorg. Chem., 1990, 29, 3896. M. S. Balakrishna, T. K. Prakasha, S. S. Krishnamurthy, U. Siriwardane, and N. S. Hosmane, J. Organometal. Chem., 1990, 390, 203. J. T. Mague and M. P. Johnson, Organometallics, 1990, 9, 1254. A. P. Marchenko, G. N. Koidan, G. 0. Baran, A. A. Kudryavtsev, and A. M. Pinchuk, J. Gen. Chem. USSR, 1990, 60, 847. R. V. Davis, D. J. Wintergrass, M.N. Janakiraman, E. M.Hyatt, R. A. Jacobson, L. M. Daniels, A. Wroblewski, J. P. Amma, S. K. Das, and J. G. Verkade, Inorg. Chem., 1991, 30, 1330. A. Alexakis, S. Mutti, J. F. Normant, and P. Mangeney, Tetrahedron: Asymmetry, 1990, 1, 437. E. G. Bent, R. C. Haltiwanger, and A. D. Norman, Inorg. Chem., 1990, 29, 4310. J. M. Barendt, R. C. Haltiwanger, C. A. Squier, and A. D. Norman, Inorg. Chem., 1991, 30, 2342. P. Jacob, W. Richter, and I. Ugi, Liebigs Ann. Chem., 1991, 519. W. Richter and I . Ugi, Synthesis, 1990, 661. S. E. Pipko, Y. V. Valitskii, T. V. Kolodka, A. D. Sinitsa, and M. I. Povolotskii, J. Gen. Chem. USSR, 1990, 60, 849. D. M. Malenko, L. I. Nesterova, S. N. Luk'yanenko, and A. D. Sinitsa, J. Gen. Chem. USSR, 1989, 59, 2347. E. Y. Levina, A. N. Pudovik, and A. M. Kibardin, J. Gen. Chem. USSR, 1990, 60, 663. S. Juge, M. Stephan, J. A. Lafitte, and J. P. Genet, Tetrahedron Lett., 1990, 31, 6357. M. K. Grachev, V. Y. lorish, A. R. Bekker, and E. E. Nifant'ev, J. Gen. Chem.

4:

38 39 40 41 42 43 44 45

46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Tervulent Phosphorus Acids

99

USSR, 1990, 60, 57. S. Y. Burmistrov, L. K. Vasyanina, M. K. Grachev, and E. E. Nifant’ev, J. Gen. Chem. USSR, 1989, 59, 2360. J. W. Perich and R. B. Johns, Austral. J. Chem., 1990, 43, 1633. J. W. Perich, P. F. Alewood, and R. B. Johns, Austral. J. Chem., 1991, 44, 233. J. W. Perich and R. B. Johns, Austral. J. Chem., 1991, 44, 389. R. L. Pederson, J. Esker, and C.-H. Wong, Tetrahedron, 1991, 47, 2643. W. K. Berlin, W . 4 . Zhang, and T. Y. Shen, Tetrahedron, 1991, 47, 1 . C. Schultz, T. Metschies, B. Gerlach, 6. Stadler, and B. Jastorff, Synlett., 1990, 163. H. J. G. Broxterman, P. A. Kooreman, H. van den Elst, H. C. P. F. Roelen, G. A. van der Marel, and J. H. van Boom, Recl. Trav. Chim. Pays-Bas, 1990, 109, 583. R. Stumpf and P. Lemmen, Z. Naturforsch., 1990, 45b, 1729. N. Hebert and G. Just, J. Chem. SOC., Chem. Commun., 1990, 1497. K. Misiura, I. Durrant, M. R. Evans, and M. J. Gait, Nucleic Acids Res., 1990, 18, 4345. Technical Bulletin 31019, Clontech Laboratories, Inc. Technical Bulletin N 4038, Peninsula Laboratories, Ltd. U. Pieles, B. S. Sproat, and G. M.Lamm, Nucleic Acids Res., 1990, 18, 4355. R. T. Pon, Tetrahedron Lett., 1991, 32, 1715. A. S. Modak, J. K. Gard, M.C. Merriman, K. A. Winkeler, J. K. Bashkin, and M. K. Stern, J. Am. Chem. SOC.,1991, 113, 283. H. Hosaka, Y. Suzuki, H. Sato, S. Gug-Kim, and H. Takaku, Nucleic Acids Res., 1991, 19, 2935. H. Hosaka, Y. Suzuki, S. Gug-Kim, and H. Takaku, Tetrahedron Lett., 1991, 32, 785. T. Wada, R. Kato. and T. Hata, J. Org. Chem, 1991, 56, 1243. T. Wada and T. Hata, Tetrahedron Lett., 1990, 31, 6363. T. Wada and T. Hata, Tetrahedron Lett., 1990, 31, 7461. D. Gasparutto, D. Molko, and R. TtSoule, Nucleosides Nucleotides, 1990, 9, 1087. J. F. Hau, U. Asseline, and N. T. Thuong, Tetrahedron Lett., 1991, 32, 2497.

100

61 62 63 64 65 66 67 68 69

70 71 72 73 74 75 76 77 78 79

Organophosphorus Chemistry G. Beaton, W. K.-D. Brill, A. Grandas, Y.-X. Ma, J. Nielsen, E. Yau, and M. H. Caruthers, Tetrahedron, 1991, 47, 2377. M. E. Piotto, J. N. Granger, Y. Cho, N. Farschtschi, and D. G. Gorenstein, Tetrahedron, 1991, 47, 2449. M. Mag, S. Luking, and J. W. Engels, Nucleic Acids Res., 1991, 19, 1437. H. Masotti, P. G, C. Siv, P. Courbis, M. Sergent, and R. P. T. Luu, Bull. SOC. Chim. Belg., 1991, 100, 63. H. Brunner and W. Zettlmeier, Bull. SOC. Chim. Belg., 1991, 100, 247. H. Keck, W. Kuchen, H. Renneberg, J. K. Terlouw, and H. C. Visser, Angew. Chem., Int. Ed. Engl., 1991, 30, 318. V. D. Romanenko, A. V. Ruban, G. V. Reitel', M. I. Povolotskii, A. N. Chernega, and L. N. Markovskii, J. Gen. Chem. USSR, 1989, 59, 2483. A. N. Chernega, A. A. Korkin, N. E. Aksinenko, A. V. Ruban, and V. D. Romanenko, J. Gen. Chem. USSR, 1990, 60, 2201. L. N. Markovskii, V. D. Romanenko, A. V. Ruban, A. B. Drapailo, G. V. Reitel', A. N. Chernega, and M. I. Povolotskii, J. Gen. Chem. USSR, 1990, 60, 2193. M.-R. Mazieres, T. C. Kim, R. Wolf, and M. Sanchez, Phosphorus, Sulfur, and Silicon, 1991, 55, 147. T. C. Kim, M.-R. Mazieres, R. Wolf, and M. Sanchez, Tetrahedron Lett., 1990, 31, 4459. N. Burford, A. I. Dipchand, B. W. Royan, and P. S. White, Inorg. Chem., 1990, 29, 4938. M. Sanchez, V. Romanenko, M . 4 . Mazieres, A. Gudima, and L. Markowski, Tetrahedron Lett., 1991, 32, 2775. K. Rauzy, M.-R. Mazieres, P. Page, M. Sanchez, and J. Bellan, Tetrahedron Lett., 1990, 31, 4463. A. V. Ruban, V. D. Romanenko, G. V. Reitel', and L. N. Markovskii, J. Gen. Chem. USSR, 1989, 59, 2484. Y. K. Rodi, L. Lopez, C. Malavaud, M. T. Boisdon, and J. Barrans, J. Chem. SOC., Chem. Commun., 1991, 23. G. Olah and A. H. Wu, Synlett., 1990, 54. K. Diemert, G. Hein, A. Janssen, and W. Kuchen, Phosphorus, Sulfur, and Silicon, 1990, 53, 339. U. Fleischer, H. Grutzmacher, and U. Kruger, J. Chem. SOC., Chem. Commun., 1991, 302.

4:

80 81

Tervalent Phosphorus Acids

101

E. Fluck and R. Braun, Phosphorus, Sulfur, and Silicon, 1990, 53, 153. R. Blachnik, H.-P. Baldus, P. Lonnecke, and B. W. Tattershall, Angew.

Chem., Int. Ed. Engl., 1991, 30, 605.

5

Quinquevalent Phosphorus Acids BY R. S. EDMUNDSON

The 11th International Conference on Phosphorus Chemistry was held at Tallinn in 1989. Although many of the papers read there dealt with topics embraced by this chapter, no further discussion on them is included here because of lack of space; for further details, the reader is referred to the extensive Proceedings of the C0nference.l 1.Phosphoric Acids and their Derivatives 3.1.Svnthesis of PhosDhoric Acids and their Derivatives.-Two rather unusual syntheses of dialkyl phosphorofluoridates have been described;these are (a) the reaction between 1,1,2,3,3,3hexafluoropropyl azide and dialkyl hydrogen phosphonates in the presence of triethylamine, when the co-product is CF3CHFCN,2

and (b) the interaction of a dialkyl trimethylsilyl phosphite and perfluoroepoxypropane.3 In addition, a full paper on the transformation of S-trifluoromethylphosphorothioates into phosphorofluoridates (and also of S-trifluoromethylphosphinothioates into phosphinic fluorides) has been published; here, thermolysis of the esters (1) proceeds essentially with retention of configuration. When the reaction is carried out in the presence of triethylamine or CsF, its course is independent of the stereochemistry of the Abbreviations used: Bn = benzyl; Bz = benzoyl; TBPP = tetrabenzyl pyrophosphate; All = allyl; mCPBA = meta-chloroperoxybenzoic acid; LDA = lithium diisopropylamide; HMDS = hexamethyldisilazane; 4DAP = 4-dimethylaminopyridine; DCC = dicyclohexylcarbodiimide. 102

5:

Quinquevalent Phosphorus Acids

X M e 2 N\ 0 -/ y - YR-

R10- *

;:P?5 R

H

(9)a; R = CH20Me

b; R = CH20C2H40Me c; R = CMe20Me

Ar = 2,4-dichlorophenyl

R’O(13)

103

R1O,II

CI’

0 P-ON=C(

R2

CI

104

Organophosphorus Chemistry

starting material. The uncatalyzed reaction is therefore thought to occur through the breakdown of a four-centre transition state (2) whereas the catalyzed process is assumed to proceed via a tbp intermediate such as (3).4 Alkyl 4-nitrophenyl phosphorochloridates have been prepared as intermediates required for the synthesis of phosphate diester anionsr5 and the betaines (4; R = C1 or Ph; X, Y = 0 or S ) have been obtained from the chlorides MeYP(X)RCl and 4DAP.6 Similar compounds have been obtained by the trapping of metaphosphate-type species with 4DAP.7 The phosphoryl chlorides ( 5 ) , obtained from dialkyl chlorophosphites and 1,l-dichloro-1-nitrosoalkanes, have been hydrolysed to the corresponding phosphoric acids, and isolated as their ammonium salts.8 A Perkow reaction between the appropriate P(II1) esters and ethyl bromopyruvate has afforded the phosphoenolpyruvate analogues (6; R1 = R2 = Me2N, R1 = OEt, OPr, or OPri , R2 = Me2N) .g More details have been given of the direct conversion of phosphorous acid into monoalkyl dihydrogen phosphates, and of phosphinic acid into dialkyl hydrogen phosphates, in the presence of an alcohol and through the catalytic effect of copper(I1) chloride; other Cu(I1) salts are ineffective, and the reaction is presumed to proceed through an acid chloride.1° A detailed description has been given for the preparation of the acid (7: R = OH) by the hydrolysis of the acid chloride; enantiomeric forms of the acid have been obtained.ll Cyclic phosphate esters which have been obtained conventionally include the 1,3,2-dioxaphosphepins (7: R = Ar0)12 and the 1,3,2-dioxaphosphocins (8).13 The use of the mixed dialkyl hydrogen phosphonates, (R10)(R20)P(0)H, obtained from (R10)2P(0)H and Ti(OR2)4, allows a conventional synthesis of the triesters (R10)(R20)(R30)P(0)

R ~ O .14 -

from a derived mixed chlorophosphate and

A highly enantioselective procedure for obtaining chiral trialkyl phosphates with 87-91% e.e. involves the treatment of the phosphoramidates (9: Ar = 2,4-dichlorophenyl) with alkoxide anions. This initial step displaces one aryloxy group; subsequent acidcatalyzed alcoholysis then displaces the pyrrolidine moiety from (10) to give a triester (ll), and further similar steps commencing with

5: Quinquevalent Phosphorus Acids

105

the phosphoramidate (10) lead to the chiral triester (12).The study was assisted by knowledge of the chirality of the product triesters and by an X-ray examination of the intermediate phosphoramidate (9a) The e.e. for (11) increases with an increase in the size of the group R in ( 9 ) . The view, (13), along the P-N bond in the phosphoramidates ( 9 ) suggests that sN2(P) approach from the direction

opposite to the pro-(S) ligand (Arlo) is preferred over the alternative, and thus leads to preponderant inversion of configuration at phosphorus.15 The treatment of dialkyl alkenyl phosphates (14) with dimethyldioxiran at below room temperature yields the epoxyalkyl phosphates (15); at room temperature or above, rearrangement to the oxoalkyl phosphates (16) occurs.16 The phosphates (17) are reported to be formed in the reaction between a dialkyl alkenylphosphonite and methyl pyruvate in a 1:2 ratio.17 The cage esters (18; X = 0, S , or Se) have been prepared in attempts to control the geometry around a central phosphorus atom, and in particular to generate and stabilize a rectangular-pyramidal geometry.18 Much of the reported synthetic work related to derivatives of phosphoric acid is concerned with biologically important compounds and their synthetic analogues; in much of the work, phosphorylation has been achieved through the application of phosphitylation reactions between the hydroxylic compounds and a phosphorus(II1) amide in the presence of 1,2,4-triazole or tetrazole, and followed by oxidation with t-BuOOH or mCPBA, and the methodology is proving to have a wide scope with practically unlimited variation in phosphitylation reagent. Thus, a neat synthesis of symdihydroxyacetone monophosphate (20) starts with the diol (19)(Scheme 1) which is phosphorylated using dibenzyl diethylphosphoramidite as the initial reagent.19 Aziridine-2-carbonitrile serves as a perhaps surprising precursor to 0-phosphoseronitrile (21) and thence of glycolaldehyde phosphate (Scheme 2). The inverse addition of the carbonitrile to phosphoric acid yields (21) and careful hydrolysis of this affords the glycolaldehyde as the monohydrate (22) through a retro-Strecker reaction. The inverse treatment of (21) in MeCN with

106

Organophosphorus Chemistry

0

0

II

(R10)2P-OHR4

n

c

R2 0 R3

c r. t.

(Et0)zPCR =CH2

R = H or Ph

0

+ -

:‘c-0’

CRzCH2

MeCOCOOMe D

(EtO)

Me’

Me

‘COOMe

X

I

II

OH

!

I

MeCOCOOMe

Me

R I

(Et0)2P-O-C-CH2-C=C, I

COOMe

,

-

t

~

i,~ii

~

5’

(1~9) R =~ (BnO),P ~

RO

Reagents:

II

(R10)2P-0 R3 R22 R 4

t

iii,iv

i, (Bn0)2PNEt2,tetrazole; ii, 30% H202; iii, Pd/C, H2, EtOH; iv, H30+, heat

Scheme 1

-

,COOMe Me

0 H O A O P O 3 H 2

5:

107

Quinquevalent Phosphorus Acids

Reagents: i, H3P04, heat; ii, H20, heat; iii, NH40H; iv, CF3S03H, 80 "C, MeCN

Scheme 2

J

iii

OH

O R:p: :$

II OH

0-P,

0 Reagents: i, 13noP(NEt~)~, tetrazole, MeCN; ii rn -CPBA; iii, ROH; iv, H2, PdK, EtOH Scheme 3

B n O A O H

(25)

,OR

6 OBn

108

Organophosphorus Chemistry

trifluoromethanesulphonic acid yields (23) and thence the monohydrogen phosphate (24).20 Phosphitylation methodology has been used to phosphorylate N-protected serine,21122 leading to the preparation of 0phosphoserine-containing peptides,23 a topic which has been reviewed.24 Peptides containing O4-phosphory1ated-L-tyrosine have been obtained following the phosphorylation of N-Fmoc-L-tyrosine using the same procedures.25 The considerable interest shown during recent years in the synthesis of phosphates of myo-inositol has continued. Nine (i.e. all) inositol diphosphates and 11 (out of 12) inositol triphosphates have been identified in the chemical hydrolysate of phytic acid.26 One synthesis of myo-inositol monophosphate monoesters is based on the ring opening, by alcoholysis, of the 1,3,2dioxaphospholane ring whose formation depends, in turn, on the availability of vic-hydroxyl groups (Scheme 3). Based on the reactions in Scheme 3, the tetra-O-benzyl ether (25) was converted, through the monobenzyl monoalkyl esters (26; R = Bn) and ( 2 7 ; R = Bn) (the product ratio of which depends on experimental conditions) and their hydrogenolysis into the monophosphate monoalkyl esters (26; R = H) and (27; R = H).Z7 A conventional conversion of DL-(28) into (30) via (29) thereby provides a route to the 6-O-(2-aminoethyl)-DL-myo-inositol l-phosphate (31) and the cyclic monohydrogen phosphate (32); the latter is an analogue of an inositol phosphate potentially important in connection with the mode of action of insulin.28 4-0-(2-Amino-2deoxy-1,D-glucopyranosy1)-D-myo-inositol l-(dihydrogen phosphate) and the analogous .r,D-galactopyranosyl-D-chiro-inositolphosphate may have a similar function; the inositol moieties for these have been synthesized from the stereoisomeric 1,2:4,5-di-O-cyclohexylidene-DLinositol O-benzyl ethers, (33; R = Bn) and (34; R = Bn) respectively, by sequential camphanoylation, resolution, debenzylation, phosphorylation (by phosphitylation using dibenzyl NN-diisopropylphosphoramidite), and decamphanoylation (MeOH, NH3); the enantiomers of each of (33; R = P(O)(OH)2) and (34; R = P(O)(OH)2) were obtained.29

2,3,4,6-Tetra-0-benzyl-myo-inositol (35; R = Bn), also resolved through the l-O-camphanoates, has been phosphorylated (using

109

5: Quinquevalent Phosphorus Acids

(28) X = OTS-p (29) X = N3 (30) X = NH2

‘OBn

OH

(35)

(34)

OSiEt,

“OSiEt3

H203PO’*

R20

HO (37) R’ = BZ (40) I?’ = H

(38) R’ = Bz R2 = CsHd(CH20)2P(O) (41) R’ = H R2 = CeH4(CH20)2P(O)

OP03H2 (39) R’ = H (42)

R’ = PO3H2

Reagents: i, ( 3 6 ) ,tetrazole, CH2CI2;ii, rn -CPBA ; iii, H2, Pd/C, MeOH

Scheme 4

110

Organophosphorus Chemistry

di(2-cyanoethyl) NN-diethylphosphoramidite) and the product hydrolysed (0.2 M NaOH aq.) and hydrogenolysed (H2, Pd/C) to give Dmyo-inositol lt5-bis(dihydrogen phosphate) (1,5-IP2) and its Lenantiomer (~,~-D-IPz).~O The 1,4,5-IP3 was prepared in a similar

manner starting with 1,2,4-tri-O-benzyl-myo-ino~itol.~~ A synthesis of the same compound by Russian workers has also been reported, resolution being achieved through the use of a D-mannose ortho ester.32 Yet a third procedure for the preparation of the same compound used the benzodioxepin (36) as the phosphitylation agent. The last steps (Scheme 4) utilized the bis(triethylsily1) ether (37) and its conversion into (38) followed by hydrogenolytic removal of protecting groups to give lI4,5-IP3 (39). 1,3,4,5-IPq was similarly

prepared from (40) via ( 4 1 ) . ~A~ modified phosphitylating agent allowed the ready synthesis of a myo-inositol monohydrogen phosphate 4,5-bis(dihydrogen phosphate) as its 1-0-(3-aminopropyl) ester (43; Scheme 5).34 Other eaminoalkyl esters of various inositol phosphates have been reported.35 Some corrections have been made to previously published data on the total synthesis of myo-inositol polyphosphates.36 Following reaction with 2,2-dimethoxypropane, various monoand di-O-isopropylidene derivatives of phosphatidylinositols have been obtained from yeast fractions; they were evidently useful as starting materials for further phosphorylations.37 The syntheses of various deoxy-myo-inositol phosphates have been reported. Quebrachitol (44) was the starting material for the preparation of D-3-deoxy-myo-inositol lI4,5-tris(dihydrogen phosphate)(47) and the 1,5,6-triphosphate isomer (48)(Scheme 6). Several steps were required to convert the quebrachitol into the precursors (45) and (46).38 The same workers also prepared optically active 3-deoxy-3-fluoro-D-myo-~nos~tol1,4,5-tris(dihydrogen phosphate) (50) via (49), also starting from quebrachitol.38 2-Fluoro2-deoxy- (54) and 2,2-difluoro-2-deoxy-myo-inositol 1,4,5tris(dihydrogen phosphate)(55) were prepared from (51) via (52) and (53), respectively; as in Scheme 6 phosphorylations were here performed using TBPP.40 The epoxide (56) was the starting material for a synthesis of the 2~,4~-dihydroxy-lp-phosphoryloxycyclohexanes(57), potential inhibitors of inositol monophosphatase, and their isomers (58)(Scheme

5:

111

Quinquevalent Phosphorus Acids OBn

OBn

-

i, ii

"'OBn

o + ~ '-'OH ' 'OOP03H2

NHCbz

'"OBn OP03H2

~ H3+ o ~

H~o~Po***

(43)

Reagents: i, BnO(Pri2N)POCH2CH2CH2NHCbz,tetrazole; ii m -CPBA; iii, 0.1 M HCI; iv, (BnO)2PNPri2, tetrazole; v, H2, Pd/C, EtOH

Scheme 5

H O . OH , - p H MeO'**

RQ

several steps

'-'OH

BzO'-'

"OBn

HO

BzO

(44)

(45) R = H (49) R = F

yraloEE steps

Bz

OEE

RQ

i - iv

OP03H2 (47) R = H (50) R = F

- iv

Bn0'OBz

OP03H2

EE = ethoxyethyl Reagents: i, K2CO3, MeOH, r.t.; ii, NaH, TBPP, DMF, 0 "C; iii, H2/Pt02,EtOH; iv, H20, r.t.

Scheme 6

P03H2

H203 ~ 0 ' ~ - "OH

OH i

OH

D

N

0rgun op h osp horus Chemistry

112

(54)X = H

(52) X = H (53) X = F

(55) X = F

v, vi

i, ii or iii

or vii + viii + vi D B n oBnO 6 - = R

BnO

R = BnO,

(56)

Po'

OH HO

(57) R = HO, r

M e y , o r C N

O

-

o r Me(CH2)c

F!

F! or vii, viii, vi

OH (58)

BnO

Reagents; i, ROH, A1203, toluene, heat; ii, E t 2 A I C 3 X toluene, 0 "C; iii, Et2AICN, toluene, 0 "C; iv, R2CuLiCN, Et20; v, NaH, TBPP, THF; vi, H2, Pd/C, EtOH aq.; vii, (Bn0)2PNEt2,tetrazole, CH2C12, r.t.; viii, m -CPBA, CH2C12,-78 "C;

Scheme 7

9

5:

Quinquevalent Phosphorus Acids

113

7).41 Some closely related compounds have been prepared for use in affinity chromatographic work; the acids (59; R = H) and (60; R = H) with Z = NHCH2CH2NH2 (a function allowing attachment to Sephadex 4B following treatment with CNBr), are obtained by hydrogenolysis (H2, Pt02) of (1RSt3RS,4RS)- (59; R = Ph) or (1RS,3SRt4SR)- (60; R = Ph)

methyl. trans-3,4-bis[(diphenoxyphosphinoyl)oxy]cyclohexene1-carboxylate, in turn the result of phosphorylation (diphenyl phosphorochloridate, pyridine) of the oxidation products from 3cyclohexen-1-carboxaIdehydehyde.42

Descriptions have been given of the preparation of phospholipids (61) by phosphitylation of a 2,3-bis(acyloxy)-propanol with a cyclic phosphoramidochloridite (Scheme 8; route a)43 and of sulphur-containing analogues (Scheme 8; route b)44 using ethylene chlorophosphate as phosphorylating agent, as well as of the phosphorylcholine analogues (62; E = N, R2 = Me; E = P, R2 = Me, Pr, or BU) . 4 5 The interaction of diazoacetic esters and dialkoxyphosphinoyloxosulphenyl chlorides produces 0,O-dialkyl S(alkoxycarbonylchloro-methyl) phosphor~thioates,~~ and the treatment of a range of 0-propynyl phosphorothioates and phosphoramidothioates (63) with HgS04 brings about not only thione-thiol isomerization but

also a prototropic change to the S-allenyl esters (64).47 The reaction between phosphorothioites or related esters and ethyl bromopyruvate produces sulphur-containing analogues of phosphoenolpyruvate; thus (65) yields (66), and (68) is obtained from (67).48 The condensation between a reducing monosaccharide and a phosphorothioic acid dialkyl ester under phase transfer conditions is aided by TsCl to provide 0-glycosyl phosphorothioic esters; the nature of the quaternary salt in the system governs the d/f ratio of the p r o ~ ? u c t s . ~ ~ Yet another phosphitylating agent was used in the synthesis of DL-myo-inositol dihydrogen phosphorothioate (71) from racemic 2,3,4.5,6-penta-O-benzyl-myo-inositol (Scheme 9). The separate D and L forms were obtained in the same way from the resolved forms of (69).50 Other workers have used similar methodology to obtain the 1phosphorothioate 4,5-diphosphate (73), an unusual feature of the

114

Organophosphorus Chemistry

+

(b)

CI-P,

R3 = Me3Si

0

XR3

x=s

4

X = 0,R3 = H, [N,P-CI 1

Me

ii

--.:“)

R’O+

iii, iv

N Me

f

R 2 0 i

x-7-0 -0

(61) X = 0 or S

Reagents; i, Me3N; ii, Et3N or Py. ; iii, 4 -O2NC,H4/O“CGH,Me iv, Me2S04, H20

Scheme 8 0 -0.11 P-0CR3=CHCH2lh2, R’O’

R’O,

5s

R’O,

R20pbCH2CECH

(63)

R2’

50 P ‘SCH=C=CH2 (64)

R’ = Me, Et, Pr, Pr‘, Bu’; R2 = NH2 R” = Me; R2 = NHR3; I?= Me, Pr, Pr’, etc.

(65) X = OR’ (67) X = SR

bhMe3

(66)X = OR” (68) X = SR

- 4;

5:

Quinquevalent Phosphorus Acids

115

"OBn BnO

O/\/CN

iii

"OBn

(70) X = S -

iv - vi

BnO

OH

(70) X = lone pair

(711

Reagents: i, Pri2NP(OCH2CH2CN)CI,Pri2NEt, CH2CI2;ii, HOCH2CH2CN, tetrazole, MeCN; iii, '/&, Py. ; iv, MeOK, MeOH; v, Na, NH3(I); vi, Arnberlite resin IR 118

Scheme 9

i

HO'-

'"OBn

(72) R' =CH=CHMe

ii iii iv

"OBn

HO (72) R' = ally1

0

0PO, '"OBn

0

vi

0yR2)2

"'OH

(73)

0

Reagents: i, (Ph3P)sRhCI, triethylenediarnine; ii, (R20)2PNPr\, tetrazole, CH2C12; iii, Bu'OOH; iv, HgO/HgCI2, Me2CO; v, l/&-Py. ; vi, NH3(1), Na

Scheme 10

s2-

116

Organophosphorus Chemistry

reaction sequence (Scheme 10) being the use of the ally1 group for protection purposes and the manner of its removal.51 Some of the complexities of the reactions between P4S10

and alcohols have again been examined through the use of P-31 nmr spectroscopy.52 Dithiophosphoric acids derived from 1- and 2hydroxyadamantane have been described.53 Cyclic phosphorodithioic acids have been converted into S-Ge(IV)54 and S-Sb55 derivatives. Organoselenium (74)56 and organotellurium (75)57 derivatives of acyclic and cyclic phosphorodithioic acids (as well as of phosphonodithioic acids) have been prepared by the interaction of th chalcogen (IV) halide and a metal salt of the acid, or from the free acid with R3TeOMe or R2Se(OEt)2. The acid (76; R = SH) and some of

its derivatives (76; R = C1, Br, alkoxy, amido) have been obtained from racemic or (R)-2 ,2'-dihydroxy-l ,1'-binaphthyl.58 59 0-Dithiophosphorylation of the hydroxyamino carboxylic acid tyrosine, serine, and threonine protected at nitrogen (boc) and carboxyl (di-p-tolyl ester) is achieved using S,S-diphenyl phosphorodithioate anion in the presence of isodurenedisulphonyl dichloride together with tetrazole in pyridine.60 A useful tabulation of data on chiral esters and amides of phosphorothioic, phosphorodithioic, phosphorotrithioic, and phosphoroselenothioic acids, has been published. Examples of the reactions used to obtain these compounds are illustrated in Scheme 11; they involve the use of enantiomers of 1-phenylethylamine, followed by cleavage of the P-N bond by treatment of the amide anion with CS2 and methylation (MeI), a process occurring with retention o I

configuration at phosphorus. Typical final products are the esters (78), (79), and (81), obtained via the thioamides (77) and (80).61 Treatment of the diazoles (82; X = N or CH) with phosphoric anhydride yields not only the phosphoramidic acids (83) but also the anhydrides (84).62 The simple transformation of N-propynylphosphoramidates into 3-(phosphorylamido)propanoic acids (Scheme 12),63 and the synthesis of the diethylphosphorylformamidines (85)64 have been effected in the ways indicated. Some attempted syntheses of phosphorus-containing cryptands from (S)P(NMeNH2)3 have proved unsuccessful.65 Reactions between P4S10 and 2-aminobenzamides have provided examples of the system

5: Quinquevalent Phosphorus Acids

117

Reagents: i, (S)-PhCHMeNH2; ii, Se; iii, Mel; iv, NaH, CS2; v, EtOH, AgNO3; vi, Etl; vii, Prl Scheme 11

Organophosphorus Chemistry

118

R2 = H or NO2 R2

R’ (82) R’ = H (83) R’ = PO3H2 (84) R’ = P(O)(OH)OP(O)(OH)2

?

(R’O)2PNR2CH2CECH

-

ii

?

(R10)2PNR2CH2CZCSi Me3

?

1

iii - v

( R’0)2PNR2CH2CH2COOH

THF; Reagents: i, BuLi, THF, -78 “C; ii, Me3SiCI,-78 “C; iii, HB(C6H11)2, iv, H202, NaOH; v, H30+

Scheme 12 0

-

II

(EtO)*PN=CHOEt

CGH6

0

S

X A

nruru2

i

II

(Et0)2PN=CHNR’R2

ii

I I /CI Arur, A..firn

N.NH,

+

X I10SCH2COOEt ArOP, N.NH2

(87) Reagents: i, MeNHNH2; ii, NaSCH2COOEt, MeCN; iii, MeCN, reflux

Scheme 13

EtOH

(85)

X

*

+

5: Quinquevalent Phosphorus Acids

119

(86), some reactions of which will be referred to later.66 Cyclic phosphorothioic hydrazides in the form of 2-aryloxy-3-methylhexahydro-1,3,4,2-thiadiazaphosphorin-5-one 2-oxides and 2-sulphides (87) have been prepared as indicated in Scheme 13.6’

.

.

~eactinnsof phmghzric k Further examples of the base (LDA) catalyzed rearrangement of

1.2.

phosphoryl groups attached to oxygen bonded to aryl dysterns have been reported, this time in the naphthalene series. Thus diethyl 1-naphthyl phosphate yields diethyl (1-hydroxy-2-naphthy1)phosphonate, and diethyl 2-naphthyl phosphate affords diethyl (3-hydroxy-2-naphthy1)phosphonate. Tri-1-naphthyl phosphate gives tris(1-hydroxy-2-naphthy1)phosphine oxide, and in general (88)

affords (89). 6 8 In contrast to the ready rearrangement of diethyl phenyl phosphate, even at -1004, aryl phosphorodiamidates (90) are effectively o-lithiated by EtMeCHLi in THF at the same temperature, and the species can be trapped by reaction with elecpophiles such as MegSiC1, MeI, or carbonyl compounds. However, at -78 the

phosphoryldiamido group migrates rapidly and regiosele~tively.~9 The stereochemistry of the same rearrangement in the 1,3,2oxazaphospholidine series has also been examined. Using an inseparable mixture of the (2R) and ( 2 s ) compounds (91) and (92) in the ratio 95:5 and derived from pseudo-ephedrine, the rearranged (LDA, THF) material, isolated in 38% yield, corlsisted of only one component (93) of (2R,4S,5S) configuration. On the other hand, the (2S,4R,5S) and (2R,4R,5S) diastereoisomers, derived from ephedrine, were separable; the action of LDA on the former produced 34% of ring opened product and only 14% of a compound in which the ring was retained, whereas the latter stereoisomer, possessing the least congested system with ArO trans to cis Me and Ph groups, afforded 85% of a product in which the ring was retained as was the stereochemistry at phosphorus.70 In the base-catalyzed hydrolysis of the acyl phosphate (94), Cu(II), Ni(II), Co(II), and Zn(I1) ions have a pronounced rate increasing effect, by a factor of up to 107; the effect of Mg(I1) ions is less pronounced, the difference being a factor of 104.71 A detailed study of the displacements within diphenyl 4-nitrophenyl phosphate by aryloxide anions reveals results consistent with a

120

Organophosphorus Chemistry

OMe

OMe

(94)

(b)

Me Me H

(c)

H

Me Me

H, 4-Me0, 4-NO2, 2 +(Nod2 H, 4-NO2

5: Quinquevalent Phosphorus Acids

121

mechanism involving either a single transition state or a two-step process with two reactive intermediates, for formation and breakdown, with almost identical transition states. For the displacement by 4nitrophenoxide the vvsymmetricalreactionvvis slightly unbalanced, and bond formation does not keep up with bond fission in the transition state which thereby acquires some phosphorylium ion character. The transfer of the diphenyl phosphoryl group is thought to proceed through an intermediate species having less tbp character than that for the transfer of the diethyl phosphoryl moiety.72 I7O Nmr spectroscopy has been applied in a study of the alkaline hydrolysis of a series of cyclic phosphate esters (95) in the 1,3,2-dioxaphosphorinane series. Following the hydrolysis step, using aq. NaOH containing H2170, the product(s) were methylated (diazomethane). In all cases the ring appeared to be retained, and the distribution of hydrolysis products, obtained by exo hydrolysis through either retention or inversion (Scheme 14), was determined by analysis of the spectra, there being significant differences in the 170 chemical shifts for singly and doubly bonded oxygen, and for axial and equatorial oxygens.Through the series (95), the retention/inversion ratio varied from 1:l to 3:l. For Ar = Ph or 4MeOC6H4 the predominant reaction was retention of configuration, but

for the 4-nitrophenyl compounds there was slight predominant inversion. The results were rationalized by postulating that the direct displacement with inversion competes with pseudorotation in P f V ) intermediates leading to retention of configuration.73 Under alkaline conditions in aqueous alcohols ROH, loss of aryloxy groups from diary1 N-arylphosphoramidates occurs by an sp.~2(P) process rather than by an ElcB mechanism judging from the steric effects on increasing the size of the group R.74 In connection with the design of phosphitylating agents for the 0-phosphorylation of aminohydroxycarboxylic acids and of the peptides derived from them, studies have been made of the stability under acid conditions of dibenzyl isobutyl phosphate itself and also of Ar-substituted dibenzyl isobutyl phosphates (96; X = H, F, C1, or Br) derived from the phosphitylating reagents (97) and (98) and isobutanol in the presence of tetrazole, followed by oxidation with mCPBA.22 For the parent dibenzyl isobutyl phosphate, treatment with 4M HCl/dioxan or 50% trifluoroacetic acid in dichloromethane, results

122

Organophosphorus Chemistry

(97) R = Et, X = H or Br (98) R = Pr’, X = F or CI

5: Quinquevalent Phosphorus Acids

123

in predominant loss of the benzyl groups; this process assumes a minor significance in reactions with 1M HC1 in acetic acid. In the synthesis of 0-dibenzyl phosphorylated tripeptides, the use of either 98% formic acid or 1M HC1 in acetic acid to remove N-protection (Boc) is satisfactory. For the halogenated dibenzyl isobutyl phosphates, the di-4-bromo compound has the greatest stability in formic acid or 1M HC1 in acetic acid, and the 4-bromobenzyl group is the group best suited for protection purposes in the acidolytic removal of boc protection in such cases.22 It has been observed that, during long periods (1 - 4 years), the peptides ( 9 9 ; R = Bn) afford H-Ser.NHMe as salts with dibenzyl hydrogen phosphate. A possible explanation lies in an 0 to N migration of the dibenzyl phosphoryl group through a P(V) intermediate followed by loss of the N-Ac group, and fission of the P-N bond by acidolysis.75 A study has been made of the reactions which take place between epoxides and metaphosphates or related species.76 The metaphosphate species were obtained by the thermolysis of appropriate compounds based on the 2,3-oxaphospha[2.2.2]octane structure, a procedure recently reviewed.77 The reactions between the epoxides (104; R2 = Me, t-Bu, Ph, CH2Br, or CH2OMe) and ethyl metaphosphate

(103)(from 100) yielded stereoisomers of the 1,3,2-dioxaphospholanes (105; R1 = EtO, X = 0). Three possible mechanisms for the reaction were considered and although two of these seemed unlikely from theoretical considerations, the slight positive evidence for the third, involving an enol phosphate, was not considered sufficient to positively characterize this mechanism as the one operating.The reaction of (103) (from 101) with (104; R2 = Me) also proceeded to give a mixture of diastereoisomeric 1,3,2-dioxaphospholanes (105; R1 = EtzN, R2 = Me, X = 0). However the final product from (102) was

a mixture of the diastereoisomers of (106) and (107)(R1 = EtO, R2 = Me, X = S ) and the corresponding (105) was absent. Interestingly, the same ratios of stereoisomers and regioisomers of products were obtained from 2-methyloxiran and 0,O-diethyl phosphorothioate as from the metathiophosphate. Available evidence would seem to indicate that a similar reaction involving a methyloxetane yields stereoisomers of an analogous 4-methyl-1,3,2-dioxaphosphorinane 2-0xide.~~

124

Organophosphorus Chemistry

A somewhat novel reaction leading to phosphoric amides or to phosphonic amides, consists in the displacement of alkoxy groups from trialkyl phosphates or dialkyl alkylphosphonates by Ti(IV)(NRz)nC14-, or M ~ ( N E ~ z ) ~ . ~ ~

The cyclic phosphoric acids (108; R = H or halogen) have been synthesized and their potentiality as resolving agents explored.79 The 2-chlorophenyl-substituted acid can resolve ephedrine whereas (108; R = H) cannot. A second chlorine atom introduced into either the remaining ortho position, or the para position, increases the resolving ability: the latter appears to be related to the enthalpy of fusion. The crystal structures of pairs of diastereoisomeric salts have been analyzed in some detail.80 2,2f-Dihydroxy-l,lt-binaphthyl has been resolved in a new, efficient process in which the racemic cyclic phosphorochloridate (7; R = Cl) is converted into the amide using (S)-(-)-2-phenylethylamine, and the resolved amides reduced directly to the diol with LiA1H4.81 In an alternative procedure, the resolved methyl phosphate (7; R = MeO) is reduced with Red-A1 with retention of configuration.82 The chemistry of lIl'-binaphthyl-2,2'-diyl hydrogen phosphate, including its use as a resolving agent, has been reviewed.83 Photolysis of dialkyl benzyl phosphates (109) in solution in an alcohol R20H affords mixtures of the two ethers (111, 112) and the bibenzyl (112). For the diethyl esters (109; R1 = Et) in t-butanol, the main product is the ether (110) accompanied by the ethyl ether (111) and the bibenzyl. Using diethyl (S)-(-)-l-phenylethyl phosphate in BuOH, the main product, i.e. butyl l-phenylethyl ether, showed a small net retention of configuration whilst the recovered phosphate ester was 28% racemized. Evidence based on l80 scrambling and substituent effects on reaction rates favoured an intermediate benzyl cation-phosphate ion pair.84 In the presence of potassium carbonate simple dialkyl chlorophosphates and chlorothiophosphates act as alkylating agents on nitrogen or sulphur for tautomeric N=C-SH/HN-C=S triad systems in thiazoles.85 LDA, normally considered a strong base, although weakly nucleophilic, nevertheless behaves as a strong nucleophile towards 010-diethyl S-phenyl phosphorothioate,and attacks the hard P=O centre to give diethyl NN-diisopropylphosphoramidate; no reaction occurs

125

5: Quinquevalent Phosphorus Acids

E

(EtO),PSCH,CONMeCOOEt (1 15)

E

E

(EtO),PSCH,P(OEt)2 (1 16)

EtO, //x /p\ EphO R (117) R = OH, X = S (118)R=H, X = O

(119)R=OH, X = S (120) R = H, X = 0 (121) R = PhO, X = S (122) R = EtS, X = S

126

Organophosphorus Chemistry

with diisopropylamine itself. A reaction between the same phosphorothioate and a Grignard reagent RMgX yields the phosphonate (EtO)2P(0)R, and also (Et0)2POMgX, together with PhSMgX and RSPh.B6

In the alkaline hydrolysis of S-butenyl thiophosphates (113 X = H, C1, C1, or N+Me3) the nature of the substituent X appears to

control, to some extent, the reaction pathway.87 Alkaline hydrolysis of chloromephos (114) and mecarbam (115) involves attack by HO’ at phosphorus with P-S bond cleavage; at the S-Me carbon atom with C-S cleavage; or, in the case of (115), at the carbonyl carbon atom with C-N bond fission. Initial hydrolysis of the carboxylic ester group from (115) is not observed, but unusual reactions in the case of (114) include S-alkylation of 0,O-diethyl phosphorodithioate anion to give theO,O,S-triethylester; attack of the anion on the starting material to give a trithiopyrophosphate; and at the chloromethyl carbon to give (116).88 The oxidation of triester phosphorothioates and diester phosphorodithioates with magnesium monoperoxyphthalate in water give up to 70% dialkyl hydrogen phosphonate; a mechanism for the process has been advanced (Scheme 15).89 For the individual diastereoisomers of the diesters (117) and (119), the reaction proceeds with ratentio of configuration to give the products (118) and (120), and with inversion of configuration for the triesters (121) and (122). In non hydroxylic solvents the intermediate (123) collapses with the expulsion of sulphur; otherwise oxidative activation of the thiophosphoryl bond is followed by attack at phosphorus by solvent with subsequent loss of substituent followed by further oxidation at sulphur.90 In another study, the formation of pyrophosphates from the oxidation of 0s-dimethyl phosphoramidothioate in non-aqueous media (absence of nucleophiles) has been stressed (Scheme 16).91 A new study, employing P-31 nmr spectroscopy in particular, has examined the behaviour of chlorine, bromine, iodine, and sulphuryl chloride on the sulphur-containing triesters (126).92 [For results pertaining to analogous phosphonic triesters see Section 2.2 Previous studies on the chlorination or bromination of phosphinothioic esters have already been summarized (Organophosphoru Chemistry:1988, 19, 170; 1991, 23, to be published)]. When (126a) was treated with sulphuryl chloride in dichloromethane at about -70 , the nmr signals suggested the presence of (130; Y = S02C1), a decision

[

5: Quinquevalent Phosphorus Acids

[OI

S II

(R10)2pS]

H2;)

~

[

127 R1o‘~-S-OH] OMH

R’O’

( R’O)2P-R2

Scheme 15

t

PI

MeO-P-SMe I

-

0

0

r\

II

MeS-P-OMe

MeO-P-0-SMe I

NH2

NH2

(1 24)

0 II MeO-P-OH I

+

t

MeSOH

MeO-7-0-

+

MeO-PLSMe I

NH2

NH2

/(I241 (125)

+

MeSOH

MeSOSMe + H20

E

E

MeO-P-0-P-OMe I

NH,

1

NH2

(1 25)

Scheme 16

+

MeSSMe

128

Organophosphorus Chemistry

?

(Me3C.CH20)2POP(OCH2CMe3)2 (139)

(134)

(135)

Forall : (a)

(b)

(c) (d)

R' M83CCH2 Et Pr Me

(Me3C.CH20)2P(S)SSP(S)(OCH2CMe3)2 R2

R'O

R3 Me

R'O R1O But

Me Me

Et

Scheme 17

(140)

5:

Quinquevalent Phosphorus Acids

129

reached following an independent synthesis of (130; Y = C1) from (139) and MeSC1. By contrast to results described in earlier papers, there were no nmr signals for (128; X = C1, Y = SOzCl), and it would therefore appear that this converts into [130;Y = cl(c13) or SO2ClI

and /or (129; Y = C1) i.e. it Actually, (128) does not give to -50'. The reaction between that with sulphuryl chloride, (127)/(128)(X = C1, Y = C1 or

is removed as fast as it is formed. rise to (129) but rather to (130) at up (126a) and chlorine is much faster than and (129; Y = C1) is formed from Cl3) via pathway (A) in competition

with routes (B) and (C). The relatively high nucleophilicity of C1(compared with that of the chlorosulphonyl anion) would cause the decomposition of (130; Y = C1 or C13) more rapidly giving monophosphorus products, and in fact, the substance was not observed at above -50: Apart from unreacted starting material , the products at -80'' were (130; Y = C1 or Cl3) and (129; Y = Cl). As the reaction

temperature was raised the amounts of (126a) and (130) decreased to leave only (129) together with some (138). The reactions of (126b,c) gave the corrresponding (130) at -8d'to -50', but the yields of (129) were lower than from (126a) and some side-products (135) and (136) were produced presumably by attack of Y- on carbon attached to oxygen. The phosphonium salt (130c: Y = Br or Br3) was the main

product from (126a) and bromine in dichloromethane; it is stable to +loc but decomposes at room temperature to give 6% (129b), 10% (137a)(by attack of 'Y on carbon attached to sulphur), 13% (136a), 20% (138a), 15% bis(2,2-dimethylpropyl) hydrogen phosphate, and 7% of the disulphide (140). The reactions between (126 a,b,c) and iodine in dichloromethane were all much slower, and the products were not identified.92 Reactions between salts of 0,O-diethyl hydrogen phosphorodithioate and N-benzyltrifluoroacetimidoyl chloride (141) or the isomeric compounds (142) and (143) have been described.93 In benzene, and in the absence of a strong base, the initial product from (141) comprises the equilibrium mixture of (144) and (145), evidently stable at room temperature, and not undergoing a 1,3hydrogen shift even on warming. However, in the presence of 1,4diazabicyclo[2.2.2]octane, the irreversible isomerization of the mixture into (146) occurs in chloroform at room temperature. The

Organophosphorus Chemistry

130

I

S II

- F3CCHZNCPh

F&CH2N=CPh

- F&CHZN=FPh

SP(S)(OEt)2

(149)

hv

c

Q

]

0 II

“N-PR,

-Q-!R2 -N

R‘R~P(X)NI+

(R’0)2P-NH-CR2

!

V

(155) a X = Y = S b X=O,Y=S

c X=S,Y=O d X=Y=O

CI,CCH=NAc

I

R1R2P(X)NHCSF?

R’ R ~ P -N=

!

(156)

c-SCHNHAC I

R3

I

CCI3

-

X

RW~NH~HNHA~

cc13

5: Quinquevalent Phosphorus Acids

131

product from (142) i.e. (147), also undergoes a phosphorotropic shift to (148) in the presence of triethylamine in boiling toluene; prototropy then affords (149) obtained, in equilibrium with (150), by reaction of the phosphorothioate salt with (143). The interaction of (141) with ammonium 0,O-diethyl phosphorothioate affords a phosphorotropic mixture of the S-phosphoryl analogue of (144) and the phosphoryl analogue of (145) which converts slowly into the Sphosphoryl analogue of (146). In summary, the ease and mode of migration of a P=X species in the triad S-C-N is highly dependent on X and other groups. 1,3-Hydride shifts in the C-N-C triad depend to a lesser extent on substituents on phosphorus, and they occur less readily than phosphorotropic shifts. Thus, the transfer of a hydrogen atom from the benzyl group to the imidoyl carbon is irreversible and requires the presence of a basic catalyst.93 N-Phenylphosphoramidates are readily converted into phosphoric acid salts when treated with sodium or tetrabutyl-ammonium nitrite in acetic anhydride.94 The rearrangement of (151) into (152) is catalyzed by TmsC1, BzC1, or TsC1.95 That of (153; R = E t O , PhO, or Ph) into the corresponding (154) is photocatalyzed.96 Hydroborations of dialkyl N-alkyl-N-propargylphosphoramidates have been carried out.97 The compounds (155) possess three active reaction sites, on N, X, and Y. The salts of N-phosphorylated derivatives of thiobenzamide as well those of N-phosphorylated thiobenzamides themselves are alkylated at P=X ( X = 0 or S ) to give monophosphazenes; alkylation at N does not occur.98 The heterocyclic compounds (86; R2 = R3 = H) are methylated (Me2S04, H O ' ) to give a mixture of the methyl ester, its iminothiol methyl ether, and a trimethyl derivative of the parent system; when the alkylation is performed with Me1 and methoxide, partial replacement of sulphur by oxygen may occur.99 The reaction of N-acetyltrichloroacetaldimine with the amides (156; R1 = R2 = alkoxy, X = 0 or S) proceeds more slowly when X = 0. The reaction between the aldimine and the acylated amides (157) proceed readily irrespective of whether X is oxygen or sulphur.loO Ring opening of the oxadiazaphospholes (158) by alkoxide

132

Organophosphorus Chemistry

yields the two hydrazides (159) and (160).101 1.3. Uses of PhosDhoric Acids and their Derivatives.-The cyclic phosphoramidochloridothioate (161) is effective as a phosphorylating agent when used to prepare mixed dialkyl phosphates through sequential reaction with alcohols in the presence of a tertiary amine.1°2 The cyclic chloride (162; X = 0, R = S02Me) likewise

phosphorylates with ring opening to give triesters, whereas the last stage of this process does not proceed with (162; X = S , R = Me).103 2-Deoxy-carbohydrate S-phosphorodithioate dialkyl esters act as glycosyl donors to partially protected sugars to give 2'-deoxydisa~charides.~~~

Compound (163) is useful in the cyclization of (?-aminoacids to p-lactams,1°5 and compound (164) is a reagent useful in peptide synthesis.lo6 Further examples of the use of cyanohydrin diethyl phosphates (here used in conjunction with SmI2) to give

nitriles have been recorded.lo7

2,Phos~honicand PhosDhinic Acids and their Derivatives 2.1. Svnthesis of PhosDhonic and P h o m'nic Acids and their Derivatives.- (a)phosr>honic Halides and related comDounds . The inevitable examples of C-phosphorylation of unsaturated systems (PC15 followed by SO2 or HCOOH) have appeared108 but more interesting

examples of this reaction sequence include the formation of the 1,4dihydro-1,4-azaphosphinine 4-oxide (165) from diacetamidelo9 and the diazaphosphinine (166) from N-acetyl-N'-methylurea.llo Perfluoroalkylphosphonic dichlorides have been prepared from the free acids in their reactions with 2,2,2-trichloro-2,2,2trihydro-l,3,2-dio~abenzophosphole.~~~ Several preparations of phosphonic acid monochlorides (as their mono esters) have been recorded: they were obtained from diesters by the action of PCl5, POC13, or (C0C1)2.112'116 Of particular interest here are those

compounds derived from isoprenoid phosphonic acids116 used (see later) to prepare analogous phosphinic acids, and the compound (167) used in the synthesis of inhibitors of cholesterol biosynthesis115. The mild conditions required when using the pyridinium salts with oxalyl chloride are worthy of note.117

5:

133

Quinquevalent Phosphorus Acids

S,

P

R’OH

,NMe

Et3N

0” ‘CI

-

S,

R20H

,NMe P

Melrn

0” ‘OR’

~

R1O,I

R20’

0

PSCH2CONHMe I

i, eq.NaOH ii, H3O +

/p R200 ‘\OH R’O,

H

o

x

A f

\

(168) X = I

OH

0 OSiPh2But : MeO, I I ,P+COOMe CI

t

A 2

\

OH

134

Organophosphorus Chemistry

The breakdown of S-trifluoromethyl phosphorothioates into phosphoryl fluorides has already been referred to; that of (S)-(-)-S-trifluoromethyl t-butylphenylphosphinothioate in pyridine at 0-20 yields racemic t-butylphenylphosphinic fluoride.4 The reaction between 1,1,2,3,3,3-hexafluoropropyl azide and diphenylphosphine oxide yields diphenylphosphinic fluoride.2 (b) Alkvl and Aralkvl Acids. Perfluoroalkylphosphonic acids have been prepared following the alkaline hydrolysis of difluorotris(perfluoroalkyl)phosphoranes, and they have been converted into their One-pot conversion of trimethylsilyl esters using E t ~ N S i M e 3 . lA~ ~

aralkyl chlorides into aralkylphosphonic acids (mostly already known) using the Arbuzov reaction has been reported.l18 The latter reaction still receives considerable attention, e.g. in the synthesis of intermediates leading to phosphonic acid derivatives of amino carboxylic acids I other interesting applications being the synthesis of the carbohydrate phosphonates (169; R = Me or Ph) from the iodide (168),120 and of esters of 3,5-di-t-butyl-4hydroxybenzylphosphonic acid (170); the latter are also obtainable from a trialkyl phosphite and the appropriate aralkyl alcohol.121 With N-bromosuccinimide, the ester (170; R = Et) yields the M-bromo derivative which can then be made to undergo a further Arbuzov reaction to give the gem-diphosphonic acid tetraethyl ester (171),122 also obtainable from triethyl phosphite, diethyl malonate, and 3,5-di-t-butyl-4-hydroxybenzaldehyde.l23 Treatment of the esters (171) with bromotrimethylsilane followed by hydrolysis yields the corresponding gem-diphosphonic acid (171; R = H) acidolysis of which results in the loss of both t-butyl groups.122 When the esters (170) are treated with Pb02,124 or (171) likewise with alkaline potassium ferricyanide,123 their conversion into the quinonoid acid esters (172) or (173) occurs. Base-catalyzed addition of dialkyl hydrogen phosphonate to (173) affords the trisphosphonic acid hexaalkyl esters (174).124 More details have now emerged of the reactions between trialkyl phosphites and benzothiete. The latter evidently acts through its o-quinonoid form (175). The products are the phosphonic esters (176), also obtainable from the sequential treatment of (175) with phosphorus trichloride and the alcohol ROH; the use of dimethyl phenylphosphonite leads to the phosphinic ester (177). By contrast,

5:

as

Quinquevalent Phosphorus Acids

P(OR)3

@s

-

-

[ w-&( 135

~

(175)

t

Ph-P-OMe

(177)

-Ph

(183)

(184)

(185)

Reagents: i, CI2P(O)CH2Y, Et3N, C6H6; ii, LDA, THF; iii, RX; iv, H 3 0 +

Scheme 18

136

Organophosphorus Chemistry

the cyclic phenylphosphonites (178; n = 2-5) yield 2:l adducts, consisting of 12- to 15-membered ring compounds (179). A reaction using (180) gives the dibenzo[d,h][l,6,2]oxathiaphosphepin 7-oxide (181) whilst cyclic pinacolyl phenylphosphonite yields (182). 125 Perkow reactions have provided phosphonic and phosphinic acid analogues of phosphoenol pyruvate (6; R1 = Me, R2 = OPr or NMe2; R1 = Ph, R2 = OEt or Ph).9

Scheme 18 outlines a procedure for the synthesis of chiral alkylphosphonic acids commencing with (R,R)-1,2-bis(methylamino)cyclohexane as the chiral auxiliary. The cyclic phosphonic diamide (183; Y = Me) is alkylated via the carbanion (LDA used as base) at temperatures lower than those employed previously and the products (184) obtained with even better selectivity. No racemization is observed during the acid hydrolysis step to the free acids (185). The formation of the major diastereoisomer (184), and hence of (185), is the result of attack by the lone electron pair in the more exposed position in the planar carbanion (186) on the alkylating reagent.126 The initial alkylation of the esters (R0)2P(O)CH22 (Z = CN, PhS02, MeS02, COOEt, or P(0)(OEt)2) with the dihalides Br(CHz),Br (n = 2 - 6 ) followed by cyclization, occurs under phase transfer conditions (K2CO3 in MeCN or DMSO), or in the presence of

NaH in THF/DMS0,127-130 (see also ref. 178) or, if Z = Ar, PhS, or MeS, in the presence of LDA/THF,lZ7 to give the cycloalkanephosphonic acid esters (187; R1 = OR); the reaction is also applicable to the cyclic phosphinic acid derivatives (187; R1 = Me).128t129 Another study employed the methylenebis(phosphonic acid) esters CH2[P(O)(OR)2]2 and the alkylating agents X(CH2)nX (X = Br or OTs, n = 3-5) in the presence of KH to give the esters (188) from which the free acids were obtained in the usual way. The acids (189), (190), and (191) were also obtained as esters. When n>5, substantial amounts of alkane- !?-,~-diphosphonic acids were produced.130 A one-pot synthesis of tetraethyl methylenediphosphonate has been described.131 Compounds of type (192; R1 = Me, X = H) have been obtained from dialkyl (iodomethy1)phosphonates by Arbuzov reactions130 or, for (192; R = H or alkyl, R1 = isoprenoid chain, X = H or F) by the alkylation of a phosphonochloridic ester with a lithiated dialkyl alkylphosphonate.l16 The action of an organolithium reagent on a trialkyl phosphate yields a lithiated dialkyl alkylphosphonate, but

5: Quinquevalent Phosphorus Acids

(189) X = C H (190) X = N

137

138

Organophosphorus Chemistry

the course and extent of this process depends on the particular lithium reagent and its method of preparation, and on the nature of the (thio)phosphoric acid substrate.132 The potential of the procedure for the synthesis of phosphonic diesters and diamides is discussed further in Section 2.l.i. Lithiated alkyl- and benzyl-phosphonic diesters have been treated with trialkyltin chlorides to give dialkyl [l-(triorganylstannyl)alkyl]phosphonates.133 The thermally-initiated rearrangement of ally1 phosphites e.g. (193), into allylphosphonates, here (194), is facilitated when R2 = COOMe; the products are then exclusively of the Z geometry. When R2 = CN, mixtures of E and Z products, the former in preponderance, are obtained.134 Reactions between phenylphosphonic acid or methylphosphonic acid and germanium(1V) dihalides have provided a variety of cyclic germanium esters of these acids. The compounds (195; R1 = R2 = Me, R3 = Ph) readily dimerize to the respective eight-membered ring compounds. The compounds (195; R3 = Me) are stable in solution, but readily decompose on attempted isolation even when R1 = R2 = mesityl.135 Other cyclic phosphonic esters and diamides have been reported.117 2,4-Dimethyl-1,3,2,4-dioxadiphosphetane 2,4-dioxide reacts with ethylene oxide to give 2-methyl-1,3,2-dioxaphospholane 2oxide.135 l-Phosphonoethane-2-sulphonic acid has been prepared from diethyl (2-bromoethy1)phosphonate and N a ~ S 0 3 . ~ ~ ~ Inosityl esters of short to medium chain length alkylphosphonic acid have been prepared through reaction between the phosphonic acid and the appropriate inositol penta-0-benzyl ether.137 Racemic 1,2:4,5-di-O-cyclohexylidene-myo-inositol is the source of the key intermediate (197; R = Bn) employed (Scheme 19) in the preparation of the methylphosphonic acid ester (200) and its phosphorylated derivatives (205) and (206) through a sequence of phosphorylation, esterification, and deprotection in the removal of benzyl groups by hydrogenolysis and of the propenyl group under mild acid conditions. The formation of (201) by the phosphorylation of (197; R = MeCH=CH) followed by mild acid hydrolysis, releases two

5:

Quinquevalent Phosphorus Acids

139

I Me

i, ii

“OCH=CHMe OBn (197)

OBn (198) R = Bn (201) R = CH=CHMe

YBnO’” R0Qif;OBn

f

0-P-OH I Me

iv

‘“OH

HO‘.

OBn

OH

(199) R = B n (202) R = H

1

(200)

v, vi

E1

0-P-OBn Me BnO’”

iv

w

”OP( OBn), OBn (203) R = B n (204) R = P(O)(OBn),

O H ;!- 0

ROQ HO”.

6

“OPO,H,

OH (205) R = H (206) R = PO3H2

Reagents: i, (196), dioxan; ii, BnOH, N-Melm; iii, 0.1 M HCI, CH2Cl2, MeOH; iv, H2, Pd/C, MeOH; v, (BnO),PNPrL, tetrazole, MeCN; vi, Bu’OOH

& R3w Scheme 19

R20’ R’,O; , , H

R4

7 ; S i

R‘

w

K2COdROH

Me3

R4

R3

I

OH (207)

140

Organophosphorus Chemistry

free hydroxyl groups thus allowing the preparation of the phosphorylated product (206) via (204), whilst if R = Bn, (205) is obtainable through (203).138 The synthesis of glycosylphosphonates and phosphonate analogues of myo-inositol tris(dihydrogen phosphate) has been reviewed.139 Dialkyl hydrogen phosphonates add to 1-aryl-2-nitroalkenes in the presence of a mild base to yield 3-(dialkoxyphosphinoyl)1-hydroxyindoles (207; R1 = OR2); the compounds (207; R1 = Ph) are obtained similarly.140 The addition of alkyl trimethylsilyl arylphosphonites to the same alkenes in a one-pot reaction yields the phosphinic acid esters (208) in good to excellent ~ i e 1 d s . lSome ~~ modifications to the preparation of dialkylphosphinic acids by the alkylation of phosphorus iodides and hydrolysis of the resultant polyiodophosphoranes takes into account the problem of water solubility of the products. 142 Bis(0-trimethylsilyl) phosphonite reacts with chloroacetic esters to give either the phosphonite (209), from which the corresponding phosphonate could presumably be obtained, or, the diester (210; R = Me) and hence, by hydrolysis, the phosphinic acid (210; R = H).l43 The optimum conditions for the reaction between 1,4-butanediyldimagnesium dibromide and an alkyl phosphorodichloridate have been investigated. The reaction leads to esters of the phospholanic acids (211; R1 = H). The comparable reaction between 2,5-hexanediyldimagnesium dibromide and ethyl phosphorodichloridate yielded a 1:2:1 mixture of diastereoisomeric 2,5-dimethylphospholanes, separable by liquid chromatography. Other ringsubstituted compounds were prepared by alkylation of ring lithiated compounds.144 (c): and ‘ c Acids. The interaction of trialkyl phosphites and various unsaturated halogen-containing compounds provides routes to alkenylphosphonic acid esters, although the course of the reaction may be influenced by the nature of the substituents at the double bond. Thus, the esters (212; R = Me or C1) yield the corresponding products (213) through a Perkow reaction, whereas (212; R = CN or P(O)(OEt)2 yield the esters (214).145 The related compounds (215) with triethyl phosphite-triethylamine yield mixtures of the

5: Quinquevalent Phosphorus Acids

141

0 HOP(CH,COOR), II

(Me3Si0)2PCH2COOMe

(210)

(209)

C12C=C.CH R(CO0Et) O=P(OEt), 1

CI,C.CH=CR.COOEt (212)

C13C.CH<

T

(214)

COMe COR

(215)

(217)

F,CC=NCHMePh (218) X = C I (219) X = P(O)(OEtb

O=y(OEt), H2C=CMe.C=NBn

H2C=CMe.CCI=NBn (220)

(221)

H2C=CMe.yHN=CHPh O=P(OEt),

C13C.CHCI.N=CHCI (224)

(222)

CI3C.CH =N.CHCI[P(0)(0Et)2]

(225) CI2C=CH.~.CH[P(O)(OEt),l, (Et0)2P=O (227)

F,S.CF=CF2

+

(RO),POSiMe,

(229)

CI2C=CH.N=CCI[P(O)(OEt)*] (226)

CI2C=CH.N=C[P(O)(OEt)& (228) 0 (RO),PCF=CF(SF,) II (230)

0 II

(R0)2PCEC.CMe,

142

Organophosphorus Chemistry

furan derivatives (216) and the alkenylphosphonates (217) which are inseparable by distillation, but which can be separated by extraction with 5% aqueous potassium carbonate since (217) are acidic and are soluble under these conditions.146 A normal Arbuzov replacement of chlorine attached to sp2 carbon in the C=N bond, e.g. in the formation of (219) from (218),147 may be accompanied by the formation of tautomeric products, as well as that of other types of products. Thus the compound (220) affords the tautomeric products (222) and (223) as well as the expected product (221);148 (224) suffers partial dehydrochlorination, and the products include the monophosphonic acid esters (225) and (226) as well as esters of gem-diphosphonic acids (227) and (228).149 Loss of fluorine occurs when a trimethylsilyl phosphorus(II1) ester interacts with (229) to give the phosphonates (230), in which the phosphorus and sulphur atoms lie t r a n s to each other.l5O Reactions between l-chloro-3,3-dimethylbutyne and triethyl or triisopropyl phosphite in the presence of aluminium chloride afford the expected acetylenic phosphonic diester (231; R = Et or i-Pr) but the dimethyl ester cannot be prepared in this manner. Such esters form useful starting materials for the preparation of alkane and alkene di- and tri-(gem or vic)phosphonic acid derivatives by base-catalyzed reaction with dialkyl hydrogen phosphonates.151 The base-initiated decomposition of diethyl (3-methyl-3-hydroxybut-1yny1)phosphonate yields diethyl ethynylphosphonate.152 A full paper concerned with the radical synthesis of unsaturated phosphonic esters (232; R = heptyl, cyclohexyl, or 1-adamantyl) from vinylphosphonates and acylthiohydroxamates, has appeared;153 a brief notification of the preliminary results was included in last year's Report. The reactions summarized in Scheme 20, in which X is a good leaving group, have been adapted to the regiospecific synthesis of alkenylphosphonic diesters. The reaction between (233; R = alkyl, cycloalkyl, or Ph) and lithium dimethyl phosphonate thus provides the esters (234).154 Two unusual procedures for the synthesis of d,F-unsaturated phosphonate diesters are summarized in Schemes 21 and 22. In the former the allenephosphonic diesters (235) are first converted into the azides (236); when these are heated in boiling benzene, a mixture

5:

Quinquevalent Phosphorus Acids

143

Nu-

X

4

* ,X J

,

Scheme 20

f

Me2C=C=CHP(OEt)2

* Me& , (;OE)t2 /

EtOH NaN3

Me

(235)

/

(236)

CsH6 reflux

0 Me

(237)

Scheme 21

(238)

(2411

Scheme 22

144

Organophosphorus Chemistry

of (237) and the 1,2-oxaphospholene (238) is obtained; the respective yields are 62% and 23%. The oxaphospholene appears to be derived from (237) through rearrangement, and its ring structure has been confirmed by X-ray analysis of an analogue.155 In the second procedure, appropriate ketones are converted, via their enol trimethylsilyl ethers and subsequent reaction with dialkoxyphosphinothioylsulphenyl bromides into the dithio esters (239). Under the influence of sodium dialkyl phosphonate, transformation into the thiirane (241) occurs via (240). When treated with either triethyl phosphite or triphenylphosphine, desulphurization of the thiiranes (241) occurs with retention of geometry.156 The nitrile oxide derived from diethyl (nitromethyl)phosphonate with POC13/Et3N adds to alkenes to give 4,5-

dihydroisoxazoles (242), and to terminal alkynes to give the isoxazoles (243) Additions of nitrilimines to acetylenic phosphonites can provide cyclic phosphinic acid systems via phosphonium salts, e.g. (245; Ar = Ph or 4-nitrophenyl) from (244).158,159 Sulphonation of phenylphosphonic acid with neat liquid sulphur trioxide yields initially the 3-sulphonic acid; the 3,5disulphonic acid arises from extended reaction based on reactant ratios and higher reaction temperature.160 (d) Haloaenoalkvl A cids. Diethyl (l-chloroalkyl)phosphonates161 and (l-bromoalkyl)phosphonatesl62 have been prepared from the corresponding (1-hydroxyalky1)phosphonates by reaction with triphenylphosphine in the presence of carbon tetrachloride or bromide. The addition of diethyl (dif1uoroiodomethyl)phosphonate across the double bond of 1-alkenes is catalyzed by Pd(PPh3)4 at room temperature and affords diethyl (l,l-difluoro-3-iodoalkyl)phosphonates; the latter, with Zn/NiC12 in THF give diethyl (l,l-difluoroalkyl)phosphonates.163

The fluorinated cyclic phosphonate,(249), based on the myoinositol system, and of potential biological interest, was synthesized from the orthoformate ester (246)(Scheme 23) by oxidation and subsequent condensation of the ketone (247) with tetraethyl fluoromethylenediphosphonate giving (248). The orthoformate and phosphonic acid ester groups were removed by acid hydrolysis, and the

5: Quinquevalent Phosphorus Acids

145

ArTpIH2c F3

+ +

(F,CCH20)2PC32Ph (244)

-

*

ArC=N.NPh

N,N

Ph

I

Ph (245)

i, ii

iii

HO

(247)

7 J (248)

iv, v

HOf$-OH

!

vi

HOQ

H CHF(P03H2)

H0'-

'"OH

*

"'OH

HO'*' OH (249)

OH (250)

Reagents: i, NaH, BnBr, DMF; ii, (COC1)2, DMSO, -78 "C, CH2C12; iii, LDA, (EtO)2P(0)CHFP(O)(OEt)2,THF, -78 "C; iv, CF&OOH, H20 (4:l); v, H2, Pd/C, EtOH;vi, NaOH aq. 1.8 M, r.t.

Scheme 23

146

Organophosphorus Chemistry

benzyl groups by hydrogenolysis, a step which also reduced the fluorovinyl group. There resulted a mixture of the phosphonates (250)(with axial and equatorial forms in the ratio 70:30) and the cyclic phosphonate (249). The total product yield was 25%. The axial isomer of (250) cyclizes to (249) under the acid conditions of the deprotection step. Compound (249) is a specific potent inhibitor of a phosphatidyl inositol specific phospholipase C.I64A synthesis of chiral (1-chloroalky1)phosphonic acids follows the procedure described earlier for the preparation of chiral alkylphosphonic acids (Scheme 18) with Y = C1.126 (el. Bvdroxvalkqrl and El3oxvalkvl Ac ids. The standard reaction between an aldehyde and a diakyl hydrogen phosphonate has provided esters of the o(-hydroxy derivatives of chromone-2- (and 3-)methanephosphonic acids, reducible (red P, HI) to the parent (chromonemethy1)phosphonic acids.165 The use of the readily acid labile di-t-butyl hydrogen phosphonate has allowed the facile synthesis of benzylic phosphonates which are inhibitors of tyrosine specific protein kinases (Scheme 24).0btainable from the aldehyde (251), the esters (252; R = OH) can be deprotected to give (253; R = OH) or reduced to (254) and then deprotected to give (255). Both (253) and (255) are convertible into the compounds (256) in which X and Y are CN or CONH2.166

Scheme 25 outlines possible modes of interaction of dimethyl hydrogen phosphonate and a conjugate alkenone. Earlier work demonstrated that under thermodynamic control the product (258) is the result of effective addition across the C=C bond. Further kinetically controlled reaction then provides the diphosphonate (259) which, under basic conditions can rearrange to the mixed phosphonatephosphate (260) or cyclize to the C-phosphorylated 1,2-oxaphospholane (261).The present communications describe reactions under basecatalyzed conditions subject to kinetic control, from which the main products (257) are arrived at effectively by P-H addition across the carbonyl group. Acetylation of the compounds (257) under basic or acid conditions brings about the further changes illustrated in Scheme 25.167,168 (1-Hydroxyalky1)phosphonic acids have additionally been prepared by the acid hydrolysis of 1,4,2,5-dithiadiphosphorinanes

5: Quinquevalent Phosphorus Acids

p\p""" &

147

OEt

(Bu'0)pP

/ 1

R

(252) (252) R = OCSSMe

CH(OEt)2 (2511

?PC

(Bu'O)~P

R = OH iii

R

(253)

Jv

iv

(254) (252;R = H)

]

ii

(255) (253;R = H)

R

I

(256)

t

V

Reagents: i, (Bu'O)~P(O)H,A1203;ii, aq. HCI, CHC13; iii, NaH, CS2, Mel; iv, Bu3SnH, AIBN; v, CH2XY Scheme 24

W

P

R2

H

-

0

E

?

R 1 n P ( O M e ) ,

0

?

(MeO)2PnP(OMe)2

'

R2

OH

R2

(258)

(257)

(261)

R' R'

OH Reagents: i, (Me0)2P(O)H;ii, NaOMe; iii, Ac20/H +; iv, AczO/Py. Scheme 25

0

148

Organophosphorus Chemistry

(see ref.231). (2-Amino-1-hydroxyethy1)phosphonic acid has been obtained by ring opening of (epoxyethane)phosphonic acid by ammonia (see refs. 223, 224), and other examples of such acids have been obtained by the reduction (with NaBH3CN) of the corresponding

(2-amino-1-oxoa1kyl)phosphonic acid (see ref. 177). Phosphonolactic acid was prepared analogously using sodium borohydride as reductant (see ref. 183). Other (hydroxyalky1)phosphonic acids have been obtained as their silylated ethers (see e.g. ref. 115). Ephedrine was used to resolve benzyl hydrogen (1-hydroxy-3-methylbuty1)phosphonic acid, and the enantiomers hydrogenolysed to the corresponding enantiomers of the free acid. In turn, the enantiomeric dibenzyl esters have been condensed with N-boc amino acids, using DCC in the presence of 4DAP to give (262; X = boc, R1 = iPr, iBu, or Ph; R2 = iPr or Bn; R3 = Bn), hydrogenolysed and acidolysed to the corresponding free acids (262; x = R3 = H).169,170

Hammerschmidt has continued his studies on the biosynthesis of natural products with the P-C bond with an examination of the incorporation of various deuteriated (hydroxyalky1)phosphonic acids into fosfomycin in $trm tomvces fradiae. The aim of the work was to get a deeper insight into the mode of construction of the oxiran rinc and to determine the stereochemistry at C(1). Various deuteriated (2hydroxyethy1)phosphonic acids (266) were synthesized via the diethyl esters (265) [in turn obtained from the alcohols (263) via the bromides (264)] by sequential reaction with bromotrimethylsilane, ethanol, and subsequent hydrogenolysis. The same acid, although monodeuteriated, was obtained in the S-form (270) through the corresponding intermediates (267)-(269); the R-form was obtained similarly. When fed to S.frad iae, the acids (226b,c) were each incorporated into the fosfomycin (271). Thus, when the latter was acted upon by gaseous ammonia the resultant (lR,2R)-(-)(2-amino-1-hydroxypropy1)phosphonic acid (272) was found to contain 42% deuterium at C(1). The acid (266c) similarly led to the incorporation of 34% deuterium at C(2) in (272). The conclusion reached was that one deuterium from each acid is being incorporated into fosfomycin. An estimation of the loss of deuterium after feeding either (R) or (S)-(270) to S . fradiae showed that the deuterium of the

5:

Quinquevalent Phosphorus Acids

?

A’

149

(R30)2P-CH0.0CCHR2NHX

(262)

(263) X = O H (264) X = Br (265) X = P(O)(OEt)2

H D B n O A X

H

O

.

I

X P03H2

(267) X = O H (268) X = Br (269) X = P(O)(OEt)2 H.

(266) For all (a) R’ = R2 = H (b) . . R’ = D, R2 = H (C) R’ = H, R2 = D

H HH3CCH(OH)CR2P(O)(OH)2

MeWk(OH), 0

YHO i

BnO

I

BnO

OSiMe,

+

6

BnO erythro

i

ii,iii, iv

HO +

0

0 threo

v, vi

$LR2)2 BnO

OSiMe, D

R’

H

oH

HO

0

*P(0R2)2 BnO

6

Reagents: i, (R0)2POSiMe3ii, Me3SiBr; iii, EtOH, aq.; iv, H2, Pd/C; v, (R20)2P(0)H,DBU; vi, MeCOOH

Scheme 26

(274) Reagents: i, (MeOhPOSiMe3, CH2C12; ii, Me3SiBr, allylSiMe3, CCI4, 20 OC, EtOH; iii, H2, Pd/C, EtOH

Scheme 27

150

Organophosphorus Chemistry

latter form was retained [30% deuterium in (-)-(272)], whereas the deuterium of (R)-(270) was lost. Thus the pro-(R) hydrogen at C(1) in (2-hydroxypropy1)phosphonic acid (possibly produced through the biological methylation of phosphonoacetaldehyde), is replaced with inversion of configuration by the C-0 bond, a result in agreement with hydroxylation at C(l)(retention of configuration), activation and displacement by OH at C(2) with inversion of configuration. The results of experiments on the possible incorporation of labelled (2hydroxypropy1)- and (1,2-dihydroxypropyl)-phosphonic acids are promised.171 Meanwhile the synthesis of racemic and enantiomeric forms of (2-hydroxypropy1)phosphonic acid (273), both labelled and unlabelled, and also that of (RS)-(2-[180]hydroxypropyl)phosphonic acid, by a reaction scheme similar to that used for the (2-hydroxyethy1)phosphonic acid, has been published.172 Additionally all four stereoisomers of (1,2-dihydroxy-[l-2Hl]propyl)phosphonic acid have been prepared from chiral lactates using the reactions outlined in Scheme 26 in which R = H or iPr, R1 = H, R2 = Me or iPr, and R1 = D, R2 = iPr. The (lR,2R)-acid has also been prepared from fosfomycin by acidolysis.173 (RS)-(1,2-dihydroxy-l-[2Hl]ethyl)phosphonic acid,

synthesized as indicated in Scheme 27, is not incorporated into the fosfomycin of S.fradiae.l7I The ring opening of an epoxide ring through reaction with diethyl trimethylsilyl phosphite leads to a (2-trimethylsilyloxyethy1)phosphonic diethyl ester. Thus (275) provides (276; R = Tms) convertible into (276; R = H) by the action of tetrabutylammonium fluoride. Further alkaline hydrolysis yields D-l-deoxyfructose-lphosphonic acid as a mixture of isomeric forms.174 (f) oxoalkvl A cids. (Bromoacety1)phosphonic acid has been prepared from dimethyl acetylphosphonate.175 (1-0xoalkyl)phosphonic acid derivatives have been obtained by reactions between N-(benzyloxycarbony1)propyl chloride and trimethyl p h ~ s p h i t e land ~ ~ from triethyl phosphite and 1-(phtha1imido)acyl chlorides.177 The acylation of phosphonic acids possessing active methylene groups has provided examples of (3-oxoalkyl)phosphonic acids.1781179 A useful synthesis of (1-hydroxy-2-oxoalkyl)phosphonic

151

5: Quinquevalent Phosphorus Acids

dZ -

BzO

OBz

+i(oEt OBz

(EtO)21+R COR’

BzO

(275)

f

(EtO),PMe

0 OSiMe3

)2

(276)

(277)

f

i, ii

* (RO),PCH2COCOOEt

(278) R = Et

f

(HO),PCH2COCOOH

iv 4

1

iii

(278) R = MeSi

(279) Reagents: i, BuLi; ii, BrCOCOOEt; iii, MQSiBr;iv, b0

Scheme 28

152

Organophosphorus Chemistry

diesters (as the trimethylsilyl ethers) utilizes the initial interaction of an aldehyde, RCHO, triethyl phosphite and chlorotrimethylsilane (effectively diethyl trimethylsilyl phosphite) to give diethyl [(1-trimethylsilyloxy)alkyl]phosphonates, the anions of which (prepared using LDA) are acylated (using the acid chlorides RICOC1) to give the required compounds (277; R = R1 = Bu, Ph, or 1-adamantyl). Acidolysis of the compounds (277) yields the diketones RCOCORl. 180 Other (2-oxoalkyl)phosphonates have been prepared by the acid hydrolysis of enaminephosphonic esters,l81 whilst acylation of lithiated diethyl methylphosphonate has provided a 2-0x0 triester (278) convertible into the phosphonopyruvate (279), and isolated as its tris(cyclohexy1ammonium) salt, (Scheme 28).la2 An alternative route to the same compound lies in the transamination between glyoxylic acid and 3-phosphonoalanine, a reaction which is catalyzed by copper(I1) acetate in pyridine-acetic acid.183 Phosphorylation, by phosphitylation methodology, of the compounds (280) yields the carbonyl-masked (2-oxoa1kyl)phosphonates (281) Phosphoranes derived from enones and trialkyl phosphites undergo reactions with aldehydes to give mixtures of stereoisomeric products with syn and a n t i geometry. Thus the interaction of (282; R = Et) and RlCHO (R1 = iPr or Ph) yields mixtures of the 2,3-syn (283) and 2,3-anti (284) products in the ratio of ca.3.5:l to 5:l under neutral conditions.185 Arbuzov reactions (Scheme 29) provided the esters (285); partial or complete alkaline hydrolysis then afforded a range of salts which were of special interest as potential inhibitors of squalene synthetase. Of those salts examined, (286;n = 2, M = Et) proved to be the most potent inhibitor.186 ( g ) A m i n o i The great surge of interest apparent during very recent years in this particular group of phosphonic and related acids, has continued through the past year. The esters of (1-aminoalky1)phosphonic and analogous phosphinic acids have been prepared by the addition of the appropriate hydrogen phosphonate (or phosphinate) to enamines;l87 to imines (or their precursor^);^^^-^^^ to oximinium salts;lg3 and also by the reactions between phosphorus trichloride,or phosphorus(II1) triesters, including trimethylsilyl esters, and mixtures of aldehydes

5:

153

Quinquevalent Phosphorus Acids

(CH2),-X

t

7/ 'Iii

(CH2),-P-COOEt &Et

rR'

X=l,n =2or4 X=Br, n = 3 X=OH,n =2or3

!?

(CH2),-O-P-COOEt

(285)

vii

I

t

(CH2),-0-P-COOM I

CI

(286)

ONa

Reagents: i, ButLi/pentane-Et20for X = I; Mg, BrCH2CH2Br,Et20, for X = Br; ii, (Et0)2PCI; iii, CICOOEt; iv, Me3Sil, 2,4,6-Me3Py., CH2C12, 0 "C; v, Et3N; CH2C12 1 M aq. HCI; 1 M KOH-MeOH; vi, C12P(O)COOEt, THF, -30 "C; vii, 2M aq. NaOH for M = Na; Et20/H20partition, 1 M NaOH, aq. EtOH for M = Et

Scheme 29

f

(EtO)2PyHPh NHR

PhCH=N-N=CHPh

[

(Et0)2!CHPh. (2911

NH

4

!?

(EtO)sPCHPhNHN=CHPh

(290)

(288) R = H (289) R = P(O)(OEt)2

f?

?

(Et0)2PN=CHPh

(H0)2PCH2NHCHZCOOH

(292)

(293)

154

Organophosphorus Chemistry

or ketones and a nitrogen source e.g. amides, amines or imines.191,194-198

The formation of (aminobenzy1)phosphonic acid esters by the catalyzed addition of dialkyl hydrogen phosphonate to aromatic aldazines is well recorded. Some aspects of the process have now bee further investigated. Using a 3:4 mixture of sodium diethyl phosphonate and diethyl hydrogen phosphonate, benzaldazine (287) yields 67% (288) plus 66% (289), but the reaction can be stopped at the halfway stage (290) using the phosphorus reactants in the ratio 3:2. The product (291) is obtained from (287) with diethyl trimethylsilyl phosphite; it reacts no further with the phosphonate mixtures. In a crossover experiment, the phosphonate mixture reacted with Ph2P(O)CHPhNH.N=CHPh to give Ph2P(O)CHPhNH2 as the main product

(67%) together with 7% (288) and 58% (289); the low yield of (288) i here the result of the reversibility of the monoaddition reaction. I is surmized that single electron transfer from diethoxyphosphinoyl anion (a well-known single electron donor) to the PhCH=N grouping of (287)( a conjugated system is essential) affords an anion radical which undergoes N-N bond heterolysis to give (289) and a radical pai which then combines to form (292), the key intermediate; the last of these then reacts with diethyl hydrogen phosphonate to give (289).19 Simple (1-aminoalky1)phosphonic acid esters have been modified to furnish N-substituted products; thus substituents have been introduced using nitroarenes,2oo and modifications have also been made to glyphosate (293) and related compounds.189t201 Oximinium salts e.g. (294), obtained from aldonitrones by alkylation, react with hydrogen phosphonates to give [1-(Nalkoxyamino)alkyl]phosphonic diesters (295)(Scheme 30). The scheme allows some modifications rendering feasible the synthesis of, for example, the (d-hydroxy-1-aminoalky1)phosphonic acids (297) from (296).I93 The addition of trimethylsilyl phosphorus(II1) esters, often prepared in situ, to imines at room temperature (Scheme 31; R4 = Bn or allyl) is a mild and selective route to (1-aminoalky1)phosphonic and (1-aminoalky1)phenylphosphinic acid diesters. The reactions between the same phosphorus(II1) esters and isocyanates and carbodiimides were also investigated.195~196 According to other (Russian) workers, the interaction of dialkyl trimethylsilyl

5:

155

Quinquevalent Phosphorus Acids

I

X = CH2,R4 = OEt

iv

t

x=o

+ P(O)(OH)O(297) Reagents: i, Et30+BF4-; ii, (R0)2P(O)H; iii, R4Y;iv, 9M HCI aq., Pd/C-H* Scheme 30

Reagents: i, R1R2POSiMe3;ii, H20; iii, H2, Pd/C Scheme 31 PhN=C=NPh

+

(R0)2POSiMe3

dH2P03H2 (299)

f

(R0J2P-C:

NPh

NPh(SiMe3) (298)

156

Organophosphorus Chemistry

phosphites and NN-diphenylcarbodiimide is reversible, the product consisting of the silyl formamidines (298) which are desilylated when treated with alcohols.202 When formaldehyde, phosphorous acid, and 1,2-aminoalkanols react together, the products are the derivatives (299; R1,R2,R3 = H, Me, Et, or Ph) of the already recorded perhydro-1,4,2oxazaphosphinine ring system.203 Unusual (1-aminoalky1)phosphonic acids have been prepared by unusual routes. Bromination of either the N-benzoyl or the N-benzenesulphonyl derivative of (aminomethy1)phosphonic acid diester, and subsequent treatment with triethylamine evidently liberates the species (300) which is capable of addition to dienes; examples of such reactions are illustrated.204 A useful transformation of aminocarboxylic acids into (1-aminoalky1)phosphonic acids is illustrated in Scheme 32:205 it involves the oxidative decarboxylation of the carboxylic acid using lead tetraacetate to give a mixture of products which is acted upon by trimethyl phosphite in the presence of titanium(1V) chloride. A substituent of the allyl type can be introduced on to the C(1) atom of the N-protected ester (301) using the allyl ester of a carboxylic acid in the presence of Pd(dppe)2 catalyst at 80'.206

The use of (R,R)-1,2-bis(methylamino)cyclohexane in the procedure outlined earlier in this report (Scheme 18) has been extended to include the synthesis of chiral (1-aminoalky1)-phosphonic acids; the modifications to the procedure are indicated in Scheme 3 3 . The chloride (183; Y = C1) is converted, via the azide (183; Y = N3)

into the imide (303), the anion from which is alkylated and the product hydrolysed under acidic conditions when the (R)-phosphonic acid (305) is the main product.2O7 The explanation for the stereoselectivity of the scheme lies in complex formation involving the phosphoryl oxygen and the nitrogen atom. Other (1-aminoalky1)phosphonic acids have been resolved by stereoselective enzymic hydrolysis of the amides following initial N-phenylacetylation. The unsubstituted L acid is isolated, whereas the D-acid derivative fails to undergo hydrolytic reaction.208 Phosphonopeptides are obtainable from (1-aminoalky1)-

5:

157

Quinquevalent Phosphorus Acids

R = BZ

Bz

0

!?

(EtO)2PCH=NR

(300)

R = BZ

R = 02

(302) (183; Y = N3)

(305) Reagents: i, Hz/Pt02, EtOH; ii, CS2, BrCH2CH2Br, Et3N; iii, KHMDS; iv, RX; v, 1 M HCI

Scheme 33

158

Organophosphorus Chemistry

phosphonic acid diesters and the mixed anhydrides from aminocarboxylic acids and pivaloyl chloride.209 The compounds (306), obtained by the coupling of the appropriate aminocarboxylic ester an1 N-protected (l-aminoalky1)phenylphosphinic acid in the presence of diphenyl phosphorazidate, may be deprotected by hydrogenolysis when the liberated (307) cyclize in the presence of butanol in toluene. The ring compounds (308) exist in the boat conformation with the Ph and R2 groups cis 210 Other peptide-like compounds have been preparec by the enzyme-catalyzed condensations between esters of alkylphosphonic or of dialkylphosphinic acids and esters of L-OCaminocarboxylic acids; thus, condensations involving (309)-(311) occur in the presence of alkaline phosphatase or phosphodiesterase.211 The preparation of the enantiomeric phosphonic acid analogues (312) of 3-aminocardianic acid (313) has been described.212 Tetraalkyl esters of [(dimethylamino)methylene]diphosphonic acid (314) have been prepared from dialkyl trimethylsilyl phosphites by reaction with dimethylformamide dimethylacetal in the presence of zinc chloride. When methylenediamines are employed with the same phosphorus(II1) esters, or with phosphonite esters (315), also in the presence of zinc chloride, the products are the phosphonates (or phosphinates) (316).213 [(Dimethylamino)methylene]diphosphonic acid itself has been carefully characterized and both the anhydrous compound and the monohydrate have been recognized.214 The addition of dialkyl hydrogen phosphonates to nitroxides e.g. (317), yields N-hydroxyaminomethylphosphonic acid diesters, in this case, the product (318).215 Such compounds may also be obtained by the removal of O-benzyl groups from (N-benzyloxyaminoalky1)phosphonic acid derivatives (themselves prepared by reduction of 0benzyl oximes by trialkylamine-borane216) by treatment with boron tris(trifluoroacetate), or by transfer hydrogenation using Pd/Cammonium formate.217 N-protected (d-amino-l-oxoalky1)phosphonic diesters have been partially dealkylated (LiBr in MeCN) to the monoalkyl ester state, and also converted into the l-hydroxyimino derivatives from which the 0 -N-protecting group (fmoc or phthaloyl) can be removed bh appropriate means.176 Further reaction at the liberated 0-nitrogen atom, e.g. peptide formation, then becomes feasible.218

-

5:

159

Quinquevalent Phosphorus Acids

!

R4NHCHR3-P-NHCHR2COOR’ I

Ph

0

(306) R4=Cbz (307) R4 = H

(308) (309) X = NHCbCOOEt

CH,X

(310) x = CH=CHCH(COOEt)NHAc (311) X = Cl+CH(COOEt)NHAc (312) R‘, $ = H or PQH2 (313) R’ = H, Ff = COOH

( Me0)2CHNMe2

(R0)2POSiMe3

R’ 0,

X

, P-OSiMe3 (315)

ZnCla

(R22N)2CH2

-- [

(RO)2F]

R’O,

ZnC12

X = EtO, (EtOhCH, or M%SiOCH2

2CHNMe2

/O

X’p‘CH2NR22

(316)

160

Organophosphorus Chemistry

Enantiomeric forms of (2-aminoalkyl)phosphonic acids have been prepared from, for example, (S)-alanine and (S)-leucine, without racemization ( > 9 9 % e.e.). The procedure, outlined in Scheme 34, involves conversion of the N-protected amino acid into the similarly protected (2-amino-1-oxoalkyl)phosphonic diester, reduction of the 10x0 group to hydroxyl, and removal of the latter through formation of its imidazolylthiocarbonyl derivative, and final N-deprotection. The products from the starting compounds stipulated, are (S)-(2-aminopropy1)phosphonic (319) and (S)-(2-amino-4-methylpentyl)phosphonic (320) acids.177 The preparation of 3-phosphonoalanine (2-amino-3phosphonopropanoic acid)(321) is described in two reports. The first procedure consists in a Strecker reaction based on dilithium phosphonoacetaldehyde 183 An enantioselective synthesis of the D-(-) and L-(+) acids starts with N-boc-3-amino-2-oxetanone, the (R) form of which provided the (R) form of the required amino phosphonic a ~ i d . ~ 1The 9 synthesis has also been described of azetidine-3-phosphonic (324) and azetidine-3-phosphinic (325) acids by the initial reaction of the mesylate (322) to give (323) followed by hydrogenolytic removal of the diphenylmethyl group, and ester dealkylation with bromotrimethylsilane.220 4-N-Phosphonomethyl-2,4-diaminobutanoate esters are inhibitors of glutamine synthetase; they (327) have been prepared from aminomethylphosphonic diesters and the bromide (326) followed by acid hydrolysis. The N-hydroxy compound was obtained following an initial reaction of (326) with O-benzylhydroxylamine.221 The interaction of dimethyl hydrogen phosphonate with the aldehyde (328) gives mixtures of the stereoisomers of the (2-amino-1-hydroxyalkyl)phosphonates (329); the latter were characterized as dimethyloxazolidinones. Peptides e.g. (331) were synthesized from the deprotected (330).2Z2 Analogous starting materials were used in the preparation of [180]-labelled (2-amino-1-hydroxypropyl)phosphonic acid from N-boc-L-alaninal.z23 The biochemically important (2-aminoethy1)phosphonic acid (AEP) is not taken up by S. fradiae during the biosynthesis of fosfomycin. On the other hand when L-alanine or L-alanyl-L-alanine is attached to the amino group of deuteriated AEP, the resultant

.

5: Quinquevalent Phosphorus Acids PhtN

E

PhtN

i

RACOCI

___)

R>P(OEt)2

161

ii

PhtN

0

(319) R = Me (320) R = Bu’

?

RyP(OEt),

iii

PhtN

E

OH

Pht = phthaloyl

Reagents: i, (Et0)3P; ii, NaBH&N; iii, ImCSlm; iv, Bu3SnH; v, N2H4; vi, H3O +

Scheme 34

A

N

izI

Ph X (322) X = OS02Me (323) X = P(0)R’(OR2)

Npht

(326)

(324) X = O H (325) X = H

162

Organophosphorus Chemistry

(329) R = B o c (330) R = H

(331)

99 Hr:G (),. 9 0

R2

H2N

R2

P03H2

~

H Me

R'\

0

RI ' ~ 1

H Me

(b) R' (a) R1 = D, R2 R2 = =H

(c) R' = H, R2 = D

~1 'RI

(333)

/O

Me0°'
PO&

~

(332)

For (332)/(333)

p2

0

R2

I

+

ArCH=NCHCOOMe

R3N

II

R1-P-CH2CH2yR2.COChk I N=CHAr

I

Meo

t

0 II

R' -P -CH2CH2CR2.COCH I

I

OH

i

OEt

(335) R = M e -

V

MeAy+OR RO

- :

M e H r q o E t EtO

" \ iv

NHCOR'

NH2 (334)

ii, iii

M e ' p' RO

4

(335) R = H, R' = Me

Reagents: i, EtO-; ii, (EtOOC)2, EtONa; iii, H30+;iv, MeCONH2, TsOH; v, MeC(OEt)3;vi, NCCH2COOEt, NaCN; vii, Bu'O-

Scheme 35

O 0

H

5: Quinquevalent Phosphorus Acids

163

dipeptides (332a-c) and tripeptides (333a-c) can be incorporated into the A preparation of 1-aminomethylcycloalkane-1phosphonic acids uses intermediates whose synthesis has been summarized earlier. Catalytic hydrogenation of (187; R1 = OR, Z = CN, n = 2-5) and phosphorylation of the products (187; Z = CH2NH2) affords (187; R1 = OR, Z = CH2NHP(O)(OEt)2 , n = 2-5).

N-Alkylation and acid hydrolysis then yields the (187; R1 R = H I Z = NH2R2+, n = 2-5).225

= 0-,

The synthesis and properties of (2-aminoethy1)phosphonates and analogous phosphinates have been reviewed.226 In a survey, by Mastryukova, of methods for the preparation of (3-aminoalky1)phosphonic acids and related compounds, the additions of Schiff bases ofd-aminoacid esters to various vinylphosphonous compounds has been advocated for use in the case of phosphinothricin (334; R1 = Me, R2 = H) and its analogues. The additions occur easily in the presence of catalytic amounts of strong nitrogenous bases in aprotic solvents.178 Scheme 35 illustrates how the additions of acrylic esters to hydrogen phosphonates or phosphinates can lead to the N-acylated enamine phosphinic (or phosphonic) derivatives (335). Asymmetric hydrogenation of these compounds in the presence of (R,R)-NORPHOS or (S,S)-CHIRAPHOS derived catalysts leads to optically active phosphinothricins.179 Starting with the N-protected triethyl phosphonoglycine (336; Scheme 36), a Wittig reaction yielded a separable mixture of the (E) and ( Z ) alkenes (337). Subsequently for each, a cyclopropane ring was then constructed on the C=C using diazomethane followed by photolytic degradation of the intermediate pyrazoline (338). Acidolysis of the cyclopropane triesters (339) afforded the (E) [or ( Z ) ] 2-amino-2,3-methano-4-phosphonobutanoic acids (340), each as a racemic mixture.227 Various other cyclopropane analogues of 2-amino-5phosphonopentanoic acid, [including compounds (342)-(344)], have also been prepared by standard procedures commencing with the esters (341; n = 1-3).l19 Other workers have concentrated on the cyclobutane compounds e.g. (345)-(347), as agonists or antagonists of N-methylD-aspartic acid receptors.228 (h).SulDhur-containins Acids. The conventional approach using

164

Organophosphorus Chemistry

Reagents: i; BuLi, NaH, or BU'OK; ii, (EtO),P(0)CH2CHO; iii, CH2N2; iv, CHC13, h v ; v, 6M HCI, heat

Scheme 36

(HO)2!&NH2

n

COOH

(347)

H2°3P

HacooH NH2

X

(348)

5:

Quinquevalent Phosphorus Acids

165

(-)-lo-mercaptoisoborneol and the appropriate RP(X)C12 was adopted in

the preparation of the optically active 1,3,2-oxathiaphosphorinane 2oxides (348; X = 0, R = Ph, PhO, Bn, allyl, allenyl, etc.) and the 2sulphide (348; X = S, R = Ph). The configurations at phosphorus were assigned on the basis of nmr spectroscopic and X-ray diffraction data.229 The methodology applied to the synthesis of enantiomers of phosphorothioic, phosphorodithioic, phosphorotrithioic, and phosphoroselenothioic acid esters, has been adapted to the phosphono(di)thioic acid series to include the esters MeP(O)(SMe)(XEt) (X = 0 or S ) , as well as MePhP(O)SMe, and their absolute stereochemistries have been assigned'.61 Chiral [170,~80]-thiophosphonoacetaldehyde has been synthesized according to the reactions in Scheme 37, with (2-ethoxyetheny1)phosphonothioic dichloride as the starting material.230 The resolution of the thiophosphonic amides (349) was followed by removal of the 0-protecting group, leaving behind the l80, and the last step involved the introduction of the second oxygen label through acid catalyzed fission of the P-N bond in the presence of H2170. Overall, (Rp,Sc)-( 349) gave (Sp)-( 351). The very unusual reaction between tetraphosphorus decasulphide and trialkylamines provides the salts (352; Scheme 38) of 2,5-dithiolo-1,4,2,5-dithiadiphosphorinane 2,5-disulphideI methylation of which (using MeI) gives their 2,5-bis(methylthio) derivative (353).231,232 When compound (352) is heated,232 or acted upon by thiophosphoryl chloride,233 conversion into the 3,6dialkyl(aryl)-1,4-dithioxo-2,5,7-trithia-l,4-d~phospha(V)b~cyclo-

[2.2.l]heptanes (355) is initiated by the replacement of one X group (in 352) by C1, to give (354) followed by its elimination aided by attack of the second group X at P-C1. L o s s of sulphur from (355) to give (356) is accomplished by the use of tributyl- or triphenylphosphine. Phenylphosphonotrithioate dianion has been obtained from dichlorophenylphosphine and the complex (357) and isolated as (358).234 The phosphonotrithioic acid esters (359) and phosphonodithioic esters (360) have been obtained, together with phosphorotetrathioic esters, thioethers, and dialkyl sulphides, in reactions between tetraphosphorus trisulphide and dithioacetals of

166

Organophosphorus Chemistry

Reagents: i, Lil8OCH2CH2SiMe3;ii, LiNH-F, iv, CsF; v, p -TSOH, H2170 Scheme 37

i

p4sio

RC-SI + RCH2-NLP-S-P-N(CH2R), RCH2

/ ; ;

..-H

ph Me

; iii, separate;

-

s,\ s,,

S

//

-SAT+ RCH,-N+R

‘\SH

I

CH2R

x11-\\E c

(356)

(355)

s

(352) x’ = x2= - ~ H , ( c H ~ R ) ~ (353) X’ = X2 = SMe (354) x’ = s-, x = CI

*

Reagents: i , (RCH&N; ii, PSC13; iii, Ph3P Scheme 38

167

5: Quinquevalent Phosphorus Acids

R

-7?-SCH(SR)Ph

R2P:

CH(SR)Ph


Ph36

X TeH

$212

S

M? e: Pri2N,,P+AlClb CI

Me H

FH

+

'

N/FH

P r i 2 N , r s 1 +AIcIT CI'

NMe2

NMe2

H20

I

I

NMe2

(364)

(365) R2CH

E

f

(Me2N)2PCH2CCHR2

(Me2N)2PCH=C=CR2

E.~.NHR~

(366)

(367)

(368) CI

EtMeCHN,
-

CH2R2

N / P ', EtMeCH // 0

0l""Ph

(369)

R2

Ph

(370) Reagents: i, CI+,Cl3, NaOH aq., EbBnN +;ii, heat Scheme 39

Me O-P +N'

(MB~N)~P?~

(371)

Me

(372)

Ph

(373)

Ph

N-Ph

(374)

168

Organophosphorus Chemistry

b e n ~ a l d e h y d e .Several ~~~ derivatives (halides, esters, amides) of arylphosphonoselenoic acids have been described,236 as have derivatives of the new tellurium-containing acids (361; R = cyclohexyl or Ph, X = 0, S, Se, or Te).237 Earlier references in this report describe triphenyltellurium esters of phosphinodithioic acids, which were obtained from chlorotriphenyltellurium(1V) and the free dithio acid.561571238 (i).PhosDhorus-nitrogen bonded ComDounds. Several new ring compounds possessing direct P-N bonding have been described as well as new reactions leading to them. Thus, the betaine (362) is cleaved photolytically to afford the azaphosphetanes (363) as stereoisomeric mixtures.239 1,3-Dimethyl-1,3,2-diazaphosphetidin-4-one 2-oxides were obtained by the oxidation of the P(II1) compounds in turn obtained from the phosphorus(II1) dichloride and NN'-dimethylurea.240 The chlorodiisopropylaminophosphonium salt (364) and crotonaldehyde dimethylhydrazone interact through an intermediate phosphonium salt to yield the 1,2-azaphospholine 2-oxide (365).241 The addition of hydrazines to the allenylphosphonic diamide (366) yields hydrazones of (2-oxoalkyl)phosphonic acid diamides (367); these, when heated, give the 1,2,3-diazaphospholines (368).242 Ring expansion reactions have been performed on 2,3-dihydro-lH-l,2-azaphosphole 2-oxides (369; Scheme 39) following addition of dichlorocarbene; thermolysis of the intermediates leads to the 5-chloro-1,2-dihydro-lI2-azaphosphinine 2oxides (370).243 Tetramethylphosphorodiamidic chloride (371; X = C1) reacts readily with an alkyllithium reagent RCH2Li to give the lithiated

phosphonic acid diamide (371; X = CHRLi) but the corresponding ethyl ester (371; X = EtO) does not so react; neither does the ester cyclic diamide (372; X = EtO, n = 1). However, the diamides (372; X = EtO or C1, n = 0) do afford (372; X = CHRLi, n = 0). The chloride (372; X = C 1 , n = 1) also reacts with alkyllithium reagent, but the products were not characterized.244 Following the dipolar addition of C,N-diphenylnitrilimine to 2-isocyanato-1,3,2-dioxaphosph(III)olanel the intermediate phosphonium salt cyclizes to the spiro compound (373) which rearranges to the fused system (374), a result which may be peculiar to the system based on the five-membered phosphorus(II1)containing ring.245

5: Quinquevalent Phosphorus Acids

169

Work has continued on the synthesis, reactivity, and structure of polyaza phosphorus-containing macrocyclic compounds. The saturated ring systems (375) are obtainable by the lithium aluminium hydride reduction of precursors containing C=N bonds. The saturated systems react with HCHO to form products for which three structures have been advanced but, in the absence of X-ray data, arguments seem to favour the formation of a system of individual 1,2,4,5-tetraazaperhydro-3-phosphinine rings.246 New systems recently synthesized include the imino compounds (376; X = 0 or S, Z = S or Se).247 The synthesis and reactivity of polyazaphosphorus containing macrocyclic compounds has been reviewed.248 2.2. ReactiQm

and ProDert ies of PhosDhonic A c i d s m

.

.

i

n

.i . c

Acids and their Derivatives. --The reactions observed to occur between dialkyl benzylphosphonate anion and isothiocyanates, RCNS (R = Me,

Et, allyl, Bu, or Ph) lead to an equilibrium (a) depicted in Scheme 40. When the mixture is acidified, the tautomeric equilibrium (b) in the product lies well over to the thione form.249 A study has been made of the stereochemistry of alkylation (methylation, butylation) of carbanions derived from the phosphonic amides (377; R = H) and the axial anomers (378; R = H). The alkylation of (377; R1 = R2 = Me; R1 = Me, R2 = H) as their lithiated derivatives (prepared using t-butyllithium) proceeds with high diastereoselectivity, and the latter of these two compounds provides ready access to optically active alkylphosphonic acids by appropriate hydrolytic work up of the alkylated (377). However, an explanation of the difference in alkylation selectivities of the anions from the four compounds (377; R1 = R2 = H or Me) and (377,378; R1 = Me, R2 = H) requires extensive conformational analysis. A deprotonation reprotonation (deuteriation) experiment resulting in identical ratios of products from (379) and (380) would appear to indicate a common intermediate, a result consistent with a low barrier to carbanion rotation.250 Trimethylsilylation (chlorotrimethylsilane) of diethyl lithioallylphosphonate yields the 3-trimethylsilyl derivative at reaction temperatures between -60° and -20: resulting from the rearrangement of the l-trimethylsilyl compound; at -20"to -10" further silylation gives the [1,3-bis(trimethylsilyl)allyl]phosphonate.25~

Organophosphorus Chemistry

170

Me S+p,N-NH

Me NH-N, ,Ph P NH-N’ ‘.\S

Ph/ ‘N-NH

(375)

x=

/(-&

,

or

Me ,N-N P Ph’ ‘N-N Me

,x,

fQ,

MLpEI

Z /‘\Ph

/

0 II (Et0)2PCHPh Na

i

-

,Ph ’pa N-N Me X

a

-Q-

% M e N-N,

(376) X = O o r S Y=SorSe

(Eto)2y (a)

NR

NaS

PNR

HS

j

ii

RHN

Reagents: i, RNCS; ii, H3O+

Scheme 40

(377)

(378)

(379) R3 = H, R4 = Me (380) R3 = Me, R4 = H

5: Quinquevalent Phosphorus Acids

171

The deoxygenation of the nitroso phosphonic diester (381) yields products dependent on the deoxygenating reagent. Thus, the use of trimethyl phosphite affords a phosphoramidate (383) whereas triphenylphosphine gives the compound (382) detected only spectroscopically,since it rapidly converts into (383).252 An unusual rearrangement reaction, depicted in Scheme 41, has been observed when certain 8-aminoalkyl-1,l-bis(phosphonic acids) are silylated with HMDS. In the example shown silylation of (3-amino1-hydroxypropan-1,l-diyl)bis(phosphonic acid) is followed by sequential loss of tris(trimethylsiy1) phosphite and Si,Si,Sitrimethylsilylamine to give bis(trimethylsily1) (ethenylcarbony1)phosphonate (384); all three compounds recombine to give the single observed product (385). In the case of the corresponding butan-1,lbis-acid substrate, the product consists of a mixture of the pyrrolinephosphonic diester (386) and the pyrrolidine-1,lbis(phosphonic diester) (387).253 Prototropic conversion into ( + ) (388) occurs when (-)-(218) is acted upon by triethylamine in toluene. The presence of a chiral centre leads to asymmetric induction in the product, in which the proportion of enantiomers depends on the particular base used in the conversion, the ratio being 1:l with triethylamine, but 19:l with diazabicyclooctane.147 Numerous addition reactions of unsaturated phosphonic acid derivatives have been described. These include the cycloaddition of vinyl ethers to the diphosphonic acid esters (389)[ analogues of which have been synthesized from dialkyl (1-oxoalky1)phosphonates and ~ ~ ]give the reduced pyridine dialkyl ( l - a m i n o a l k y l ) p h o ~ p h o n a t e s ~to derivatives (391l);25~that of (1,3-butadien-2-yl)phosphonic acid diester (391) with tetracyanoethylene to give the tetracyanocyclohexenes (392);256 and that of the phosphorylated hexa1,2,4-triene (393) with NN-dimethylaminomethylidene(pheny1)phosphine to give the 3-phosphorylated dehydrophosphorinane (394).257 The addition of dithiocarbamic acids to allenylphosphonic diesters (395) occurs across the C(l) to C(2) double bond, although differently when the vinyl group is introduced at C(l) as in (396).258 Grignard reagents add to the allenylphosphonic diesters (397) to give (1,3-butadien-2-yl)phosphonic diesters.259 The allenylphosphinic acid amides (398) undergo heterocyclization to the

Organophosphorus Chemistry

172

(?

N=O (EtO),P+COOMe

Ph3P

(?

(Et0)2P-N=CMe

=

COOMe

Me

(381)

(382)

(Me013P

\

!

rapid

E

(Et0)2P-NH--C=CHZ

(383)

H2NCH2CH&(OH)( PO3H2)2

AOOMe

??

TmsNHCH,CH,C-P(OTms), - TrnsNH2

?(?

H2C=CH C-P(OTms),

(384) + P(OTrns)3

-I

N

(?

P(0Trn~)~

1

+ TrnsNH2

( T r n ~ 0 ) ~ P ~ O T m s P(OTrns):,

h

Tms = MeaSi

(385)

Scheme 41

=?

0 (OEt)2 F3CCHN=CMePh

(388)

(389)

(390)

0 II

H2C=C-C-CR1Me

I

\

(R0)2P=O

(3911

(NC),C=C(CN)~

b

NR2,

R1 Me (392)

5: Quinquevalent Phosphorus Acids

173

0

f

( R0)2P-C=C =CMe2

[PhP =CHNMe,]

I CH=CH2

i

Ph

(393)

(394)

(R10)2P(0)-C=C=CMe2 I CH=CH2

+ R2NCSSH

-

(396) (R1O),P(O)-7=C=CMe2 CH20Me

R2MgX

(398)

H2C=C-C=CMe2

I

( w 2 ;

0

(397) Me2C=C=CR-P<

-

(R10)2p:z=CHMe Me2C=C, SSCNR;!

I

R2

R

NHAr

Me2CO/Ht

H

1

(399)

OH

174

Organophosphorus Chemistry

dihydro-1,2-oxaphospholes (399) when acted upon with acetone under acidic conditions;260 the analogous compounds (401; R = alkyl or 2chloroethyl) are obtained by the addition of (dialkoxyphosphinoy1)oxosulphenyl chlorides to the allenylphosphonic esters (400) by mechanisms summarized in earlier Reports in this series.261 3-Acetyloxy-2-(dimethoxyphosphinoyl)acrylates (402) are new dienophiles. They react with cyclopentadienes and, in principle (Scheme 42), the [4 + 21 adducts can be made to undergo a reductive retrograde aldol (RRA) reaction to form carbocyclic compounds which are themselves novel phosphonic acid derivatives. Specific examples of such transformations are illustrated in Scheme 43 for the case of the stereoisomers with the endo AcO group.262 Diethoxyphosphinoylacetaldehyde reacts with butyllithium at low temperature to give the enolate (403) which, at higher temperatures, or at normal temperatures in the presence of zinc acetate, reacts further with butyllithium to give complexes of the di-phosphorylated butadienolate (404).263 In the nitrosation of the halogenated dialkyl (2oxoethy1)phosphonates (405; X = C1 or Br), the initially-formed 1nitroso compounds (406) decompose to give the oximes of the dialkoxyphosphinoylformyl halides (407) [a similar reaction between (405; X = C1 or Br) and aryldiazonium salts was discussed in last year's Report]. With increasing reaction temperature however, loss of halogen and formation of (408) take over.264 A full paper dealing with the base-induced rearrangements of alkylated diphenylphosphinoylhydrazines (409) to phosphinoylated aminals (410), has appeared.265 The usefulness of phosphonate analogues of nucleotides in studies on enzyme-catalyzed reactions, because of their lack of cleavable P-0 bonds at appropriate points, has been discussed.266 Dialkoxyphosphinoylformate esters are hydrolysed to dialkyl hydrogen phosphonates and phosphonoformic mono- or di-esters, the rates of reactions and the product distributiuons being dependent on the pH and the ester leaving group ability.267 In the hydrolysis of 4-nitrophenyl (trichloromethyl)phenylphosphinate, cleavage at the PCCl3 bond occurs (yielding chloroform) under neutral or acidic

conditions. Fission at P-0 and loss of 4-nitrophenol accounts for only 0-8% of the reaction products at pH 1.3 -

5: Quinquevalent Phosphorus Acids

175

HO

Reagents: i, NaBH,; ii, K2CO3, MeOH Scheme 42

Reagents: i, rn-CPBA, CH2C12; ii, NaBH,; iii, K2C03,MeOH; iv, H2, Pd/C; v; OsO,,

n

MefJ-0, 0

AcOEt; vi, Me2C(OMe)2,TsOH;

Scheme 43

Organophosphorus Chemistry

176 0

[

(RO)$CHXCHO

(RO),PCX=CHOH

8

(R0)2b(+CHO

O ,:

1

?!

YOH (R0)2P-C-X (407)

(405)

Ph2P(0)NMe. NMe3 I -

(RO)$'-C=CH(OH)

6(408) A0

(409)

Ph2P(O)NMeCH2NMe2 (410)

w\ Me

Me

I IC ,I

"

NEtp

Me'

(413) R = Me (414) R = H

(415)

02Nas II C ,I p\ NMe,

NMe,

5: Quinquevalent Phosphorus Acids

177

The apparent involvement of metaphosphate and related species in a variety of reactions under both aqueous or non-aqueous conditions has emerged. Thus, irradiation of the 2,3-oxaphosphabicyclo[2.2.2]oct-5-ene 3-oxides (411) with ethyl or mesityl substituents in THF at -75 , affords the species (412), of finite lifetime, characterized spectroscopically and by the addition of ethanol. to give phosphoramidic monoethyl esters.269 The alkaline hydrolysis of the compound (413) proceeds by an SN~(P)mechanism and

this, taken with the fact that the reaction is much slower than that of (414) under comparable conditions, has led to the suggestion that in the latter case the reaction mechanism is ElcB, and proceeds via a metaphosphate-like transition state and the intermediate (415).270 Similarly, the very high rate of reaction of (416) with diethylamine, and the presence of deuterium in the benzylic methylene group of the product formed using Et2ND, suggest the involvement of a

metaphosphonate species.271 The flash vacuum pyrolysis of dialkyl (d-diazobenzy1)phosphonates (417) provides a synthetic route to styrene derivatives; the formation of the phosphorylated carbene is followed by that of a 1,2-oxaphosphetane 2-oxide. The latter decomposes with the loss of a metaphosphate ester.272 Alkyl metaphosphate is also evidently produced in the decomposition of an alkyl [ (hydroxyimino)benzyllphosphonate into benzonitrile. 273 The (E) isomer of each of the oximes predominates when dimethyl benzoylphosphonate and methyl benzoylphenylphosphinate are treated with hydroxylamine. The ( 2 ) forms, (418) and (419), decompose into benzonitrile and the respective (420) and (421; R = Me0 or Ph), the latter being formed by a Beckmann-like rearrangement of the ( Z ) oxime. On the other hand, the sole products from the (E)-oximes, were (422; R = Me0 or Ph),z74 The methanesulphonates (423; R = Me, Et, iPr, or Ph) react rapidly with an excess of a neat equimolar mixture of isopropylamine and t-butylamine to give (425). The ratio of products formed at 0 was found to be 1.45-1.65:l. With other mixtures of amines, the reaction exhibits little by way of selectivity in terms of the steric effects of R1. This might suggest a reaction scheme proceeding by way of a metaphosphonimidic species (424). However, in the presence of a solvent e.g. dichloromethane, the more dilute the solution the greater the selectivity (up to 1OO:l) for the least bulky amine. It

Organophosphorus Chemistry

178

N

A r y R ’

ArJ[(OCHR1

R2

R2)2

/o

0

R’ R~CHOP< 0

(417)

I

Ph-C-P(

-

? R

E.l ‘OH

OMe

I

R 0\ Ph-C-P-OMe

/A

1 1 2 1

N-0 -1

L

(418) R = Me0 (419) R = P h

+

-

PhCN

+

R‘P-OH MeO’ (420)

H

t

0 II

PhNHCOPOMe

PhCONHYOMe R (422)

I

R (421 )

Kpl’P R’NH’

‘NHPh (425)

Kp”P PhNH’

O ,

Ph,

PhNH “0

Ph2P(0)NHOP(0)Ph2 (427)

-I!

(428)

t

/O_NHOPPh2

NC

0 Ph2

/O_NHNMePh

NC

‘OMS

5: Quinquevalent Phosphorus Acids

179

was suggested that the reaction might progress initially through the phosphonimidic derivative (neat conditions) or, when in solution, through a complex of the latter. There is no direct evidence for the involvement of a mixed anhydride of the type (426) in the process, although there are precedents e.g. the formation of (428) in the base-induced rearrangement of (427). There are also other reaction features which are consistent with the proposed mechanism. Thus, the way in which the mixed anhydride reacts with added nucleophile should be influenced by the size of the group R and the nature of the sulphonic acid leaving group. In the former case bulky groups, whilst retarding an sN2(P) process, have little influence on eliminationaddition reactions, and the sN2(P) mechanism should decline in importance and the amine selectivity decrease as the group R becomes larger: this was found experimentally to be so. Moreover, the loss of the p-nitrobenzenesulphonyl group from the diphenylphosphinic derivative occurred with reduced selectivity by comparison with the corresponding methanesulphonate, consistent with the reaction proceeding with the EA mechanism. Further work is needed to identifiy the reaction intermediates.275 When heated in N-methylaniline, N-(4-cyanophenyl) 0diphenylphosphinoylhydroxylamine (429) affords the hydrazine (430) and the phosphinic ester (431) besides diphenylphosphinic acid. The formation of the free acid and (430) is thought to occur by no more than an sN2 process.276

The intermolecular rearrangement of (432) into (433) has been shown to occur under the influence of LDA.2T7 Papers have been published describing the photolysis of pyridiniummethylphosphonic acids (434) when R = H1278 Bn,279 or long chain alkyl.280 The products are the methyl-substituted quaternary pyridinium salt and phosphoric acid. Cleavage of the C - 0 bond has also been observed during the photolysis of the p-methoxyphenyl esters of phosphonic acids (435; R = Me, vinyl, ally1).281 The main products from the photolysis of the more complex acid esters (436; Ar = Ph or p-methylphenyl, R = Me) are the corresponding phosphonic esters (437) and (438), but traces of biphenyl are also obtained. The ester (438) is stable to further prolonged irradiation.282 Further uses for Lawesson's reagent and its analogues (439) in thiation have been reported. The expected conversion of C=O into

180

Organophosphorus Chemistry

1

(434)

H20

R+J

f

R -P(0C6HqOMe-4)2

(435)

hv MeOH

-

M

e

vMe + -

HOP(O)(O-)2

O

-

w

O

-

M

e

+

0

R-7-0’ II

MeOH, CH2N2

0’

J

RP(O)(OMe)2

S

R-P,

11s.,

s

,P-R 11

S

(443)

(444)

5: Quinquevalent Phosphorus Acids

181

c=S occurs for benzopyran itself and for 2-phenylchromone. On the other hand, (440) yields (441) as the sole product, and for 2phenylchromone, (442) is an additional product.283t284 Compound (443) is said to be slightly less reactive than Lawesson's reagent in the thiation of simple ArCOX compounds. When acted upon by MeOH, (443) affords (444).285 In a continuation of the study of the halogenation of phosphorothioic esters (Scheme 17), the behaviour of 0s-dimethyl t-butylphosphonothioate was examined.92 The (S)-(-)-ester (126d) reacts with sulphuryl chloride in benzene, or with chlorine in carbon tetrachloride, with retention of configuration at phosphorus; in dichloromethane, the stereochemistry of reaction is reversed for each reagent. In the case of sulphuryl chloride, the products are (130d), (129d) and (136d). When chlorine itself is used, the last product is contaminated with (445). Using bromine in dichloromethane, the relatively stable (130d; Y = Br or Br3) is formed and decomposes at oL'

into (138d); when toluene is the solvent, the phenoxyphosphonium salt is detectable only between -50° and ' 0 , when the final product is (136d). A s in the case of the phosphorothioate esters, reactions involving iodine are extremely slow. The thiophosphorylated nitrilimine (446) is very stable, being a solid m.p. l o o o , reactive towards sulphur, selenium, and phenyl azide with the formation of the phosphorylated diazaphosph(V)oles (447; X = S, Se, or NPh), probably by a two-step mechanism. A reaction also occurs with acetylenedicarboxylic esters to give the 1,2,3-diazaphosph(V)inines (448); with tetracyanoethene, the 1,2,4,3-triazaphosph(V)inine (449) is obtained.286 N,N,N,N-Tetramethyl-P-phosphonothioic diamide is ortholithiated using butyllithium, and the carbanion can be trapped with ele~trophiles.~~~ 0-Ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate, also known as the nerve gas VX, (450; R = Et) exhibits unusual reactivity towards oxidizing agents, the amino nitrogen being more reactive than the thiolo sulphur. Compound (450) and other phosphonothioates were reactive, or unreactive, towards a variety of oxidizing reagents by one of three possible processes. With mCPBA, VX yields an N-oxide, unstable in organic solvents, relatively stable in neutral aqueous solution. For many systems other than VX, oxidation

Organophosphorus Chemistry

182 !B ,ut CI

f? But

,P-0-P;

OMe

(445)

E

+ -

(Pr'2N)2P-C fN-N-P(

NPri2)2 (447)

0 t

(RO)MeP(O)SCH&H2N Pr',

(451)

(450)

I Me (452)

(455)

(456)

w

H (457)

i

HOS02CH2CH2NPr2

Q X

(458)

5: Quinquevalent Phosphorus Acids

183

occurs initially at sulphur.89-91 Under aqueous conditions, hydrolysis can occur with cleavage of P-S, P-0, or C-S bonds to give several products. According to this report, and in contrast to the results of other workers, VX is itself hydrolysed at pH>10 in NaOH solution when the products are (450; R = H) and monoethyl methylphosphonate; the former is almost as toxic as VX itself, and hence aqueous hydrolysis serves no purpose in attempted detoxification. However, preliminary oxidation at nitrogen, as outlined above, followed by treatment with alkali, leads to other breakdown pathways, including the formation of 0-ethyl S-vinyl methylphosphonothioate and NN-diisopropylhydroxylamine and, and under aqueous conditions, the liberation of monoethyl methylphosphonate and release of (451).288 3. Structures of Ouinauevalent PhosDhorus Acid Derivatives

In addition to those structures determined as already indicated, many other structures of compounds derived from the quinquevalent phosphorus acids have been determined by nmr spectroscopy (very often multinuclear), or by X-ray diffraction, either separately or in combination. Amongst the compounds and systems studied from the spectroscopic point of view are 6-iodomethyl-1,2-oxaphosph(V)orinanes,289 1,3,2-dioxaphosphorinane 2 - ~ u l p h i d e s , ~ ~ 0 and 5-d~methoxyphosphinoyl-2-methoxy-l,2-oxaphospholan-2-ones.2g1 The stereochemistry of 1,2-dihydroxyethane-l,2-diphosphonic acid derivatives292 and of 1,2-O-cyclohexylidene-~-D-xylofuranose 3 ,5-0methylphosphonates (and also the sulphur and selenium analogues) (452)293 have been determined by multinuclear nmr spectroscopy. Compounds previously reported to be 4-aryl-2,3,3-triphenyl-l,2oxaphosphetane 2-oxides have likewise been shown, to be 1 - a r ~ l - 3 ~ 4 diphenyl-3,4-dihydro-lH-2,3-benzoxaphosphorin 3-oxides (453).zg4 X-Ray diffraction techniques have been used to determine the crystal structure of the following compounds: compound (444)285; 2chloromethyl-2-oxo-3H-1,4,2-benzoxazapho~phor~ne;~~~

184

Organophosphorus Chemistry

3-chloromethyl-3-oxo-2H-1,4,3-benzoxazaphosphorine;~~~ the methylenebis(phosphonic acid) tetramethyl esters (454; R = Me or Ph);297 c ~ s - 2 , 6 - d ~ - t - b u t y l d i b e n z o [ d , g 1 [ 1 , 3 , 2 , 6 ] d ~ o x a d i p h o s p h o c i n 2 , 6 - d i ~ u l p h i d e ;2e-diethylamino-3e,4e-dimethyl-5e-phenyl-2a~~~ thioxo-1,3,2-oxazaphospholidine;~~~ 2-methanesulphonyl-l(dimethoxyphosphinoyl) phthalazine;300 2,4-dimethyl-3 ,6-diphenyl-30x0-1 ,2 ,3 ,4-tetrahydro-1 ,2 ,4 ,5-tetraaza-3-phosphinine;3O1 the norbornene-fused 1,3,2-dioxaphosphepanes (455; R = Ph or OPh);302 the 1,4,2-diazaphospholidine (456).303 A combination of spectroscopi and crystallographic investigations have been made on the perhydro1,3,2-oxazaphosphinines (457; X = H, F, and NMe2)304 and (458; X = F or NMe2).305

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and R.Burgada, PhosDhorus. Sulfur. Silicon. Relat. Elem., 1991, 56, 95. E.Nietzschmann, K.Jurkschat, U.Baumeister, M.Dargatz, H.Hartung, and A.Tzschach, Z. Anoru. Allaem Chem., 1989, 578, 99. A.M.Gazaliev, M.Kh.Zhurinov, O.A.Nurkenov, K.M.Turdybekov, S.V.Lindeman, and Yu.T.Struchkov, &him. Prir. Soedin., 1990, 386; Chem. Abstr 1991, 114, 23670. I.Takeuchi, Y.Hamada, K.Hatano, Y.Kureno, and T.Yashiro, Chem. Pharm, Bull. I 1990, 38, 1504. Yu.M.Chumakov, V.N.Biyushkin, T.I.Malinovskii, L.N.Markovskii, and O.M.Polumbrik, Zh. Strukt Khim 1990, 31, 164; Chem. Abstr., 1991, 114, 154311. W.N.Setzer, M.L.Brown, A.Arif, and D.G.Vanderveer, PhosDhorus. Sulfur, Silicon. Relat. Elem., 1990, 54, 187. A.N.Chekhlov, A.Yu.Aksinenko, O.V.Korenchenko, V.B.Sokolov, E.A.Fokin, and I.V.Martynov, J. Gen . Chem.

.

.,

.

JJSSR, 1990, hp, 1552. 304. W.G.Bentrude, W.N.Setzer, M.G.Newton, E.J.Meehan,

E.Ramli, M.Khan, and S.Ealick, -us. Sulfur, ilicon. Relat. Elem., 1991, 57, 25. 305. W.G.Bentrude, W.N.Setzer, A.A.Kergaye, V.Ethridge, M.R. Saadein, and A.M.Arif, PhosDhorus . Sulfur. Silicon. Relat. Elem 1991, 57, 37. a

.

.,

. .

6

Nucleotides and Nucleic Acids BY R. COSSTICK AND A. M. COSSTICK

The synthesis and evaluation of nucleotide analogues as potential chemotherapeutic agents and particularly as anti-HIV drugs continues to dominate the field. In the anti-sense field, although several types of oligonucleotide analogues can be routinely prepared by automated procedures many significant challenges still remain. In particular, some recent studies have attempted to examine methods and strategies for the kilogram scale preparation of oligonucleotides which will become necessary as more is learnt about the therapeutic use of DNA. The considerable interest in catalytic RNA continues to stimulate the development of RNA synthesis and in the case of the hammerhead system studies with modified oligoribonucleotides have made a significant contribution to our current understanding of the recognition processes involved in the cleavage reaction. Two elegant studies have appeared which provide a system to select variants of the Tetrahymena self-splicing intron which have ligase activity. The system has been designed so that only active intron variants are selected and propagated. World-wide initiatives in molecular recognition have produced a wealth of high quality work on the interaction of nucleic acids with many diverse ligands which bind and cleave DNA. Particularly notable examples include the use of isotopically labelled oligonucleotides in the study of ligand-inducedcleavage of DNA and RNA. Most of the major developments in the field have been reviewed in the proceedings of the IXth International Round Table on Nucleosides and Nucleotides, Uppsala, 19901 and the symposium on Synthetic Oligonucleotides: Problems and Frontiers of Practical Application,Moscow, 1991.2 2,l Nucleoside Acvclic Phosphate5 - Di-t-butyl-N,N-diethylphosphoramidite was recently introduced as a new reagent for the phosphorylation of alcohols. However, deprotection of the resulting bis(t-buty1)alkyl phosphates has necessitated rather drastic acidic conditions. A new method for de-t-butylation has been developed which uses trimethylsilyl chloride and triethylamine.3 These very mild conditions enable selective removal of the t-butyl groups from bis(t-buty1)phosphate esters of 5 ' 4 -(4,4'dimethoxytrity1)deoxyribonucleosides(1). Deprotection occurs via a t-butyl/trimethylsilyl exchange reaction that results from the greater nucleophilicity of the P=O double bond in bis(t-buty1)esters because of the inductive effect. Adenylsuccinic acid (2) has 196

6: Nucleotides and Nucleic Acids

197 HOOCXCHH,COOH HN

DMTo

? yBase -0-P-0 I

-0

HO

OH

(1 1

(2)

S

HO

? HO

OH

HO H -N-CH-C-

(5) R=CH2NH2 ( 6 ) R = CH2NHCHO (7) R = CH2Br, CHCICH2NH2,

or

II

0

b

(8)

N H

m ?

N Y N - T - O F G u a Me

-0

(9)

HO

OH

OH

198

Organophosphorus Chemistry

been known for many years to be the intermediate in the biosynthetic conversion of inosine 5'-phosphate into adenosine 5'-phosphate. The unambiguous synthesis of the ammonium salt of (2) has been reported using 6-(4-chlorophenylthio)-9-(2,3-0cyclopentylidene-~-D-ribofuranosyl)-9H-purine (3) as the key intermediate.4 Oxidation of (3) to the sulphone with m-chloroperbenzoic acid and treatment with dibenzyl-Laspartate at 70OC in N,N-dimethylacetamide gave the aspartate nucleoside (4)in about 50% yield from (3). Subsequent phosphorylation of (4)with dibenzylchlorophosphate and a two-step deprotection procedure using aqueous formic acid and hydrogenolysis gave the product (2) which was identical to the enzymatically prepared sample. Glycinamide ribonucleotide (GAR) transformylase catalyses the conversion of glycinamide ribonucleotide ( 5 ) to formylglycinamide ribonucleotide (FGAR) (6) and is an important step in purine nucleoside biosynthesis. A series of GAR analogues has been prepared in which the glycinamide side chain has been partially replaced by alkylating functions (7).5 All of these analogues were shown to be inhibitors of GAR transformylase and competitive with respect to GAR, but none proved to be enzyme inactivators. None of the analogues containing amino functions were substrates for the enzyme catalysed transformylation reaction. A novel two-stage strategy has been developed for the specific 0-phosphorylation of tyrosine residues in peptides.6 In the first step glutamine synthetase adenylyltransferase is used to transfer an AMP moiety to the U-tyrosyl side chain of the peptide to produce a stable adenylated intermediate (8). The second step involves either the enzymatic or chemical degradation of (8) to produce the phosphotyrosine-containing peptide. The degradation step can be accomplished in near quantitative yield using either micrococcal nuclease or sodium periodate. The procedure appears to be generally applicable and gives overall yields ranging from 340%. It is well established that guanosine 5'-phosphate 2-methylimidazolide (9) can polymerise in the presence of poly(C) to form oligoguanylates that are up to 40 units long. In the absence of the poly(C) template degradation through hydrolysis of the P-N bond occurs to form guanosine 5'-phosphate and 2-methylimidazole. More recently nucleophilic substitution reactions of these phosphoimidazolide-activated nucleotides have been studied in the presence of phosphate buffers? The results show that degradation of these derivatives is enhanced in the presence of aqueous inorganic phosphate in the pH range 4.0-8.6. The phosphate acts as a general base in the hydrolysis reaction and also as a nucleophile to form a nucleoside 5'-diphosphate. A kinetic study on the cleavage of the ribonucleotide UpU by imidazole buffers has shown that a sequential bifunctional mechanism is in operation in which imidazolium ion acts first to protonate the phosphate anion (scheme 1).8 Imidazole is then able to catalyse attack of the 2'-hydroxy group on the resulting phosphate diester by removing a proton to produce the phosphorane monoanion (10). The involvement of imidazole as a catalyst in the next step means that deprotonation of the phosphorane monoanion

6: Nucleotides and Nucleic Acids

199

HoY7ura y OH

-0-P=O

HO

OH

HoYura HoY7ura 0

:Im

OH-

'8

~

IJ

HO'

HO-P=O

I' 0 O

OH

HO

,,f0

F HO u OHr

a

How Howura HO

HO

OH

+

ImH

Scheme 1

+-J

200

Organophosphorus Chemistry

occurs to give the dianion (11) which is then able to fragment with protonation of the leaving group to give the 2',3'-cyclic phosphate. The cleavage of ApA has been shown to be accelerated by a factor lO5-fold in the presence of 0.2M [Co(triethylenetetramine)(H20)2]3+ at pD6 and 500C.9 Kinetic studies suggest that hydroxide ion coordinated to the cobalt complex is responsible for the catalysis and the proposed mechanism involves coordination of the complex to the phosphate of ApA so that the complex-bound hydroxide ion is able to function as a general base catalyst promoting intramolecular attack of the 2'-hydroxy residue. First order rate constants for the mutual isomerisation and hydrolytic cleavage of the monomethyl- and monoisopropyl-esters of adenosine 2'- and 3'-phosphates have been determined over a wide pH range.10 Both reactions proceed at comparable rates below pH4 and in the pH range 4-9, a pH-independent phosphate migration prevails. By contrast, in alkaline solutions the methylesters are hydrolysed to a mixture of 2'- and 3'-AMP with no sign of mutual isomerisation. With the isopropylesters alkaline degradation of the adenine base was considerably faster than phosphodiester hydrolysis. The pH-independent depurination of 7-alkylguanosine 5'-monophosphates has been examined.11 A moderate steric acceleration was observed for 8-substituted 7alkylguanosine 5'-monophosphates. Most nucleoside analogues owe their biological activity to the fact that in living cells they are metabolised initially to phosphomonoesters. For this reason there has been considerable interest in the synthesis and study of nucleoside phosphotriesters (and in some cases phosphodiesters) that can penetrate cell walls and liberate the biologically active nucleotide. Several cyclic phosphoramidate nucleoside analogues (e.g. 12) have been prepared that are designed to breakdown (scheme 2) without the necessity of enzymatic activity to release the phosphorylated nucleoside.12 Unfortunately, these nucleotide analogues were not sufficiently stable for in vivo testing. Phosphate derivatives of 3'-azido-3'-deoxythymidine(AZT) esterified with a carbohydrate and a hexadecyl alkyl chain have been prepared from glucose 6-phosphate or D-mannose precursors.13 31P Nmr studies on the mannosyl phosphotriester series (e.g. 13) in the presence of large unilamellar vesicles demonstrated that transportation into the intravesicular water-membraneinterface was possible for some analogues. The antiviral activity of the analogues was comparable to that of AZT. It has recently been established that some ether lipids have potent activity against human immunodeficiency virus (HIV-1) replication due to a shift in virus assembly from the plasma membrane to the intracytoplasmic vacuoles which results in the production of defective virus.14 As a natural development of this finding a series of ether lipid conjugates of the anti-HIV-1 nucleosides AZT and 2',3'-dideoxyinosine have been prepared.15 The ether lipids are attached to the 5'-position of the nucleoside via either a phosphate or phosphonate linkage and were prepared by a standard DCC mediated condensation of the 2 moieties. The most active compound, in an in vitro anti-

6: Nucteotides and Nucteic Acids y

201

3

y

60)pcR L

3

NH 0-

H H

‘PGO

O’

‘OR

H H

(12) R = thymidin-5-yl

-4 -9 P0,

P 0 ’ ‘OR 1

q y

y-43

+

0 I1

-0-T-OR

4

-0

roH

I

EtO-CH

co,

p-

P 0 ’ ‘OR

Scheme 2

CH3(CH,)3-NHCO-CH2

3

0

(15) R = H (16) R = F

202

Organophosphorus Chemistry

HIV-1 screen, contained an amidoalkyl ether lipid conjugated to AZT (14) and had a greater selectivity index than AZT. Hostetler et a / . have also synthesised phospholipid analogues of AZT derived from naturally occurring membrane phospholipids.16 The most active compound was a phosphatidyl AZT conjugate. Water-soluble derivatives of 7-~-hydroxycholesterolhave been prepared by conjugation to pyrimidine nucleotides.17 3-[7-~-(Triethylsiloxy)cholesteryl]-2chlorophenyl phosphate was activated by 1-(2-mesitylenesulphonyl)-3-nitro-1,2,4triazole and used to selectively phosphorylate the 5'-position of either 2'-deoxyuridine or 5-fluoro-2'-deoxyuridine to give, after deprotection, the conjugates (15) and (16) respectively. Compounds (15) and (16) showed equally potent anti-tumour activity suggesting that activity was derived from the oxysterol. Nucleoside phosphonates are attractive therapeutic nucleotide analogues since the phosphorus-carbon bond is resistant to enzymatic degradation. 5'-0 Phosphonomethylation of different pyrimidine dideoxynucleosides has been accomplished by reaction of the latter with diethy[@-tolylsulphonyl)oxy] methanephosphonate (17) in the presence of sodium hydride.18 Basephosphonomethylation at the N(3) position occurred as a side reaction although this could be prevented by the use of 4-0-methyl-protected pyrimidine nucleosides. The 5'0-phosphonomethyl derivatives of 3'-fluoro-3'-deoxythymidine(18) and AZT (19), prepared by this procedure, had comparable anti-HIV-1 activity reducing HIV- 1 cytopathogenicity by 50% at a concentration of about 1pM. More recently this phosphonomethylation procedure has been improved by protection of the N(3)position of pyrimidine nucleosides with the 4-methoxybenzyl group.19 This group is conveniently introduced under Mitsunobu conditions, is stable to the basic conditions of alkylation and is efficiently removed with ceric ammonium nitrate. This strategy has been used for the preparation of 5'-0-phosphonomethyl-2',3'-didehydro-2',3~dideoxyuridine (20). A closely related series of nucleotide analogues has been prepared by using the regiospecific and highly stereoselective addition of dimethyl(hydroxymethy1)phosphonate (21) to furanoid glycals (22) as the key step.20 Using this methodology the phosphonomethoxy analogue of 2',3'-didehydro-2',3'-dideoxythymidine (23) was synthesised. The acyclic phosphonate analogue 9-(2-phosphonomethoxyethyl)adenine (PMEA) (24) has been shown to be a potent and selective inhibitor of HIV-1 and has a stronger in vivo anti-retrovirus activity than AZT against Moloney murine sarcoma virus-induced tumour formation.21 Following cellular penetration, bisphosphorylation of PMEA is catalysed by host kinases and the resulting triphosphate analogue has been shown to inhibit DNA polymerase,22 ribonucleotide reductase23 and reverse transcriptase.24 More recently PMEA has been crystallised and X-ray diffraction studies have revealed that the structure is a zwitterion protonated at N( 1) and with an unusual "glycosidic" torsion angle.25 PMEA can be regarded as an analogue of

6: Nucleotides and Nucleic Acids

203 0

FI

C H 3 0 1-OCH2-P(OE1)Z

R

0

-6

-0-P

llAo

W"'" f

(18) R = F (19) R = N3

eB

(MeO),PAOH

-0 (23)

y

(24)

y

2

- 0

2

y

2

204

Organophosphorus Chemistry

adenosine 5'-monophosphate (AMP) in which O(1') and C(4') of the ribose unit have been interchanged and O(5') has been omitted. The shortening of the path from N(9) to phosphorus by one atom in PMEA is compensated by its more circuitous route in AMP so that the N(9) to phosphorus distance in PMEA (5.31A) is similar to that in the monoclinic form of AMP monohydrate (5.4581). An improved route to the previously reported and potent anti-herpetic agent (S)- 1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine~~ [(S)-HPMPC, 251 has been developed27 (scheme 3). Transient protection of (S)-N-l-[(2-hydroxy-3triphenylmethoxy)propyl]cytosine (26) with dimethylformamide dimethylacetal, alkylation with diethyl[(tosyloxy)methyl]phosphonate and acid catalysed deprotection gave the diethylphosphonate (27) in 64% yield. Bromotrimethylsilane mediated deethylation of (27) gave (S)-HpMpC in 87% yield. Analysis of the product by C-18 reverse-phase hplc using a mobile phase containing phenylalanine and cupric sulphate established the optical purity to be greater than 99%. An acyclic acetal-containing phosphonate analogue (28) has been prepared, using as the key step, the reaction of the chloromethyl ether (29) with the sodium salt of 2-amino-6-chloropurine.28Pyrimidine derivatives (e.g. 30) were most readily synthesised by reaction of a pyrimidine acyl acetal (3 1) with diethylhydroxymethylphosphonate in the presence of trimethylsilyltrifluoromethane sulphonate. It is interesting to note that the nucleoside analogue 1-[(2-hydroxyethoxy)methyl-6-(phenylthio)]thymine (HEPT, 32) does not appear to require phosphorylation to produce its anti-HIV-1 effect, since the 5'triphosphate is not as potent an inhibitor of HIV-1 reverse transcriptase as HEPT itself.29 Additionally, the 5-ethyl-5'-deoxy analogue (33), which cannot be phosphorylated is more active than HEPT and has a much greater selectivity index than AZT. The anti-viral properties of nucleotide analogues30 and acyclic nucleotide analogues31 have been reviewed. 9-(5,5-Difluoro-5-phosphonopentyl)guanine(34) has been synthesised as a potential multisubstrate analogue of purine nucleoside phosphorylase (PNP).32 At pH 6.2 (34) has a ki value for human erythrocyte PNP that is 96-fold lower than that of the nonfluorinated analogue (35). The superiority of the difluorophosphonate over the phosphonate is not solely explained by the lower second dissociation constant (pka's of 5.3 and 7.2 respectively), since there remains an 8-fold difference in ki at pH 8.8 at which point both compounds should essentially be present in the unprotonated forms. With the aim of increasing the selectivity of the 2,2-dimethylphosphoraziridinetype anti-tumour agents towards the intracellular site of DNA synthesis, a series of compounds has been prepared in which the reactive bis(2,2-dimethyl- 1aziridiny1)phosphinyl (2,2-DMAP) group is linked to a pyrimidine nucleoside via a carbamate or amide linkage.33 The peracylated 4-N-(2,2-DMAP) amides of 2'deoxycytidine (36) and cytosine arabinoside (37) were the most stable and active compounds. They were readily prepared by reaction of the peracylated cytosine

6: Nucleotides and Nucleic Acids

(32) R’ = Me, R2 = CH20H (33) R’ = Me, R2 = Et

205

d? 6

L-Ser-N-S-0

AcO

y

(34) X = F (35) X = H

Thy

HO (38)

k2

(36) R’ = R 2 = H (37) R’ = OAC, R2 = H

HO

OH

(39)

I ,.OMe

cl&o CI

0-P

I’Ol (40) R, X = 0, Y =s s, x = s, Y = 0

COOH HO OH

206

Organophosphorus Chemistry

nucleoside with triethylamine and phosphorus oxychloride and subsequent treatment with 2,2-dimethylaziridine. Several 5'-0-[N-(aminoacyl)sulphamoyl]thymidine derivatives (e.g. 38) have been synthesised as uncharged phosphate analogues which are closely related to the naturally occurring nucleoside antibiotic ascamycin (39).34 Papers which report the synthesis of dinucleoside monophosphates, or their analogues, as model studies for oligonucleotidesynthesis are covered in section 4. 2.2 Nucleoside Cv.clic PhoSphates- The effect of pressure on cyclodextrin-catalysed regiospecific P - 0 cleavage of nucleotide 2',3'-cyclic monophosphates has been investigated.35 In general, regiospecificity was reduced at higher pressure and this is explained on the basis of different activation volumes for P-O(2') and P-O(3') cleavage. A series of 6-N,N-dialkyladenosine 3',5'-cyclic phosphates has been prepared from 2'-0-p-toluenesulphonyl 3',5'-cyclic adenosine monophosphates by treatment with sodium hydride and an excess of the appropriate alkyl halide, followed by detosylation with aqueous sodium hydroxide.36 The detosylation step proceeds to give the alcohol with retention of configuration and hydrolysis studies in the presence of H2180 indicate that the mechanism involves nucleophilic attack by hydroxide on the sulphonate sulphur. The conformation of 3',5'-cyclic AMP and both diastereoisomersof cyclic AMPS (40) have been examined and compared using 1H nrnr and 31P nrnr spectroscopy.37 The chair conformation of the 1,3,2-dioxaphosphorinanering predominates for all 3 compounds and the phosphorothioate derivatives have the same C(3')-endo-C(4')-exo arrangement of the ribose ring as cyclic AMP. Surprisingly there is no discernible difference in the conformations of the 2 phosphorothioatediastereoisomers despite their grossly different biological properties. The conformations of nucleoside 3',5'-PVtrigonal-bipyramidal compounds (e.g. 41) have been studied as models of 3',5'-cyclic AMP.38 1H Nmr experiments reveal that the 3',5'-dioxaphosphorinanering favours the equatorial-axial (e,a) orientation over the equatorial-equatorial (e,e) arrangement. Energy-minimised structures were shown to prefer a twist conformation of the e,aorientated 3',5'-dioxaphosphorinane ring. Cyclic AMP analogues (e.g. 42) in which a sulphone ring replaces the dioxaphosphorinane ring have been prepared by oxidation of the corresponding thiane with oxone.39 The conformation of the thiane ring has also been studied by 1H nmr. Several methods for the synthesis of cyclic nucleotide analogues have been reported and compared.40

3. Nucl~QSiaeEQlyDhosDhates Nucleoside polyphosphates are attractive targets for enzymatic synthesis as very clean products can be obtained under mild conditions. Additionally, the wide

6: Nucleotides and Nucleic Acids

207

range of nucleotide-processing enzymes available often enables multiple phosphorylation steps to be performed in a one-pot procedure. The enzymatic conversion of guanosine 5'-phosphate to guanosine 5'-triphosphate has been accomplished using an enzyme reactor containing guanylate kinase and pyruvate kinase.41 ATP functions as the phosphate donor and is regenerated by pyruvate kinase and phosphoenolpyruvate. The conversion can be performed in a dialysis bag to facilitate the recovery of the expensive guanylate kinase. The preparative synthesis of cytidine 5'-triphosphate (CTP) from the monophosphate has also been accomplished by an enzymatic process using adenylate kinase and pyruvate kinase.42 Furthermore, cytidine 5'-monophosphosialate synthase from calf brain and inorganic pyrophosphatase were used to prepare the activated neuramic acid, cytidine 5'-monophosphosialate (43) from CTP and neuramic acid in 76% yield. Starting from UTP and Nacetylglucosamine 1-phosphate (44),uridine 5'-diphosphoro-N-acetylglucosamine (45), an important intermediate in glycoprotein metabolism, has been synthesised enzymatically using uridine 5'-diphosphoro-N-acetylglucosaminepyrophosphorylase isolated from calf liver.43 The reaction proceeds to completion in the absence of pyrophosphatase to pull the equilibrium over to the product side and is readily scaled-up for the preparation of gram quantities of the product. The non-enzyme-catalysed phosphorylation of ADP to ATP has been shown to occur readily in aqueous solution in the presence of iron(III).44 At ambient temperature using acetylphosphate as the phosphoryl donor a 20% yield of ATP was obtained. The phosphorylation of AMP using acetylphosphate and other phosphoryl donors was unsuccessful. The 5'-diphosphate of 2'-deoxy-2'-methylenecytidine(46) has been prepared and used in an elegant mechanistic study on Escherichia coli ribonucleoside diphosphate reductase (RDPR).45 This analogue acts as an irreversible inhibitor of the enzyme and inactivation is thought to proceed via initial homolytic cleavage of the 3'CH bond to leave a nucleotide 3'-radical in which the electron could be delocalised onto the exocyclic 2'-methylene group (scheme 4). Quenching of the radical by hydrogen atom abstraction and elimination of cytosine and pyrophosphate gives the methyl analogue (47) of the furanose species (48) which has previously been shown to inactivate RDPR.46 In an attempt to develop improved anti-HIV agents many nucleoside 5'triphosphate analogues have been synthesised and studied as inhibitors of HIV reverse transcriptase. Pyrrolo[2,3-d]pyrimidine2',3'-deoxyribonucleoside 5'-triphosphates have been prepared that are related to 2',3'-dideoxyadenosine (ddA) and 2',3'dideoxyguanosine (ddG).47 The triphosphates were prepared by a one-pot phosphorylation procedure using phosphoryl chloride and tetrabutylammonium diphosphate in trimethyl phosphate. Some of the 7-deazapurine nucleoside triphosphates were shown to be strong inhibitors of HIV-1 reverse transcriptase with

Organophosphorus Chemistry

208

H HO-HO

AcHN

O

Z

o

,

?

Ho%?

? 0-7-0-

0-P-0-P-0 I

-&

-O

-0 (44)

(45)

vu HO

Ho

?

B

-0

-0

OH

1

CH2

PP = -0-7-0-7-0-

(47) R=CH3 (48) R = H Scheme 4

0

?

B

-0

-0

-0

- 0 - IIP I - O -I P - OI - P - O y T h y

0 II

0 II

0 II

- O-P-O-P-O-P-CH~-O I

-0

?

?

?

-0

-0

-0-P-0-P-0-P-0 I

-0

I

I

-0

I

-0

wTh '

HoY CH3

6: Nucleotides and Nucleic Acids

209

activity similar to the corresponding purine 2',3'-dideoxynucleotides. It would appear from these results that the N(7)-position of the purine ring is not an essential site for binding ddATP or ddGTP at the active centre of HIV-1 reverse transcriptase. The 5'triphosphate (49) of a 6-fluorocarbocyclic analogue of AZT has been prepared through initial phosphitylation of the nucleoside with di-t-butyl-N,N-diethylphosphoramidite, and oxidation with rn-chloroperbenzoic acid.48 The triphosphate was obtained after removal of the t-butyl groups with trifluoroacetic acid and subsequent reaction with tributylammoniumpyrophosphate and 1.1'-carbonyldimidazole in anhydrous DMF.This analogue showed only weak inhibition of HIV-1 reverse transcriptase in comparison to AZT 5'-triphosphate. The 5'-diphosphorylphosphonate derivative (50) of a related 6'fluorocarbocyclic nucleoside has also been prepared and evaluated as an inhibitor of HIV-1 reverse transcriptase.49 Compound (50) was shown to be a potent inhibitor (IC50 = 0.01 pM) of this enzyme with activity comparable to that of AZT 5'triphosphate. Perhaps more interestingly the corresponding 5'-hiphosphate (5 1) was a much less effective inhibitor (IC50 = 200 pM)of HIV-1 reverse transcriptase. Several 3'-deoxy-3'-(1,2,3-tiazol-l-yl)thymidine derivatives (e.g. 52) have been synthesised as cyclic analogues of AZT, based on the hypothesis that the triazole nitrogen atoms could mimic a distorted azido group.50 The 5'-triphosphate of (52) was prepared by a standard route based on initial phosphorylation with phosphorus oxychloride and subsequent reaction of the monophosphate with tetrabutylammonium pyrophosphate in the presence of 1,l'-carbonyldimidazole. This analogue showed no inhibitory activity against HIV- 1 reverse transcriptase. 3'-Deoxy-3'-azidothymidine 5'-0-( 1,3-dithiotriphosphate) (53) has been prepared by phosphitylation of the 5'-hydroxy group of the nucleoside with 2-chloro4H- 1,3,2-benzodioxaphosphorin-4-oneto give the salicyl protected intermediate (54, (55) scheme 3.51 Treatment of (54) with Pl-0-(2-cyanoethyl)-P~-thiopyrophosphate and sulphur followed by treatment with base gave (53) as a mixture of diastereoisomers which could not be separated by chromatography on DEAE Sephadex. The same authors also report the synthesis of thymidine 5'-0-( 1,l-dithiotriphosphate) (56) which was obtained by ring opening of thymidine 5'-0-( 1-thiocyclotriphosphate) (57) with lithium sulphide in DMF (scheme 6). The triphosphate analogue (56) is a potential substrate for the enzymatic synthesis of phosphorodithioate DNA, but unfortunately (56) was not a substrate for the Klenow fragment of DNA polymerase. The synthesis and properties of nucleoside 5'-thiotiphosphates labelled with the sulphur-35 isotope have been reviewed.52 Bisnucleoside-5',5'-oligophosphatescontinue to be both challenging targets for organic synthesis and useful substrates for biological studies. A wide range of analogues of diadensoine 5',5"'-P1,P3-triphosphates(Ap3A) (58) have been prepared 53 and used as part of a programme to investigate the mechanism of action of dinucleoside polyphosphate hydrolases.54 The Pl,P2-carbon-bridged analogues (59a-f) of Ap3A

Organophosphorus Chemistry

210

(53)

(54)

! !

Reagents: i, - O-P-O-P-SI

I

-0

; ii, S8; iii, NH3(aq)

OCH2CH2CN

(55)

Scheme 5

i, ii

HO

OAc (57)

(56)

Reagents: i, Li2S; ii, NH3(aq)

Scheme 6 HO

OH

HO OH (58) X = Y = O (59) Y = 0;a; X = CH2, b; X = CHF, c; X = CF2, d; X=CHCI, e; X=CCI2, f; X=C2H4 (60) X = Y = C H 2 HO

OH

(61) X = O (62) a; X = CH2, b; X = CF2, c; X = CHF

HO

OH

6: Nucleotides and Nucleic Acids

211

were obtained from condensation reactions with a range of a$-methylene analogues of ADP with adenosine 5'-phosphoromorpholidate. The Pl,P2:P2,P3-bismethylene analogue (60) was obtained in only very low yield from the reaction between bis(dihydroxyphosphinomethy1)phosphinic acid with 2',3'-O-isopropylideneadenosine5'tosylate. The diastereoisomers of PI ,P4-dithio-5',5"'-diadenosyl-P1,P4-tetraphosphate (61) and some P2,P3-methylene analogues (62 a-c) have been prepared and separated.55 A simple and effective synthesis was used which involved the activation of adenosine 5'-monophosphorothioate with diphenyl chlorophosphate and subsequent reaction with the appropriate bisphosphonic acid. The AP(S)PCHFPP(S)A analogue (62c) is particularly interesting since a third new chiral centre exists at the PCHFP locus and as a result 4 diastereoisomersare possible. The stereochemicalcourse of synthesis of 5',5"'-diadenosyl-P1 ,P4-tetraphosphate (Ap4A) from ATP, catalysed by phenylalanine tRNA synthetase in the presence of Zn2+ has been demonstrated to proceed with retention of configuration at Pa.56 The result is in accord with the mechanism involving phenylalanine adenylate as an intermediate. The hydrolysis of Ap4A by the unsymmetrical Ap4A phosphodiesterase from lupin seeds has also been studied and was shown to take place with inversion of configuration at Pa, consistent with a direct in-line displacementmechanism.57 A general method has been developed for the synthesis of some 2'-substituted arabinonicotinamide adenine dinucleotide analogues (63) starting from 1,2:5,6-di-Oisopropylidene-a-D-allofuranose.58The nicotinamide nucleosides were phosphorylated using rn-cresol and pyrophosphoryl chloride and the pyrophosphate linkage formed by activation of the nicotinamide nucleotide with diphenyl chlorophosphate prior to reaction with AMP. The synthesis of potential inhibitors (e.g. 64)of uridine 5'-diphosphate (UDP) glucuronosyl transferase in which the P-phosphate moiety of UDP is linked to a phenolic hydroxy group has been described.59 Key intermediates in the formation of the diphosphates are S-(4-methylphenyl)-2-cyanoethyl phosphorothioate triesters, which after conversion into the corresponding S-(4-methylphenyl)phosphorothioate diesters, react with phosphate monoesters in the presence of iodine to give the target molecule. Several ADP analogues (e.g. 65) have been prepared which were designed to have increased metabolic stability, but retain biological activity.60 Based on previous studies the purine base was simplified to a 2,4-diaminopyridine nucleus and the ribose sugar and pyrophosphate structural features replaced by a carbocyclic ring and phosphonacetyl group respectively. Introduction of the phosphonacetyl group was accomplished using dimethylphosphonoacetic acid and 1,3-dicyclohexylcarbodiimide and the resulting phosphonate ester demethyIated using trimethylsilyl iodide.

212

Organophosphorus Chemistry

(63) X = F, NH2, or N3

0

0

-0

-0

HO

R O ii - ~ -i~ O - ~ - O y U r a

HO

OH

(65) R = B r or S-Me

0

CONH-LCAAP-CPG

4 C O N H - L C A A P - C P G n

HO NO2

(67)

6: Nucleotides and Nucleic Acids

213

Oligo- and Polvnucleotida 4.1 DNA Svnthesis 4.1.1 Chemical Svnthesis - Whilst the chemical synthesis of DNA is highly developed there is still considerable scope for fine-tuning. In particular, a number of developments have been reported which enable oligonucleotides to be constructed and deprotected under very mild conditions. Improvements of this type are of considerable importance with respect to the synthesis of modified oligonucleotides which may contain chemically sensitive functional groups. A simplified procedure for the attachment of nucleosides onto long chain alkylamidopropanoic acid controlled-pore glass (LCAAP-CPG) has been developed.61 5I-O-Tritylated nucleosides were coupled directly to LCAAP-CPG in excellent yields using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide as a coupling reagent. This procedure avoids the time consuming preparation of the nucleoside 3'-succinates. 3'Terminal nucleosides have also been linked to controlled-pore glass or a polystyrene support by means of an oxalyl tether.62 The nucleoside-oxalyl link was cleaved within a few minutes when treated with aqueous ammonia in methanol at room temperature and is therefore particularly useful in the preparation of oligonucleotides containing basesensitive residues. The utility of the supports was demonstrated by the synthesis of oligonucleotides containing methyl phosphotriester linkages. New polymeric supports that contain a 2-(2-nitrophenyl)ethyI linkage susceptible to cleavage by p -elimination under basic conditions have been developed.63 A carbonate linkage (e.g. 66) was used for the preparation of oligonucleotides without 3'-phosphate groups. Cleavage of the oligomer from the resin was achieved in less than one hour using 0.5 M DBU in dioxane or pyridine. The CPG derivative (67) can be used as a universal support for the preparation of 3'phosphorylated oligonucleotides. Reaction of 2-cyanoethyl phosphoramidites with the primary alcohol function and subsequent oxidation gave a phosphotriester linkage that is stable during synthesis, but is cleaved by concentrated aqueous ammonia during deprotection. These supports can be used in conjunction with (4-nitropheny1)ethyl protected nucleoside 2-cyanoethyl phosphoramidites for the preparation of oligonucleotides containing ammonia-sensitive nucleoside analogues since all the deprotection steps can be performed using DBU. A related method has been described for the solid-phase synthesis of oligonucleotide 3'-phosphates using a controlled-pore glass support functionalised with dimethoxytrityloxy-2-mercapto groups linked to the support by a disulphide bridge (68).64 Following oligonucleotide synthesis, deblocking was carried out by treatment with 50 mM dithiothreitol in concentrated aqueous ammonia at 55OC for 16 hours. This one-step process allows removal of the base and phosphate protecting groups and also cleaves the oligomer from the support. The 2-(acetoxymethy1)benzoyl (AMB, 69) group has been proposed as a new base-labile group for the protection of the exocyclic amino functions in oligonucleotide

214

Organophosphorus Chemistry

synthesis.65 It is rapidly cleaved by either aqueous ammonia or potassium carbonate in methanol. The latter deprotection conditions make this blocking group particularly appropriate for the synthesis of DNA containing methyl phosphotriester linkages. A new combination of readily removable amide protecting groups has been proposed for the rapid synthesis and deprotection of oligodeoxyribonucleotides.66 The adenine and guanine bases were protected as dimethylformamidinederivatives whilst the isobutyryl group was used for the protection of cytosine. Complete deprotection of the assembled oligomer could be achieved using concentrated aqueous ammonia for 1 hour at 55OC or 8 hours at room temperature. Boron trifluoride-methanol complex has been used to effect detritylation in automated DNA synthesis.67 This reagent gave better results in comparison to dichloroacetic acid for the synthesis of purine rich sequences. However, a major disadvantage of this method is the absence of an orange colouration produced during the detritylation step which normally serves as a visual indicator of a successful coupling step. An alternative procedure has been described for the preparation of nucleoside 3'-O-phosphoramidites which avoids the use of either on aqueous work-up or column chromatography.68 Phosphitylation was performed in the standard manner using 2cyanoethyl-ZV,N-diisopropylchlorophosphoramiditewith triethylamine in tetrahydrofuran-dichloromethane (1 :1). After filtration and concentration, purification of the nucleoside product was achieved by trituration into benzene. This method appears to be especially suitable for labile phosphoramiditederivatives and has been applied to the preparation of the oxygen-sensitive 8-oxo-2'-deoxy-7H-guanosine phosphoramidite.69 The phosphite method of solid-phase synthesis based on the use of deoxyribonucleoside 3'-bis(1,1,1,3,3,3-hexafluoro-2-propyl)phosphiteunits (e.g. 70) has been shown to produce oligonucleotide contaminants of greater length than the desired sequence. This problem has been solved by inserting a brief hydrolysis step after coupling followed by capping with bis( 1,1,1,3,3,3-hexafluoro-2-propyl)-2-propyl phosphite (71) activated by N-methylimidazole.70 Polyacrylamidegel analysis indicates that the quality of the oligodeoxyribonucleotides prepared by this procedure is comparable to that obtained by the phosphoramidite approach. Alkyl nucleoside 3'phosphonates (e.g. 72) have been transformed into the corresponding phosphorochloridites (73) with the chlorinating agent tris(2,4,6-tribromophenoxy)dichlorophosphorane (BDCP, 74).71 Thus, the 2-cyanoethyl- (72a) and methyl- (72b) nucleoside 3'-phosphonates were converted to the phosphorochloridites (73a) and (73b) and used immediately as building blocks for the solid-phase synthesis of oligodeoxyribonucleotides. A comparative synthesis of dodecathymidylate using either (72a) or (72b) revealed the former to be more effective although this is probably due to side reactions in the thiophenolate deprotection step. The same group has used BDCP to convert nucleoside 3'-N,N-diisopropylphosphonamidates (75) to the corresponding

215

6: Nucleotides and Nucleic Acids

[Basel-NH * O

(0q0 Me

o\

40 fP\ H OR

(72) a; R=CH2CH2CN b; R=CH3

DM o\

RO'

(73) a; R=CH2CH2CN b; R=CH3

DMTo

vB 0, 40 .p\

(Pri),N

H

(75)

(74)

DMTo

P-CI

vBas I

0,

(P &N ,'

P-CI

O

V

" " " OCOPh

(77)

O (78)

N(Pri),

Me

"

216

Organophosphorus Chemistry

phosphorochloridites (76).72 Addition of a pyridine solution of a 3'-protected nucleoside to compound (76), generated in situ, gave the dinucleoside phosphoramidite (77) quantitatively in less than 5 minutes. Conversion of (77) to the dinucleoside phosphate was achieved in 2 steps by hydrolysis and subsequent oxidation. Disodium 2-carbamoyl-2-cyanoethylene- 1,l -dithioate (78) has been shown to be an attractive alternative to thiophenol-triethylamine for the deprotection of nucleoside phosphotriesters.73 This reagent is odourless, but more importantly removes methyl or benzyl groups from phosphates considerably faster than thiophenolate. The rapid rate of dealkylation makes (78) useful for the deprotection of modified phosphotriesters such as alkylphosphorodithioates which are otherwise difficult to dealkylate. The 5'-phosphorylation of oligonucleotides in automated synthesis has been studied using phosphorous acid and pivaloyl chloride as the activating agent.74 The resulting 5'-H-phosphonates were converted to phosphates by silylation and oxidation. Additionally, the phosphorous acid produced a novel 5'-5'-dimerisation reaction which proceeds in competition with the formation of the 5'-H-phosphonate. The purification of synthetic oligonucleotides by hplc has been reviewed.75

4.1.2 Enzvmatic Svnthesis- The enzymatic synthesis and manipulation of DNA

encompasses a large proportion of molecular biology and it cannot therefore be dealt with comprehensively in this review. However, several studies have appeared which have examined this area from a chemical perspective. A new method for the over production of proteins has been described, the expression-cassette polymerase chain reaction (ECPCR), that greatly simplifies the manipulations necessary to generate an over-producing plasmid construction and is particularly suitable for chemistry laboratories unskilled in the manipulation of DNA.76 ECPCR is an extension of the polymerase chain reaction (PCR has recently been reviewed77-79) in which expression and restriction elements are designed into the synthetic primers and these become fused to the intervening coding sequences during the amplification step. The result is an expression cassette which contains all the sequence information for cloning and expression. An alternative strategy for the generation of substantial quantities of singly 5'3*P-end-labelled double-stranded DNA has been described which is based on M13 cloning techniques.80 The 32P-label is introduced on to the free 5'-hydroxy group of a chemically synthesised universal primer which is subsequently used to initiate DNA synthesis on a M13-derived single-stranded DNA template. Following polymerisation using the Klenow fragment of DNA polymerase I, cleavage with the appropriate restriction endonuclease produces a uniform length duplex suitable for binding studies. This method of generating singly radiolabelled DNA duplexes has been used to study the alkylation of DNA by the drug (+)-CC-1065. This approach also permits the direct

6: Nucleotides and Nucleic Acids

217

application of the Sanger dideoxynucleotide sequencing technique for identification of cleavage sites introduced by (+)-CC- 1065. A review on the mechanistic aspects of DNA synthesis by the Klenow fragment of DNA polymerase I has recently appeared.81 4.2 RNA Svnthesis 4.2.1 Chemical Svnthesis- Selection of suitable protecting groups for the 2'-hydroxy functions of the ribonucleoside building blocks is of critical importance in RNA synthesis. Many different protecting group strategies have been proposed although the most commonly used automated procedure relies on the use of alkylsilyl ethers. A detailed study has been performed on the fidelity of RNA synthesis using the phosphoramidite chemistry in conjunction with t-butyldimethylsilyl (TBDMS) protection of the 2'-position.82 The isomeric purity of the 2'-TBDMS ribonucleoside 3'phosphoramidites (79), key intermediates in oligoribonucleotide synthesis, was established by comparison of the 1H and 31P nmr spectra to those of the isomeric 3'silylated phosphoramidites (80). Using the 3'-amidites several diribonucleoside monophosphates were synthesised in solution and compared to the isomeric dimers containing 2-5'- phosphate linkages. Comparison of the analytical data on the 2 series of compounds clearly demonstrated the absence of the 2'-5'-linkage in the natural series. The fidelity of this strategy has also been established by Scaringe et ~ 1 . 8 3in studies which showed that oligoribonucleotides containing up to 35 residues were free of the aberrant 2'-5'-linkage when analysed by enzymatic digestion and hplc analysis. The 3'-phosphoramidites derived from fully protected ribonucleosides generally give poorer yields in the coupling reactions than the corresponding DNA synthons and also require substantially longer coupling times. Both problems are associated with the steric hindrance introduced by the 2'-hydroxy protecting group and prevent the efficient synthesis of long RNA fragments. Several N,N-dialkylaminocyanoethylphosphoramidites, protected at the 2'-position by the TBDMS group, have been evaluated for use in the solid-phase synthesis of homouridine RNA fragments.g4 The Nethyl-N-methylamino derivatives (8 1) were shown to give the best results with coupling yields of 97% achieved after 4 minutes using tetrazole as the activating agent. The monomers were amenable to purification by hplc and were stable for several months. TBDMS protection has also been investigated in combination with the H-phosphonate coupling procedure.85 Synthetic cycles were optimised to use only 8- 10-fold excess of the monomers at each coupling step, leading to an average coupling yield of 97%. Catalytic transfer hydrogenation conditions using Pd(I1)O in methanolcyclohexene (1:l) has been used to remove the TBDMS group from both the 5'- and 3'position of uridine.86 Although the tetrahydropyranyl protecting group has proved extremely useful in traditional solution synthesis, its applicability to solid-phase synthesis, when used in

218

MTo

Organophosphorus Chemistry

w

Base

oyo\cl

" " ' O F B a s e NC-"P/O ..

F

)o

I

N(

~ t - 9 ~

6: Nucleotides and Nucleic Acids

219

conjunction with acid labile 5'-protecting groups, has been questioned. Contrary to these reports Tanimura and Imada87 have described the synthesis of RNA oligomers up to 30 residues in length using the 2-0-tetrahydropyranyl group in combination with the acid labile moxyl group for protection of the 5'-position. Best results were obtained when the moxyl group was removed by a 1 minute treatment with 2% dichloroacetic acid. The same group have reported that improved results are obtained when the 2-0tetrahydropyranyl 3'-phosphoramidite monomers are rigorously purified by silica gel chromatography using CH~C12-hexanemixtures containing 2% triethylamine as the eluent.88 The phosphoramidite approach has also been used in conjunction with 2-0tetrahydrofuranyl and 5'-O-levulinyl protection for the large scale (10 pmol) solid-phase synthesis of oligoribonucleotides.~~ Removal of the levulinyl group was accomplished using hydrazine in pyridine-acetic acid and was completely compatible with the use of the tetrahydropyranyl group. The 1-(2-fluoropheny1)-4-methoxypiperidin-4-y1(Fpmp) group represents a highly developed tetrahydropyranyl-type 2'-protecting group which has been specifically designed for use in automated RNA synthesis in conjunction with acid labile 5'-blocking groups. RNA building blocks (e.g. 82) constructed to contain 2'-Fpmp and 5'-pixy1 protecting groups and employing the 2-cyanoethylphosphoramiditechemistry have been used to prepare the 3'-terminal 37-mer sequence of the unmodified alanine tRNA from yeast.90 Using 5-(3-nitrophenyl)-1H-tetrazole as the activating agent coupling yields were in the order of 97%. The 2'-0-Fpmp groups and the 5'-0-pixyl groups were removed after purification by treatment with 0.01M HC1 at room temperature. Equally good results have been achieved when the Fpmp group has been used in combination with 5'-0-4,4'-dimethoxytrityl group.91 Sakatsume et al. have developed a similar strategy using the l-(2-chloroethoxy)ethyl (Cee) group to protect the 2-position.92 Using 5'-0-4,4'-dimethoxyttyl3'-phosphoramiditesynthons (e.g. 83) activated with tetrazole, coupling yields were 95-98%. Removal of the Cee group was performed using 0.01 M HCl at room temperature for 6 hours. This method has been used to construct oligoribonucleotides of up to 20 residues in length. The "2-(methylthio)phenyl]thio]methyl (MPTM) group has been proposed as a new blocking group for the 2'-hydroxy function.93 The MPTM protected ribonucleosides (e.g. 84) were prepared from the 1,3-benzodithio1-2-y1 nucleoside (85) via a two-step reaction involving reductive ring opening followed by S-methylation. The MPTM group is stable to prolonged treatment with 1%trifluoroacetic acid, but can be removed efficiently with silver nitrate in aqueous DMF. Monomer building blocks protected by the MFTM group have been used to synthesise CpUpG by the phosphotriester approach. The introduction of the t-butyloxycarbonyl group preferentially into the 2'-position of the ribonucleosides cytidine, uridine, adenosine and guanosine has been described94 resulting in derivatives especially applicable to oligoribonucleotide synthesis.

220

Organophosphorus Chemistry

u , 2 Enzvmatic Svnthesis- The chemical acylation of suppressor tRNAs with unnatural amino acids is of considerable importance since their use in a protein biosynthesis reaction results in the specific incorporation of the novel amino acid into the polypeptide chain. A general method for the synthesis of aminoacyl tRNAs has been developed which enables aminoacyl pdCpA to be prepared in one-step by reaction of a cyanomethyl-activated ester of a N-protected a-amino acid with pdCpA.95 The utility of this procedure has been demonstrated by using T4 RNA ligase to enzymatically ligate nitroveratryloxycarbonyl (NVOC) protected phenylalanine pdCpA (86) to a tRNA(-CA) molecule. Following removal of the NVOC group by photolysis, the resulting phenylalanine-charged tRNA species was shown to be competent in an in v i m protein biosynthesis assay. This strategy for unnatural mutagenesis has been used in combination with 2-nitrobenzyl protection of aspartic acid to produce an inactive protein which is activated on removal of the nitrobenzyl group by photolysis.96 A systematic survey of the structural requirements for the biosynthetic incorporation of unnatural residues into a polypeptide has been made.97 For a series of 12 semisynthetic acylated suppressor tRNAs the relative translational efficiencies ranged from 0-9 1% depending on the structure of the residue incorporated. The results suggest that Damino acids are unlikely to be incorporated and that increased steric bulk at the pcarbon reduces incorporation dramatically. Chemical techniques useful in studying the molecular mechanisms for the synthesis of RNA by the RNA polymerase complex have been reviewed.98

4.3 Modified Oliponucleotides 4.3.1 Olipowcleotides containing Modified PhosDhodiester LinkaPg.- Activity in this area continues unabated especially with regard to the synthesis and evaluation of modified oligonucleotides as potential chemotherapeutic agents.g9,100 Much of the attention has been focused on the phosphorothioate, phosphorodithioate and phosphonate modifications and many diverse studies have appeared on these analogues. A number of polysulphides have been tested as potential sulphur-transfer reagents for the automated synthesis of phosphorothioate-containing oligonucleotides.101 The thiosulphonate3H- 1,2-benzodithio1-3-one 1,l-dioxide (87) (0.2M solution in acetonitrile) was found to be particularly effective for the sulphurisation of dinucleoside phosphite triesters, giving complete conversion to the corresponding phosphorothioates within 30 seconds. This reagent has been used to prepare a homooligoribonucleotide S-rC14 (composed entirely of phosphorothioate linkages).l02 The modified oligomer was approximately 10-fold more resistant to enzymatic degradation than the corresponding unmodified sequence (rC14) and was able to hybridise to a complementary RNA sequence.

22 1

6: Nucleotides and Nucleic Acids

N H Y O

(87)

‘

O

y

B

a

s

e

DMTo

YTh 0, /H y’/ P\

0

\

(89)

O

Y OAc T

(90) Y = 0 (91) Y = S

h

Y

222

Organophosphorus Chemistry

Tetraethylthiuram disulphide (TETD, 88) has also been proposed as a sulphurisation reagent for the automated synthesis of phosphorothioate oligonucleotides via the phosphoramidite approach.103 The sulphurisation step is complete within 15 minutes at room temperature and has been used in the large scale (200 pmol) synthesis of oligonucleotides containing up to 100 residues. The mechanism is presumed to involve a rate-determining nucleophilic attack by phosphorus on the disulphide bond (89) and subsequent attack by dithiocarbonate anion on the thiocarbonyl group to give the phosphorothioate triester. A convenient method has been developed for the conversion of dinucleoside H-phosphonates (90) and dinucleoside H-phosphonothioates (91) into the corresponding phosphorothioates (92) and phosphorodithioates (93) respectively.104 For example, tre,atment of (90) with Nbenzylthiosuccinimide and diisopropylamine resulted in rapid and essentially quantitative conversion to the S-benzylphosphorothioate(92) which could be isolated in 95% yield as a mixture of diastereoisomers. The benzyl group was subsequently removed with thiophenolate. Trifluoroacetic anhydride has been shown to react with organophosphorus compounds containing thiophosphoryl groups, converting them in high yield to the corresponding oxygenated systems.105 The reaction provides an efficient method for the conversion of a dinucleoside phosphorothioate into its oxygenated analogue. A 31P nmr study of a model oxygenation reaction on triphenylphosphine sulphide indicates that the reaction proceeds via 2 tetracoordinate and 1 pentacoordinate species (scheme 7). 35s-Labelled phosphorothioate oligodeoxyribonucleotides have been synthesised by use of the H-phosphonate approach.106 Sulphurisation of 5'-0-4,4'dimethoxytrityl support-bound H-phosphonate oligomers by base-catalysed reaction with 35s-enriched sulphur gave oligonucleotides with a specific activity of 107 cpm/pmol-equivalent of phosphorothioate linkage. One mode of action of the anti-viral activity of interferon is associated with the presence of 5'-triphosphates of (2'-5')-oligoadenylates which activate the latent endonuclease RNAseL. Activation of this enzyme results in cleavage of viral mRNA and the inhibition of protein synthesis. Since the (2'-5')-oligoadenylates are not easily taken up into eukaryotic cells and are also readily hydrolysed by phosphodiesterases there is interest in the modification of the natural structure to provide increased stability and retained biological activity. The diastereoisomers of P-adenylyl-(3'-5')-P-thioadenylyl-(3'-5')-adenosine have been synthesised as standards for the in vivo and in vitro study of the biological properties of (2'-5')-oligonucleotide analogues.107 None of these compounds either bound to, or activated RNAseL. The chemistry of phosphorothioate containing oligonucleotideslog and their kilogram-scale synthesis by automated procedures109 has been reviewed.

6: Nucleotides and Nucleic Acids

(92) Y = 0 (93) Y = s

Ph,P=S

223

OH

OAc (94)

+

TFAA

* [Ph3P-SCOCF3

-

+

Ph3P=SCOCF3] CF3COO-

+

Ph3POCOCF3

+

+

Ph3PO

CF3COO-

Scheme 7

#o-

s+Fo

O\

P

0 0JP' 1

s#\oY OH

(95)

224

Organophosphorus Chemistry

Several hyper-modified oligonucleotides have been prepared which contain phosphorothioate linkages. Octathymidylates containing alternating stereoregular neopentylphosphothionotriester linkages (e.g. 94) have been prepared from chromatographically resolved dimers.110 The oligomers were covalently attached to an acridine derivative through the 3'-hydroxy group and their stability to nuclease degradation compared to an octathymidylate acridine-conjugate containing only phosphodiester linkages. The oligonucleotides containing the modified linkages were about 15 times more resistant to enzymatic hydrolysis than the phosphodiestercontaining oligomer. Two abasic oligodeoxyribonucleotide phosphorothioate analogues containing either 1,2-dideoxy-D-ribofuranose(95) or (*)-butane- 1,3-diol(96) have been prepared and evaluated as anti-HIV agents.111 Neither compound was as active as the parent S-dC28 in protection against de novo HIV-1 infection of H-9 cells. A number of biological studies have been conducted on phosphorothioatecontaining oligonucleotides in order to evaluate their potential as chemotherapeutic agents. It is established that phosphorothioate oligonucleotides with chain lengths greater than 14 residues are capable of inhibiting HIV-1 replication and that the potency increases with phosphorothioate chain length. Studies using S-dC28 have demonstrated that the oligonucleotide inhibits 3 enzymes expressed by HIV-1; RNase H, reverse transcriptase (RT) and DNA polymerase and that inhibition of RT is competitive with respect to the template.112 More interestingly phosphorothioate oligonucleotides directed against the Rev sequence are also able to induce in vivo sequence specific suppression of HIV- 1 viral expression.113 Phosphorothioate oligonucleotides, both with and without sequence specificity have been shown to have activity against herpes simplex virus type-2.1 14 A variety of anti-sense oligonucleotide constructs have been synthesised for screening against HIV- 1.1 15 Phosphorothioate oligonucleotides targeted against RNA coding for the Rev protein were the most effective producing 50% inhibition of gene expression at an oligonucleotide concentration 5 pM. The subject of retroviruses and oncogenes has been reviewed.116, 117 The intracellular transport and fate of nucleic acids has been studied by the injection of fluorescently labelled oligodeoxyribonucleotide analogues into the cytoplasm of CV-1 epithelial cells.118 Rapid nuclear accumulation was observed for the phosphorothioate and methylphosphonate analogues of a 28-residue oligonucleotide complementary to the Rev mRNA of HIV-1 and the intranuclear distribution of the oligomers was shown to be influenced by the type of internucleotide linkage. The cellular distribution of natural and phosphorothioate-containing oligonucleotides, that were previously shown to have a specific anti-sense effect on LTK-cells infected with HSV-1, has been studied.119 Using 32P-labelled oligomers it was shown that oligonucleotides are not equally distributed in the cytosol, nuclear or membrane components and the results suggest that anti-sense agents may be able to affect processes such as RNA transport and receptor function.

6: Nucleotides and Nucleic Acids

225

Phosphorodithioate oligonucleotides are potentially more attractive anti-sense agents than the corresponding phosphorothioate analogues, because of the absence of an asymmetric centre in the dithioate linkage. The synthesis of phosphorodithioate analogues of oligodeoxyribonucleotideshas been studied by 2 methods that are based on the phosphoramidite approach.120 In the first, deoxynucleoside phosphordiamidites (97) were converted to a dinucleoside phosphoramidite (98) by treatment with a 3'-protected nucleoside and tetrazole. Sequential reaction of (98) with 4chlorobenzylmercaptan and sulphur yields the dinucleoside phosphorodithioate triester (99). The second route used deoxynucleoside phosphorothioamidites in a procedure that is directly analogous to the use of standard phosphoramidites for the synthesis of unmodified DNA. The deoxynucleoside 3'-N,N-dimethyl- (100) and 3'4,N-tetramethylene- (101) phosphorothioamidites could both be prepared via a one-flask procedure and reacted rapidly in the presence of tetrazole to form the dinucleoside phosphorothioite. Subsequent oxidation with elemental sulphur, gave the fully protected phosphorodithioate linkage. For the large scale preparation of dithioatecontaining DNA the classical phosphotiester approach using dithiophosphate diesters (e.g. 102) remains attractive. Condensation of (102) with the 5'-hydroxy group of another nucleoside unit, using triisopropylbenzenesulphonyl chloride and 1methylimidazole, gives the dinucleoside phosphorodithioate in 95% yield contaminated with 1% of the dinucleoside phosphorothioate. 12 1 For protection of the phosphorodithioate linkage the 2,4-dichlorobenzyl group is preferred over the 4chlorobenzyl group since the latter leads to a higher percentage of contaminating phosphorothiolate linkages. In a model study for the synthesis of oligonucleoside phosphorodithioates, a one-pot, three-step procedure has been developed for the conversion of a nucleoside phosphonate (103) to the corresponding dithioate (105, scheme 8).122 Reaction of (103) with BDCP gave quantitatively the nucleoside phosphorochloridite (104) which was converted to the product by sequential treatment with dry hydrogen sulphide and elemental sulphur. A phosphorodithioate-containinganalogue of d(CGCGTTAACGCG) has been prepared on a solid-phase support using deoxythymidine 3'-S-( 2,4-dichlorobenzyl)dimethylthiophosphoramidite and oxidation with sulphur to introduce the phosphorodithioate linkages.123- 124 The structure of the modified dodecamer d(CGCGTpS2TpS2AACGCG) was investigated by 1H 2-D nmr spectroscopy. An unusual connectivity between H(8) of the sixth dA residue and H(1') of the fourth dT residue and many other features in the NOESY spectrum were consistent with a hairpinloop structure. The destabilisation of the duplex has been attributed to unfavourable phosphorodithioate electrostatic repulsion. A study on the biological activity of oligonucleotide dithioates has shown that these analogues are able to induce RNase H activity in Hela cell nuclear extract.125

Organophosphorus Chemistry

226

O\ ,o-

MTo

P

FyHMe

O

y

B a OAc

s

-vB o\

,N(Pr’)2

P I

N(Pri)2

e

CI‘

DM ‘7c/o-c’ o\p+s-PC (98)

(99)

’eyBase

MTo R’N R’

-0’

S

(100) R = M e (101)

R=

3

\s

CI

(102)

6: Nucleotides and Nucleic Acids

227

Experiments have also revealed that phosphorodithioate DNA is a potent inhibitor of HIV-1 reverse transcriptase. In particular, an oligodeoxycytidine 14-mer containing all phosphorodithioate linkages was 28-fold more inhibitory to this enzyme than the corresponding phosphorothioate analogue. Diastereomerically pure Rp- and Sp-dinucleoside H-phosphonates have been prepared and the stereochemical course of their conversion into methyl phosphonatesl26 phosphorothioatesl26, 127 and 180 chiral phosphatesl26, 127 has been studied. Methylation of diastereomerically pure H-phosphonates using n-butyl lithium and methyl iodide was stereospecific and occurred with retention of configuration. Sulphurisation of the in situ formed trimethylsilyl phosphite triesters also proceeds with retention of configuration. However, oxidation with iodine/ [ 180]H20/pyridine leads preferentially to the Sp-configuration of the phosphate triester regardless of which diastereoisomer is used. Accordingly, oxidation could be used to synthesise a mostly Sp-configured, oxygen labelled DNA fragment, even by automated synthesis. Molecular dynamics simulations have been performed on fully substituted methylphosphonate oligonucleotides with alternating (I?)- and (S)-configurations (to simulate the approximate experimental yield since stereospecific synthesis of this linkage is not readily controlled).l28 The results appear to indicate that charge neutralisation of the backbone has relatively small effects on the conformational properties of DNA, but the negative phosphates are important for interactions with solvent and counter ions. The configuration of diastereomeric dinucleoside methylphosphonates has been determined using the 2-D nmr ROESY technique.129 Psoralen derivatised oligodeoxyribonucleotidemethylphosphonates have been prepared that are complementary to the initiation codon region of vesicular stomatitis virus (VSV) M-protein-RNA.130 Experiments indicate that these anti-sense agents inhibit the synthesis of M-protein in a specific manner and that psoralen derivatisation increases the efficiency of inhibition by about 10-fold. Thymidine 5'-0-pyrophosphoryl methylphosphonate (106) has been chemically synthesised by condensation of thymidine 5'-0-methylphosphonate with pyrophosphate.131 In the presence of an oligonucleotide initiator, (106) was able to serve as a substrate for terminal deoxynucleotidyl transferase to produce methylphosphonate containing dimers and trimers. The enzymatically formed linkages were shown to have the Sp-configuration by comparison with standard compounds. A new deprotection procedure has been developed for the synthesis of DNA fragments containing phosphate-methylated residues at defined positions. 132 The approach involves the application of the 9-fluorenylmethoxycarbonyl (Fmoc) group for protection of the heterocyclic bases, the use of the 2-cyanoethyl group for blocking the phosphodiester functions and potassium carbonate in methanol for deprotection. This

Organophosphorus Chemistry

228

OH

bAde HO

R

(108) R = H o r O H

HO

HO

R

(109) R = H o r O H

(110) R =

yAd 0

(111) R =

(112) R =

w vAd OH Ade

wAd OH

(113) R =

OH

X=CIorF

6: Nucleotides and Nucleic Acids

229

deprotection reagent cleanly removes both the base and phosphate blocking groups, but does not affect the methylphosphotriester linkages. Several other types of modified phosphodiester linkages have been investigated including; dinucleotide analogues containing dimethylene sulphonyl groups133 (107) and methoxyethylphosphoramidate linkages.134 The synthesis of several 5'-deoxy-5'nucleoside carboxylic acid derivatives has been accomplished by the reaction of alkoxycarbonylmethylene triphenylphosphoranes with adenosine 5'-aldehydes and their oligomerisation using a water-soluble carbodiimide investigated.135 The saturated acids (e.g. 108) were shown to cyclise to the lactone whereas the unsaturated acids (e.g. 109) oligomerisedefficiently especially in the presence of a poly(U) template. 4.3.2 0lieonucleotides Containine Modified Su aA series of 2'-5'oligonucleotide trimers carrying a 9-(2,3-anhydro-P-D-ribofuranosyl)-(110) 9-(3-deoxyP-D-glycero-pent-3-enofuranosy1)-(1 1l), 9-(3-azido-3-deoxy-~-D-xylofuranosyl)(1 12) and 9-(3-halo-3-deoxy-~-D-xylofuranosyl)-adenine (1 13) moiety at the 2'-terminus have been synthesised via the phosphotriester method.136 The same group has reported a set of closely related 2'-5'-oligoadenylates (1 14 a-d) containing the nucleoside analogue cordycepin (3'-deoxyadenosine) and carrying a 2'- terminal acyclic analogue of adenosine.137 The design of these compounds was based on previous studies which had shown that the incorporation of an acyclic nucleoside into 2'-5'-oligoadenylates decreased their rate of enzymatic hydrolysis. Cordycepin analogues of the 2'-5'oligoadenylate core trimer have been shown to display pronounced anti-HIV activity in vitro which arises through the inhibition of reverse transcriptase.138 The 3'-H-phosphonate and 3'-phosphoramidite derivatives of 1-(2-deoxy-P-Dxylofuranosy1)thymine (dxT, 115) have been synthesised and used to prepare, by solidphase synthesis, DNA oligomers containing 3'-5'-linked 2'-deoxy-P-D-xylonucleosides.139 The circular dichroism spectrum of d[(xT)12T] exhibited a reversed Cotton effect when compared to d(T12) implying a left-handed single strand. Melting studies confirmed that d[(xT)12T] formed a duplex (possibly left-handed) with d(A12). d[(xT)12]T Was also shown to be resistant to degradation by the enzyme calf-spleen phosphodiesterase although it was hydrolysed by snake venom phosphodiesterase. A hexamer of enantio-deoxyadenylic acid (containing 2-deoxy-L-erythropentose instead of 2-deoxy-D-ribose as the sugar backbone) has been prepared using the phosphotriester approach and shown to be resistant to digestion with bovine-spleen phosphodiesterase.140 UV Mixing curves were used to compare the interaction of the modified hexamer (L-dA6) and the natural oligomer (D-dA6) with complementary polynucleotides. L-dA6 demonstrated a hypochromic effect with poly(U) that was similar to that obtained between D-dA6 and poly(U). Interestingly, no hypochromic effect was observed when L-dA6 was mixed with poly(dT). Although the LdAg.poly(U) complex is weaker than the D-dA.poly(U) complex (Tm values of 32.4 and

230

Organophosphorus Chemistry

57OC respectively) these results suggest that enantio-DNA may have the unusual ability to act as an RNA-specific anti-sense agent. Similar studies have been performed on oligonucleotides containing both L- and D-2'-deoxyribonucleosides.~41 Thermal melting studies performed on a non-self-complementary duplex (1 16) in which one strand contained 3 5'-terminal L-2'-deoxycytidine residues (dC*) has established that the modified strand forms a stable duplex with a complementary sequence. The similar thermal melting curves for duplex (1 16) (490C) and for the corresponding unmodified duplex (117) (52OC) indicates that the terminal L-dC units interact with the D-dG residues by hydrogen bonding. Energy-minimised molecular modelling studies suggest that the distances of the hydrogen-bonds between each D-dG-L-dCpair are comparable to those in the natural C-Gpairs. Alternating a$-oligothymidylates with alternating 3'-3'- and 5'-5'-internucleotide phosphodiester linkages have been prepared as models for anti-sense oligodeoxyribonucleotides.142 The synthetic design was based on the assumption that the alternating 3'-3'- and 5'-5'-linkages would not be recognised as readily as natural linkages and would perhaps lead to enhanced enzymatic stability. To optimise hybridisation in such a structural motif it was necessary to alternate a-and pdeoxyribonucleotideresidues. Two alternating a,P-dT2g motifs were synthesis4 (118) and (1 19). Both oligothymidylates formed equally stable duplexes with P-dA28 (Tm = 55OC) and poly(rA) (Tm = 44OC) and were also resistant to both exo- and endonucleolytic hydrolysis. 2'-O-Methyloligoribonucleotideshave been shown to be useful for the study of RNA processing and as potential anti-sense agents. More recently 2'-0-ally1 oligomers have been demonstrated to have improved properties as anti-sense probes. A new procedure has been developed for the synthesis of 2-0-allyl ribonucleoside building blocks which uses allylethyl carbonate and a palladium catalyst in refluxing THF.1439144 Under these mild conditions nucleoside 2'-O-allyletherscan be obtained in excess of 80% yield. Several studies have appeared in which oligomers have been prepared from sugar analogues modified at the 3'- or 5'-position. A self-complementary oligodeoxyribonucleotide dodecamer containing an achiral 5'-phosphorothiolate linkage (3'-0-P-S5') has been prepared using the solid-phase phosphoramidite procedure. 145 The incorporation of the phosphorothiolate linkage was accomplished using a 5'4strityl)mercapto-5'-deoxythymidine3'-phosphoramidite (120). After coupling of this building block the trityl group was removed by treatment with silver nitrate solution and the free thiol function coupled with a standard phosphoramidite in the presence of tetrazole. The resulting phosphorothioite was oxidised with iodine-water under standard conditions. The modified dodecamer could be cleaved selectively and quantitatively at the P-S bond using either silver or mercuric salts under very mild

23 1

6: Nucleotides and Nucleic Acids

HoYAd 4 40

a; X=CH2

b; X = (CH2)2

Ade O

C;

b

X = (CH&

d; X = (CH&O

0, 40

O;%X- CH2-Ade

5'-d(66 6T C T C CC T T CT)

5'-d(CC C T C T C CC T T C T) 3'-d(GG G A G A G GG A A G A) 3'-d(GG GA G A G GG A A G A)

HowThy

TT

h3CS

0, p-0 q hy p N

0 -"

I

HO (121) a-or p- anomer

232

Organophosphorus Chemistry

conditions. Oligonucleotides containing 5'-N-phosphoramidate linkages have been synthesised in a self-replicating, non-enzymatic template-directed system. 146 A self-complementary DNA octamer d(GCCCGpGGC) containing a 3'-deoxy-3methylene phosphonate (denoted by p) has been prepared and its three-dimensional structure determined by X-ray crystallography.147 Comparison with the crystal structure of the unmodified octamer shows that the presence of an isolated 3'-methylene phosphonate linkage has very little effect on DNA helix conformation. 4.3.3 0lifonucleotides Containinp Modified Bases, - Several studies have appeared on abasic sites that arise from hydrolytic cleavage of the glycosidic bond and are considered to be common intermediates in mutagenesis. The lability of abasic DNA strands towards base represents a hindrance to the synthesis of short oligonucleotides containing this modification. A procedure has been developed which uses the photolabile 2-nitrobenzyl group for the protection of the anomeric hydroxy group during the solid-phase synthesis of abasic oligodeoxyribonucleotides.~~~ The key intermediate (121) was prepared by Konigs-Knorr-type glycosidation on 3,5-di-O-toluyl-2deoxyribofuranosyl chloride and subsequent alkaline treatment. The anomers of (121) were separated by chromatography, reacted with 4,4'-dimethoxytrityl chloride, phosphitylated to give (122) and used for the automated synthesis of oligodeoxyribonucleotides. After cleavage from the support, using standard procedures, the 2-nitrobenzyl group was removed by irradiating a solution of the purified oligomer in dilute acetic acid with a high pressure mercury lamp. The same group has shown that reaction of an abasic site with 9-aminoellipticine in the presence of sodium cyanoborohydride causes chain cleavage and reduction of the Schiff base to produce an oligonucleotide functionalised at the 3'-end with ellipticine (123).149 This procedure provides a general method for oligonucleotide derivatisation based on transient abasic site formation. The conformational properties of the 2-deoxy-a- and 2-deoxy-P-Derythro-pentofuranosyl sugar rings that are present at the abasic sites may play a role in mediating recognition processes during DNA repair. Recent studies suggest that 5-0methyl-2-deoxy-D-erythro-pentose (124) (which anomerises spontaneously in aqueous solution) is a better model of an abasic site than the recently proposed a-and P-2-deoxyD-erythro-pentofuranosides(125).150 When DNA is submitted to ionising radiation thymidine and 2'-deoxycytidine undergo fragmentation resulting in a nucleotide analogue in which a simple urea moiety is attached to the sugar-phosphate backbone. In order to study the recognition and repair of this lesion oligodeoxyribonucleotides containing a deoxyribosylurea residue have been prepared.151 Oxidation of 5'-0-4-monomethoxytritylthymidinewith potassium permanganate solution at pH 8.0 and subsequent treatment with lead tetraacetate in anhydrous pyridine gave approximately equal amounts of the deoxyribosylurea (1 26) and the corresponding N- 1-carboxyaldehyde ( 127). Brief

233

6: Nucleotides and Nucleic Acids

5 ' - O l i g o n u c l e o t i d e - O ~

~N NH

Me /

HO

I

Me

cH30P HO

(124)

HO

(125)

*OH

NH "OH

""YR HO

HO (129) R = /\/\/

(130)

234

Organophosphorus Chemistry

ammonolysis converted (127) to (126) in almost quantitative yield and the 3'phosphoramidite of (126) was subsequently prepared by standard methods. For oligodeoxyribonucleotide synthesis this synthon was used in combination with nucleotide monomers containing base protecting groups that are removed under mild conditions of ammonolysis (phenoxyacetyl for adenine and guanine and isobutyryl for cytosine) since the deoxyribosylureamodification is sensitive to alkali. Nucleoside analogues with a primary amide function attached by a polymethylene chain to C( 1) of 2-deoxy-D-ribofuranose (e.g. 128) have been synthesised and incorporated into short duplexes.152 The conformationally mobile polymethylene chain was chosen Eo al4ow the terminal amide function to hydrogen bond with A, T, G or C with a relative lack of specificity to produce an ambiguous nucleoside. Surprisingly, thermal melting studies showed that greater helix stability was achieved when a hydrophobic carbon chain (e.g. 129) was attached to C(1) instead of the more hydrophilic amide group. The continuing interest in the molecular basis of disease has stimulated studies on the synthesis and chemistry of carcinogenic DNA analogues and this topic has recently been reviewed.153 Oligodeoxyribonueleotides containing a naphthalene diolepoxide deoxycytidine adduct (130) have been prepared by the phosphotriester approach.154 The nucleoside composition of all the oligonucleotides was analysed quantitatively by hplc. The major DNA adduct formed from the reaction with the diol epoxide metabolite of benzo[a]pyrene arises from trans-addition of the exocyclic amino group of deoxyguanosine to the epoxide ring. As a model for this metabolite a structurally related adduct formed by covalently attaching 1-methylpyrene to the 2-amino function of 2'-deoxyguanosine has been prepared and incorporated into an oligodeoxyribonucleotide.~~~ The adduct (131) was prepared by a displacement reaction of 1-aminomethylpyrenewith 2-fluoro-O-6-(4-nitrophenylethyl)-9-(2-deoxy-~D-ribofuranosy1)purine (132) and deprotection with DBU. The corresponding N(6) adduct of 2'-deoxyadenosine (133) has also been synthesised by a similar strategy. Using the phosphoramidite approach both of these adducts have been incorporated into oligodeoxyribonucleotides in order to investigate the mechanism of polycyclic aromatic hydrocarbon carcinogenesis. DNA oligomers having a deoxyguanosine residue substituted at the C(8) position with the carcinogenic amine, 2-aminofluorene (134) have been shown to be very sensitive to oxidation.156 The degradation pathway mechanistically parallels the much studied oxidation of uric acid in alkali and gives rise to an abasic site which eventually undergoes strand scission under alkaline conditions. This mechanism may also be important in the mutagenic behaviour of other dG(C8) adducts derived from carcinogenic amines. A number of very useful convergent strategies have been developed for the synthesis of oligodeoxynucleotidesbearing adducts at the exocyclic amino groups. The key step is generally a post-oligomerisation nucleophilic displacement reaction at an

6: Nucleotides and Nucleic Acids

235

0

How

HO

(131)

HO

0

0

(135)

CI

P h V O H HN

G A C

A G C

HO Reagents: i, D-(-)-phenylglycinol; ii, NHs(aq)

Scheme 9

O 'H

236

OrganophosphorusChemistry

activated purine or pyrimidine residue. Using this procedure the styrene adducts at guanine N(2) (135), and adenine N(6) (136) were prepared by treatment of oligodeoxyribonucleotides containing 2-fluorodeoxyinosine and 6-chloropurine deoxyribonucleoside respectively, with D-(-)-phenylglycinol (scheme 9).157 In both cases elevated temperature and prolonged reaction times were necessary in order to obtain satisfactory yields of the oligonucleotides. This strategy has the advantage that the oligomer adducts can be prepared with complete regio- and stereo-specificity since the site of the reaction is controlled by the placement of the halonucleoside and the configuration at the a-position of the styrene moiety is determined by the choice of the phenylglycinol enantiomer. A very similar strategy has been developed for the incorporation of a variety of N-4-alkyldeoxycytidine residues into oligodeoxyribonucleotides. The nucleoside 4-0(2,4,6-trimethylphenyl)-2'-deoxyuridine,as its phosphoramidite derivative (137), has been incorporated into oligonucleotides by standard solid-phase procedures.158 After deprotection by mild ammonolysis, reaction of this precursor oligonucleotide with a wide variety of amines yields a series of oligomers bearing tethered nonnative functional groups. The synthesis of oligonucleotides containing tethered functional groups has also been developed by Verdine and coworkers.159 In particular they have used oligodeoxyribonucleotides containing the convertible nucleoside 6-0-phenyl-2'deoxyinosine (0dI) in a novel procedure for site-specific cross-linking 160 Thus synthesis of DMT-d(GCGA-01-'ITCGC) and subsequent treatment with the disulphide of aminopropylthiol quantitatively converted OdI to an N-6-thiopropyldeoxyadenosine derivative protected as a mixed disulphide. Dimerisation of the self-complementary strands results in a duplex in which the thiol-tethered adenines ( A ) are located on opposite strands in consecutive base pairs (1 38). On reduction with dithiothreitol (DTT) and aerobic dialysis interstrand cross-linking occurs through the formation of a disulphide bridge (139) which is reversible in the presence of DTT. Analysis by polyacrylamide gel electrophoresis and thermal melting studies confirm the presence of a cross-link. Energy-minimised molecular modelling indicates that the dithiobispropane tether resides in the major groove and does little to distort the DNA secondary structure. A potential alternative method for site-specific cross-linking has been proposed which involves the incorporation of 6-N-(2-aminoethyl)-2'-deoxyadenosine ( 140) into oligonucleotides.161 In a model study (140) was incorporated into 6-N-(Zaminoethyl)2'-deoxyadenylyl-(3'-5')-thymidine using a phosphoramiditeintermediate (141) in which the primary amino function was protected with a trifluoroacetyl group. It has been postulated that the primary amino function, when positioned in close proximity with a pyrimidine residue in a complementary strand, could be triggered to bring about crosslinking by activation of the pyrimidine with bisulphite. The synthesis of oligonucleotides containing 15N isotopically labelled nucleosides and their subsequent study using 15N nmr spectroscopy provides a new

237

6: Nucleotides and Nucleic Acids

5’-d(GCGAA TTCGC) 3’-d(CGCTTA AGCG)

DMTO

(138)

(3;(ky r-”7

5’ G

C G C T

3’

A-p-ov

G C

0-P-T

T-P-0

3’

T C G C

‘ q 0 - p - A

G

C G

5’

.NHCOCF,

238

Organophosphorus Chemistry

technique for investigating DNA recognition processes. This method has been used to investigate hydrogen bonding interactions in an oligonucleotide duplex containing a [115NIadenine residue, d[CGT[15N( l)A]CG]2,162 Comparison of the 15N nmr spectra of the duplex in mixtures of D20 and H20 demonstrated that the adenine N(l) chemical shift in an A.T Watson-Crick base pair is influenced by the hydrogen isotope present in the hydrogen bond. This solvent isotope effect could prove useful in studying nucleic acid structure and protein-nucleic acid interactions. The synthesis of [3-15N]-2'deoxyadenosinel63 and [ 1-15N]- and [2-15N]-2'-deoxyguanosine164have also been reported. 0-4-Alkylthymine cyanoethylphosphoramidites have been used in the routine synthesis of oligodeoxyribonucleotides containing 0-4-methylthymine. 165 The amino functions on adenine and guanine were blocked with the phenoxyacetyl group whilst cytosine was protected with the isobutyryl group. Additionally, protection of the phosphodiesters with cyanoethyl groups allowed complete deprotection of the oligomer with alkoxide ions (methanol-DBU for oligomers containing 4-0-methylthymine and ethanol-DBU for those containing 4-0-ethylthymine). This procedure avoids the use of ammonia which is known to lead to formation of 5-methylcytosine. A similar procedure has been reported for the synthesis of oligodeoxyribonucleotides containing 4-0ethylthymine, but using p-nitrophenylethyl-type base protecting groups for adenine, guanine and cytosine bases.166 Short self-complementary oligodeoxyribonucleotides containing 4 - 0 -ethylthymine and adenine bases have been prepared by the phosphotriester method.167 Variable temperature nmr studies show that these oligomers form right-handed minihelices at low temperature. The presence of the 4-0ethyl group was shown not to have a drastic effect on the stacking geometry of the thymine base. A number of 5-modified pyrimidine nucleosides have been incorporated into oligonucleotides. As a step towards the development of a chemical ribonuclease a uridine-imidazole conjugate has been prepared in which a histidine derivative is joined by a variable length tether to a C(5) substituted deoxyuridine residue (e.g. 142).168 This histidine nucleopeptide has been incorporated into a dinucleotide and an undecanucleotide using the phosphotriester and phosphoramidite procedures respectively.169 The t-butyloxycarbonyl group, used to protect the amino function, was removed by a 10 minute treatment with 10% trifluoroacetic acid in dichloromethane and detailed nmr experiments have established that the nucleopeptide remained intact after this deprotection step. The synthesis and characterisation has been reported for an anti-sense oligonucleotide containing a,a,a-trifluorothymidine residues that was designed to target gene sequences that encode the serine proteases in T-lymphocytes.17O lH nmr studies confirm that the oligonucleotide anneals in the normal manner to its complementary sequence and CD studies indicate that the duplex adopts a B-form

6: Nucleotides and Nucleic Acids

239

d ( G c p o P o OpGC)

(143) +

A-

d(GCp0+ *-

Scheme 10

OpGC)

240

Organophosphorus Chemistry

geometry. In addition, thermal melting studies demonstrate that the duplex is not destabilised by the trifluorothymidineresidues. Oligodeoxyribonucleotide duplexes containing an adenine base as the 5'neighbour to 5-bromouracil (BrU) undergo an extremely facile photoreaction to produce a 2-deoxyribolactone residue (143) with release of free adenine.171 An attractive mechanism for this reaction involves an intramolecular electron transfer from adenine to the adjacent BrU residue (scheme 10). The resulting BrU anion radical could then release bromide to produce a uracil-5-yl radical and abstraction of the adjacent C(1') hydrogen eventually leads to hydrolytic cleavage of the deoxyadenosyl Nglycosyl bond. The incorporation of 5-bromouridine into RNA and UV-induced RNAprotein cross-linking has been used to investigate the binding site of bacteriophage R17 coat protein. 172 Several base-modified 2'-deoxyadenosine and thymidine analogues have been incorporated into the self-complementaq oligonucleotide d(GACGATATCGTC) at the Eco RV restriction endonuclease recognition site (in italics).173,174 The analogues were specifically designed to study the interaction of the endonuclease and modification methylase with their target sequence. 175 The incorporation of 2'-deoxy-4thiouridine into oligonucleotides should be facilitated by the preparation of the S-(2cyanoethy1)-protected derivative of this nucleoside.176 The S-(2-cyanoethyl) protecting group is stable to the reagents commonly encountered during the phosphoramidite approach and is readily deprotected using concentrated aqueous ammonia at 25OC The enzyme DNA photolyase reverses the harmful effects of far-UV radiation by splitting the cyclobutane ring of pyrimidine dimers in DNA by a light-driven reaction. Using Escherichia coli photolyase, containing 1,5-dihydroflavinadeninedinucleotide (FADH2) as a catalytic cofactor, and deoxyuridine dinucleotide photodimer as a substrate, picosecond flash photolysis has provided evidence for a radical intermediate in the reaction.177 This result indicates that the photorepair process is initiated by photoinduced electron transfer between the pyrimidine dimer and the FADH2 cofactor. The proposed mechanism is also consistent with the previous observation that FADH2 in photolyase is fluorescent.178 The contribution of hydrogen bonding to the stability of G-A mismatches in RNA has been investigated by making functional group substitutions in the mismatched G and A residues.179 In particular, replacing the 6-amino group of internal loop adenosines with hydrogen atoms destabilises the duplexes and the results suggest that hydrogen bonding within each G-A mismatch contributes at least -1.4 K cal mol-1 to duplex stability. The results provide an explanation of the recently observed and unusual stability of RNA duplexes with internal loops containing G-A mismatches.180 Tautomerism of the nucleic acids bases has recently been reviewed.181

6: Nucleotides and Nucleic Acids

241

Several studies have appeared on oligonucleotides containing more unusual heterocyclic bases. Oligonucleotides containing 6-(2-deoxy-P-D-ribofuranosyl)-5,6dihydroimidazo-[ 1,2-c]-pyrimidine-5-0ne (DP, 144) have been prepared by the phosphoramidite procedure.182 Incorporation of this analogue into the octanucleotide d(TDPAATTCC) at the Eco R1 recognition site completely inhibited cleavage by the Eco R1 restriction enzyme. Enzymatic digestion with nuclease S1 and endonuclease (111) was unaffected by this modification. Base pairing between N-1-N-Gethenodeoxyadenosine and both thymidine183 and deoxyguanosinel84 has been investigated by 1H nmr. The 5'-triphosphate of 5-amino-l-(deoxy-~-D-ribofuranosyl)imidazole-4carboxamide ( 145) has been prepared from the corresponding 5'-phosphoromorpholidate using tri-n-octylammoniumpyrophosphate.185 Enzymatic polymerisation studies on (145) have shown that it is a substrate for terminal deoxynucleotidyltransferase and that it can be incorporated into DNA by E.coZi DNA polymerase in place of dATP and dGTP.

5 . 0ligonucleotide Labelling. Coniugation and Affinitv Stud ies.- The development of new and efficient methods for the preparation of non-radiolabelled oligonucleotides continues to be an important area, particularly with regard to the use of oligonucleotides as diagnostic reagents. Labelling techniques that enable a reporter group to be directly introduced into the 5'-position have proved most popular, since they can generally be used in conjunction with automated methods of oligonucleotide synthesis. 5'-Biotinylated-oligonucleotideshave been prepared by solid-phase synthesis using [ 1-N-(4,4'-dimethoxytrityl)biotinyl-6-aminohexyl]-2-cyanoethyl-N~diisopropylaminophosphoramidite ( 146).186 This reagent is readily soluble in acetonitrile and can be used in a standard automated coupling cycle. The N-DMT group on the biotin moiety was removed by treatment with 5% dichloroacetic acid for 3 minutes. The comparatively long linker arm provides maximum sensitivity as the biotin group is accessible to the large proteins used in the detection system. In an analogous procedure 2-(9-acridinyl)ethyl phosphoramidite (147) and 2-(9-acridinyl)ethyl Hphosphonates (148) were used for the synthesis of acridine-labelled oligonucleotides.187 Oligonucleotides terminating with a 5'-amino function have been synthesised on a solid-support using 5-N-(4,4'-dimethoxytrityl)aminopentan-1-O-(methyl-N~-diisopropy1amino)phosphoramidite ( 149) in the last coupling step.188 After deprotection the 5'-terminal amino group was further derivatised by reaction with N-succinimidyl-3-(2pyridy1dithio)propionate(150) and subsequently reduced with DTT to produce a 5'thiol-terminated oligonucleotide. The introduction of the thiol function was confirmed and quantified by measuring the absorbance of the released pyridine-2-thione. Direct biotinylation could also be achieved by reaction of the 5'-amino nucleoside with biotinyl-N-hydroxysuccinimidyl ester. An unusual but versatile labelling procedure has

Organophosphorus Chemistry

242

DMTNH-(CH,)SO-P,

(147) R = P ,

,OMe

0

N(Pri)2

II

(148) R = p - O I

H

OMe

Q-. 0

0

R

,OMe N(Pri),

6: Nucleotides and Nucleic Acids

243

been reported that uses a 4,4'-dimethoxytrityl group derivatised with an activated-ester function.189 Incorporation of a nucleoside residue bearing this modified trityl group at the 5'-terminus of an oligonucleotide (151) during solid-phase synthesis, results in an oligomer that is capable of further elaboration. For example, treatment of (15 1) with 1,6diaminohexane followed by concentrated aqueous ammonia produces an oligomer containing a 5'-terminal amino group. Subsequent conjugation with biotin enabled the oligonucleotide to be purified on streptavidine agarose. Biotinylated primers prepared in this way have been used in PCR to enable the rapid purification of the amplified products. A method has been described which enables an unprotected amino acid to be attached to either the 5'- or 3'-end to produce modified oligonucleotides containing carboxylic acid groups.190 Attachment at the 3'-terminus, via a phosphoramidate linkage, was achieved by activation of a 3'-phosphate with N-hydroxybenzotriazole in the presence of a water-soluble carbodiimide and subsequent reaction with 6aminocaproic acid. At the 5'-end, attachment through a carbamate linkage was accomplished by reaction of the 5'-hydroxy group with 1,l-carbonyldiimidazole prior to treatment with 6-aminocaproic acid. Interstrand DNA cross-linking has been achieved by conjugation of a naphthoquinone to the 5'-end of an oligodeoxyribonucleotide. 191 5-Methyl- 1,4naphthoquinone was condensed with 3-mercaptopropanoic acid and the product, two inseparable regioisomers, attached to the 5'-terminus of a 15-residue oligodeoxyribonucleotide via a hexamethylene tether (152). After annealing the derivatised oligonucleotide to a target sequence, covalent interstrand cross-linking could be induced by irradiation (345 nm). Whilst the exact structure of the cross-linked adduct is unknown, covalent attachment does not occur at guanine N(7) since no strand cleavage was observed under alkaline conditions. 1,2-Di-O-hexadecyl-ruc-gfycero-3-H-phosphonate (153) has been coupled to the 5'-terminus of oligodeoxyribonucleotides using the hydrogen phosphonate method of automated DNA synthesis.192 Duplex DNA oligomers with a single 5'-phospholipid melted at lower temperatures than the corresponding unmodified duplex, but duplexes bearing lipids at each 5'-end had higher melting temperatures. The preparation of the nucleopeptide H-Phe-Tyr-(pATAT)-NHz, which contains bond, has been achieved using the 2-(tthe base labile nucleotide-(5'-O-P-O-)-tyrosine butyldiphenylsilyloxymethy1)benzoyl(SiOMB) group for protection of the N-6-amino function of deoxyadenosine.193 The SiOMB group is removed under mild conditions with fluoride ion. A protein-oligonucleotide conjugate has been prepared by initial reaction of an oligodeoxyribonucleotide bearing a 5'-amino function with succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate to produce the maleimide derivative (1 54).194 Reaction of this derivative with a recombinant interleukin-1 p mutant, engineered to contain a surface-exposed cysteine residue (cysteine replacing lysine 138

Organophosphorus Chemistry

244

n-Cl 6H330

n-C1 GH330

I? A 0-P-0-

TEAH+

(153)

H

HN'K'"

6: Nucleotides and Nucleic Acids

245

in the wild-type),l95 results in a 1:1, DNA-interleukin-1p conjugate. Experiments demonstrated that the conjugate retained its ability to bind specific interleukin receptors on T-cells and that the oligonucleotide hybridisation properties were unchanged. Peptide-oligonucleotide hybrids have been prepared to ascertain whether peptide sequences can be used for the in vitro targeting of anti-sense oligonucleotides.196 In particular, hybrids containing the SV40 large-T antigen nuclear-transport sequence ProLys-Ly s-Arg-Lys-Val have been evaluated. Oligonucleotides were prepared containing a thiol function attached to the 5'-terminus via a hexamethylene linker and then coupled to a peptide containing a thiol reactive group (normally a cysteine residue or a maleimido group). Thermal melting studies indicate that there is considerable stabilisation of the duplex by the peptide, probably as a result of the interaction of the protonated lysine and arginine residues interacting with the negatively charged phosphates. The use of modified nucleotide synthons for the labelling of synthetic DNA is particularly attractive since multiple incorporation of the nucleotide provides a means to amplify the label. Multiple biotin-labelled oligodeoxyribonucleotides have been prepared using a modified 2'-deoxycytidine 3'-O-phosphoramidite (155) carrying an Nprotected biotin label attached to the 4-N-position via a long spacer-arm.197 The lipophilic t-butylbenzoyl protecting group on biotin facilitates solid-phase synthesis and no modification of the biotin moiety was observed, The kinetics of biotin binding to streptavidin are improved by the long, polar spacer arm. A similar strategy has been adopted by Gait and coworkers using nonnucleosidic phosphoramidite linker units based on a 3-carbon glyceryl backbone.198 Multiple biotin and phosphotyrosine reporter groups were introduced using the monomer units (156) and (157) respectively. Spacing of the biotinyl moieties by thymidyl residues gave increased signal strength. Oligothymidylates with a sequence-specifically incorporated C(5)-nitroxidelabelled nucleoside (15 8 ) have been synthesised by the phosphotriester approach.199 Deprotection of the phosphate groups was achieved using oximate in pyridine, rather than aqueous dioxane, to minimise the destruction of the nitroxide label. The epr (electron paramagnetic resonance) specific activity of the purified nitroxide-containing oligomers was found to be in agreement with enzymatically prepared spin-labelled nucleic acids. Annealing the nitroxide-labelled oligothymidylates to poly(dA) or oligo(dA) resulted in different epr line-shapes, suggesting a strong coupling of the shorttethered nitroxide to global molecular motion. A comparative study of the phosphotriester versus the phosphoramidite approach has been performed for the synthesis of nitroxide-labelled oligonucleotides.200 Lower epr specific activity was obtained for the phosphoramidite product indicating that the phosphotriester approach is superior for nitroxide-labelledoligomers. Labelling of the 3'-end of synthetic oligonucleotides is generally more complicated than 5'-labelling since the former requires a modified solid-support. A

246

0rganop h osph orus Chemistry

0

\

6: Nucleotides and Nucleic Acids

247

universal support has been developed for automated synthesis of oligonucleotides containing a 3'-thiol function (159).201 The oligonucleotide, initially bearing a disulphide tail at the 3'-end, is cleaved from the support with concentrated aqueous ammonia. After purification, the 3'-thiol group can be made available for conjugation by reduction with DTT. Gupta et al. have developed a similar support for the synthesis of 3'-thiol-containing oligonucleotides.202 The synthesis of an oligonucleotide functionalised to attach two different reporter groups at specific internucleotide linkages has been described.203 Aminespecific reporter groups were attached to an internucleotide N -1-aminoalkyl phosphoramidate group, whilst a thiol-specific probe was introduced at an internucleotide phosphorothioate diester. The utility of the method has been demonstrated by the attachment of 9,1O-dioxa-syn-3,4,6,7-tetramethylbimane (bimane) and fluorescein labels (e.g. 160). The use of N-1-aminophosphoroamidatelinkages has been developed further for the incorporation of multiple reporter gr0ups.20~ A 2'-deoxyuridine triphosphate alkylated at the 5-position by glycosides of either a-D-mannose (161) or P-D-glucosamine(162) have been prepared from 5-C-mercuriated dUTP using the Heck reaction.205 The carbohydrate moieties are intended to serve as reporter groups by virtue of their high affinity for the lecitin plant storage proteins. The procedure is intended as an alternative to the biotin-avidin (or streptavidin) complex which has been reported to give spurious results. The enzymatic incorporation of these nucleotide residues into DNA is under investigation. Porcine heart lactate dehydrogenase is inactivated by the NAD+ analogue, Pl-6N-(4-azidophenylethyl)adenosine-P~-[4-(3-azidopyridinio)butyl]diphosphate ( 163) upon irradiation with UV light (300-380 nm).206 The decrease in enzyme activity could be prevented by addition of NAD+ and oxylate. The fluorescence of bimane has been found to be quenched in the presence of guanosine 5'-monophosphate. This phenomenon has been used to design bimanederived nucleotides for the micro-determination of phosphodiesterase 1.207 Bimane 5'GTP (164) was prepared and used in a fluorescence assay to detect as little as 1.9 ng/ml of phosphodiesterase I. 6. Nucleic Acid TriDle-Helices and Other Unusual Structurest- Interest in triplehelix formation has expanded rapidly since it is likely that this recognition process will be exploited in the design and development of therapeutic oligonucleotides. Triplehelix formation occurs by binding of a homopyrimidine oligonucleotide to the major groove of a homopurine-homopyrimidine duplex. Binding is parallel to the purine strand and sequence specificity results from Hoogsteen pairing between thymine and protonated cytosine in the third strand and the Watson-Crick A.T and G C pairs of the duplex respectively. Whilst triplex formation inhibits protein binding to DNA, the C-G-C+ mad is unstable at physiological pH. To overcome this limitation oligodeoxy-

248

Organophosphorus Chemistry

OH (161) R = a D-mannose (162) R = p - D-glucosamine

-

N3

Me

-wie

u o I

-0

I

-0

6: Nucleotides and Nucleic Acids

249

ribonucleotides containing 2'-O-methylpseudoisocytidine (165) have been prepared, since this nucleoside already contains a hydrogen at the N(3)-position for forming the Hoogsteen base pair of the triad.208 Additionally, the 2'-methoxy substituent is also able to stabilise the triplex. UV absorption studies at pH 7.0 show that the duplex 5'd(AAGAAGAAGAA).5'-d('ITCITC'ITCTT) forms a 1:1 complex with S-d('ITClTC'IT) (C = 165). Thermal melting studies on the mixture show 2 transitions, one at 42OC corresponding to the melting of the duplex and another at 12OC for the dissociation of the third strand from the duplex. It has also been shown that modification of the third strand by replacement of cytosine by 5-methylcytosine and attachment of an acridine intercalator to the 5'-end increases its affinity for the duplex by about 30-fold.209 Natural abundance 15N nrnr studies have revealed that the character of a protonated cytosine base varies depending whether it is in a triplex or duplex structure.210 In a triple-helix the chemical shift values for N(3) are consistent with it being sp3 hybridised, whilst in an oligonucleotide duplex the nmr data is consistent with the positive charge being delocalised between N(3) and the amino nitrogen. The synthesis of [7-15N]labelled 2'-deoxyadenosine and 2'-deoxyguanosine has recently been reported.211 Incorporation of these labelled nucleosides into oligodeoxyribonucleotidesshould be of considerable utility in the investigation of Hoogsteen base pairing and triple-helix formation. Sequence-specific alkylation and cleavage of double-helical DNA has been achieved using a pyrimidine oligodeoxyribonucleotidecontaining a 5-bromoacetyluraciI moiety (166) at the 5'-terminus.212 Triple-helix formation of the pyrimidine oligodeoxyribonucleotide with the purine strand of the duplex positions the electrophile in the proximity of a guanine base located two base pairs from the 5'-end of the target sequence. Alkylation at N(7) of the proximal guanine followed by warming and treatment with base results in cleavage of the DNA at the site of alkylation. The same group has developed an elegant method for the single-site enzymatic cleavage of yeast genomic DNA which is mediated by triple-helix formation.213 The intercalation of ethidium bromide into a triple-stranded oligonucleotide has been studied using UV absorption spectrophotometry and a gel retardation assay.214 The results show that ethidium bromide binds with a lower affinity to the triple-helix than it does to the duplex. The structure of DNA hairpin-loops containing 4 nucleotides in the loop have been studied by high resolution nmr spectroscopy.215 In general it was found that the loop region follows a course that can be derived by applying the rule that the stacking of the bases in the stem is continued in the 3'-direction by 3 nucleotides after which a sharp turn in the backbone occurs so that the loop can be closed by a single nucleotide. The unusual stability of RNA hairpins containing GNAA and GNGA (where N can be any nucleotide) has also been studied by nmr techniques.216 Two additional nmr studies on RNA hairpins have appeared.2179218

250

Organophosphorus Chemistry

Monoclonal antibodies have been raised against an oligonucleotide with a hairpin-loop structure (167).219 The oligonucleotide hapten was prepared using a disulphide-modified controlled-pore glass support and conjugated to the carrier protein via a disulphide linkage. Antibody 41H7 was found to bind the hairpin with a dissociation constant of 2.0 x 10-6 M and showed sequence specificity in its interaction with the oligonucleotide as there was no detectable binding to a sequence differing by only 3 bases in the loop. A change in 10 base pairs in the stem region led to a 4-fold reduction in antibody affinity. These results indicate that the monoclonal antibody binds to the oligonucleotide through mainly sequence specific contacts with the loop portion. The chemical synthesis of a DNA dumbbell (168) has been achieved by cyclisation of a linear 3'- or 5'-phosphorylated oligomer of sequence d(GCG-T4CGCCGC-T4-GCG) using l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.~~~ Formation of the circular product was confirmed by a 28OC increase in the melting temperature. The assembly and characterisation of 5-arm and 6-arm DNA branched junctions has been achieved.221 It has been suggested that DNA could be used to construct networks and objects on a nanometre scale and the assembly of this complex junction increases the diversity of structures that can be built from branched DNA components. A molecule with the connectivity of a cube has also been synthesised from DNA and represents the first construction of a closed polyhedral object from ~ ~ ~ 3 2 2 RNA pseudoknots are widely proposed structural motifs which are likely to have important biological roles (e.g. as regulatory elements in certain mRNAs).223 The structure, stability and analytical methods for investigating RNA pseudoknots has been reviewed.224 The structure of RNA pseudoknots has also been studied by nmr spectroscopy.225 It has been shown that cationic oligopeptides [e.g. octadecyl(L-lysine)] can induce the formation of a parallel duplex for the natural DNA oligomer dTlo with the strands held together by thymine-thymine base pairs.226 Complexation of the ammonium groups in the peptide side chains with the DNA phosphates leads to diminished electrostatic phosphate repulsions which allows formation of the T.T base pair. 7. Cleavage of Nucleic Acids Including Self-CleavinP RNA.- The majority of publications in this area have been concerned with studies on the Tetruhymena-type and hammerhead-type ribozymes, and in particular some elegant work has appeared in which modified oligoribonucleotideshave been used to probe the cleavage mechanisms. The catalytic properties of RNA have recently been reviewed.227, 228 Variants of the consensus hammerhead structure (169) have shown an absolute requirement for 3 helices and 10 of the 13 conserved nucleotides (shown in boxes).229

6: Nucleotides and Nucleic Acids

ACCGGCCAATTCCGGCC TGGCCGGTTAAGGCCGG

25 1 T

T

C G

T

(167)

T

C

T GCGGCG CGCCGC

T

T

T

(168)

.. .cleavage

3’

5’CCUGU C ACCGC GGACA UGGCG 5’ A C A U GA A G AGU C G A U G C G C 5’ (170)

U G I11 C C A A A A

5’ A C G G T G

G A ~ G G C C C U A CCGG G A G I1 G U A

GTTGCC CAACGG T

I

252

Organophosphorus Chemistry

Whilst the exact sequences in the helices can vary, sequence changes can affect the rate of cleavage reactions by a factor of loOO.230 Nmr and other spectroscopic techniques have demonstrated that the rate difference may result from the formation of catalytically inactive conformations in the RNA enzyme which interfere with the assembly of the enzyme-substrate complex. A hammerhead-type ribozyme system has been designed which consists of 3 RNA fragments (170).231 A nmr study of the system has shown that the complex forms a hammerhead structure and the loop regions assume an ordered conformation in the absence of Mg2+. A hammerhead 34-mer RNA enzyme (171) that forms a complex with a 13-mer DNA substrate has been studied and all the imino protons assigned in helices I and I1 using standard techniques.232 In order to obtain additional information on the 3-dimensional structure of this ribozyme complex a novel sequential resonance assignment pathway for RNA has been employed which involves identification of NOE connectivities between base-paired guanosine imino and C(1’) protons.233 The method also serves as a probe for the identification of A-type helices and in this particular case demonstrates that the RNA-DNA regions also adopt an Aform helix. Oligoribonucleotides containing a single phosphorothioate linkage of defined Rp- or Sp-configuration have been used as substrates in the study of a RNAhammerhead complex having a phosphorothioate group at the cleavage site.234 Cleavage of the oligonucleotide containing the Sp-isomer in the presence of Mg2+ was only marginally reduced from that of the unmodified phosphodiester, whereas the Rpconfiguration was cleaved only very slowly. The results provide further evidence that Mg2+ is bound to the pro-R oxygen atom in the transition-state of the hammerhead cleavage reaction.235 Hammerhead-RNA transcripts partially substituted with phosphorothioate residues have been used in an interference assay to locate phosphodiester groups which are important in the hammerhead self-cleavage reaction.236 Four phosphates have been identified that play a role in the cleavage process. The role of the 2’-hydroxy groups in binding Mg2+ in the hammerhead RNA domain has been studied by deoxyribonucleoside substitution.237 2’-Fluoro- and 2’-aminonucleosideshave been incorporated into a hammerhead ribozyme by automated chemical synthesis.238 Whilst the inclusion of 2’-fluorouridines, 2’-fluorocytidines and 2’-aminouridines did not appreciably reduce catalytic activity, incorporation of 2’-aminocytidines reduced ribozyme activity by a factor of 20. Activity was essentially abolished when 2’-fluoroadenosine replaced the adenosine residues within a conserved single-stranded region of the ribozyme. The incorporation of these analogues, as expected, stabilised the ribozymes towards nuclease degradation. The L-21 Scu I ribozyme derived from the intervening sequence of Tetruhymenu thermophifu pre-rRNA catalyses a guanosine-dependent endonuclease reaction that is analogous to the first step in self-splicing of this sequence.239 Pre-steady-statekinetic experiments using a phosphorothioate linkage of the Rp-configuration at the cleavage

6: Nucleotides and Nucleic Acids

253

site indicates, that unlike the hammerhead system, Mg2+ is not coordinated to the proR p oxygen atom in the enzyme-substrate complex or in the transition state. Oligoribonucleotides containing the 2-aminopurine base have been prepared240 in order to study the binding specificity requirement of an altered Tetrahymena group I RNA enzyme which binds to 2-aminopurineribonucleoside with greater affinity than its usual guanosine substrate.241 Two methods have been developed independently for the in vitro selection of variants of the Tetrahymena intron that have ligase activity.2429243 The systems were designed so that only the active intron variants could be amplified and propagated. The ribozyme ligated itself to an RNA oligonucleotide complementary to the internal guide sequence. Both the ligated and non-ligated ribozyme molecules were converted to cDNA with reverse transcriptase and a second primer was then able to hybridise exclusively with the added sequence resulting from ligation. With this priming system PCR was then used to selectively amplify those molecules that had undergone the RNA-catalysed ligation reaction. A detailed 500 M H z 1H nmr study of the branched RNA pentamer (figure 1) and heptamer has been reported and their conformations compared with the previously studied trimer and tetramer.244~245These structures correspond to the sequence of the branch site of the group I1 intron bl 1 from yeast mitochondria. These studies show that the trimer and pentamer possess very similar conformational features which are distinct from the tetramer and heptamer. The absence of a nucleotide unit at the 5'-side of the branch point leads to a conformation at this site that is characterised by C(2')-endo ribose conformation, a syn-orientation of the adenine base and an A2'-5'G base stacking. The introduction of a mono- or di-nucleotide unit at the 5'-side of the branch point introduces a marked conformational change at the branch point such that the conformation becomes C(3')-endo, anti-orientation and A2'-5'G base stacking is disrupted. A variety of nucleoside-2,2'-bipyridine(bpy) conjugates have been prepared and studied for their ability to hydrolytically cleave RNA.246 2'-Deoxythymidine was attached via either its 5'- (172) or 3'-position (173) to a bpy derivative using phosphoramidite chemistry. Attachment to C(5) or the uracil ring (174) was achieved through a polyamide linker. All the bpy conjugates were able to bind Cu(I1) and cleave RNA by a hydrolytic mechanism. It is likely that the position of bpy attachment, length of linker arm and charge of the complex all influence cleavage efficiency and it is noteworthy that the Cu(I1) complex of (1 74) , which contains the longest linker arm,was the most efficient. The DNA strand cleavage reaction catalysed by endonuclease I11 from E. coli has been shown to proceed on the 3'-side of aldehyde abasic sites by a syn-P-elimination involving abstraction of the 2'-pro-S-proton and results in the formation of a trans-a,punsaturated aldose product, the same stereochemical course as the reaction catalysed by UV endonuclease V from bacteriophage T4. The p-elimination reactions that occur

Organophosphorus Chemistry

254

HoYYcyt 0

,O OH

0

tetramer

pentamer

dr (174)

6: Nucleotides and Nucleic Acids

255

under alkaline conditions or in the presence of the tripeptide Lys-Trp-Lys proceed by an anti-p-elimination reaction involving abstraction of the 2’-pro-R-proton and also result in the formation of a trans-a$-unsaturated aldose product.247 The results support the hypothesis that the enzyme catalysed reactions may involve general base-catalysed abstraction of the 2’-pro-S-proton by the internucleotide phosphodiester leaving group. Photoinduced-lesions in double-stranded DNA have been studied using nanosecond pulses from a Nd:YAG laser.248 The treatment resulted in DNA strand cleavage, but without the formation of cyclobutylpyrimidinedimers. DNA cleavage was inhibited by about 60% in the presence of a free-radical quencher indicating that both radical initiated and mechanically induced strand breaks are important. Mechanical cleavage probably results from spatially lacalised pressure transients of at least several kilobars.

8. Interaction of Nucleic Acids with Small Molecules.- The bleomycins are a group of glycopeptide-derived anti-tumour antibiotics which exert their therapeutic effects through the sequence-specific cleavage of DNA that is dependent on the activation of oxygen by a metal ion. Bleomycin (BLM) is thought to contain two major functional domains; a metal binding region that is also responsible for activation of oxygen and a bithiazole region that is thought to be responsible for DNA binding. The sequence-selective DNA recognition by Fe-bleomycin has been investigated by using BLM congeners in which the two functional domains are separated by variable length oligoglycine spacers.249 Interestingly, all these BLM congeners cleaved DNA at precisely the same site, a result that is consistent with the metal binding region being predominantly responsible for determining sequence selectivity. The cleavage of RNA by Fe-BLMs has been less extensively studied. However, it has been reported that limited degradation of yeast tRNAPhe can be achieved using very high concentrations of Fe(II)-BLM.250 A more systematic study has been conducted using RNA-species obtained by RNA polymerase-catalysed transcription from an appropriate DNA template. Fe(I1)-BLM was shown to mediate strand scission of RNA substrates in a highly selective and efficient manner; the B. subtilis tRNAHis precursor was cleaved by as little as 3 m M Fe(I1)-BLM whilst other RNA substrates were not cleaved at 300 mM Fe(II)-BLM.251 Remarkably, cleavage of the B. subtilis RNA occurred at one major site, a junction between a double- and single-stranded region of the RNA.2529253 These studies indicate that RNA is another possible therapeutic target for BLM, particularly when the remarkable selectivity for cleavage of specific structural elements within the RNA is considered. The primary step in the BLM-induced cleavage of DNA is C-H bond scission at C(4‘) of a deoxyribose moiety. This event has been investigated using an oligodeoxyribonucleotide containing 2’-deoxyaristeromycin (Ar,175) at the bleomycin cleavage site.254 Fe(I1)-BLM mediated cleavage results in an unprecedented dehydrogenation

256

Organophosphorus Chemistry

at C(4') and C(6') positions of the Ar moiety to give an oligonucleotide containing 2'deoxyneoplanocinA (176) together with a minor, but stereospecific C(4') hydroxylation (177, scheme 11). As part of a study on the BLM mediated cleavage of DNA, 3'-0benzoyl-5'-deoxy-4'-hydroperoxythymidine has been chosen to model the decomposition of the putative 4'-hydroperoxynucleotide(178) intermediate.255 This model reaction has now been reinvestigated using the 180-labelled derivative [4'H~80~]-3'-0-benzoyl-5'-deoxy-4'-hydroperoxythymidine (179).256 The decomposition of (179) has been studied and is shown to produce thymine propenal accompanied by a stoichiometric amount of both benzoate and acetate containing 1 atom mole of [I801 (scheme 12). The production of the "801 benzoate and a detailed kinetic analysis demonstrate that decomposition of (179) requires the intermediacy of the 4'-perbenzoate ester (180) which greatly facilitates the heterolytic cleavage of oxygen-oxygen bond. Since these results indicate that the breakdown of (179) is initiated by rearrangement to the perester, (179) does not appear to be a good model of the DNA hydroperoxide due to the unfortunate choice of the 3'-protecting group. The first 3-dimensional structure of a BLM-Fe(I1) complex has been obtained using 2D nmr techniques.257 Neocarzinostatin chromophore (1 81)' esperamicin, dynemicin (182) and calicheamicin (183) are members of the structurally novel diynene anti-tumour antibiotics that bind in the minor groove and cleave DNA through the generation of a diyl intermediate. The thiol-activated neocarzinostatin chromophore cleaves duplex oligodeoxyribonucleotidescontaining the sequence d(5'TGTITGA) at the T residue, through a mechanism which is thought to involve hydrogen atom abstraction at C(4') and C(5') of the thymidine residue.2589259 Deuterium substitution at C(4') produces a substantial kinetic isotope effect, whereas the kinetic isotope effect at C(5') is much smaller. A model for the dynemicin A-DNA complex has been constructed by using energy-minimisation and molecular dynamics techniques.260 The model can be used to explain how dynemicin A (182) is activated for DNA cleavage, its mode of binding, its sequence specificity and also predicts its absolute configuration. Many studies have appeared on the synthesis and study of dynemicin analogues.261-265 Golfomycin A (184) has been designed and synthesised as new diyne DNA-cleaving agent.266 DNA cleavage was shown to be pH dependent and is thought to occur via nucleophilic attack on the ynone function. Of the diynene antibiotics calicheamicin (CLM, 183) shows the greatest sequence selectivity in its cleavage of double-strandedDNA. Site-specific atom-transfer has been used to derive detailed structural information regarding the interaction of CLM and DNA.267 To establish the suspected transfer of a deoxyribose 5'-hydrogen from the DNA to CLM and to ascertain the orientation of the antibiotic in the minor groove at a specific cleavage site, oligodeoxyribonucleotides specifically labelled with deuterium have been synthesised. The dodecamers contained an internal d(S'-TCCT) in which the 5'-deoxycytidine (C) carried 2 deuterium atoms on C(5'). Analysis of the reaction

vA

6: Nucleotides and Nucleic Acids

5' - d(GGArAGG) 3' - d(CCT TCC)

257

- d(GGp0

HO'

(17 6 )

Scheme 11

\

0, 40 /p\

-O

-

H

O H00"y

B

a

s

e

thymine propenal

hy

+

'%-acetate

PhOC

OH

"0-benzoate

(180)

(1 79) ='80

Scheme 12

HO"I/"-

NHCH3

OH

0

OH

258

Organophosphorus Chemistry

\u’ -SSSMe --NHC02Me

= O -M e

-

q

0

0

0

Me’*‘ H

NHEt

MeJ?oMe I

OMe

0

6: Nucbotides and Nucleic Acids

259

products obtained on exposing the putative 1,4-diyl intermediate (185) (produced by activation of CLM with a thiol) shows that the major DNA cleavage process is initiated by deuterium transfer from the C(5') labelled deoxycytidine residue to the diradical (185). The deuterium is transferred to C(4) of (185) and given the absolute configuration of CLM, the aryl-linked carbohydrate moiety will therefore be directed to the 3'-side of the d(S'-TCCT) cleavage site. Detailed nmr experiments on CLM demonstrate that the oligosaccharide moiety shows considerable preorganisation that may facilitate DNA binding.268 The mechanism of action for the anti-neoplastic agent mitomycin C (186) is believed to proceed by its initial reductive activation followed by covalent binding of the activated species to DNA. Drug attachment has been proposed to occur sequentially at C(l) and C(10) in (186) leading to the formation of cross-linked DNA products. Information on the sequence specificity of mitomycin C in its binding to DNA restriction fragments has been determined by locating the stop sites induced by the processive enzyme h-exonuclease.269 The results reveal a preference for 5'-CG and 5'-GC sequences which may possibly be explained by hydrogen bonding between the activated mitomycin and a guanine base. X-ray and nmr studies have revealed that porfiromycin, an anti-tumour agent related to the mitomycins, also shows specificity for the 5'-CG sequence.270 The anti-tumour agent (+)-CC-1065 (187) is known to exert its effect through the selective alkylation of the adenine N(3) in the minor groove. Several analogues of (+)CC-1065 have been prepared and evaluated; and the results demonstrate that there is an inverse relationship between the acid-catalysed solvolysis and the cytotoxic potency of the analogues.271 This observation is likely to be useful in the design of analogues of (+)-CC-1065 with improved activity. The same group has conducted a comparative study on the selectivity and relative intensity of DNA alkylation with a series of (+)-CC1065 analogues.272 Their studies highlight the lack of selectivity of the alkylation process in the absence of noncovalent binding. The alkylation of the oligonucleotide duplex d(CGTATACG)2 by duocarmycin A (188), an anti-tumour agent related to CC1065, has been investigated.273 The studies show that the N(3) position of the sixth dA residue in the sequence attacks the cyclopropane subunit of (188) to produce an alkylated adduct which upon heating decomposes by loss of the adenine-duocarmycin adduct to give the abasic oligonucleotide. The interaction of Hoechst 33258 (189) with the minor groove of the adeninethymine tract in the duplex d(CTTTTGCAAAAG)2 has been studied by proton nmr spectroscopy.274 The data imply that the minor groove is particularly narrow and the complex is stabilised by many contacts between the complementary curved surfaces of the drug and the minor-groove. The NH group of the benzimidazole rings are positioned to make a pair of bifurcated hydrogen bonds with adenine N(3) and thymine O(2). The anthraquinone derivative (190) has been prepared as the first example of a

Organophosphorus Chemistry

260

Meon

@-iMe2A

NHS02Me

HN

I

0 (190) R = -so3-

CONHMe

(191) R = H

(192)

0

0

6: Nucteotides and Nucleic Acids

261

zwitterionic DNA-binding ligand.275 Spectrosocpic studies show that (190) interacts with the outside of the helix and not through intercalation which is characteristic of the cationic parent compound (191). The sequence-selective binding by several bis-Nmethylpymole dipeptides, which are related to netropsin and bind in the minor groove of the helix, have been investigated by DNA footprinting.276 The interaction of water in the minor groove of the DNA helix has been studied by Monte Car10 simulations and Xray diffraction.277 Molecules that bind to DNA by an intercalative process have also been widely studied and the criteria necessary to establish that binding occurs by intercalation have been reviewed.278 Detailed equilibrium and kinetic studies have been carried out on the interaction of the amsacrine 4-carboxamide-class (e.g. 192) of binding ligands with calf thymus DNA.279 The results indicate that these compounds bind to DNA by intercalation of the acridine moiety, whilst the carboxamide and anilino chains lie in the minor and major groove respectively. The binding of the benzimidazole dye Hoechst 8208 (193) with DNA has been investigated by spectrophotometric, hydrodynamic and 1H nmr techniques.280 The results clearly indicate that unlike the related dye H 33258 (189), H 8208 binds through an intercalative mode. The crown-ether 15-crown-5 has been linked to the DNA intercalator acridine-9-carboxylic acid (194).281 The binding properties of (194) were strongly influenced by the presence and nature of the metal ions present and increased in the order K+>Na+>>Li+. This observation of metalassisted drug binding suggests that the affinity and selectivity of DNA binding drugs could be modulated by the introduction of a metal binding site. A synthetic bis-9acridinyl derivative (195) containing a viologen-linker has been prepared and shown to bind strongly to DNA by bisintercalation with the viologen linker unit along the DNA major groove.282 The cyclic voltamogram of (195) was altered in the presence of DNA and indicates a potential for this compound as a reversible electrochemical labelling agent for DNA. Several series of nitrogen mustards linked to acridine283-284 and 4anilinoquinoline285 heterocycles have been prepared and their ability to bind to and cross-link DNA studied. One of the mechanisms proposed for the in vitro mutagenicity of nitrous acid involves the creation of DNA-interstrand cross-links.286 To support this mechanism enzymatic hydrolysis of nitrous acid-treated DNA yields small quantities of the bis-2'-deoxyguanosine derivative (196) indicating that spatially proximal deoxyguanosine residues can be cross-linked. This hypothesis has been proved correct by studies on radiolabelled oligodeoxyribonucleotides which show there is a preference for cross-linking at the nucleotide sequence 5'-CG relative to 5'-GC. Interstrand cross-linking of DNA is believed to account for the cytotoxicity of many bifunctional alkylating agents. The nucleotide sequences at which these crosslinks are formed have been defined at single nucleotide resolution for several agents including mechlorethamine, cis-platin and mitomycin C.287 Analysis of these results

262

Organophosphorus Chemistry

indicates that cross-linking occurs preferentially at locations which will minimise the distortion of the DNA helix and this preference is primarily expressed by minimising the energy of the transition state for conversion of monoadducts to cross-links. Treatment of calf thymus DNA in vitro with the alkylating agent N-methyl-N-nitrosourea, in phosphate buffer at pH 7.2, results in the formation of 6-0-7-N-dimethylguanine residues in addition to the previously identified adducts 7-methylguanine and 3methyladenine.288 The interaction of several water-soluble porphyrins with DNA has been investigated.289-292 In particular, it has been shown that in the presence of KHSO5, a cationic manganese porphyrin [meso-tetrakis(N-methylpyridinium-4-yl)porphyrinatomanganese(II1) pentaacetate] can cleave DNA either by attack at C1'-H or C5'-H.293 Attack at C5'-H leads to production of furfural (197, scheme 13) and detection of this aldehyde by hplc serves as a marker for cleavage via 5'-hydroxylation. A flavone-C-glycoside, aciculatin (198) has been isolated from Chryospogon aciculatis and shown to bind to calf thymus DNA with an apparent Kd of 15-50 pM.294 The manner in which this compound binds to DNA is not yet known. Irradiation of (E)-p -methoxycinnamicacid and calf thymus DNA leads to the formation of a covalent adduct which is more efficiently formed with denatured as opposed to native DNA.295 A comparative study with several polyribonucleotides showed the Reversal of adduct relative selectivity for binding to be poly(C)>poly(A)>>poly(G). formation with irradiation at 254 nm is consistent with a 2+2 cycloaddition with pyrimidine bases. The use of random screening as an efficient method to find DNA sequences that bind to proteins and other ligands has been reviewed.296 In the most general case a random mixture of oligonucleotides is incubated with the protein under investigation and the oligonucleotide-ligand complex separated from the mixture by an affinity technique. The polymerase chain reaction is then used to amplify the sequences that are bound to the ligand. Although this technique has most often been applied to the study of proteins, including the human transcription factor 297 and T4 DNA polymerase,298a similar procedure has been used to enrich RNA molecules from a random RNA pool that bind dyes resembling the redox-cofactor nicotinamide adenine dinucleotide.299 A review on the interaction of proteins with tRNA molecules, presented from a chemical perspective, has appeared.300

9. Interaction of Metals with Nucleic Acids.- The kinetics and mechanism of binding of cis-diamminedichloroplatinum(I1) (cis-DDP) and its inactive trans-isomer to DNA have been investigated by 195Pt nmr spectroscopy.301 Both isomers bind to DNA by 2 successive pseudo-first-order processes which initially form monofunctional adducts that subsequently close to produce bifunctional lesions. The monoadducts are bound predominantly at the N(7) position of guanine and retain a chloride ligand. Both

6: Nucleotides and Nucleic Acids

263

0 I -

H&OyBase

- Base

o+

P

/ \

-0

‘3

lo

0,

Scheme 13

HO

OH

H3h -‘3CH2CH2CH2’3CH2fNH2CH2CH2CH2CH:NH3

OH

0

(198)

(199)

264

OrganophosphorusChemistry

the cis- and trans-DDP monofunctional adducts react with glutathione to form sulphurcontaining species that cannot close to form the intrastrand DNA lesions. Preliminary experiments indicate that the trans-DDP monofunctional adducts react more rapidly then the corresponding cis-adducts suggesting that selective trapping of trans-DDP adducts in vivo could contribute to the biological inactivity of this isomer. The influence of glutathione on cis- and trans-DDP-induced alterations of DNA structure has also been investigated by polarography.302 The binding of cis-DDP to DNA induces a significant decrease in the melting temperature of platinated oligonucleotide duplexes. Whilst this effect can be attributed mainly to the kinked-cis-DDP-DNA structure destabilisation could also result from the reduced ability of the platinated guanine residues to base pair with cytosine. Oligonucleotide duplexes containing a base pair mismatch at the site complementary to the platination site have been investigated by thermal melting studies.303 The results demonstrate that cis-DDP coordination to N(7) of 2 adjacent guanines does not noticeably affect base pairing ability and therefore reestablishes the importance of the kinked structure. The effect on DNA of intrastrand cross-linking by a platinum anti-cancer drug has been studied by 13C-1H heteronuclear nmr using the model oligonucleotide d(TGGT) and cis-Pt(ethylenediamine)C12.304 The purine base 13C signals were characteristic of N(7) metallation whilst a large upfield shift of the C(3') signal in the first dG residue was attributed to an alteration of the sugar pucker. The same techniques have also been used to define metal binding sites in mononucleotides.~~~ 31P Nmr has been used to study the phosphato chelates formed when CTP and CDP are treated with cis-DDP.306 The major products result from platinum coordination through 2 adjacent phosphate groups of the nucleotides. Diplatinum complexes in which 2 nucleotide units bridge platinum centres through N(3) and terminal phosphate coordination in a head-to-tail fashion are the minor products. The efficiency with which Pt(I1) complexes cross-link phosphorothioate containing oligonucleotides to complementary DNA targets has been investigated.307 Cross-linking via a 5'-terminal phosphorothioate is more efficient than cross-linking through an internal phosphorothioate linkage and internal phosphorothioate linkages of the Sp-configuration cross-link more efficiently than those of the Rp-configuration. Several analogues of DDP have been prepared and evaluated as potential anti-tumour agents.3089309 It has been demonstrated that 6-coordinate ruthenium complexes containing bidentate aromatic diimine ligands are capable of enantiomerically selective interactions with double-stranded DNA.310 The basis of this enantioselectivity is believed to be the more favourable steric fit of the A (as opposed to the A) isomer within the minor groove of the DNA. Resolution of mixed-ligand diimine complexes of ruthenium has been performed by immobilising double-stranded DNA on a column of hydroxyapatite.311 Simple passage of the complexes through the column gives the A and A isomers in 95% or higher purity. 1H nmr studies on the interaction of the A and A isomers of [Ru(l,lO-

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265

phenanthroline)3]2+ with the self-complementary oligonucleotide d(CGCGATCGCG)2 indicate that both enantiomers bind into the central AT-TA regions with a rapid exchange between bound and unbound states.312 The behaviour of the A enantiomer is essentially that of a minor groove binder with a preference for AT regions whilst the A enantiomer displays some major groove binding. Sequence-dependent structural modulations of the DNA helix have been studied using the A and A enantiomers of [Rh(1,1O-phenanthroline)2-9,lO-phenanthrenequinonediimide]3+ as shape-selective DNA binders that recognise and distinguish propeller twisted DNA sites on the basis of shape and symmetry.313 For example the propeller-twist of purines at the 5'-pyrimidinepurine-3' site is disposed in an orientation that permits facile intercalation of the Aenantiomer. The chiral discrimination demonstrates that the propeller twisting evident in crystal structures also occurs in solution and can serve as an important recognition determinant. The binding of Mg2+ to E. coli 5s ribosomal RNA has been investigated using 25Mg nmr spe~troscopy31~The results suggest that the binding sites fall into 2 categories: one in which Mg2+ is readily displaced by Na+ or K+ and a second that is less readily displaced by monovalent cations. More detailed studies of the coordination chemistry indicate that Mg2+-RNA interactions are dominated by hexahydrated ions held in the major groove.3 15 The interaction of the synthetic oligonucleotide d ( C G C G A A T T C G C G ) z with Zn2+ and Mn2+ has been studied by nmr spectroscopy.316 1H Nmr spectra recorded during titration of the transition metals showed distinct broadening effects on certain resonance lines. The results imply that the binding of both metals occurs in a sequence-specific manner which could be accounted for by local differences in the structure of the DNA and the basicities of potential binding sites, The rate of interaction between hydrogen peroxide and the DNA-Cu(1) complex has been shown to increase with pH and with increasing salt concentration, suggesting that H02- is involved.317 The interactions cause DNA damage due to the formation of -OH radicals near the site of Cu(1) fixation at DNA bases. The resultant DNA .OH species is able to reduce Cu(I1) to regenerate the DNA-Cu(1) complex and it thus appears as though a limited chain reaction is possible involving reductive propagation of DNA+OHspecies. 10. Analvtical and Phvsical Studies.- A variety of studies have appeared which have used new nmr techniques for the structural study of nucleic acids. Spectral congestion of the deoxyribose signals presents serious problems for nmr studies on oligodeoxyribonucleotides. A solution to this problem involves the suppression of nonessential proton resonances by regiospecific incorporation of deuterium. Deuterium incorporation at the l', 2, and 2" positions is particularly valuable because of the strategic involvement of these protons in the assignment process where by NOES are

266

Organophosphorus Chemistry

followed down a DNA strand from a base proton to the sugar to which the base is attached and on to the H(1') of the adjacent 5'-sugar. The methodology has been developed for the synthesis of thymidine, 2'-deoxyadenosine and 2'-deoxycytidine and 2'-deoxyguanosine containing deuterium at the l', 2' and 2" positions.318 The strategy involves the preparation of deuterated deoxyribose from ribolactone followed by nucleoside synthesis. A method for the simplification of NOESY spectra of DNA oligomers is presented that enables the selective tracing of the NOE connectivities of cytosine H(6) resonances by selective excitation of these protons via in-phase coherence-transfer from the cytosine H(5) protons.3 19 The dodecamer duplex d(CGCGAATTCGCG)2 containing a CG mismatch has been studied using 1H 3-D NOESY-total correlated nmr spectroscopy.3~The 3-D spectrum provides information for assigning all of the non-exchangeable protons including strongly over-lapping peaks in the crowded spectral regions such as those in the vicinity of the H(5') and H(5") protons. Conformational mobilities in the B- and Z-forms of d(CG)3 in solution have been compared in the microsecond and nanosecond time scales using the nmr techniques of on-resonance proton rotating-frame spin-latice relaxation and NOE respectively.321 The results indicate that the B-form d(CG)3 is more mobile than Zd(CG)3 on the nanosecond time scale although the converse is true on the microsecond time scale. The aggregation of GPD and GTP has been studied by nmr spectroscopy using Mn2+ induced paramagnetic relaxation.322 The data are consistent with the formation of stacked nucleotide dimers which can associate by hydrogen bonding at concentrations greater than 190 mM to give octameric units. The conformations of ADP, ATP and some ATP analogues have been studied by 2-D ROESY nmr experiments.323 Whilst the conformation of the adenine base around the glycosidic bond in ADP is very similar to that observed for AMP, with an equivalent population of the syn- and anti-conformations, ATP shows a preference for the high-anticonformation. 13C and 15N nmr spectroscopy have been used to investigate protonation of the homodimers d(CpC), d(TpT) and d(ApA) by trifluoroacetic acid in DMS0.324 The results show that for d(CpC) the capability of the 2 N(3) nitrogens to accept a proton is slightly different. In both d(TpT) and d(ApA) the protonation of the phosphate group leads to significant variations in the chemical shifts of the carbons adjacent to phosphorus. The conformation of DNA-bound spermidine has been studied by nmr spectroscopy using a 13C double-labelling technique.325 Spermidine was prepared containing two 13C atoms spaced 4 atoms apart (199). Long-range nmr coupling ( ~ J c c ) between the two labelled atoms respond to the dihedral relationship in a typical Karplus fashion and the results demonstrate that the central bond in the C4 unit of spermidine adopts an anti-conformation when bound to DNA. Structurally aberrant base pairs that

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result from deamination of cytosine and adenine have been studied by nmr spectroscopy.326 The application of positive ion fast atom bombardment combined with collisionally-activated dissociationlmass-analysed ion kinetic energy spectroscopy (CADIMIKES) has been used to differentiate the 2'-, 3'- and 5'-monophosphate isomers of adenosine, guanosine and cytidine.327 Pentacoordinated oxyphosphoranes are intermediates/transition states for the hydrolysis of RNA. Whilst the properties of these pentacoordinated species are not easily elucidated experimentally a number of recent ab initio studies on the cyclic oxyphosphorane dianion have been carried out as models for the RNA cleaving process.328-330 The results of these and similar studies on an acyclic oxyphosphorane system 33 1 suggest that these dianionic species should exist as true intermediates although their stability is likely to depend on the nature of the axial substituents. The opening of a central base pair in a B-DNA oligomer has been simulated by Brownian dynamics using a previously developed model for DNA opening in which a base is allowed to rotate towards the major groove.332 Analysis of the rotation angle as a function of time enables the lifetime of the base pair and activation energy for the process to be estimated. This study indicates that the bases are continually subjected to rapidly fluctuating deviations from their equilibrium positions. Over longer periods the fluctuations add up statistically to produce states where the base pair hydrogen bonds are broken and the base protons are fully accessible to solvent. The first images of DNA have been obtained by photoelectron imaging.333 Since the image is formed by valence electrons emitted from the highest occupied orbitals the information obtained complements existing methods of imaging. Poly(9-vinyladenine) has been conjugated with agarose and its application to the electrophoretic separation of nucleic acids investigated.334 The conjugated agarose gel was able to discriminate between single- and double-stranded DNA and showed nucleobase-selective separation of RNA. In particular, the mobility of poly(U) was significantly retarded. As part of a model study to examine the effects of ionising radiation on DNA the products obtained from exposing a frozen aqueous solution of thymidine to y-radiation have been examined.335 Evidence has been obtained for an N(3)-centered radical formed by deprotonation at this position of the thymidine radical cation.

Organophosphorw Chemistry

268

1.

2. 3. 4. 51 6.

7. 8. 9. 10. 11.

12. 13.

14. 15.

16.

17.

18.

19. 20. 21.

22.

23.

24.

25. 26.

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Organophosphorus Chemistry

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303. H. Urata, K. Fujikawa, M. Tamura and M. Akagi, J. Am. Chem. SOC., 1990,112, 8611. 304. S. Mukundan Jr., Y. Xu, G. Zon and L.G. Marzilli, J. Am. Chem. Soc., 1991, 113, 3021. 305. X. Jia, G. Zon and L.G. Marzilli, Znorg. Chem., 1991,30,228. 306. L.L. Slavin and R.N. Bose, J. Chem. SOC., Chem. Commun., 1990,1257. 307. B.C.F. Chu and L.E. Orgel, Nucleic Acids Res., 1990,18,5163. 308. N. Farrell, Y. Qu and M.P. Hacker, J. Med. Chem., 1990,33,2179. 309. B.D. Palmer, H.H. Lee, P. Johnson, B.C. Baguley, G. Wickham, L.P.G. Wakelin, W.D. McFadyen and W.A. Denny. J. Med. Chem., 1990,33,3008. 310. C . Hiort,B. Norden and A.J. Rodger, J. Am. Chem. SOC., 1990,112,1971. 311. A.D. Baker, RJ. Morgan and T.C. Strekas,J. Am. Chem. SOC.,1991,113,1411. 312. B. Norden, N. Patel, C. Hiort, A. Grklund and S.K.Kim., Nucleosides Nucleotides, 1991.10, 195. 313. A.M. Pyle, T. Mori and J.K. Barton, J. Am. Chem. SOC.,1990,112,9432. 314. S.S. Reid and J.A. Cowan, J.Am. Chem. SOC., 1991,113,673. 315. J.A. Cowan, J. Am. Chem. SOC., 1991,113,675. 316. N.A. Frprystein and E. Stetten, Acta Chem. Scand., 1991,45,219. 317. W.A. Priitz, Z. Naturforsch., 1990,45c, 1197. 318. R.P. Hodge, C.K. Brush, C.M. Harris and T.M. Harris, J. Org. Chem., 1991,56, 1553. 319. V. Sklenar and J. Feigon, J. Am. Chem. SOC., 1990,112,5644. 320. M.E. Piotto and D.G. Gorenstein, J. Am. Chem. SOC., 1991,113,1438. 321. S . Ikuta and Y.4. Wang, J. Am. Chem. SOC., 1990,112,5901. 322. G.E. Wilson, C.J. Falzone and H. Dong, J. Am. Chem. SOC., 1990,112,8269. 323. F. Andre, V. Demassier, G. Bloch and J.-M. Neuman, J. Am. Chem. Soc., 1990, 112, 6784. 324. G. Barbarella, M.L. Capobianco, L. Tondelli and V. Tugnolli, Can. J. Chem., 1990,68,2033. 325. F.M. Menger and L.L. D’Angelo, J. Org. Chem., 1991,56,3467. 326. C. Carbonnaux, G.V. Fazakerley and L.C. Sowers, Nucleic Acids Res., 1990,18, 4075. 327. T.J. Walton, D. Gohsh, R.P. Newton, A.G. Brenton and F.M. Harris, Nucleosides Nucleotides, 1990, 9, 967. 328. K. Taira, M. Uebayasi, H. Maeda and K. Furukawa, Protein Eng., 1990,3,691. 329. C. Lim and M. Karplus, J. Am. Chem. SOC.,1991,112,5872. 330. A. Dejaegree, C. Lim and M. Karplus, J. Am. Chem. SOC., 1991,113,4353. 331. T. Uchimaru, K. Tanabc, S. Nishikawa and K. Taira, J. Am. Chem. SOC., 1991,113, 435 1. 332. F. Briki, J. Ramstein, R. Lavery and D. Genest, J. Am. Chem. SOC.,1991,113, 2490. 333. O.H. Griffith, D.L. Habliston, G.B. Birrell and E. Schabtach, Biopolymers, 1990, 29, 1491. 334. E. Yashima, N. Suehiro, M. Akashi and N. Miyauchi, Chem.Lett., 1990,1113. 335. A.A. Shaw and J. Cadet. J. Chem. SOC., Perkin Trans. 2 , 1990,2063.

7

Ylides and Related Compounds BY B. J. WALKER

1 Introduction Reports of theoretical and, especially, mechanistic studies are much reduced this year although phosphorus-stabilised carbanions continue to be very extensively used in synthesis. The range of heterocyclic systems synthesised by aza-Wittig reactions and related methods continues to increase as does the number and complexity of the phosphonates used i n natural product synthesis. A variety of new methods of introducing fluorinated-alkyl functions have been reported. 2 Methylenephosphoranes 2.1 Preparation and Structure.- Ylide formation from the reaction of carbenes and carbenoids with heteroatom loan pairs1 and the synthesis and chemistry of P-halogeno-substituted phosphorus ylides2 have been reviewed. Yet another ab iriitio M. 0. study of the structures, energies and electronic properties of the phosphorus and nitrogen ylides (1) has appeared.3 The results indicate that the phosphine imine structure (2) is c a 29 kcalmol-1 less stable than the isomeric aminophosphine (3). Variable temperature 13C n.m.r. studies of specifically deuterated alkylidenetriphenylphosphoranes (4) show that rotation about Ca-P, aryl-P, and Ca-CS bonds is tortionally unrestricted even at -1000 C . 4 I11 the case of the corresponding benzylidene ylides ( 5 ) both 1H and 13C n.m.r. spectra show temperature dependence. This is rationalised as restricted rotation (with a barrier of 8.5 kcalmol-1) about the C,-phenyl bond arising from resonance stabilisation of the carbanion by the phenyl substituent. Substituent effects on 15N, 31P, and 13C n.m.r. spectra of a range of N-phenyl-P,P,P-tri(4s u b s t i t u t e d p h e n y 1) - p h o s p h a - h 5 -azenes, triarylphosphines and triarylphosphine oxides have been reported.5 The ylide (8) has been generated, for use in a synthesis of the ichthyotoxin (+)-latrunculin A , by reaction of butadienyltriphenylphosphonium bromide (6) (generated in situ) with the dilithio dianion ( 7 ) (Scheme 1).6 The ylide-cation ( 1 0 ) has been prepared from 0 xylenebis(tripheny1phosphonium) ion (9) by reaction with phosphorus trichloride and triethylamine.7 Compound (10) reacts with methoxide and hydroxide to give (11) and (12), respectively, and can be protonated to give the symmetric dication (13) which, on the basis of 3 1 P - H c o u p l i n g 277

278

Organophosphorus Chemistry

+ -

+ -

H3X-Y H

H3P-NH

H,P-NH,

(3)

(2)

(l)X=Y =N X=Y=P X=N,Y=P X=P,Y=N

+

Ph3P-E{

R

H (4) R = H, Me, CMe3, or SiMe3 (5) R = Ph

P

+

h

3

P

w

Br

Ph,fp-

i

Br-

ph3 OLi Reagents: i, LDA, THF, -50

O O T M S

OLi (8)

"C;i i , & O w T M S (7)

Scheme 1

+ -AM I

Et3N

Ph,P=

o P P h 3

Ph3P

r

+

(9)

ol"

g +3LPh3 Ph3P

Ph3P

H

PPh,

p\

OMe

'H

7: Ylides and Related Compounds

279

measurements, is suggested to have a planar, tervalent phosphorus atom. 2 Oxocycloalkyltriphenylphosphonium ylides (14) have been prepared from triphenylphosphine by an electrochemical, one-pot synthesis of the corresponding salts followed by base treatment.8 Further investigations of the reactions of trialkyl phosphites with activated acetylenes have been reported and show, by trapping and 13C labelling studies, that such reactions involve the ketene ylides (15) as intermediates when carried out i n the presence of carbon dioxide.9 1,2hS-Azaphosphines (17) have been prepared from 1 - t - b u t y l - 1 , 2 - d i h y d r o - 1,2h3-azaphosphinines (16) by methylation on phosphorus, thermolysis of the resulting phosphonium salts and, finally, treatment with potassium carbonate.10 On exposure to air the h 5 azaphosphinines are oxidised to phosphine oxides (18). X-Ray diffraction has been used to determine the structure of a wide range of ylides. A dimeric structure, hydrogen bonded via carboxylic acid and keto groups, has been revealed for the keto acid ylide ( 1 9 ) by this technique.11 The structure of the thiole-containing ylide (21), formed by the reaction of the zwitterionic tri-ti-butylphosphine-carbon disulphide adduct (20) with two equivalents of dimethyl acetylenedicarboxylate, has been confirmed by X-ray crystallography. 12 X-ray determined structures have also been reported for the adduct (22)13, formed from the reaction of dimethyl acetylenedicarboxylate with acetylenebis[phosphonobis(dimethylamide)], the novel ylide (23),14 and the crystalline lithium compound (24) formed by treatment of the appropriate borane-ylide adduct with butyllithium. 15 Finally an X-ray structural analysis of the bismuthio-ylide ( 2 5 ) shows that the BiCylide bond length is 2.16A, only 0.05A shorter than the Bi-Cph single bond.16 2.2

Reactions

of

Methylenephosphoranes

2.2.1 Aldehydes.- P-Oxidobenzylidene ylides of phosphorus (26, X = P ) and arsenic (26, X=As) have been generated and allowed to react with aliphatic a l d e h y d e s . 1 7 In both cases styrene derivatives (27) were the only alkenes formed however, whereas i n the phosphorus case stereoselectivity was poor, in the arsenic case the reaction was (E)-stereospecific. 3-Hydroxypropyltriphenylphosphonium ylide ( 2 8 ) has been used as a 3-carbon synthon to construct the 6-membered ring in a new enantiocontrolled synthesis of indolizidine alkaloids (29) from prolinals.1 8 The highly substituted ylides (30) have been used in Wittig reactions to synthesise trans-alkene dipeptide isosteres.I9 The phosphonium salt ( 3 1 ) , which has been prepared from serine, is a nucleophilic alaninol, and hence alanine, synthon.20 Wittig reactions with (31) proceed with >93% retention of optical purity and, depending on the reaction conditions and the aldehyde used, high stereoselectivity to provide a new route to a,P-unsaturated amino

Organophosphorus Chemistry

280

R&pph3

(14) n = 1 , 2

(RIO),P

COP

+ R202CCECC02R2

+ (R'O)3PHC02R2 /

-

/

C

C02R2

d'

OR2

C02Et r-&o,Hph3p+0..

EtO2C

+

Bun3P-C:

s S-

*'?PPh3

o +, 0

28 1

7: Ylides and Related Compounds 3NaN(SiMe3)2

(Me3N)$CH2PC12 BPh4

-

,SiMe3 (Me3N),P=C,

P=N, (23)

SiMe,

BiPh, Me

(OH Ph2X +/

X=As, P

Br-

2BuLi

lm RCHO

Ph2Xf R

0-

1

282

Organophosphorus Chemistry

0 P~~P=$XO~BU X (30) X = CHzPh, C H ~ C O ~ B U ’

N H O ’

+

+

y01

1-

0PPh3

CH2PPh3

(31)

(32)

+ +

NaN(SiMe3)p

R1R2NH + Ph,P--CH&ECH Br-

R’R2N

R’ R2N

CH,

(33)

R3CH0

R3

+

Ph3P=CHC02Et

R2W +

R3

\

R4

/

C02Et

o +

*2R

R3

\ ~4

R2@

R3 CHCO2Et

H

‘ R4

CH2C02Et

7:

Ylides and Related Compounds

283

acids and alcohols.Trans-4-alkenyl oxazoles have been synthesised with >95 % stereoselectivity by Wittig reactions of the tri-a-butylphosphonium ylides ( 3 2 ) .2 1 These ylides were superior to the corresponding triphenylphosphonium ylides and to the phosphonate analogues. Treatment of the P enamino phosphonium salts ( 3 3 ) , available from the addition of amines to propargyltriphenylphosphonium salts, with base followed by addition of aldehydes provides a convenient synthesis of 2-amino- 1,3-butadienes i n generally good yields.22 Similar reactions with a,P-unsaturated aldehydes lead to cyclisation to give ( 3 4 ) . Aldehydes are converted to alkenes by palladium-catalysed reaction in the presence of tri-n-butylphosphine.23 The reaction gives moderate to good yields, is mostly highly stereoselective and takes place under neutral conditions.23 2.2.2 Ketones.- Methylenation of ketones can cause difficulties. A study comparing the use of the Wittig and Tebbe reagents in this reaction has appeared.24 Investigations of Wittig reactions with 1,4-naphthoquinones,2s 1 , 4 benzoquinones,26 and 1,2-benzoquinones27 have been reported. The reactions of 1,2-benzoquinones with ethoxycarbonylmethylenetriphenylphosphorane give a variety of products, e.g. ( 3 7 ) and ( 3 8 ) , in addition to the expected coumarin derivatives ( 3 6 ) .27 The initially formed 1,2-quinone methanide intermediate ( 3 5 ) can be trapped as a pyran derivative by carrying out the reaction in the presence of ethylvinyl ether. Wittig reactions of phosphacumulenes, e.g. ( 3 9 ) and ( 4 0 ) , have been i n v e s ti g a t e d .2 8 Sta bil i sed tri bu t y 1s t i boni um met h y 1ides ( 4 1) u nderg o olefination reactions with carbonyl compounds to give moderate to excellent yields of (E)-a,P-unsaturated acrylic acid derivatives.29 2.2.3 Ylides Coordinated to Metals.- The aza-rhenium (VII) ylide ( 4 2 ) has been reported.30 X-Ray crystallography shows that the rhenium atom in ( 4 2 ) is tetrahedrally coordinated to the four nitrogen atoms. The metal complex (44) is formed by the oxidative addition of methylenetriphenylphosphorane to the ruthenium carbonyl ( 4 3 ) .3 1 the structure of ( 4 4 ) has been determined by X-ray methods. Alkylidene transfer from a phosphonium ylide to tungsten has been used to prepare the complex ( 4 5 ) .32 Other examples of ylides coordinated to metals reported include complexes with rhodium (I) and rhodium (III)33 and the novel ylidicaluminium heterocycle (46).34 2.2.4 Miscellaneous Reactions.- a-Vinylidene-y-butyrolactones ( 4 8 ) have been prepared in excellent yield by Wittig reactions of the ylides ( 4 7 ) with gaseous ketene.35 The thermolysis of 2-diazo- 1,3-diketones ( 4 9 ) with 1,3-

284

Organophosphorus Chemistry

Ph,P=C

=C =X

Bu3~b-EHE

(39) x = 0 (40) X = S

NAr -NAr \ NAr

/

Ph,P=N-Re

(41) E = C02R, CN, or CONR2 (42) A r =

+

C,I

Al

Ph3P=CH2

M ,e O*pph3

Me2

? r12

ArC-CAr

(49)

CH2=C=O-

C4-h

+o R

R

A

+

? Tr

ArC-C=C=O

__.I

, xI

Ph3P-CH-C-R

(51) X = NPh (52) X = O (53) x = s

7: Ylides and Related Compounds

285

ambident-nucleophilic ylides ( 5 1 ) . ( 5 2 ) , and (53) leads to reaction either directly with ( 4 9 ) or with the ketene ( 5 0 ) formed from ( 4 9 ) by Wolff r e a r r a n g e m e n t . 3 6 The reaction provides routes to a variety of monoheteroatomic five- and six-membered rings. The reaction of ester-stabilised phosphonium ylides with cyclic anhydrides, known to give enol lactones ( 5 4 ) , has been the subject of a detailed study.37 1 -Amino-4-triphenylphosphoranylidene-5 -0xo2-pyrrolines ( 5 6 ) or a,P-unsaturated hydrazones ( 5 7 ) have been obtained in good yield by the reaction of conjugated azoalkenes with ethoxycarbonylmethylene ylides (55).38 The structure of one example of (57) was determined by X-ray crystallography. V i c i n a l tricarbonyl compounds (59) have been prepared in excellent yield by potassium peroxymonosulphate-induced cleavage of the ylide bond in substituted ylides ( 5 8 ) . 3 9 The ozonides (60), obtained from mono-substituted alkenes, are reported to react with stabilised ylides to give the corresponding alkenes in good to excellent yields.40 Monomeric selenobenzophenone ( 6 1 ) has been prepared in solution by the reaction of diphenylmethylenetriphenylphosphorane with selenium.41 A number of reports of routes to perfluoroalkenes have appeared. Perfluoroacylmethylenephosphoranes are insufficiently reactive to undergo the Wittig reaction, even with aldehydes. However treatment of the doublystabilised ylides ( 6 2 ) with alkyllithiums generates the ylide-anion ( 6 3 ) which, following protonation, collapses to give (64), mainly as the (E)-isomer, thus providing a novel synthesis of P-perfluoroalkylated a , P - u n s a t u r a t e d nitriles,42 ketones and esters43 (Scheme 2). Benzylidene ylides, generated i n situ, react with methyl 2-perfluoroalkylynoates ( 6 5 ) to give a mixture of adducts (66) and (67).44 This mixture, on heating in aqueous methanol, gives (Z)-methyl 3-perfluoroalkyl-4-substituted phenylbut-3-onates ( 6 8 ) with high stereoselectivity. A new, one-pot synthesis of fluorinated bromoallenes ( 7 0 ) is provided by the reaction of pentafluorophenylmethylenetriphenylphosphoranes (69) with bromoacetyl bromide (Scheme 3).45 The flash vacuum pyrolysis of sulphonyl-stabilised phosphonium ylides ( 7 1 ) has been investigated and shown to result in the loss of triphenylphosphine and sulphur dioxide to give alkenes ( 7 2 ) as the major products, possibly by a carbene mechanism.46 It is suggested that a new 0 to C rearrangement of allylphosphinic esters ( 7 3 ) to give ( 7 5 ) proceeds v i a an intramolecular mechanism involving an intermediate ylide ( 7 4 ) (Scheme 4).47 This C-C bond forming reaction has been applied to the synthesis of squalene. Reactions of the phosphonium aza-ylide anion (76) with electrophiles have been extended to provide a one-pot synthesis of various N-substituted phosphinines ( 7 7 ) .4* The reactions of N-vinylic-(78) and N-dienyl-(79) 15phosphazenes with various electrophiles have been investigated and shown to

Organophosphorus Chemistry

286

-o2c9-&:' 0

11

(54)

+PPh, R=H

H02c9?-(c02Et 0

=A-

Me

RICH

N=N -R2

+

cH/

PPh3

y

Ph3P= CHC02R3

THF or MeOH, -20 "C

Me R2NHN=,&-C=CHCO2R3 I

NNHR~

R1 Ph3P R$e

(56)

0 (57)

"'do) + 0-0

Ph,P=CHX

X = C02Me, COPh (60)

-

R

'

d

X

287

7: Ylides and Related Compounds Se Ph3P=CPh2

+

II

Se

-

Se

(61)

(63)

(62)

Reagents: i, RLi, THF, -60 "C; ii, CH3C02H, 0 "C; iii, 20 "C

Scheme 2

Ph,&H2Ar

B r + RfCECC02Me (65)

1

C02Me Ph, P =C' )=CHAr

K2CQ

Ar Ph3P=C' )=CHCO,CH,

+

Rf (66)

Rf

1

Me02C RfH

(67) MeOH, H20

y

r

(68)

Ph,P=CHR

i

- Ph,P=CRCeF,

ii

H,,c=c=c: Br

(69)

Scheme 3

Ph3pYAr' S02CH2Ar2

(711

c6F5

(70)

Reagents: i, C6Fs,THF, -20 "C; ii, BrCH2COBr, THF, -60 "C

Ar CH=C HAr2

R

Organophosphorus Chemistry

288

E

osi Prig

i, ii

Me2C=CHCH,yOCH2CH=CMe2

I

Me2C=CH CH=P-Ph I

OCH,CH=CH,

Ph

(74)

(73)

I

1

n

V

II OH

Me2C=CH-CH-P(

Ph

I

Me,C=CH CH,

.

0

II

Reagents: i, 2xLDA, THF, -78 OC; ii, Pf3SiOSCF3,THF, -78 "C

II

0 Scheme 4

Ph,P=NLi

RX

Ph3P=NR

flPPh2,

(77) R = 02S-@H3, -

(76)

Br, S03Et, or S02NEt2

N//PPh3 Et02CL

P

Ph

JJ ~

h

5

~

~

~

EtO2C

(78)

(79)

R1*H Ph3P+

Br-

(82)

I

Ph3P+ (83)

Reagents: i, CH2CI2,25 "C; ii, R'CHO; iii, R'CH=CHCHO Scheme 5

Br-

3

7:

Ylides and Related Compounds

289

provide routes to 2-aza-l,3-dienes, conjugated carbodiimides, Z-azahexa1,3,5-trienes, and pyridines.49 The phosphinimine ( 8 0 ) and prop-2ynyltriphenylphosphonium bromide react at room temperature to give the adduct ( 8 1 ) . Addition of aldehydes to (81) leads to the formation of p enaminophosphonium salts ( 8 2 ) or substituted tetrahydropyridines ( 8 3 ) depending on the nature of the aldehyde used (Scheme 5 ) . 5 0 The p enaminophosphonium salts ( 8 2 ) will undergo further reaction with aldehydes to provide routes to 2-vinyl- 1 -aza-1,3-dienes and penta- 1,4-dien3-ones. 3 The Structure and Reactions of Phosphonate Anions An X-ray structure determination of lithium diethyl benzylphosphonate carbanion has been carried out.51 the carbanion is crystallised in the presence of DABCO and the adduct formed has the structure ( 8 4 ) . The slightly pyramidalised configuration at the benzylidene carbon and the conformation around the C-P bond are reproduced by uD initio M. 0. calculations. N.m.r. (13C, 6Li, and 31P) and X-ray crystallographic analyses of the anion ( 8 5 ) of 1,3dimethyl-2-isopropyl- I ,3,2-diazaphosphorinane 2-oxide have been reported.52 The results show that the carbanion is almost planar and that the barrier to rotation about the P-C carbanion bond is very low. A new, more economical route to enantiomerically pure phosphonate ( 8 6 ) , which is a synthon for the preparation of mevinic acid, has been reported (Scheme 6 ) . 5 3 The method avoids the disadvantages of the competitive retro-aldol and @-elimination of the siloxy group observed i n an ear 1 i e r route . I sopr e no i d ( p h o sp h i n y 1met h y 1)p h 0 s p h o n ate s ( 87) have bee n synthesised by the reaction of methyl- or difluoromethyl-phosphonate carbanions with isoprenoid phosphonochloridates (Scheme 7).54 The electrochemical reduction of 1 -chloroalkylphosphonates ( 8 8 ) and ( 8 9 ) i n the presence of various electrophiles has been investigated.55 The initially formed carbanion is shown to undergo protonation, alkylation or olefination in the presence of acid, alkyl iodides or carbonyl compounds, respectively. Carbanions ( 9 0 ) , derived from cyclic phosphoramidate carboxylate esters, react with aldehydes in the presence of certain secondary amines to give (2)-alkenes highly stereoselectively.56 The new Wadsworth-Emmons reagents ( 9 l ) a n d ( 9 2 ) have been synthesised and shown to undergo olefination reactions with carbonyl compounds to give, ultimately, 2,4-pentadienals and 3-methyl-2,4-pentadienals, respectively, predominantly as the (2E,4E)-isomers.57 The reagent (91) has been used in the key step in a short synthesis of (E,E)-coriolic acid (93). Phosphonate-based olefinations involving (94) are reported to be superior to ylide or aldol methods in a new synthesis of 3-(polyen)oyltetramic acids ( 9 5 ) . 5 8 The olefination reaction of the aldehyde ( 9 6 ) with the bisphosphonate ( 9 7 ) under very specific conditions has been used to synthesise the isosteric bisphosphono analogue ( 9 8 ) of p - D -

Organophosphorus Chemistry

290

I DN/ M 5 PyMe +

OSiMe2But C02H

i,ii

I

C02Me 0 I1

Reagents: i, LiCH,P(OMe),

-

0

0

OSiMe2But

(MeO)2~&C02Me

(86) , THF, -78 O C ; ii, CH2N2, Et20 Scheme 6

I":

$?:

$?

(R10)2PCX2Li+ R2PCI

R2rCX2P(OR1)2 0

6R3

~

3

i, ii

? :

R2PCX2P-OI

0-

I

0-

(87)

X =HorF Reagents: i, TMSI, CH2CI2;ii, KOH Scheme 7

Me R1

(91) R = H (92) R = Me

29 1

Ylides and Related Compounds

7:

OH

MeA

(93)

yu{

1(0Et)2

II

BuO

(Et0)2PCHZCH2

!

OCOPh

+ [(EtO)2P12CH2

i, ii b

(96) Reagents: i, DBU, LICI, MeCN; ii, H2, Pt02

Scheme 8

0

+ PhS02CF$(OEt)2

f-:

PPW2 OCOPh

BuO (98)

(97)

R'R2C0

= 0-3

y

0

0

OH

Me

(95)IJ

(94)

RWC=C:

(99)

(100) z = 3-6

F

502ph

292

Organophosphorus Chemistry

fructose 2,6-bisphosphate (Scheme 8 ) . 5 9 A new, convenient, phosphonatebased r o u t e t o vinyl fluorides has been reported.60 The a f l u o r o m e t h y l p h o s p h o n a t e carbanion ( 9 9 ) was generated itz situ from fluoromethylphenylsulphone and allowed to react with ketones to give a fluoro-a,p-unsaturated sulphones. The phenylsulphonyl group is easily removed by reduction. A range of a,o-dithienyl polyenes ( 1 0 0 ) have been prepared by ylide-based or phosphonate-based olefination reactions with the appropriate bis-ylide or bis-carbanion.6 1 Phosphonate-based olefination continues to be used in the synthesis of tetrathiafulvenes and their derivatives. Three new vinylogous derivatives ( 1 0 1 ) of bis(ethy1enedithio)tetrathiafulvene have been prepared by such methods.62 A wide range of symmetrical and unsymmetrical 1,3-dithiole, e.g. ( 1 0 2 ) and ( 1 0 4 ) , and 1,3-selenothiole, e.g. ( 1 0 3 ) and ( 1 0 5 ) , derivatives have been synthesised by olefination reactions of the carbanions of phosphonates (106).63 Both symmetrical ( 1 0 7 ) and dissymmetrical ( 1 0 8 ) acetylene analogues of tetrathiafulvene have been prepared by the use of ylide-based and phosphonate-based methods.64 The report contains a discussion of the limitations of such methods. Some of the difficulties encountered can be overcome by using cobalt complexes, e.g. ( 1 0 9 ) , rather than the free acetylenic aldehyde in the olefination reactions.65 The base-induced reaction of P-substituted cyclohex-2-en-1 -ones with diethyl cyanomethylphosphonate ( 1 10) has been carried out and the effect of various reaction conditions on the stereochemistry of the olefin formed investigated.66 The reaction of 2,2-disubstituted 1,3-cyclohexadiones with dimethyl methylphosphonate anion provides a synthesis of 3-substituted 2cyclohexenones ( 1 1 1) rather than the expected olefin product.67 The yields are improved by the presence of trimethylchlorosilane i n the reaction mixture and a mechanism involving (a) initial addition of carbanion to the carbonyl group, (b) retroaldol cleavage, (c) proton exchange, and ( d ) intramolecular olefination is suggested. The reaction has been used in a new a-acoradiene ( 1 12). synthesis of (2)The alkylation of phospholanate ester carbanions ( 1 1 3 ) has been i n v e s t i g a t e d . 6 8 The stereochemistry of the reaction can be controlled to a large extent by varying the reaction conditions and by the choice of ester function. Alkylation reactions of the chiral, phosphorus-stabilised carbanions ( 1 1 4 ) are reported to be generally highly stereoselective and the stereoselec tivity is independent of the nature of solvent, additives and base.69 a - P h o s p h o n o - i o d o ( 1 1 5 ) and -seleno ( 1 1 6 ) lactones have been prepared from ethyl (diethoxyphosphory1)acetate anion by alkylation with allylic bromides and iodo- and seieno-lactonisation, respectively.7 0 Compounds ( 1 1 5 ) and ( 1 1 6 ) undergo olefination reactions with paraformaldehyde to provide a convenient synthesis of a - m e t h y l e n e - y -

7: Ylides and Related Compounds

(102) (103)

293

x=s

(106) X = S, Se

X = Se (104) X = S (105) X = S e

R’

OHC-CiC-CHO [CO~(CO)~I 4

R2

Is)=CH-C3-CH<sX R’

R2

0 II

(EtO),PCH,CN

(107) R 1 = R 2 (108) R’ + R2

R2

-

c“ R2

:

“OR’

R3X

Li + (113) RZ = H, CH2Ph

*

OR’

R3

R2

o

+

CP

“OR’

R3

But (114)

294

Organophosphorus Chemistry

*

0

x (115) X = I (116) X=SePh

0

k (117)

Reagents: i, R2C=CHCHzBr; ii, - OH; iii, NaHC03, 12,KI,or PhSeBr, THF; iv, DBU, Benzene: v, Na, (HCHO), , THF

Scheme 9

R O

Li 0 I

I1

RC-P(OEt)Z OSiMe,

i

.

I

II

R1COy-P(OEt)2 OSiMe,

(122)

Reagents: i, RICOCI; ii, H30+

Scheme 10

Ph,P=C,

,C02CHzPh OCH2Ph

ii +

R~COCOR

7: Ylides and Related Compounds

295

lactones (117) (Scheme 9) and the method has been applied to the synthesis of frullanolide (1 18). A range of a-fluoro P-keto esters, e.g. (121), have been prepared by acylation of fluorocarbethoxymethylenetri-n-butylphosphorane ( 1 19) and the carbanion of a -fluoroalkylphosphonate (120) followed by hydrolysis.7 1 The reaction with the phosphonate (120) could be extended to fluorinated acyl chlorides. A new route to 1,2-diketones is provided by the reaction of the phosphonate carbanion (122) with non-enolisable acyl chlorides followed by hydrolysis (Scheme lO).72

4 Selected Applications in Synthesis 4.1 Carbohydrates.- A Wittig reaction of [(benzyloxy)(benzyloxycarbonyl)methyl] triphenylphosphorane (123) with 4-0-benzyl-2,3 :5,6-di-O-isopropylidene-D-mannose has been used to synthesise 3-deoxy-D-m a 11 110- 2 octulosonic acid (124).73 A diastereoselective synthesis of P-C-ribofuranosyl glycines (1 25) by reaction of ribofuranoses with phosphoryl glycine ester carbanions has been reported.74 4.2 Carotenoids, Retenoids and Pheromones.- C h i r a l pheromone components (126) and (127) of A d o x o p h y e s species have been synthesised using Wittig reactions foIlowed by catalytic hydrogenation to construct the carbon chain.75 Standard Wittig methods have been used to synthesised (128) and (129), the main sex-pheromone components of Leucotera scirella and Perileucotera coffeella, respectively.76 Wadsworth-Emmons reactions of the 1,4-diacyl-( lE),(3E)-butadienes, obtained from rhodium-catalysed reactions of furans with ethyl diazoacetate, have been used to synthesise retinol-carotene fragments, (2) - 6 ( E ) - LTB 3 leukotrienes, and the dodecahexaenoic dicarboxylic acid, corticrocin.77 Standard Wittig methods have been used in the synthesis of photoactivatable analogues (130) of 1 I-cis-retinal.7 8 4.3 P - L a c t a m s . - A thiolester-phosphorane cyclisation strategy has been applied to the formation of the five-membered ring in the synthesis of olivanic acid analogues, e.g. (131)? One unexpected problem encountered was the partial isomerisation at C-3 in the P-lactam precursor used to form the intermediate phosphonium ylide. The carbon framework of the carbopenam ( 1 3 2 ) has been constructed using an intramolecular phosphonate-based olefination to form the five-membered ring.*() An alternative intramolecular Wittig route to penams involving the ylides ( 1 3 5 ) has been reported.81 The ylides ( 1 3 5 ) are prepared by the reaction of either stabilised or unstabilised ylides with the p - 1 a c t a m

Organophosphorus Chemistry

296

e.g. KOBU', CH2C12

(CH2)"OAc (128) -R (129) -R

(126) n = 9 (127) I/ = 1 1

= .---Me = -Me

I

C02p NB

-JSiMBL .. ...

g + R i

11, 111

0

C02R

(133) Y = CMe2 (134) Y = 0 X = 2-benzothiazolyl

C02R

(135)

Reagents: i, Ph3P=CHR1 ; ii, 03;iii, A, Benzene

Scheme 1 1

C02R

7: Ylides and Related Compounds

297

disulphide (133) (Scheme 11). The method was also applied directly to the keto analogue (134) of (133), thus precluding the ozonolysis step.

4.4 Leukotrienes, Prostaglandins and Related Compounds.- T h e c o n f o r m a t i o n a l l y - r e s t r i c t e d LTD4 analogues (136) and ( 1 3 7 ) have been synthesised using stereoselective Wittig olefination to give (Z)-(138) and (Z)( 1 3 9 ) , respectively, as the key step.82 The phosphonates ( 1 4 1 ) and ( 1 4 2 ) have been synthesised by acylation of the cupromethylphosphonate ( 1 4 0 ) and used in olefination reactions.83 The olefination method, involving simultaneous addition of the phosphonate( 1 4 1 ) and the appropriate aldehyde to a suspension of sodium hydride, has been applied successfully to a synthesis of the keto-12 leukotriene LTB3 ( 1 4 3 ) . Both phosphonium-based ( 1 4 4 ) and arsonium-based ( 1 4 5 ) ylides have been used to synthesise lipoxins A4 and B 4 . 8 4 Other examples of the use of Wittig olefination i n syntheses of this type include that of the acetylenic ylide ( 1 4 6 ) i n a new total synthesis of ( l l R , 1 2 S ) diHETE (147)85 and a concise synthesis of fatty acids, e.g. ( 1 4 9 ) , containing the (R)-hydroxy-(E,Z)-diene subunit.86 I n the latter case three equivalents of ylide are used to induce elimination i n the tosylate (148) and subsequent Wittig condensation. Wittig reactions of the phosphonium salt ( 1 5 0 ) have been used to synthesise the arachidonic acid analogues (151) and (152)87 arld consecutive Wittig reactions provide a route to the eight, rigid analogues (153) ( S c h e m e 12)P Phosphorus-based olefination methods continue to be widely used i n prostaglandin synthesis. Examples include that of the thromboxane receptor antagonists EP90289 and the calcium salt (154),90 the latter is orally active, and various analogues for use as F2a photoaffinity probes.91 4.5 Macrolides and Related Compounds.Phosphonate-based olefinations continue to be widely used in the synthesis of a wide range of macrocyclic compounds. An intramolecular olefination of the complex phosphonate (155) has been used as the cyclisation step in a synthesis of the aglycon methyl ester of the polene macrolide pimaricin.92 Other examples of the use of reactions of complex phosphonates include the construction of the carbon skeleton i n a synthesis of the twelve-membered macrolide m e t h y n o l i d e 9 3 and a total synthesis of FK506, a potent inhibitor of the expression of early T cell activation genes, involving the phosphonaniide carbanion (156).94 Model studies and theoretical methods have shown the feasibility of using a tethered phosphonate reagent of the appropriate chain length to establish the correct stereochemistry of the exocyclic unsaturated ester at C-13 in a synthesis of bryostatins.95 The method was then applied to the synthesis of ( 1 5 8 ) , a lactonised derivative of an advanced intermediate

298

Organophosphorus Chemistry

I"$:.... C13H27

do (1 36)

$?

(E~O)~PCH~CU

$?

RCOCI

(Et0)2PCH2COR (141) R = C R H ~ ~

(141)

+

OHC-

C02Et

1

OCOPh

NaH THF

.

7

1

H

s

C

C02Et OCOPh

(143)

299

7: Ylidrs and Related Compounds

OH

+

-

3Ph3Po

(CH2)3C02R

TsO

r

(148)

C02Me

+PPh,

q

I-

p

+

i,ii

I-

c

q

PPh3

\

-

f?ii,i"

R'

{ R 2

\

R'

R'

(153)

/=\ R' = n-C5HI1,H2C n-C,H,, R2 = (CH2),C02Me ,H2C/-7(

\

CH2),C02 Me

Reagents: i, Bu"Li; ii, R'CHO; iii, R2CHO; iv, LiOH, DME, H20

Scheme 12

Ca.2H20 2

300

Organophosphorus Chemistry

0

OTBS

(157)

\LiCI,

Lq EtsN, CH3CN

\

0

R

; OCH20R

C02Me

OTBS Ph3P+

Br-

Ph,P

OSiBu‘ Me2

7:

Ylides and Rrluted C'ompoirntls

30 1

in the synthesis of bryostatin, through the use of the phosphonate ( 1 5 7 ) . A Wittig reaction of the ylide derived from the complex phosphonium salt ( 1 5 9 ) has been used as the key step i n a total synthesis of milbemycin a1.96 An improved procedure, in which the ylide ( 1 6 0 ) is generated i n the presence of the aldehyde, has been applied to the synthesis of a number of milbemycin derivatives.97 Other examples of the use of Wittig reactions to construct complex carbon skeletons for the synthesis of macrocycles include a highly convergent synthesis of (+)-latrunculin A.98 T h e 26-membered macrocycle ( 1 6 l ) , containing two bipyridyl units, has been synthesised through the use of a quadruple Wittig reaction (Scheme 13).99

4.6 Nitrogen Heterocycles.- The application of the aza-Wittig reaction to the synthesis of heterocyclic compounds has been reviewed.100 Examples of heterocycles synthesised recently by this method include the isoindolol 1,2b ] [1,3,4]benzotriazepinone ( 1 6 2 ) , 4-quinolones (163),101 isoquinolines ( 1 6 4 ) , 1,9-diazaphenalenes (165),102 indolines and imidazoindoles,103 I H 1,2,4-benzotriazepines ( 166),104 SH-indeno( 1,2-h]pyridines (167),105 2Hindazoles (168) and the bicyclic derivative (169).106 The reactions of iminophosphoranes with heterocumulenes have also been widely used in heterocyclic synthesis. Hetero-condensed 2-alkoxy-4pyrimidinones, e.g. (171), have been prepared by the reaction of hetero- and carbo-cyclic 2-( triphenylphosphoranylidene)-3-~arboxylates, e.g. (170), with isocyanatesl07 and reactions of aromatic isocyanates with iminophosplioranes provide routes to pyrimido[4,5-d]pyrimidine derivatives (172).108 T a n d e m aza-Wittig/heterocumulene-mediated methods have been used to prepare lH-1,2,4-triazolo[2,3-b]indazoles(173)109 and fused [ 1,3,5]benzotriazepines (174) (Scheme 14).110 2-Methoxy-substituted pyrroles (175) have been prepared viu an azaWittig reaction by treatment of the appropriate azide with t r i p h e n y l p h o s p h i n e l l 1 and the aza-Wittig has been used to form the hydantin ring without epimerisation in a synthesis of (+)-hydantocidin (17 6 ) from fructose.112 The reaction of iminophosphoranes (177) with symmetrical dicarbonyl ( 178), dichlorides provides a route to N-substituted-phthalimides pyrrolidine-2,5-diones ( 1 7 9 ) , and piperidine-2,6-diones (180).113 2 - H Imidazoles (181) have been prepared by the reaction of N , N ' bi s ( t rip he n y 1p ho s p h oran y 1 i de ne ) bi s - ( be n zo tr i azol - 2 - y 1) me t h a ne d i am i n e w i t li aryl and alkyl Grignard reagents and subsequently with benzil.1 1 4 4.7 Miscellaneous Reactions.- The Wittig reaction of phthalaldehyde with the ylides ( 1 8 2 ) has been used to construct the carbon skeleton i n a new synthesis of dihydrocatalpalactone and catalpalactone (183, R=Me).I 15 A

Organophosphorus Chemistry

302

gCHO+ +

-

C h 3

i, ii

CHZPPh,

CHO

Reagents: i, LiOEt, EtOH, DMF; ii, H2/Pd/C

Scheme 13

303

7: Ylides and Related Compounds

~

0

NHN=C-N=PPh3 I

~

~

H 3

w

c

o -N

R2

COR'

R'

dr N-N

=PPh, H

2

~

3

Organophosphorus Chemistry

304

e

,

N

-N=PPh3

I \

I

NxR1

*

ii

@N=PPh3

iii

N"

N"

Reagents: i, Ph3P, CH2C12, 0 "C; ii, R'NCS, CH2C12, R.T.; iii, R2NCS, CH2C12, R.T.

Scheme 14

HocyL--p;

H

HO OH (176)

(175)

Ph3P=NR

X

NR

a

(177) R = Ph, CH2Ph,

(178) X =

CH2C02R, or QCH2

(179) X = (CH& (180) X = (CH2)3

N RXR N PhHPh

305

7: Ylides and Related Compounds

Qo

R

R

R' 02C

0

/C02Me Ph,P=CHOMe

KH

DMSO

Me

M e O o C H C 0 2 f v l e

,

.

&c

0

306

Organophosphorus Chemistry

short, total synthesis of (+)-norpatchoulenol ( 1 8 4 ) has been reported i n which a key step is the trapping of the unstable diketone intermediate ( 1 8 5 ) with methoxymethylenetriphenylphosphorane to provide ( 1 8 6 ) . 1 1 6 Both Wittig and phosphonate-based olefination has been used to prepare ( 18 7 ) and (188) which are readily converted into patulin ( 1 8 9 ) and neopatulin (190), thus providing a concise synthesis of the two latter compounds.117 An intramolecular olefination of the complex phosphonate ( 19 1 ) to generate (192) is a key step in a total synthesis of the aglycone of the novel cyclic diacetylenic antibiotic calicheamicin.118 The complex phosphonate ( 1 9 3 ) has been used as a late intermediate to construct the A-ring i n a synthesis of the ABC- ring system of brevetoxin B, a neurotoxin associated with the "red tide" phenomenon.119 The antibiotic, methylenomycin ( 1 9 4 ) has been prepared i n three-steps starting from diethyl 2-oxobutane(195) or diethyl 3-oxobutanephosphonate (196) o r phosphonate diphenyl(3-oxobuty1)phosphine oxide ( 1 9 7 ) . 1 2 0 In each case the c x o methylene function is introduced via an olefination reaction of the corresponding a-phosphorylcyclopentenone, e.g. (198). The carbanion of the chiral phosphonate ( 1 9 9 ) has been used as a key intermediate in a new synthesis of enantiomerically pure muscarine analogues.121 Both (+)-trans( 2 0 0 ) and (+)-cis-(201)-neocnidlides have been synthesised using an intramolecular olefination reaction of the phosphonates ( 2 0 2 ) and ( 2 0 3 ) . respectively, to form the 6-membered ring.122 The Wittig reaction has been used to generate "carba"peptide bond replacements, for example, i n the synthesis of the phenylalaninealanine analogue ( 2 0 4 ) . I 2 3 Alternatively, phosphonate-based methods can be used and these have been applied to the synthesis of the pseudodipeptides ( 2 0 5 ) and (206) (Scheme 15).124 REFERENCES A. Padwa and S. F. Hornbuckle, Chenz. REV., 1991, 91, 263. 1.

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7: Ylides and Related Compounds

307

LiBr

OCOCH,P(OEt), 0 It

HO

Et3N

Cgo

~

HO

\\\ Ill

\\\ 111

(191)

(192)

\-I

\-I

H

Me

H

H

H

H

Me&CH2 OSiBu'Ph,

f

(Et0)2PCH,C02E t

Me

0

!?

Z2PCH,CH2COMe

(Et0)2F&Me

b((OMe), Me

(1 96) Z = EtO (197) Z = Ph

(1 95)

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(198)

Bu

BocNH

/

0

(200) -H (201) -H

0

= ----H

==-H

OHC (202) -H (203) -H

= ----H

=-H

CO2H

308

Organophosphorus Chemistry

Reagents: i, NaH, DME; ii, Hz,Pd/C; iii, Column Chromat.; iv, 6M HCI; v, Boc20

Scheme 15

309

7: YIides a n d Related C o m p o u n d s

14.

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C.W. Spangler, P-K. Liu, A.A. Denibek, and K.O. Havelka, J. Clzenz. Soc., Perkin Trans. I ,

62.

A.J. Moore, M.R. Bryce, D.J. Ando, and M.B. Hursthouse, J. Cheni. Soc., Cheni. Cnniniun.,

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A.J. Moore and M.R. Bryce, J. Chent. SOL'., Perkin Trans.], 1991. 157.

64.

A. Khanous, A. Gorgues. and F. Texier, Tetrahedron Letters. 1990. 31. 7307.

65.

A. Khanous, A. Gorgues, and M. Jubault, Tetrahedron Letters, 1990. 31. 7311.

66.

S. Geribaldi and M. Rouillard, Tetrahedron. 1991, 47, 993.

1991. 799. 1991, 320.

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Y. Yamamoto and T. Furuta. J. Org. Cheni., 1990, 5 5 , 3971.

68.

R.P. Polniaszek and A.L. Foster, J. Org. Cheni., 1991, 5 6 , 3137.

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Perkin Trans. 1. 1990. 2385. 71.

A. Thenappan and D.J. Burton, J. Org. Cliem., 1991, 56, 273.

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W. Frick. T. Krulle and K.R. Schmidt, Liehigs Ann. Cheni., 1991, 435.

74.

A. Lieberknecht. J. Schmidt, and J.J. Stezowski, Tetrahedron Letters, 1991, 32, 21 13.

75.

H.J. Bestmann, R.T.S. Frighetto, N. Frighetto, and 0. Vostrowsky, Liehigs Ann. Clienr.,

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L. Poppe. L. Novak, J. Devenyi, and C.S. Szantay, Tetrahedron Letters, 1991, 32, 2643.

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E. Wenkert, M. Guo, R. Lavilla, B. Porter. K. Ramachandran and J-H. Sheu. J. Org. Clieni..

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T.A. Nakayama and H.G. Khorana, J. Org. Cheni., 1990, 5 5 , 4953.

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311

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J.H. Bateson, A.M. Robins, and R. Southgate, J. Chem. SOC., Perkin Trans.1, 1991, 29.

80.

N.Z. Huang. V.J. Kalish, and M.J. Miller, Tetrahedron, 1990, 46, 8067.

81.

A.J. Barker, M.M. Campbell, and M.J. Jenkins, Tetrahedron Letters, 1990, 31, 4359.

82.

J.S. Sabol.. P.M. Weintraub, T.H. Gieske, and R.J. Cregge. Terrahedron, 1990, 46, 4155.

83.

T. Durand. Ph. Savignac, J-P. Girard, R. Escale, and J-C. Rossi, Tetrahedron Letters, 1990.

31, 4131. 84.

C. Gravier-Pelletier, J. Dumas, Y. Le Merrer, and J.C. Depazay, Tetrahedron Letters,

85.

A. Gigon, J-P. Beaucourt, J-P. Lellouche, and R. Gree, Tetrahedron Letters. 1991, 32,

1991, 32, 1165. 635. 86.

S. Lumin, J.R. Falck, and M.L. Schwartzman, Tetrahedron Letters, 1991, 32, 2315.

87.

M. Labelle, J-P. Falgueyret, D. Riendeau, and J. Rokach, Tetrahedron, 1990, 46. 6301.

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A. Stoller, C. Mioskowski. J. Millet, C. Sepulchre. and F. Bellamy, Tetrahedron Letters.

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R.B. Garland, M. Miyano, D. Pireh, M. Clare, P.M. Finnegan. and L. Swenton. J. Org. Chem.,

90.

M. Ohtani, T. Matsuura, F. Watanabe. and M. Narisada, J. Org. Chem., 1991, 56, 2122.

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M. Golinski, M. Heine, and D.S. Watt, Tetrahedron Letters, 1991, 32, 1553.

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K. Ditrich, Liebigs, Ann. Chem., 1990, 789.

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M. Nakatsuka. J.A. Ragan, T. Sammakia, D.B. Smith, D.E. Uehling, and S.L. Schreiber. .I. Am. Chem. Soc., 1990, 112, 5583.

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A.B. Smith, 111, I. Noda, S.W. Remiszewsk, N.J. Liverton, and R. Zibuck, J. Org. Chenr.,

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Chem. Ber., 1990, 123, 2181. N.I. Gusar, Uspekhi Khimii, 1991, 60, 285.

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P. Molina, M. Alajarin, and A. Vidal, J. Org. Chem., 1990, 55. 6140.

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Chem., 1990, 901. P. Molina, M.J. Vilaplana, and J. Perez, Tetrahedron, 1990, 46, 7855.

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P. Molina, A. Arques, and M.V. Vinader, J. Org. Chem.. 1990, 55, 4724.

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Organophosphorus Chemistry F-P. Montforts, U.M. Schwartz. P. Maib, and G. Mai, Liebigs Ann. Cheni., 1990, 1037.

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8

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. The high volume of activity balanced between basic and applied chemistry continues in this area. While there have not been any general reviews, the collected papers, including abstracts of posters, from the 11th International Conference of Phosphorus Chemistry (Tallin, 1989) have been published.' As in previous years, focused reviews will be cited in the appropriate sections below. 2

Acyclic Phosphaeenes

Interest continues in the area of acyclic phosphazenes, which are variously referred to as phosphazo derivatives, phosphine imines, or phosphoranimines. Reviews include a comprehensive and valuable survey of synthesis and reactivity of linear phosphazenes with emphasis on uses as synthetic intermediates in organic chemistry' , the use of N-vinyliminophosphoranes for the synthesis of nitrogen heterocycles ( in Japanese) , the synthesis of P-functional N-silylphosph~ranimes~, and the chemistry of iminophosphanes, phosph(III)azenes, including their conversion to phosph (V)azenes5. Ab initio MO calculations at a variety of levels of sophistication have been performed on monomeric and short chain phosphazenes. Calculations leading to estimation of heats of formation lead to the proposing of the experimentally unknown PNN-, NPN-, PNP-, and PPN- entities as new gas phase species.6 Two sets of calculations on H,PNH agree that the PN bond has high ylidic ~haracter.~'~ While H,PNH is calculated to be less stable than 313

Organophosphorus Chemistry

314

its tautomer, H,PNH,, the barrier to rearrangement is high.' The PN bond has multiple bond character but is dominated by coulombic interactions and shows little or no d orbital participation.' Conjugation effects have been explored at an LCAO-SCF level by investigation of the model compounds: (H,B) H,P-NH , (H,N) H,P=NH , H,P=NBH, and H3P=NNH2.9' lo The interaction of lone pairs which are coplanar with the formal double bond can strongly effect the stability and parameters of the geometric and electronic structures." The effect of inplane r1 bonding on the electronic transition energies of linear phosphazenes has been explored using semi-empirical CNDO/1 calculations. These (n') interactions lead to large optical transitions which can be modified by substituent electronegativity l1 Ab initio calculation on model short chain phosphazenes H3P(NPH,),NH (n=1-4) indicate the existence of PN bond length alteration.l2 Physical property measurements are dominated by NMR studies. The solid state 15N and 31PNMR spectra of [ 2,4 ,6-(Me$) ,C,H,N=P] +A1C14-have been obtained. The three components of the shift tensor have been resolved with the principle component being along the PN bond. The electronic environment is similar to other compounds with triple bonds to a nitrogen atom.13 The 15N, 31P and 13C NMR chemical shifts for a series of triarylphosphazenes, (pRC,H,),P=NPh, are controlled by the dipole of the RC,H, moiety which induces polarization of electron density within the PNPh unit. Correlations of the 'J,, data were examined using both the Hammett monosubstituent and the Taft dual substituent parameters.l4 A series of N=PPh, substituted pyrazoles, 1, provided a set of 13C shifts along with J13C3'P values. Coupling of the heterocyclic carbon atoms to phosphorus ('J, 3J, 4 J ) was observed.l5 The previously reported multiple NMR signals for Me,SiNPPh,CH,PPh, which were associated with restricted rotation about the PN bond have been shown instead to arise from chemical reactions of the molecule in question.l6 The dipole moments for a series of three coordinate phosph(V)azenes, R,P(=NR,)=NR,, have been obtained and used to calculate a PN bond polarity of 3.14D in the direction of phosphorus to nitrogen.l7 The use (MeZN),P=N-P ( NMe2)+, or P [ N=P ( NMe2)3] 4+ ions as phase transfer catalysts promotes 0-alkylation in the

.

8:

Phosphazenes

315

CI

Me

I

Ph

(7)

R’

2

CH2CH2CI

(9)

R

316

Organophosphorus Chemistry

reaction of dimethylsulfate with deoxybenzoin.“ The Staudinger reaction continues to be the most widely employed method of synthesis of acyclic phosphazenes. A few Staudinger reactions will be discussed in this paragraph, but most are the first step in a sequence where the phosphazene undergoes further synthetic transformation (see below). The C-2 symmetrical phospholane, (2R,5R)-l-phenyl-2,5dimethylphospholane has been used in the first enantioselective Staudinger reaction.‘ 9 The reaction of phenylazide with trans[PhNP(NMe,)], leads to the four membered ring with exocyclic phosphazene units (2,R=Ph; X=NMe,) A new synthesis of a valuable building block for metallocycle phosphazenes, Ph,P(=NSiMe,) NSiMe,, involves the reaction of Ph,PSiMe, with Me,SiN,. The Staudinger reaction of Me,SiN, with PhPR( CH2SiMe3) (R=Et, CH2CHMe2, Ph) gives PhPR ( CH2SiMe3)(=NSiMe,) .22 The phosphazotellurium derivative, Me,Te(N=PPh,), is obtained from the reaction of triphenylphosphine with the organotellurium diazide.,, The reaction of 3 (X=O, Y=N,) with triethylphosphite gives 3 [ X=O,Y=NP (OEt),] 24 A novel reaction of the coordinated o-benzoquine diimine 4 with triphenyl phosphine leads to 1,3,4RC,H, (NH,) N=PR, which is the major component of a tautomeric equilibrium with the cyclized h5-benzodiazaphosphole. The atrifluoro diazo compounds CF,CR=N, were characterized by derivatization with triphenylphosphine to the CF,CR=N-N=Ph, species.26 The reaction of ( [ 2- (diethylamino)methyl ] phenyl Jdiphenylphosphine with ethylcarbonazidate yields 1,2C6H4(CH,NRR’)PPh2=NC02R1’ which function as diuretics in rats.27 The use of carbon tetrachloride as an oxidant leads, via chloroform elimination, to dioxaphosphorinanes with exocyclic phosphoranimines. Thus, the reaction of 3 (X=lone pair, Y=NEt,) with CC1, and anilines gives 3 (X=NAr, Y=NEt,) and 3 (X=lone pair, Y=NHPh) with secondary amines and CC1, gives 3 (X=NRR’, Y=NPh) .24 Oxidative addition to phosph(II1) azenes represents another recently explored route to acyclic phosph(V)azenes. The reaction of RPClSiMe, with Et3CP=NCMe, gives the three membered heterocycle RkNCMe,P’CEt, via a phosphazene intermediate Me,CN=P (CEt,) =PR. The addition of RN3 to ClP=NAr gives a heterocyclic intermediate ClbN(R)N=NkAr which, in the case of large R groups, undergoes thermolysis to

.,’

.

‘*

8: Phosphazenes

317

a spectroscopically detected ClP(=NR)=NAr and on to the dimer 2 (X=Cl).29 In the case of the heterocyclic intermediate with R=CMe,, reactions with R’Li gives isolable R’P(=NAr)=NCMe,. 29 The attack of a-chlorolithium reagents, Cl(Li)C(SiMe,), on RP=NAr gives ArN=P(R)=C(SiMe,), presumable via a carbene route.,’ The reaction of RN=PPh, (R=l,2,4-trizenes) with diimides R’N=C=NR’ (R’=aliphatic) gives the Zwitterionic species (R’N)2E$(R)=PPh,.7 The oxidative addition of methanol to ( Me3Si),NN (SiMe,) P=NSiMe, gives (Me$ i) ,NN (SiMe,) PH (OMe)=NS iMe,.31 Sulfur or selenium oxidation of (Me2N),P=C (SiMe,) P=NSiMe, occurs at the phosph(II1)azenes center to form (Me2N),P=C (SiMe,) P=NSiMe, (X=S,se) 32 A one pot reaction of pRC,H,CN (R=CF,,Me,N) with LiN (SiMe,) 2, Ph,PCl and Me,SiN, gives a mixture of RC6H4C[N (SiMe,),] [ =NPPh,=N (SiMe,) ] and RC,H,C [ =N (SiMe,) 3 [ N (SiMe,) PPh,=N (SiMe,) 3 .33 A complex reaction is followed in the conversion of (EtO),PN(SiMe,)R to (EtO),P (=NR)C (CF,) ( OSiMe,) R’ by reaction with CF3COR’ A cyclic addition product 6C (CF,) ,C (CF,) ,Oh (OEt)=NCMe3 was also observed.34 The same silylaminophosphite when allowed to react with Me,CNO gives (EtO),P (=NR)N (CMe,) OSiMe,.35 The first triply bridging phosphazo coordination geometry is obtained in the photolysis of trans-NiC1(N3)(PMe3)2 which yields 5 or 6 depending on the wavelength employed. A direct synthesis of 6 from the Ni(I1) starting material and LiNPMe, was also established.,, Phosphorus(V) starting materials have also been used for synthesis of acyclic phosphazenes. The reaction of perfluoronitriles, RCN (R=C,F,, C,F,,, C,F,,) , with Ph,P=CR,’COR’’ provides cis and trans Ph,P=NCR=CR’COR” .37 The interactions of N-acetyltrichloroacetaldimine with [Ph2P(S)],NH leads to Ph,P ( S ) N=P (Ph),SCH (CC1,)NHCO,CH,. 38 The potassium salt of the C,H,CH,NP(X) (OCHMe,), (X=O,S) anion combines with Me1 in Me,CO to give C6H5CH2N=P(XMe)(OCHMe,) 39 Treatment of MeNHCONHC0,Me with PC1, gives [ C1,P=NCC1=CHPC1,]+PC1,-40 The reaction of (EtO),P(O)SiMe, with Me,CN=N(O) CMe, gave a mixture of products including Me,CN=P(OEt),OSiMe, which can also be obtained (along with other products) from (EtO),P (0) C1 and LiN ( SiMe,) CMe,. 41 The widely used I1PPN+I1ion can be easily obtained (in the form of (Ph,P),N+Cl-) from the reaction of Ph,P, PU1, and NH20H*HC1.42 Interest in reactions of the phosphazene unit, especially

.

.

,.

318

Organophosphorus Chemistry

in the synthesis of nitrogen heterocycles, continues to increase. The general strategy in these transformations is to generate a phosphoranimine, by the Staudinger reaction unless otherwise noted, which is allowed to react with a carbonyl moeity thus generating a reactive imine or carbodiimide. The reactive center is often adjacent to a substrate which can effect an intramolecular ring closure. This process is illustrated in the conversion of 7 to 8 by addition of RNCO to 7.43 The particular focus of this chapter does not allow for exploration of the elegant complexity of all of these syntheses so only the bare outline, focusing on the phosphoranimine will be mentioned for each citation. The most common carbonyl derivatives are the isocyanates which, as described above, provide carbodiimides. Heterocyclic and carbocyclic 2(triphenylphosphoranylidenamino)-3-carboxylates react with isocyanates to give 2-alkoxy-4-pyramidinones.44 The addition of ArNCO to PH,P=NCRC(O)R' followed by oxyalic acid gives amino-1,3-oxazoles.45 The interaction of aromatic isocyanates with 5-[N-arylimino]methyl-6[(triphenylphosphoranylidene)amino]-lI3-d~methyluracils gives functionalized pyramidino pyrimidines.46 Reduction of the imine gives materials which also undergo the same reactions to the hexahydropyrimido derivatives.46 In a complex series of annulations , the diazide 1,2-C6H4(N3)CH=N-2-C6H,N, upon reaction with triphenylphosphine and RNCO sequentially gives pentacyclic Enamino esters with 1,3 diamino [ 1,3 ,51benzotriazepines .47 units react with Ph,PCl, to a monoiminophosphorane which can cyclize with PhNCO to give pyrano[ 2 ,3-d]pyrimidine~.~* Pyrrolo[l,2-a]quinoxal~nesIindo[3,2-c]quinolines and indolo[l,2-c]quinazolines are available from aryl phosphoranimes with o-pyrrole or indole moieties upon reaction with isocyanates, CO, or CS2.49 The reaction of pyrimidine iminophosphoranes with isocyanates gives pyrido[2,3d]pyrimidine. Ring closure of P-aryl vinyl phosphoranimines via reaction with isocyanates leads to isoquinoline derivatives. Benzofuranones having attached p-iminoarenes are obtained from the reaction of the p-phosphoranimine with aldehydes.52 Phosphoranimines have been used in intramolecular aza-Wittig reactions to prepare pyrrolo-[1,2-a]benzimidazoles,

''

8:

319

Phosphazenes

fused quinazolinones, quinoles and an isoindolo[ 1,3 ,4 ] benzotriazepinone 53 The aza-Wittig reaction of l-(triphenylphoranylidene)-3-phenyl-2-th~oxo-4imidazolidinone with heterocumulenes gives fused imidazoles while with isothiocyanates forms imidazo[l,5d] [ 1,3 ,4 3 thiadiazines 54 Iminophosphosphoranes a to the nitrogen center in lr4-dihydropyridinesundergo addition and aza-Wittig annulation with acetylenedicarboxylates to give pyrido [ 1,2-a]pyrimidines.44 The phosphazide 2-Ph,P=NNC6H,CH=NPh cyclizes to 2,3-diamino-2H-indazole with a triphenylphosphoranylidene group in the 2-position which in turn add acyl chlorides and undergo acid catalyzed cyclization to fused indazoles.55 Anilinobenzoylpyrazoles with the anilino nitrogen atom converted to a C(0)CH2N=PPh, amide cyclize to benzodiazepinones.56 The intramolecular aza-Wittig reactions of hydrazones such as 2 ,4-Me02C(Br)C,H,NHN=C (C0,Et)N=PPh3 to give benzotriazepines is highly dependent on substituents.57 The reaction of tributy1(cyc1ohepta-1,3,5-trieny1imino)phosphoranes with a-P-unsaturated ketones gives 9H-~yclohepta[6]pyridinesvia a Michael-type carbon-carbon bond formation and subsequent azaWittig reaction.58 N-Vinyliminophosphoranes have proven to be valuable synthetic intermediates. The reaction of N-(1phenylviny1imino)triphenylphosphorane with 3 , 8 methano[ll]annulenone followed by dehydrogenation gives the 14a 1-aza-4I 9-methanocyclopentacyclo-undecene system.59 The interaction of tributyl(inden-3-y1imino)phosphorane with a,P The unsaturated ketones leads to 5H-indeno-(1,2-6)pyridines reactivity towards electrophiles of the N-vinyl iminophosphorane, EtO,CC(=CHPh)N=PPh,, has been examined. The aza-Wittig reaction with aldehydes and isocyanates gives the expected imines and carbodiimides. Treatment with acid anhydrides gives N-protected aminoacrylic acid derivatives. The reactions of PhCH=CHCH=C(CO,Et)N=PRPh, with PhCHO gives the imine when R=Me but with R=Ph cyclization to the diphenylpyridine-carboxylate occurs.61 Wittig precursors are obtained when the reaction Ph,P=NPh is allowed to react with propyl-2-ynyl-triphenylphosphonium bromide. The follow-up reaction with aromatic aldehydes gives P-enaminophosphonium salts, i.e., RCH=CHC(NHPh)=CHPPhiBr-. If a , p unsaturated

.

.

.,'

320

Organophosphorus Chemistry

aldehydes are used, tetrahydropyridines are obtained.62 Nphosphinyl-1-azaallyl anions add a, p unsaturated ketones to give phenylpyridines through an intramolecular aza-Wittig process.63 The addition of tri-n-butyl (or cyclohexyl) phosphine to ethyl-2-diazo-halonicotinoylacetates provides piperidinopyridazine carboxylates.& Arene imine derivatives of chrysene and benzo[g]chrysene can be prepared by the intramolecular reaction of vicinal alcohol and phosphoranimine functions.65 Addition reactions of phosphoranimines to give quaternary species are known. Addition of alkylhalides to Ph,PNR (NRlR”) gives quaternary ammonium compounds which on hydrolysis gives 2‘ amines& or amino acids.,’ Addition of acid chlorides to PhNHC (0) C (N=PPh,) =NNHC,H,X (X=H, Me , NO, , C1) leads to a quaternized nitrogen center which upon treatment with triethylamine give 1,2 ,4-triazoles The reaction of H2C( PPh2=NSiMe3) with Ph3GeC1 gives [Me,SiN=PPh,CH,P=N (SiMe,) GePh,]+Cl- which when treated with wet acetonitrile gives NH,PPh,=N=PPh,Me*Cl-. Direct treatment of Me,SiN=PPh,CH,PPh, with Ph3MC1 (M=Ge,Sn) in wet acetonitrile gives Ph,P(0)CH,PPh,.69 The addition of acid chlorides to Nvinyl phosphanimines gives the quaternized nitrogen species which add phenol to give azadienes or undergo hydrolysis to aamino acids. 70 The reaction of benzenediazonium The tetrafluoroborate with Ph,P=NPh gives [ Ph,PNPh,]+BF,‘. analogous quaternization occurs in the polystyrene derivative, [ CH2CH(C,H,PPh,=NPh) 3 which is prepared by radical addition polymerization of CH,=CHC,H,PPh,=NPh. 71 Hydrolysis chemistry is important in that one can consider the phosphoranimine as a protected amine. Thus hydrolysis of PhNHC(O)C(N=PPh,)=NNHC,H,X Vicinal diamines can be gives PhNHC (0) C (NH2)=NNHC,H,X. obtained from RCHBrCHR’NHP(0)(OH) by a sequence of conversion to the azide, Staudinger reaction with P (OEt) and hydrolysis.72 A preparation of the antibacterial moiety cefaclor goes through hydrolysis of the triphenylphosphino function in the last step to provide the primary amine site.n Pyridines with a C(O)C(=NN=PPh,)CO,Et entity in the 3 position can be hydrolyzed to the corresponding hydrazones.64 Alcoholysis reactions proceed in a manner analogous to hydrolysis reactions. The use of Ph2P(=NSO,C,H,CH,) 0 as a protecting group in benzoyl-protected

.,

,

321

8: Phosphazenes

glycopranose and its conversion to an RO unit upon reactions with alcohols has been developed.74*75 The reaction of Cl,P=NCH (CH,OH) CH (OH)C,H,NO, with methanol gives NHCH (CH,OH)CH (OH)C,H,N02 which along with related (MeO),P (0) species were prepared as bactericides, virucides, insecticides, ovicides and fungicides.76 A few miscellaneous phosphoranimine reactions serve to finish this section. The aziridino derivatives, (Et,N) (C,H,N) ,-,P=NR, react with the spirophosphoranes Cl,POC,H,O and C1,PN (Ph)N=C (CF,) 0 at both the phosphazene and aziridine units to provide four membered rings such as 9.77 The BF, catalyzed imide-amide rearrangement of (CX,O) ,P=NPh to (CX,O) ,P (0) N (CX,) Ph (X=H,D) has been examined. Both bimolecular and intramolecular pathways were observed.78 The reaction of Fe,(p-CH,) (CO) and RN=PPh, (R=ferrocene) gives a phosphorus free metallocycle (10).79 The other major class of reactions of acyclic phosphorazenes under consideration are those in which the phosphorus-nitrogen double bond stays intact during the transformation. The 4-phenylphenoxy derivatives, (RO),P ( 0)P (OR)3, ( RO),P ( 0)NP ( OR),NP ( OR) and (RO),PNP (OR),NP (OR),NP (OR),+PCl,- have been prepared from the chloro precursors and the aryloxide." The mercapto derivatives (RS),P=NP(O) C1, (R=Et, Pr, octyl) are available from Cl,P=NP(O)Cl, and the mercaptan in the presence of pyridine. An intermediate species, (RS),ClP=NP(O)Cl, was shown by ,'P NMR, to be in the reaction mixture.8' Bromination of RN=PCl,NR,' and Me,CN=PCl, with Me,SiBr provides RN=PBr2NR2' and Me,CN=PBr3.82 The lithio salt Ph,P=NLi can be converted to Ph,P=NR (R=C(0) R8,, C0,R8, , P (0)Ph?, S02C,H,Me67 , S0,C167) by reaction with the corresponding chloride and Ph,P=NBr by reaction with Br2.67 Reactions of Ph3PNS0,C1 with alcohols and amines give the appropriate sulfuryl derivative.67 The fluoroaryl derivatives Ph,P (=NC,F,Z) CHzPPh2 are obtained from the reactions of Ph2P(=NMMe3)CH,PPh, (M=Si,Ge) with F5C6Z (Z=N, CCN) .& The elimination of trimethylsilyl derivatives from the trimethylsilylphosphoranimines is widely used as a route to new phosphoranimine derivatives. The ReO, derivatives, ( O3ReN=PPh2) $HZ , ( 03ReN=PPh2) ,C2H4 and Ph,P=NRe03 are obtained from the trimethylsilyl precursors and Re207.85 The reaction of

,

322

Organophosphorus Chemistry

,

CF,=C ( CF,) with R,P=NSiMe, (R-OMe, OEt , We,) provides R,P=NCF=C (CF,) 86 Thermal decomposition of (EtO),P=NCF=C (CF,) The F, and CF,=C (CF,) CN. leads to ( EtO),P (0)F , (EtO)P (0) reactions of PhPF, with the trimethylsilyl precursors gives [ (Me,N),-,Me,P=NP(NMe,) ,-,Me,=N],P(Ph) F+PhPF,-(n=O,1) while { Ph,P [ N=P (NMe,) Me]2)+Ph,PF,- is obtained from Ph,PF3 and the appropriate trimethylsilyl derivative.87 Similar reactions with PCl, give ( Et,N) ,P=NPCl, , [ (Et,N) ,P=N] ,PC1 and [ (Me,N) Me,P=NP (NMe,) ,-,Me,=NPCl, 3. 87 The RNbC1, (R=$-C,Me, ; v5-C,Me,Et) reactions with trimethylsily precursors gives The reaction of Ph,P=NNbCl,R and [ RNbCl,N=PPh,] ,C,H,. Me,SiN=PPh,N=S (0) Me, with SeOC1, gives SeC1,[ N=PPh,N=S (0) Me2] .89 Derivatives of substituents on the nitrogen center in phosphoranimines also may be prepared. The reaction of 2,6diisopropylphenylisocyanate with Ph,P=NReO, gives Ph,P=NRe (NC,H,R,) 9* Silyl group exchange occurs when PhPR(CH,SiMe,) =NSiMe, is treated with Me2SiC1, to yield PhPR (CH,SiMe,) =NSiMe,Cl. 22 Phosphoranimines can function as Lewis bases in coordination compounds. The first reported borane adducts Ph3P=NR*BH3(R=Me,Et, n-Pr, i-Pr, i-Bu, t-Bu, Me,N, PhNH) can be prepared directly from BH3-THF or by reaction of the hydrobromides with LiBH,. Bis adducts, (Ph,P=NR) ,BH+I-, are obtained from the reaction of Ph3P=NR-BH21 with Ph,P=NR. The relative base strengths of the phosphoranimines have been established by BH3 exchange with other amine~.~’The reaction of [Rh$C1I2 where L=CO, cyclooctadiene (COD), with R3P=NR leads to 27 new Rh%Cl*NR=PR, complexes. The equilibrium between reactants and product depends not only on phosphoranimine substituents but also on L.92 The reactions of (CF3),PN=PPh3 with PdC1, and 0 s CO),,CH,CN and O s , (CO) (CF,),PN=Ph, lead to Pd,C1, [ (CF,) PN=PPh,] respectively. In each case, coordination is via the P(II1) center and both PN distance are equal indicating a delocalized PNP unit. Other examples of acyclic phosphazene reactions can be found in section 5. In addition to the cases noted above such as the diuretic other applications activity of 1,2-C,H, ( CH2NRR’)(Ph,P=NCO,R”) of acyclic phosphazenes have been suggested. Pyrimido[lI6,a]benzimidazoles with Ph3P=N substituents have been tested for

,.

,

,.

295

,’

6,

8: Phosphazenes

323

bactericidal and fungicidal activity.95 Phosphazocarbacyl esters, RC (0) N=PX, , have been examined for use as biocides .96 Plant growth inhibition is exhibited by Me2C=CHBuP(=NH)(OEt) 97 Rhizoxin esters with phosphono or alkylphospho substituents on the ester show antitumour activity toward mouse leukemia P388 .98 Nitro-fluorenimines with N=PR, groups on the imine nitrogen are used as electron acceptors in electrophotographic photoreceptors 99

,.

.

3 Cyclophosphazenes

The factors controlling the regio-and stereochemical pathways followed in the substitution reactions of halocyclophosphazenes have been reviewed in detail. Predictive schemes for the reaction pathways have been proposed.loo The influence of side groups on the ability of cyclophosphazenes to undergo polymerization or ring expansion has been reviewed.lo' A brief review in Japanese on inorganic phosphazenes is also available.Io2 Ab initio SCF-MO calculations on the (NPO), series have been performed. The cyclophosphazene dimer, 11, is a global minimum and the corresponding trimer is also predicted to be stable. Vibrational frequencies for these experimentally unknown species have been calculated.lo3 The nitrogen and phosphorus XPS data for (NPR,), (R=C1, F, MeO, CF,CH,O, C6H50) confirm the high polarizability of the PN bond induced by the exocyclic substituent. These results are interpreted using ab initio MO calculations.lo4 The phosphorescence spectra oi' hexakis(P-naphthoxy1)cyclotriphosphazene in both solution and rigid matrixes have been obtained and closely resemble those of naphthalene chromophore.lo5 The motion of guest molecules in cyclophosphazene inclusion compounds has been investigated using the narrow spinning side bands observed in the 'H MAS NMR spectra.lo6 The mass spectra of [NP(OPh)2]3,4 show 65 to 90% of the total ion current is carried by the M+ and [M-60]+ ions.lo7 Mass spectrometry has also been used to investigate the thermal degradation of [NP(OPh)2],,4. Above 4 4 0 ' the trimer gives a resinous solid plus volatiles include triphenylphosphate, phenylamine and phenylaminophosphates. The tetramer exhibits similar behavior at a lower onset temperature. The

Organophosphorus Chemistry

324

N

L o

O=P'

N''

8: Phosphazenes

325

decomposition of the partially substituted materials N3P3(OPh),.C1, starts at 280’ and gives the same products along with HC1.1°8 The kinetics of the reaction of N3P3C16 with CF,CH,OH under phase transfer conditions have been followed using gas chromatography. Second order rate constants for all six steps of substitution have been obtained. Interestingly, the rate of reaction for N3P3C1,0CH,CF3 is faster than N,P3C1, otherwise the expected decrease with increased degree of substitution is observed. These data indicate the operation of both electronic and steric effects.’09‘’10The rate of amidation o-nitroaniline by acetic acid in the presence of N3P3C1, and pyridine is independent of acetic acid and pyridine by linear phosphazene. The formation of N3P3C1,0C(0) CH3 followed by reaction with acetic acid to give N,P3C1,0H and acetic anhydride as the active agent was proposed.”’ The UV and NMR spectra of 12, its 1,2 naphthoxy isomer, and derivatives with the bis phenylamino and phenylenediamino moieties in place of the aryloxy groups suggest intramolecular interactions between the aryl R systems and the aziridine lone pairs. Strong intermolecular hydrogen bonding in the phenylamino and phenylenediamino derivatives was observed. It has been proposed that these interactions are related to the relative degree of cytostatic activity in these derivatives.’12 The cytostatic activity of aziridinocyclophosphazenes has also been suggested to be related to the conformation of the aziridino groups as reflected in their solid state structures.‘13 Cyclophosphazenes containing amino groups have been employed as curing agents and extensive testing of resulting resins has been reported.’14-’16 Bisphenol A type and novolak expoxy resins cured with N3P3(OPh) (NH,) , N3P3(OC,H,NH,) , N3P3( OPh) (OC6H4NH,) and N3P3(NMe,)3C13 have been subjected to viscoelasticity, tensile, thermogravimetry and chemical resistance testing.’I4 Expikote 828 expoxy resin cured with 2 ,2-N3P3(OCH,CF,) (NHZ) was superior to resins cured with N3P3(OPh) (NH2) or N3P3(NMe,) 3C13 as shown in modulus of rigidity, tensile strength, and chemical resistance testing. Similar studies show 2 ,2N,P3(OC,H,C1),(NH,), superior to 2,2-N3P3(OPh),(NH2), as a curing agent. l6 The only cyclophosphazene synthesis from non-cyclic

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precursors this year involves the photolysis of R,P(S)C=N-NPR, (R=i-Pr) which undergoes elimination of R,P(S)CN to give (R,PN) presumably via the monomeric phosphazyne.'17 Mixed substituent isothiocyanato derivatives N3P3R5NCS (R=OPh, OCH,CF, , OCH,CH,OCH,CH,OCH,) and N3P3(NMe,) (NCS) were mathematically prepared from the chloro precursor and KNCS.118 The reaction of the (NPC1,)3,, mixture with liquid ammmonia has been studied.'19 The diaryloxy derivative 12, its 1,2 naphthoxy isomer, the 2,2bis anilino and phenylenediamino derivatives are obtained from the reaction of aziridine with the appropriate chloro precursors.112 The remaining amine derivatives are all obtained from di or polyamines. The reaction of hydrazine and (NH,NH),P(O) OPh with N3P,C1, give the spirocyclic derivatives 13 (R=P3N3C1,, P(0) OPh) .120 The para substituted diamino linked phosphazene oligomers N3P3C1,[ NHRNHN,P,Cl,] "C1 [ n=1-5 : R=p-C,H, , p-C,H,C,H,, 1,11'-binaphthyl-4,4l-diylr p-C,H,EC6H, (M=O, S, SO,, CH,, CMe, N=N)] are available from N,P3C1, as are the analogous oxyo (0 in place of NH) derivatives.12' The reactions of oxodiamines continue to supply a plethora of interesting new structures. The reaction of NH, (CH,)3O (CH,),O (CH,),NH, with N,P3C1, in a two phase (Et,O/Na,CO, water) system gives the trans "dibinol'derivative ( N,P,Cl, [ NH (CH,),O (CH,),OCH,) ,NH] ) (14 n=2) .122 The products of the reaction of N,P3C1, with NH, (CH,) 3O (CH,),O (CH,),NH, are remarkably sensitive to reaction conditions.123 In a stirred homogeneous or heterogeneous THF solution the bridged species N3P3C15NH(CH,) 3O (CH,),O (CH,) ,NHN,P,Cl, is obtained.123'124 The spiro derivative N3P,C1, [ NH (CH,)3O (CH,)0(CH,),NH] is obtained as a by-product of this reaction.123 If an unstirred heterogeneous, THF/Na,CO, aqueous, medium is employed the reaction proceeds stereospecifically to trans 1 4 (n=6) 123*125 The reaction of N,P,Cl, with spermidine gives two products , 15 and 16, involving bridged tetramer units. The corresponding spermine reaction leads a single product, 17, which also has two bridged tetramer units. The NMR parameters for these new materials are compared to those for the analogous derivatives of N,P,Cl,. 126 The reactions of cyclophosphazenes with oxyanions continues to be the most widely explored of phosphazene reactions. This is in large part due to using the reactions at

,,

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the trimer level to model reactions of poly(dich1orophosphazene). The simplest oxyanion, the hydroxide anion, has a complex pattern of reactivity which has again attracted attention. A detailed 31PNMR study of the hydrolysis of N,P3C1, in THF has been reported.'27*"8 The initially formed N3P3C1,0H or its tautomer (NPC1,),NHP(O) OH, reacts with additional hydroxide by both geminal and nongeminal pathways both eventually leading to the geminal , and NPCl, (NHP( 0 )OH) species. Oxobridged dimers ( N,P3C1,0H) O (N,P,Cl,) 2O have also been proposed"8 but the assignment of the latter has been shown to be incorrect from the NMR of an authentic (crystallographically established) sample.129 This sample was obtained from a reaction of N,P,Cl, with the monosodium salt of uracil in the presence of Bu,NBr which in addition to the substitution product 18 showed two hydrolysis products, the aforementioned dimer and N,P3C1,0-.129 The synthesis of N3P3C16-n(OR), (R=CF3,CH,109 , Phl3O) via phase trans catalysis (NaOH, Bu,NBr) has been shown to be a very efficient procedure. Significant rate accelerations have been observed and both mass transfer and chemical kinetics influence the rates of reaction. Column chromatography proved to be effective in separation of the trifluoroethoxy derivatives.lo9 Optimum conditions for the preparation of N,P, (OPh) (OC,H,NO,) have been patented."' The synthesis of the potential polymer precursors, 2 ,4-N3P3( OPh) (OR) (R=C,H,-p-CHO , C,H,-p-OH , CH,C=CH) , has been described.132 The treatment of 2 ,2N,P,Cl, (N=PCl,) with NaOR (R=Ph, CH,CF,) proceeds with sequential substitution initially at the exocyclic positions to provide 2,2-N3P,C1,[N=P(OR),], followed by formation of 2,2N3P3(OR) [ N=P (OR)3 ] 133 Numerous oxyanion derivatives with one substituent containing a reactive center suitable for further transformation have been prepared. These include N3P,C1,0 (CH,) ,OC ( 0 )C (CH,) =CH,l3, , N,P, (OR)5O ( CH2CH,0)3C,H4CH=CHC,H,N0,'35 , N,P, (OPh),O (CH,O)O , (CH,) ,NHOC ( 0 )OCMe313, and N3P3X,0C,H,CH0 , (X=C1, OCH2CH3).13' Fully substituted derivatives have also been ,CH,CH=CH, explored. The reaction HO ( CH2CH,0)7 M e and HO ( CH2CH20) with N3P,C1, was carried out to prepare precursors to polyelectrolytes Cyclophosphazenes with biphenyl mesogenic

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Organophosphorus Chemistry

groups have been prepared by reactions of the appropriate oxyanion with N3P3Cl,. Monotropic nematic texture in the range of 59-102 was observed for N3P3[ 0(CH2CH20) ,C,H,C,H,CN] but none of the related species, N3P3[ 0( CH2CH20),C,H,C,H,OR] 6 (R=Me, Et I Pr , iPr, Bu), were liquid ~rystalline.’~~ A nematic phase was detected for N,P, (OC6H,C,H,CN) by DSC and polarized microscopy but the related N,P, (OC,H,N=NPh) showed no mesomorphic activity.140 Both the trimeric and tetrameric 4-phenylphenoxy derivatives,

,

,

[ NP ( OC,H,C6H4) 2 ] 3 , 4 , have been prepared and examined by x-ray crystallography Treatment of a mixture of cyclic oligomersI (NPCl,),, with KOC,H,Br gives cyclic materials with bromophenoxy substituents.14’ Polyfunctional oxyanions have also been investigated as nucleophiles towards cyclochlorophosphazenes. The spiro derivatives, N,P,Cl,~,,R, (n=l,2 : R=2 ,2l-dioxy-1,1’biphenyl are available in two phase reactions from the alcohols and in turn treatment of the disubstituted material with sodium phenoxide or aziridine gives N,P, (R’) (R) (R’=OPh, NC2H4) 142 The reactions of N,P,Cl, with 2,2-dimethylpropane-1,3-diol results in the formation of a wide range of products reminiscent of the behavior of other alkane diols. The mono, di and tri spiro derivatives N,P3C1,-,,[ OCH2CMe2CH20], (n=l,2 ,3) , the 2 ,4 bridged (ansa) species, 2 ,4-N3P3C1,( OCH2CMe2CH20) I the mono spiro , mono ansa species, 18, and the doubly bridged species analogous to 14 with OCH2CMe2CH20in place of the oxodiamines have been dete~ted.’,~A similar array of products is obtained in the reactions of N3P,C1, with bis(2-hydroxyethy1)ether. The three spiro derivatives, N3P3C16-,,, [ (OCH,CH,) ,0], (n=1-3) I the ansa , i.e. , 2 ,4-N3P,C1,[ (OCH,CH,) 20] the spiro-ansa derivative analogous to 18 , the bridged species N3P3C1,0(CH,),O (CH2),0N,P3C1, and the doubly bridged entity analogous to 14 have been observed. An 0x0 bridged dimeric hydrolysis product N,P3C1, [ 0(CH,)2O (CH,),OH]ON3P,C1, was also obtained.144 The reactions of another diol, diethyl bis(hydroxymethyl)malonate, with N,P4C18 results in the formation of a series of spirocyclic materials which include N,P,C16[ (OCH,),C (C0,Et),] , 2 ,2 I 4,4N,P,Cl,[ (OCH,)2c (CO2Et)2 1 2‘ 2 I 2 I 6 ,6-N,P,C1, [ (OCH,)2c (CO,Et)212 and The product distribution and NMR N,P4 [ (OCH,)2C( C02Et)2]4. spectra were compared to those obtained in the propane-lI3-diol and the 2 ,2-dimethyl propane-1 ,3-diol series.145 The

.”

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tetrafunctional pentaerythritol has been shown to undergo extensive reactions with both (NPCl,),,&. Products include the spiro bridged dimers 19 (n=l,2), the trimeric spiro ansa bridged dimer 2 0 and a mono spiro derivative with two free diol functions, N,P,Cl, [ OCH,C (CH,OH) ,CH,O] 146 The chemistry of heavier congers in the oxygen group is limited but interesting. The 1,l'-dichalcogenato ferrocene anions undergo reaction with N,P,Cl, to provide the spirocyclic derivatives N3P3C16(EC,H,) ,Fe],, (n=1,2,3i E=S,Se) of which 21 is an e~arnple."~ A limited number of new reports of the syntheses of phosphazenes with phosphorus-carbon bonds have appeared. The reaction of N,P3C1, with RMgCl in the presence of (n-Bu),PCuI followed by addition of Me3SiCH21 leads to 2,2'-N3P3C1,( CH2SiMe3)R (R=Et, CHMe,, Bu, CMe,, CH2CMe3,Ph) . Displacement of the remaining chlorine atoms by the trifluoroethoxide ion occurs clearly in toluene but some carbon-silicon bond cleavage occurs when THF is the solvent.148 The reaction of N,P,F, with LiCH,SiMe, provides N,P, (CH,SiMe,) in nearly quantitative yield. The geminal di- and tetrasubstituted species have been detected in solution.149 The appropriate Grignard reaction leads to N3P,C1, [ C,H, ( CMe,) ,] which undergoes ortho group activation upon treatment with aluminum chloride to yield 2 2 . 150 The sequential reaction of N3P3C1, with RMgX/ (Bu3P),CuI followed by aldehydes or ketones provides a general synthesis of the series 2,2'N,P,Cl,(R)C(OH)R'R" (R=Me, i-Pr, t-Bu; R'=H, Me: R"=Me, Et, CO,Et, CH=CHMe, C,H,FeC,H,, Ph, etc) . If R1+R1',the two =PC1, centers become non-equivalent and coupling may be observed in the ,'P NMR spectrum. Evidence has been obtained for coordination of the copper ion to the phosphorus center in the phosphazenocuprate intermediate.15' The reactions at exocyclic positions of cyclophosphazenes continues to play an important role in the chemistry of these materials. Some of these processes have been mentioned above. Fluoride ion induced carbon-silicon bond cleavage allows for conversion of N3P,(CH,SiMe,) to N,P,Me, in good yield. Treatment of 2,2-N,P3F4(CH,SiMe,) with NaOCH,CF, also leads to carbonsilicon cleavage to generate 2 ,2-N3P3(OCH2CF3) ,Me,. 149 The thermal rearrangement of N,P, (OR)6-n ( OC6H,Me) (R=Me, n=1-3 ; R=Et , CH,Ph, n=3) yields [ (NR)P(0) (OC6H4Me)1, with retention of the

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Organophosphorus Chemistry

330

Ph ,E=N, N II R2K

R3 I

R’

XNYPT)

rlR2

N N=E’ Ph

F;’? R2

(23)

R3

(24)

R

I

(25)

8: Phosphazenes

33 1

geometrical disposition of the aryloxy group. The mono and dimethoxy derivatives, N,P,(OMe)n(OC,H,Me),~, (n=1,2), provide Thiourethane and [ (NR)P (0) ( OC6H4Me)3 ,[ NP (OC,H,Me) ,] 152 thiourea derivatives are available from the reactions of alcohols and amines with isothiocyanato cyclophosphazenes.'la Thus the reaction of N,P, (NCS) with ROH provides N,P, [ NHC (S)OR], (R=Me, Et, Pr, Bu, Me,CH). The reaction follows a non-geminal pathway as shown by ,'P NMR detection of intermediates. Under similar conditions the mixed derivatives, N,P,(OR),NCS (R=Ph, CH,CF,, CH,CH,OCH,CH,OCH,) were unreactive. At higher temperatures the trifluoroethoxy derivative gives the expected reaction while 2,4,6-N3P,(NMe,)3(NCS)3 gives N,P3(NMe2)3(0Et)3 through a labile N,P,(NMe,),[NHC(S)OEt]3 intermediate. Reactions of N,P,(NCS), with amines lead to N,P,[NHC(S)NHR], (R=H, Me, Ph, Bu, C,H17) The tetramer, N,P,(NCS)a, undergoes similar reactions but with lower reactivity.'la Careful hydrolysis of N,P,Cl,-,(HNCN) , (n=2,4 ) gives the trimetaphosphimates, Na,[ (NH),P,O,-,(NCN) "1 .153 Radical addition polymerization of the olefin in N3P3C150(CH,),OC (0) C ( CH,) =CH2 gives a carbon chain polymer with the cyclophosphazene as a substituent. Copolymerization with methylmethacrylate has also been investigated. Reactivity ration data and the derived AlfreyPrice parameters show the phosphazene exerts a significant effect on the olefin rea~tivity.'~~ The sequential reaction of N,P, ( OCH2CF3)50C6H,CH0 with borohydride and methacryloyl chloride gives another organofunctional monomer, N3P,(OCH,CF,) ,OC,H,CH,OC (0) C (CH,) =CH,, which also undergoes radical addition polymerization at the olefinic center. Interestingly higher molecular weights are obtained at low conversion than at high conversion.13' Sidewise coupling reactions allow for synthesis of primary amino groups as side chains. The deprotection of N,P, (OPh),O (CH,),O (CH,),NHOC (0) OCMe, with trifluoroacetic acid gives a amine at the end of the CH,CH,C (0) substituent. Coupling with CMe30C(0)ONHCH,CO,hC (0) gives a 0(CH,) ,O (CH,)NHCOCH,NHOC (0) OCMe, side chain and the process may be repeated to give tripeptide substituents.'36 A cyclomatrix shift base phosphazene polymer is obtained from the The treatment of N3P3(OC,H,CHO) with p-phenylenediamine.15' synthesis of tetraphenylporphrine with N,P,(OPh)O units in the

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meta position of the phenyl groups is accomplished by the interaction of N,P3 (OPh),OC,H,-m-CHO with pyrrole. The Zn2* and Cu2* pyrophrin complexes are obtained from reaction of the neutral ligand with M(OAc), (M=Zn, Cu). The metal uptake rate is 100 fold slower than that for tetraphenylporphyrin.lS5 Metal complexes of a spiro oxodiamino derivative, N,P3C1, [ NH ( CH,) 3O ( CH,) ,O (CH,),NH] have been reported. Reaction with butyl lithium leads to the lithium complex of the monodeprotonated ligand which in turn adds MEt, (M=Zn, Mg) to give N,P,Cl, [ N (CH,),O (CH,) ,O (CH,),N] OM. All three complexes are dimers in the solid state with the Mg2+ complex involving one endocyclic nitrogen atom in the coordination sphere. The ionic conductivity of complexes obtained from the reaction of LiClO, [ OCH, ( CHZOCHZ) .CH20CH3] ) (n=l 2 ) is with ( CH2CHC6H4C6H40P3N3 comparable to that of the oligo(oxyethy1ene) derivatives of the poly (phosphazenes) lS7 Other cyclic oxyethylene derivatives such as N,P,R, [ R=O (CH,CH,O) ,C,H,-p-C,H,,] are excellent ligands for alkali metal salts and function as effective phase-transfer catalysts.'51 Preliminary reports of metal carbonyl activation of N3P3F5C=CPhhave appeared. Excess phosphazene in the presence of Co, (CO) gives the cyclotrimer 1 3 4-C, (N3P3Fs) ,Ph, which exhibits restricted rotation about the carbon-phosphorus bonds. The reaction with q5-C,H,Co (CO) gives a Co coordination cyclodimer, carbonyl insertion products and the cyclotrimer. similar reactions with Fe2(CO), are even more complex providing in addition to the species described above, a metallocycle and a novel product arising from an alkyne bridging iron and the oxygen of a coordinated cyclobutadienone.lS9 The formation of q6Cr(CO) coordination to phenyl groups on cyclophosphazenes has been examined in detail. The direction reaction of N,P,X,R with Cr (CO) gives N,P,X,R*Cr (CO) (X=F, R=Ph ; X=OCH,CF, R=Ph , OPh; X=C1 R=OPh; X=NH,C,H,, R=OPh) Alternatively N,P,Cl, and NaOPh. Cr (CO) gives N3P3C150Ph-Cr (CO) and N3P3X,R*Cr(CO) (X=F, R=Ph; X=C1, R=OPh) with NaOCH,CF, gives the trifluoroethoxy derivatives. Partial substitution can be accomplished as shown by the reaction of N,P,R, with Cr(CO), to give N,P,R,R*Cr(CO), (R=Ph, OPh, OC,H,Me, OCH,CH,OPh, NHPh) . Full loading of the metal carbonyl fragment can also be obtained as shown by the formation of N3P3[OR Cr (CO),] from N,P3C1, and NaOR Cr ( CO)3 . 160 I

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I

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I

I

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Phosphazenes

333

While not an exocyclic group reaction, it is of interest to note the formation of sulfur trioxide complexes of N,P,(OPh),. Coordination is believed to occur at the endocyclic nitrogen atoms leading to N,P,(OPh),.nSO, (n=1-3). Different coordination arrangements in the tris adduct give rise to an A2B ,‘P NMR spectrum.’6’ The continued high level of commercial interest in cyclophosphazenes is demonstrated by the numerous patents filed citing applications of these materials. The extraordinary level of interest shown in derivatives of hydroxyethylmethacrylate , HO (CH,),OC (0) C (Me)=CH, (HEMA), noted last year continues unabated. Cyclomatrix materials from thermal or photochemical curing HEMA/cyclophosphazene derivatives exhibit good hardness, dimensional stability, mechanical strength, and chemical resistance.162 Improved properties are obtained by combining the HEMA derivatives with polymeric (or polymer precursors) materials. This approach has been used with fibers (glass ~ 1 0 t hpolyester’&) ’~~~ , to provide surface coated materials, acrylic resins’65, polyester containers’66, polyester film167,polyester sheets for ink ribbons in magnetic recording, etc. 168’169, in combination with siloxanes or reactive silanes to give water repellency and other low surface adhesion properties ( C,F12CH2CH,SiMeC1,’70, NH, ( CH,) ,S iMeOSiMe,171 , hydroxy1 terminated dimethy1s i1oxanes’72 ) and styrene based resin composites.ln Other HEMA applications include components of transparent laminated films in electronic devices’74, as antioxidants in powdered iron magnetic coatings’75 and in x-ray blocking materials.176 Mixed amido/alkoxy, aryloxy, alkylamino on dialkyl amino induce shrink resistance Amidophosphazenes provide wash and stain into cotton.17’ resistance in cellulosic fabrics.178 Other cyclophosphazene applications include antiradiation cover layers for electronic component^'^^, cross linking of expoxy resins114-116’180, aminophenoxyphosphazenes as flame retardants in polystrene blends’” , flame proofing of lignin and lignosulfonates with , heat resistant rnaterialsla3, chlorophosphazenes’s2 amidophosphazenes as catalysts for the condensation reaction of aminoplasts’% , and fluoroalkoxy derivatives as superior lubricants for metals.185

334

Organophosphorus Chemistry

There is a surprising absence of publications in this year. It remains to be seen if this reflects a trend or an aberration. 7 The aromaticity index calculated for Ph,P=NC(Ph)=NS(Cl)=h is in the range of the symmetrical triazines suggesting similar electron distributions. The reaction of R,P(NSiMe,) [N(SiMe,) ] with PhECl represents a good method for phospha(thia)zene synthesis. The reaction products R,P,N,E,Ph, (R=Me, Ph ; E=S , Se) exhibit the eight-membered ring structure 23. Hydrolysis of the S(V1) derivatives ~(NH,),NP(NH,),NS(O) (0M)k (M=Na+,Rb’, NH;) is reported to give the aminotrihydroxy species, h (OH),NP (OH)(NH,)NS (0)(OM)N’. 188 5 Miscellaneous PhosDhazene Containina Rina Svstems Includina MetallaDhosDhazenes

A review of the synthesis and reactivity of six and eight membered metallacyclophosphazenes1a9as well as a comprehensive review (in Russian) of the preparation, properties, structure, and reactions of five and six membered mono- and dicycl~phazenes’~~ are available. Aromaticity indices for F,hNCCCF,)NC(CF,)h are similar to the symmetrical triazenes while the values for phosphazene containing phospholes are low suggesting less aromaticity in the latter.‘& Addition of the cyclophosph(II1)azene ;=NC(Ph)=Nk(Ph) with amines and diamines and iodine or enamines give five membered monophosphazenes such as ( Et2N),b=NC (Ph)=Nh (Ph) and 2 4 . 19’ Hydrolysis of the spiro derivatives 2 4 leads to phosphorus-nitrogen cleavage in the spiro ring whereas in 2 5 the cleavage occurs at the phosphazene bond. In all cases the P=N center is the strongest base site.192 The reactions of azaphospholes, R,b=NCPh,C (C0,R)=E (C0,R) with activated arylazocarbonitriles give the 1,5,2-h5-diazaphosphorines 26 and 2 7 . 193 Six membered rings with one phosphazene , (Me,N),P=CHP (NMe,),=NC (R)=kH, are obtained in the reactions of (Me,N),b=CHP(NMe,)=CH with RCN (R=furan, pyrrolidine) .‘91 Deprotonation of the cyclic ammonium precursors gives Ph (Me);=NCH=CRCH=;R (R=Me, Et , Pr , Bu) 195 The reaction of acetylurea with PC1, provides 1

.

335

8: Phosphazenes

(C~~P=NCC~=NCC~=CH + PPCC~~~which ~ )upon treatment with SO, yields Cl,$=NCCl=NCCl=&H. 196 The addition of MeO,CC=CCO,Me and I (NC),C=C (CN) to ( R2N),P (S)CENNP ( NR,) (R=i-Pr) gives ( R2N),P=N1 N=C[P(S) (NR,),]C(CO,Me)=&(CO~e,) and (R,N),P=NN=C [ P (S)(NR,) ,] C [ C (CN)=C (CN),] =h respectively.19’ The reaction of (NPC1,) NCCl with aryloxide ions gives [ NP (OC,H,X) ,] NC (OC,H,X) (X=H, CMe,, CMe2Ph, OMe, Ph, CO,Me, CF,) .198 The remainder of the new reports in this area involved metallacyclophosphazenes. The Me,MN=PPh,CH,PPh, (M=Si, Ge) ligand can coordinate to both early and late transition metals at two sites, i.e., the nitrogen center (with or without Me,M removal) and the phosphine center. In that way monophosphazene cyclic materials SiMe,) =PPh,CH,hPh, (M=Mo,W) , such as (CO)&fi( Cl,$dN (MMe3)=PPh,CH,hPh, (M=Si, Ge) , (COD)MN=PPh,CH,PPh, (M=Rh, Ir-, COD=cyclooctadiene) and C1 (CO)RhN (MMe,) =PCH,$Ph, can be formed.84 The combination of early and late metals in the same species can also be achieved. The Me3SiN=PPh2CH2EPh2(E=P, As) i provides a core for construction of C1,Ti (Cp)h=PPh,CH,EPh,PdCl, ( Cp=qS-C,H,) by two routes, from the linear phosphazene containing the CpTiC1, unit by addition of PdCl,(CH,CN), or from the cyclic palladium complex by addition of CpTiCl3.lW The LiCH2PPh2=NR (R=C6H,-p-Me) reagents reacts with (ML2C1) dimers to give 2 8 (M=Rh, L=COD, CO; M=Ir, L=COD).200-201Reaction of 2 8 (M=Rh) with HC1 leads to disruption of the metallacycle by Rh-C bond cleavage.,O0 The acyclic diphosphazenes, CH, (PPh,=NR) (R=C6H4X; X=Me, OMe, NO,), combine with the aforementioned (MhC1) dimers to give a mixture of (L,hNR=PPh,CH,PPh,=hR) +C1and [ L 2 M w C H ( P P h 2 N R )]+C1’ the latter arising from a novel C-H to N-H hydride shift. The deprotonated form of the diphosphazene, LiCH ( PPh2=NR) gives L,MNR=PPh,CH (PPh,=NR) . The reaction of (Me,Si) ,NPPh2NSiMe3 with ZrC1, gives More complex metallacycles are C1,irN (SiMe,) PPh,=kSiMe,. obtained from TiC1,/Ph2P(=NSiMe3) OSiMe, and 1 C13V=NSiMe,/PhzP (Cl)=NSiMe, which give Cl,d?iOPPh,NTi (Cl,) OPPh,N and Cl,;NPPh,NV (Cl,)NPPh2h respectively. An unexpected ring 1 atom exchange reaction occurs when C13do=N-PPh2=N-PPh2Nreacts with Ph3SiOH and C1202MoOPPh2NHPPh20is obtained. A direct route to this compound is from C12Mo02 and O=PPh,N=PPh,OH. If Me3COH is used in place of Ph,SiOH a monophosphazene,

,

-

,

,

,

,

-

-

336

Organophosphorus Chemistry

C1 (O)doOPPh,=NPPh,b is obtained which is shown by ESR spectroscopy to exhibit little ligand-metal delocalization. A direct route to this complex is from the reaction of MoOC13 with Na[OPPh,NPPh,O]. Oxidation of the complex gives the dioxo species O,doOPPh,=NPPh,b. ,02 Similar chemistry occurs when C1,V=NPPh2=NPPh,=N is allowed to react with Me3COH, Me3COLi or Ph3SiONa and a low yield of O=+-[OPPh2N=PPh2a]2 is obtained. The ESR spectrum of this d' complex does not show any resolved 31 P hyperfine coupling again indicating low degrees of metalligand delocalization. The complex may be prepared directly from VOC1, (THF) and 2Na (OPPh,NPPh,O) ,03 Another novel reaction occurs when MoOC1, is treated with (H2NPPh2NPPh2NH2)+C1and in addition to the expected Cl,ho=NPPh,=NPPh,=k, Cl,M6 (=NPPh,=NPPh,b) is obtained.,03 The reaction of NaN [ P (0) Cl,] with Me3SiC1 gives Me3SiOPCl2=NP(0) C1, in which trimethylsilyl group exchange between oxygen atoms is seen in the low temperature 31PNMR spectrum. This silyated derivative reacts with MC1, to give h(OPCl,NPCl,b), (M=A1, Gar In) , with Me,SnCl, to give Me,SA (OPCl,NPCl,O) and TiC1, to give I The titanocycle is also available from C1,Ti (OPC12NPCl,b) LiN[P(O) Cl,] .,04 Formation constants for LN(N[P(O) (OEt)2]2)3 have been obtained.,05

,

.

,

,

,.

,

6 Polv (DhosDhazenes)

This section is devoted to polymers containing open-chain phosphazenes and related cross-linked materials. Cyclolinear and cyclomatrix phosphazene polymers are covered in section 3 . A review of the preparation, properties and uses of poly (phosphazenes) is available.206 Additionally several brief , focused reviews of the following topics have appeared: the role of side groups on the ability of cyclophosphazenes to undergo polymerization"' , the role of the leaving group on polymerization vs cyclization in the thermal decomposition of Me,SiN=P (X)R, , anionic polymerization of phosphoranimines to linear phospha~enes~~', polymers obtained from functionalization of anions derived from deprotonation of { Ph(Me) PN]n208J209r preparation and characterization of liquid crystalline poly (phosphazenes),lor use of poly (phosphazenes) as drug

337

8: Phosphazenes

controlled release"' and biodegradable materia1s2l2 and two less accessible reviews of poly (phosphazene) chemistry.213'214 The replacement of N into the PO, tetrahedron to yield nitride phosphates has been reviewed.215 The synthesis of poly(phosphazenes) from small molecular precursors continues to attract attention. Polymerization of N,P,Cl, by a catalyzed solution process yields high molecular weight with a narrower molecular weight distribution than that obtained from bulk polymerization.2'6 New elastomers have been obtained from the bulk homopolymerization of N,P,F,R (R=CMe,, Ph) , 2 ,4-N,P3C1,R2 (R=Me, Et) and (NPClMe) and copolymerization of (NPClR), (R=Me, Et) with N,P,Cl,. After derivatization with OCH,CF,, a series of elastomers with Tg ranging from -40 to -60' were ~btained."~Similar polymerization reactions of N3P3C1,0Ph alone and with N3P,C1, (OPh) occur.218 Poly (phosphazenes) with defined short chain linear phosphazene branches are obtained when 2,2N,P,Cl,(N=PCl,), is heat to 150' for two hours. Derivatization with oxyanions preferentially takes place at the side chain allowing for synthesis of (NPCl,NP[N=P(OR),],), and ( NP (OR),NP [ N=P (OR), ],) , ( R=CH2CF3, Ph) .133 The ring-opening polymerization of N3P3(NCS), leads to low molecular weight [NP(NCS),In polymers.219 Anionic initiation of (CF,CH,O) P=NSiMe, polymerization by BU,NF gives essentially a quantitative yield of [(CF,CH,O),PN],, PTFE, at temperatures below 100'. A narrow polydispersity (1.52) is observed.220'221 Heating of [NP(NH2)2]3,4leads to a material proposed to be [NP(NH2),In although previous work suggests the formation of imidophosphazenes.'19 Interest in heterophosphazene polymers I first noted last year, continues. The ring-opening polymerization of (NPCl,),NCCl occurs at 120- to yield [(NPCl,),NCCl], which maybe derivatized to a series of hydrolytically stable aryloxy polymers, [NP(OAr)2NC(OAr)],. Glass transition temperatures of these materials are 16 to 42O higher than the corresponding [NP(OAr)2]n analogs. No Tm Similar treatment of (NPC1,),NS (0) C1 process was observed.19* gives [(NPC12),NS(0)C1], which can be derivatized sequentially by phenoxide with the EPC1, centers being more reactive.222 The reaction of Li,N with P,N, gives pure LiPN, which exhibits

,,,

,

,-

338

Organophosphorus Chemistry

corner sharing PN, tetrahedra.223 Ammonolysis of (NaP03) gives phosphorus oxynitride glasses. The UV/Vis spectra of these glass with Pb2+,Nd3+ and Eu3+ probes allows for the suggestion that the nitrogen atoms are inserted between phosphorus atoms in the metaphosphate chains.224 The synthesis of poly(phosphazene) derivatives by single or multistep reactions of preformed polymers allows for the construction of otherwise unavailable polymers. Some of these reactions have been described above. High molecular weight [NP(NSC)2]n is obtained by metathesis from the chloropolymer. Reactions of the isothiocyanato polymer with alcohols leads to partial formation of thiourethenes while reactions with amines lead to complete conversion to thiourea side groups. Mixed substituent alkoxy-thiourea or thiourethane polymers also can be Vulcanization of (NPRR') (R=NHBu; R'=NHBu, NEt,) with isothiocyanato poly(phosphazene) derivatives is more effective than with OCN (CH,),NCO. 225 Preparation of [NP(NHBu)x(OPh)2-x]nand vulcanization with hexamethylene diisocyanate has been reported.226 Poly (phosphazene) derivatives of the sodium salt of diacetone D-glucose alone or mixed substituent (NHMe, OPh , OCH2CF3, OCH,CH,OCH,CH,OMe) derivatives can be prepared and converted to the free glucose containing polymers by acid hydrolysis of the protecting group.227 Mixed substituent polymers containing viologen side chains linked to the phosphazene chain by alkoxy residues have been patented.,'* Enantiotropic liquid crystallinity is observed in poly(ph0sphazenes) bearing biphenyl mesogenic groups which are obtained from (NPCl,), and the ethyleneoxy derivatives 0(CH,CH,) ,OC,H,C,H,R. '39 Liquid crystalline poly (phosphazenes) containing 0 (CH,),0C6H,C6H4CN229 , OC6H4C02R (R=Bu, amyl , decyl) 230 and OCH,CH,0C6H,N=NC6H,C,H,231 substituents have been prepared and characterized. Azoxybenzene units with chiral alkoxy terminal units have been introduced as poly (phosphazene) side chains.232 Photochromic spiropyrans have linked to poly(phosphazenes) through oxomethylene spacers, O(CH,CH,O),O (n=2,3). Solid state or solution photolysis reversibly generates merocyanine group.233 Primary amino acid groups protected by N-tert-Butylcarbonyloxo (BOC) groups can be coupled to the phosphazene via a O(CH,),O spacer. Sequential

8: Phosphazenes

339

deprotection and amide formation allows contruction of tripepiptide side chains (see section 3 ) Aminoacid esters with quaternized amines react with (NPCl,), to give the aminoacid ester derivatives.234 The synthesis of a wide range of polymers having the composition [ NP (OCH2CF3)(OR), 3 (R=O(CH,CH,O) ,C6H4(CH=CH),,,C6H,A; k, m=1-3 A=N02, CN) have been prepared and exhibit non-linear optical activity.135 The synthesis of [NP(OC6H,C(0)OEt),], followed by hydrolysis to the free acid, [ NP (OC,H,CO,H) ,] , gives a polyelectrolyte which can be crosslinked with polyvalent cations to give hydrogels. These hydrogels are the first synthetic polymers which can be used for encapsulation of cells, liposomes and proteins. Encapsulated liver cells retain their activity.235 Poly(phosphazene) electrolytes for solid state ionic conductivity have been obtained as metal salts of 01 i g o a l k y l e n e o x y p h o s p h a ~ e n e s ' ~ ~ 'and ~ ~ ~from ' ~ ~ ~ the lithium salts238 of sulfonated aniline functions prepared by the reaction of [ NP (NHPh),] ,with HS03C1.239 Surface reactions of poly(phosphazenes) have attracted attention this year. The reactions of solid PTFE with Na(OCH2CH2),R (R=OH, CN, NH,) induces displacement of trifluoroethoxy groups at the surface by the nucleophiles to more hydrophilic surfaces. The surface hydroxyl and amino group can be further functionalized by reaction with phenylisocyanate.240 Similar reactions of commercial fluoroalkoxy phosphazene rubber materials have been reported.241'242 Surface hydrolysis of PTFE with NaOH/Bu,NBr gives surface-O-NB; groups leading to adhesive properties. Cations can bind to the modified surface. Similar chemistry on aryloxy derivatives was explored.243 Plasma etching by atomic oxygen has been applied to phosphazene films. Significant backbone changes occurring in fluoroalkoxy derivatives.244 In a comparison of OCH2CF3, OEt , NHPh, NHC,H,Cl , OPh and OC6H,C1 derivatives the aromatic amine and phenoxides were more resistant with the bisanilino derivatives exhibiting stability similar to Novolak resin.245 Finally, [NP(OCH,CH,OCH,CH,OMe) ,In (MEEP) may be entrapped in poly(methylmethacry1ate) which is crosslinked with dimethylacrylate or poly(styrene) crosslinked with divinylbenzene to give the first characterized phosphazene containing interpenetrating polymer networks.246

340

Organophosphorus Chemistry

Physical measurements and calculations on poly(phosphazene) systems are an important ongoing area of concerns. Ab initio MO calculations on short chain models H,P(NPH,),NH suggest that internal bond length alternation continues to the high polymer level.’, A combination of Huckel and third-order perturbation approaches allowed for calculation of the 3rd order hyperpolarizability, for (X,PN),. The effect, which is comparable in magnitude to organic polymers, is dependent ligand electronegativity and relates to the n orbital energy difference between phosphorus and nitrogen.247 The second harmonic generation ability of poly(phosphazenes) is claimed to be related to substituent polarization and hence the ability to design desireable properties by substituent modification.248 The bond polarity indicated above does not preclude understanding of electronic structure in terms of molecular symmetry.” CNDO/1 methods have been used to calculate vertical ionization energies and electronic absorption energies. Experimental ionization energies, as measured by XPS, have been shown to relate directly to the polarizability of the PN bond which is more significant in the polymers than in cyclic systems. lo4 ESCA measurements have been used to evaluate surface effects of atomic oxygen The presence of surface modifications of PTFE reactions from treatment by nucleophiles was established by a battery of methods (XPS, SEM, TEM, ATR-IR and contact angle measurements) .240 According to XPS data, the concentration of N is lower on the surface than in bulk for PON, PON-P,N,, (PON)(P,N,) .75 , P,N, , (PNH,) (P,N,) .4 and PN,H 249 Electronic spectroscopy of poly[bis(P-naphthoxy)phosphazene] has been studied. No naphthalenic triplet-triplet absorption or phosphorescence was observed and the behavior of the polymer is significantly different from the trimer in both solution and rigid matrices. lo5 The microenvironment created by { [NP(Me) Ph] (NPPhCH,CO,H) ) ” in aqueous solution was examined using three different fluorescent probes. The polarity at high pH was similar to MeOH. The phosphazene can bind positively charged ions and repel negative ions.250 FT-Raman spectra of samples [NP(OC,H,Me)2] with different thermal histories were related to the crystalline and mesophase content of the .2441245

.

8:

Phosphazenes

341

materials .251 Cross-linked phosphazenes can be oriented in an electric field to give materials with excellent piezoelectric properties.252 Second-harmonic generation by (NP( OCH2CF3) [ 0(CH,CH,O) ,C,H, (CH=CH),C6H,H] 2-x ) films is achieved by application of electric field. The 2nd-order non-linear coefficients were determined and related to polymer composition and structure.13’ Morphological and related studies have been carried out on numerous systems. The effect of different production technologies on Tg, temperature of the secondary relaxation and m.p. of crystalline phases of PTFE has been studied.253 The thermal history of samples of [ NP(OC,H,Et) ,In strongly effects the formation of the crystalline state and its morphology as shown by small-angle light scattering and polarized microscopy during the transitions from the crystalline to the mesophase and on to the isotropic melt.254 Phases available to PTFE by changes in annealing temperature have been probed using DSC.255 A detailed study of the liquid crystalline behavior of [ NP (OCH,CH20C6H4N=C6H,C4H9) ,] by DSC, polarized optical microscopy and x-ray diffraction has appeared. Semetic A and C phases were detected and related to structural features involving the side chain.23’ The PTFE crystal-mesophase (T,) and mesophase-isotropic phase (T,) transitions have been studied as function of added solvent (DMSO and ethylacetate). DMSO lead to decreased T, until 5% DMSO when the mesophase disappeared and T, and T, merged.256 Electronmicroscopy of ultrathin PTFE films showed a radical effect of solvent (heptane, dioxane, DMSO, C2C1,) on morphology. T, was decreased by some solvents providing a mesomorphic transition at a lower temperature than the initial T,.257 Features of flow and structure of PTFE-high density polyethylene (HDPE) blends were studied by thermochemical, xray, electron microscopy, and rheological methods. Viscosity of blends is close to PTFE viscosity or below it. A specific morphology having PTFE fibers in the HDPE matrix surrounded by a poly (phosphazene) shell was proposed.258 Polyethylene with 10% PTFE exhibits a 3.5 fold decrease in melt viscosity due to concentration on the extrudate surface and behaving as a low viscosity lubricant.259 The conformationally disordered state of the PTFE mesophase has been related to these effect^.^^'-'^'

342

Organophosphorus Chemistry

The phase transitions in [ NP (OC,H,R) 2] (R=OMe, SMe) were studied by DSC, x-ray diffraction and optical microscopy. The substituent effect on thermal transitions and mesophase formation in these and related polymers have been analyzed. A significant dependence of the crystallization kinetics on the temperature of the mesophase in I and I1 was noted.',' The azoxy group suppresses side-chain crystallization in poly(phosphazenes) with azoxybenzene derivatives having chiral alkoxy terminal units as side chains. The thermal behavior depends on spacer group length and morphologies were proposed from consideration of x-ray data.232 Gas permeation of 13 gases in PTFE above the mesophase (T1)transition were measured. Notable changes above and below T, are observed and proposed to relate to gas ( C 0 2 ) dispersion in the rnesophase.262 The gas permeability and selectivity for poly(phosphazene) membranes show that [NP(OC,H,Et),], had the highest N, H selectivity while PTFE had the highest CO,, He selectivity. Dielectric constant is an important parameter in increasing gas permeability.263 Phosphazene thin film electrolytes continue to be studied extensively. Electrochemical stability of MEEP,LiSO3CF, has been carefully studied. Diffusion constants for solutions of electroactive activity solutes such as ferrocene in this system have been obtained.264 Mixed MEEP poly (propyleneoxide) LiX electrolytes have been evaluated and found to be amorphous with increased dimensional stability and slightly decreased conductivity.265 MEEP blends containing LiC10, or LiBF, have also been studied by 7 L i NMR. Significant cation mobility occurs only above the lowest Tg.'& The CO dependent solid state electrochemistry of 10 combined with MEEP/LiCF,SO, has been studied.78 The storage power of [ NP (NHPh)1.26 ( NHC6H4S03H). 7 4 ] (which could be repeatedly charged and discharged) was determined.239 Solid state conductivity and transference numbers for numerous other oligoalkyleneoxyphosphazenes have been reported.138.236-238.267 Thermal degradation of poly (phosphazenes) has been examined using 31PNMR, gas chromatography and mass spectrometry to evaluate the products.268 PTFE undergoes random chain cleavage followed volatilization of cyclics. Aryloxy species followed a similar path and also exhibited cross-linking. Cross-linking was the

8: Phosphazenes

343

exclusive mode for alkylamino, ferrocene or ruthenocene derivatives.268 Additional products were observed for [NP(OPh)2], including triphenylphosphate, aniline and phenylaminophosphates.'ol The effect of steam hydrolysis on phenoxy derivatives with variable degrees of residual phosphorus-chlorine bonds was examined.'08 The optical properties of various poly(ph0sphazene) thin films on silica or silicon were determined. The effect of laser damage to the films was related to substituent groups on the polymer."' Solution characterization of poly(phosphazenes) have received less attention this year. Two samples of [NP(OEt)2], with significant different mo3.ecular weights were characterized by light s~attering'~' and viscometry along with GPC.271 Classical parameters such as Mark-Houwink coefficients, unperturbed dimensions and 2nd viral coefficients were calculated. The Kerr constants for PTFE solutions are available and were 3 to 4 orders higher than those for flexible chain macromolecules. The high polarity of the chain depends on the dipole moment of the monomer unit.272 The heterogeneity and kinetic stability of PTFE solutions are influenced by molecular weight, solution concentration, and polymer chemical modification but not by solvent.273 High-performance size-exclusion chromatograph, gradient reversed-phase HPLC and ion chromatography were used to characterize the water soluble, biodegradable, poly (chloromethoxytrialanine methyl ester phosphazene) .274 A significant volume of applications oriented material is available indicating the ongoing commercial interest in these materials. A significant number of these relate to solid state conductivity applications in which variations on batteries typically having a lithium anode, metal oxide cathode and electrolytes made of various oligoexyethylene/poly(phosphazenes) combined with ionic salts.275-280 Poly(phosphazene) films containing oxyethelene side chains have several desirable properties such as antistatic, hardness, transparency, etc., which makes them suitable for photographic materials.281-283A particularily noteworthy system is a blend of MEEP and silica obtained by the sol-gel process.284 Phosphazene photoresists based on PTFE and related material^'^' or side chains containing carbonyl groupszw have been reported.

344

Organophosphorus Chemistry

PTFE has also been used as a component of a membrane light modulator. Surface modification chemistry of PTFE has been used for surface property improvement.288 Blends of commercial poly(ph0sphazenes) (Eypel A) and organic polymers are suitable for low-smoke and fire resistant coatings.289 Protein fibers, e.g. silk, can be shrink proofed using amidophosphazene resins.290 Biological applications have also attracted attention in areas such as controlled release of active agentsZ9’ 292 and marine antifouling.293 7 Molecular Structures o f PhOSDhaZeneS

The following structures have been determined by x-ray diffraction. All distances are in picometers and angles in degrees. ComDound

Comments

Me,S iNPPh,CH,PPh,

PN 152.9(3); LNPCH2 116.6 (1)

(RN),CN(Me) PPh,.CHCl, (R=l,2,4 triazene)

7 PN 166.2(3); LPNCR,123.1(2) weak, long distance P.. .N

(RN)2CN (Et)PPh3*1/2 C,HaO, R=1,2,4 triazene)

PN 165.6(4); f PNCR, 123.5(3)

7

(RN),CN(n-Pr) PPh3*2CHC1, (R=1,2,4 triazene)

L PNCR, iig.i(6)

PN 165.1(8);

7

PN 154.9(2);

30

PN 154.1 (2); PNCSi, 143.99 (9)

30

4-CF,C,H,C [ N ( S iMe,) 3 NPPh,NS iMe,

P=N 154.5 (3) : PN 166.8(4)

33

4-Me,NC,H,C (NSiMe,) N ( S iMe,) PPh,NS iMe,

P=N 154.8(7): PN 165.2(6)

33

2 , 4 ,6- (Me,C),C,H,NP ( CMe,) C (SiMe,)

2,4,6(Me,C),C,H,NP[

2

(X=NMe,, R=Ar=Ph)

16

.

,

,

(Me,C),C,H,] C (SiMe,)

(Me3C),PP (NMes)NCEt, Mes=2,4,6-Me3C,H,

Ref.

L PNCSi2 133.39 ( 8 ) L

PN=153.1(4) : 153.7 (4) L N=P=N 139.7 (2) N,P, ring and NPh coplanar P=N 151.8

29 20

345 s l i g h t l y d i s t o r t e d 80 from p l a n a r : c i s / t r a n s backbone PN 152.4(13), 153.3(13), 157.1(14) LPN,P 142.6: L PN,P 127.8 ( C13PNPC13)+VOCl,-

PN 157(2), 152 (2) LPNP 138(2)

294

R h (COD)C 1 (RN=PEt3) R=p -to 1y 1

NRh c o o r d i n a t i o n PN 160.8(3): LRhNP 121.0

92

PN 157.3(3), 157 ..2(3) PNH, 162.4(2); LP=N=P 142.9

69

PN=160.5 (16): L PNRe 180.0(1)

90

(NH,PPh,NPPh,Me) +C1'

Ph3P=NRe(NR) R=2,6- ( i - p r ) ,C,H3 ( 03ReNPPh,) ,C,H,

SeC1, [ NPPh,NS ( 0 )Me,]

,

Ph3PNNbC13( vS-C5Me4Et) [ (v-'C,Me,Et)

NbCl,NPPh,] C,H,

PH,Cl, [ (CF,) ,PNPPh3]

PN 157.2(7);

85

PN(Se) 158.9(9), 163.5 (9) PN(S) 162.7(9), 161.1(9)

89

PN 160.0(3);

88

L PNRe 154.1 (3)

L PNNb 168.5 (2)

PN 159.3(3); L PNNb 172.8(2)

88

(-3) ,PPd 93 coordination; PN 155.9(6), 158.3(8) LPNP 143.4(5)

(CF3) ,pas 94 coordination; PN 155.5(15), 155.3(15) LPNP 175.4(12) PN,, 157.5 (2)158.8 (2) . . PN(Me,) 161.7(7), PN (CS) 169.0 (9)

118

p l a n a r ; PN,,, 113 165.7(6), 165.6(5) PN,, 155.9 (5)-160.3 (7)

Organophosphorus Chemistry

346 2,cis-4,trans-6,trans-8-

non-planar ; PN,,, 161.8 (mean) PN,, 156.1 (mean)

14 (n=2)

planar N3P3 ring 122 trans t o 30 membered (chair) ring; PN,, 156.0 (5)-159.9 (5) PN,,, 161.1(5) 161.5(4)

N,P, ( N E t , )

,c1,

29 5

N,P, rings trans 124 to chain; PN,, 154.8 (8)-161.1 (8) PN,,, 159.4 (8): NH....OH bond

trans bridge 125 PN,, 154.9 (5)-160.5 (5) PN,,, 158.3 (5), 158.4 (6) N3P3 slightly 80 puckered ; P N 155.4 (7)-160.2 (7) L N P N 115 1 ( 4 ) - 118 0 ( 4 ) L P N P 120.9 (5)-123.2 (4)

.

.

boat; 80 P N 152.9 (9)-157.1(8) L P N P 132.1(6) -138.7 (6) 1 N P N 119.5 (5)-121.4 (5) P N 157.4(1), 129 158.3(1) I 157.9(1) L P O P 128.8(2) I 135.5(2) [ N P (OPh)2 ] ,NP ( 0 )OPh

boat ; P N 154.6-160.7

296

P3N3 147 essentially planar: P N 156-160 1 SPS 109.4(1) I 109.2(1)

21eTHF

N3P3 ( C H 2 S iMe3)6

distorted chair:

L N P N 116.5

149

PN 158.0 (5)-161.6 (5)

2 I 2 -N,P,Cl,

( CH2S iMe,) ( CMe,)

puckered chair; 148 P N 155.1(1) -162.0 (1) L C P C 108.85(9) ; L N P ( C 2 ) N 113.94(7)

2 I 2-N,P,Cl,

( C H 2 S iMe,)

puckered chair: 148 P N 155.0 (2)-163.5 (1) L C P C 107.9(1) ; L N P ( C 2 ) N 113.09 ( 8 )

347

8: Phosphazenes PN(mean) 1 6 2 . 7 ( 6 ) , 154.6(4) , 158.0(4) f CPC 9 5 . 1 ( 2 ) ; LNP(Cz)N 1 1 2 . 8 ( 3 )

22

N,P,F,C,H,

q6-Cr

(co)

150

PN 1 5 5 . 3 ( 5 ) 160 157.0(4) PFR 1 5 5 . 4 ( 3 ) ; PF, 1 5 2 . 1

,

LiN30,

(N,P3C1,RLi) R=NH (CH,) 3O (CH,) ,O (CH,) ,N

156

coordination;

P3N3 p l a n a r PNexo 1 5 8 , 166 PN, 154-165 156

ZnN302 coordination; d i s t o r t e d N3P3

156 6 coordinate Mg, includes endocyclic N; N3P3 h a l f c h a i r PN, 154-170 PNexo 161-6

(N,P,Cl,~g) 2 R=N (CH,) 0 (CH,) ,O (CH,) 3N

29

297

'endo

1 5 8 . 2 ( 9 ) -164.5 ( 9 ) PNexo 1 6 3 . 2 (10) 166.4 (11)

-

Two S atoms 187 d i s p l a c e d from P,N, p l a n e ; PN 1 6 2 . 2 ( 5 ) , 1 . 6 1 4 ( 4 ) ; L NPN 1 1 9 . 7 ( 2 )

23 (E=S)

26

(R=R1=Me,

R1'I=NOZ, R"I1=C1)

27

(R=R'=Me,

R"=NO,,

(R?N) ,+NNC [ P ( S ) (NR,) R=i-Pr

R"'=H)

,3

C ( C0,Me)

1

C 1 3 Z k N (SiMe,) PPh,NSiMe,* CH,CN

C1,T iOPPh,NT i Cl,OPPh,N

4 CH,CN

2 8 (M-Rh,

IiCOD)

1

R=p-tolyl,

o n l y minimal data given

193

o n l y minimal

193

d a t a given

t ( C0,Me)

n e a r l y p l a n a r r i n g 197 PN, 165.6 ( 4 ) PN,,,, 1 6 4 . 0 ( 3 ) , 1 6 4 . 2 ( 3 ) 'endo

161.5(5) , 160.0(5) C NPN 1 0 0 . 5 ( 2 ) ( e n d o )

21

nearly planar 21 8 membered r i n g ; PN 1 6 0 . 5 ( 2 ) s h o r t T i N ; l a r g e f PNTi PN 1 6 2 . 4 ( 2 ) ACPN 9 9 . 1 ( 2 )

200

348

Organophosphorus Chemistry I -

,

ClzOzMoOPPPh,NHPPhzd* THF

PN 1 6 5 . 5 ( 1 2 ) 165.7 ( 1 2 ) LPNP 1 2 3 . 2 ( 6 )

2 02

ClOMoOPPh,NPPh,O

PN

159.6(5) 159.6 ( 6 ) LPNP 1 2 5 . 7 ( 4 )

202

PN

202

159.1(2) 157 ( 3 ) LPNP 1 2 5 . 3 ( 2 )

O$ ( OPPh2NPPh2b) r

1

ClzMO(OPPhZNPPhzN) 3CH3CN

PN

158.9(2), 203 158.6(2) , 159.2(2) 123.7(1) , 124.2(1)

LPNP PN

156.4(14)157.6(12); 165.4 ( 8 ) -164.0 ( 7 )

203

chelate via P=O; PN 1 5 7 ( 2 ) - 1 5 3 ( 2 )

298

first triply bridging phosphoranimine PN 1 6 0 . 9 ( 7 )

36

1 5 5 ( 2 ) -150 ( 2 )

5

LiPN,

References 1. 2. 3. 4. 5.

6. 7.

8. 9. 10. 11.

PN, Td; PN 1 6 4 . 5 ( 7 ) ; L PNP 1 2 3 . 6 ( 8 )

223

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8: Phosphazenes

12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

22. 23.

24. 25. 26. 27. 28. 29. 30. 31. 32.

33. 34. 35.

36. 37. 38.

39.

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8: Phosphazenes 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80

I

81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93

I

94.

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Organophosphorus Chemistry

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95. 96. 97 98. 99.

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354

Organophosphorus Chemistrj

148. H.R. Allcock, D.J. Brennan, B. Dunn and M. Parvez, Inors. Chem., 1988, 2 7 , 3226. 149. H.R. Allcock, W.D. Coggio, M. Parvez and M.L. Turner, Orqanometallics, 1991, 10, 677. 150. B. De Ruiter, J. C. van de Grampel and F. van Bolhuis, J. Chem. SOC.. Dalton Trans., 1990, 2303. 151. P.L. Bawalda, A. Steenbergen, G.E. Oosting and J.C. van de Grampel, Inorq. Chem., 1990, 29, 2658. 152. S . Karthikeyan and S.S. Krishnamurthy, J. Chem. SOC., Dalton Trans., 1991, 299. 153. H. Koehler, S . Ahmed and L. Jaeger, 2. Anors. Allq. Chem., 1990, 588, 55. 154. I. Maruyama, H. Fujiwara, 2. Ito and H. Shigematsu, Jpn. Kokai Tokkyo Koho, JP 02024325 (Chem. Abst., 1990, 113, 60133g). 155. 1.1. Selvaraj, D. Reddy, V. Chandrasekhar and T.K. Chandrasekhar, Heterocvcles, 1991, 39, 703. 156. M. Veith, M. Kross and J.F. Labarre, J.. M o l . Struct., 1991, 243, 189. 157. K. Inoue, Y. Nisikawa and T. Tanigaki, Macromolecules, 1991, 2 4 , 3464. 158. D. Landini, A. Maia, L. Conda, A. Maccioni and G. Podda, Tetrahedron Lett., 1989, 30, 5781. 159. C.W. Allen, P. Malik, A. Bridges, J. Desorcie and B. Pellon, PhorDhorus, Sulfur Silicon Relat. Elem., 1990, 49/50, 433. 160. H.R. Allcock, A.A. Dembek, J.L. Bennet, I. Manners and Parvez, Orsanometallics, 1991, 10, 1865. 161. E. Montoneri, G. Ricca, M . Gleria and M.C. Gallazzi, Inorq. Chem., 1991, 30, 150. 162. H. Ando, Jpn. Kokai Tokkyo Koho, JP02142831 (Chem. Abst., 1990, 113, 153340n). 163. A. Kurahashi, Jpn. Kokai Tokkyo Koho, JP02199174 (Chem. Abst., 1990, 113, 213404~). 164. A. Yaguchi, Jpn. Kokai Tokkyo Koho, JP02129263 (Chem. Abst., 1990, 113, 154438n) 165. A. Yaguchi, Jpn. Kokai Tokkyo Koho, JP02133447 (Chem. Abst., 1990, 113, 117227~). 166. A. Kurahashi and S . Moni, Jpn. Kokai Tokkyo Koho, JP02057555 (Chem. Abst., 1990, 113, 134270~). 167. A. Yaguchi, Jpn. Kokai Tokkyo Koho, JP02160872 (Chem. Abst. 1991, 114, 45132h). 168. H. Ando and A. Kurahashi, Jpn. Kokai Tokkyo Koho, JP02284904 (Chem. Abst., 1991, 114, 187671g). 169. A. Yaguchi, EP368165 (Chem. Abst., 1990, 113, 117200h). 170. H. Ando, Jpn. Kokai Tokkyo Koho, JP02284925 (Chem. Abst., 1991, 114, 187703u). 171. H. Ando, Jpn. Kokai Tokkyo Koho, JP02142832 (Chem. Abst., 1991, 113, 1533233). 172. A. Kurahashi and M . Kitayama, EP394918 (Chem. Abst., 1991, 114, 16645733). 173. A. Yaguchi and K. Funaki, EP376021 (Chem. Abst., 1991, 114, 208825~). 174. A. Yaguchi, EP400625 (Chem. Abst., 1991, 114, 165916~). 175. A. Yaguchi, Jpn. Kokai Tokkyo Koho, JP02047281 (Chem. Abst., 1990, 113, 98757b). 176. S. Anzai, Jpn. Kokai Tokkyo Koho, JP02247192 (Chem. Abst., 1991, 114, 143710q).

.

8: Phosphazenes

355

177. T. Sasakura, Jpn. Kokai Tokkyo Koho, JP02014074 (Chem. Abst. , 1990, 113, 25516n) 178. T. Sasakura and Y. Anasako, Jpn. Kokai Tokkyo Koho, JP02084562 (Chem. Abst., 1990, 113, 99356g). 179. F. Quella, 0. Nuyken, K. Budde and T. Suefke, US4925772 (Chem. Abst., 1991, 114, 153928f). 180. K. Takahashi, N. Ishikawa and H.S. Yoon, Zairvo, 1990, 39, 1001 (Chem. Abst., 1990, 113, 232576~). 181. M.D. Bezoari, US486047 (Chem. Abst., 1990, 113, 24242h). 182. H. Struszczyk, PL149680 (Chem. Abst., 1991, 114, 209445r). 183. A.N. Afanas'eva, V.G. Karkozov, V.M. Mokhov and M.Ya. Surpina, Khim Tekhnol.. Svoistva: Primenenic Plastmass, L,1989, 61 (Chem. Abst.. 1990, 113,7687q). 184. M. Kouril, A. Studnicka, J. Kabela, K. Dostal, M. Alberti and J. Mencl, CS265992 (Chem. Abst., 1991, 114, 186964t). 185. T. Dekura, US4898683 (Chem. Abst., 1990, 113, 100705d). 186. C.W. Bird, Tetrahedron, 1990, 46, 5697. 187. T. Chivers, S . S . Kumaravel, A. Meetsma, J. C. van de Grampel and A. van der Lee, Inorcr. Chem., 1990, 29, 4591. 188. I.A. Rozanov, L. Ya. Medvedeva and L.V. Geova, Russ. J. Inorcr. Chem. (Ensl. Transl.), 1990, 35, 1416. 189. H.W. Roesky, Svnlett, 1990, 651. 190. R.I. Tarasova and V.V. Moskva, USD. Khim., 1990, 5 9 , 931 (Chem. Abst. , 1990, 113, 115369~). 191. O.D. Diallo, L. Lopez, Y.K. Rodi and J. Barrans, Phosphorus. sulfur Silicon Relat. Elem., 1991, 56, 17. 192. O . S . Diallo, L. Lopez and J. Barrans, Tetrahedron Lett., 1991, 3 2 , 501. 193. W. Ried, M. Fulde and J.W. Bats, Helv. Chim. Acta, 1990, 7 3 , 1888. 194. E. Fluck, M. Spahn and G. Heckmann, Z. Naturforsch. B: Chem. Sci., 1991, 46, 762. 195. c. Bedel and A. Foucaud,Tetrahedron Lett., 1991, 32, 2619. 196. V.G. Rozinov, M. Yu. Dmitrichenko, V.I. Donskikh, G.V. Dolgushin and A.V. Kalabina, SU1583423 (Chem. Abst., 1991, 114, 143704r). 197. M. Granier, A. Baceiredo, M. Nieger and G. Bertrand, Anaew. Chem. Int. Ed. Ensl., 1990, 29, 1123. 198. H.R. Allcock, S.M. Coley I. Manners, 0. Nuyken and G. Renner, Macromolecules, 1991, 24, 2024. 199. K.V. Katti and R.G. Cavell, Orcranometallics, 1991, 10, 539. 200. P. Imhoff, S.C.A. Nefkens, C. Elsevier, K. Goubitz and C.H. Stam, Orcranometallics, 1991, 10, 1421. 201. C.J. Elsevier and P. Imhoff, Phosphorus, Sulfur Silicon Relat. Elem., 1990, 49/50, 405. 202. M. Rietzel, H.W. Roesky, K.V. Katti, H.G. Schmidt, R. Herbst-Irmer, M. Noltemeyer, G.M. Sheldrick, M.C.R. Symons and A. Abu-Ragabah, J. Chem. SOC., Dalton Trans., 1990, 2387. 203. M. Rietzel, H.W. Roesky, K.V. Katti, M. Noltemeyer, M.C.R. Symons and A. Abu-Ragabah, J. Chem. SOC.. Dalton Trans., 1991, 1285. 204. A. Mazzah, H.J. Gosink, J. Lieberman and H.W. Roesky, Chem. Ber., 1991, 124, 753. 205. V.L. Rudzevich, A.O. Gudima and V.A. Kalibabchuk, Russ. J. Inoru. Chem. fEncrl. Transl.1, 1990, 35, 1560. 206. P. Potin and R. DeJaeger, Eur. Polvm. J., 1991, 27, 341.

.

356

Organophosphorus Chernistr.

207. K. Matyjaszewski, Polvm. Mat. Sci. Enu., 1991, 64, 104. 208. P. Wisian-Neilson, R.R. Ford, S. Ganapathiappan, M.S. Islam, K.S. Raguveer, M.A. Schaefer and T. Wang, Phosphorus. Sulfur Silicon Relat. Elem., 1990, 51/52, 165. 209. P. Wisian-Neilson and L.M. Huang, Polvm. PreDr. (Am. Chem. SOC.. Div. Polvm. Chem.1, 1990, 31, 428 (Chem. Abst., 1991, 114, 165029b). 210. R.E. Singler, R.A. Willingham, C.Noe1, C. Friedrich, L. Bosio, E.D.T. Atkins and R.W. Lenz, ACS Svmp. Ser., 1990, 435, 185. 211. H.R. Allcock. Druus Pharm. Sci., 1990, 45, 163. 212. H.R. Allcock, S . Kwon and S.R. Pucher, Polvm. PreDr. (Am. Chem. SOC.. Div. Polvm. Chem.), 1990, 31(2), 180 (Chem. Abst., 1991, 114, 165216k). 213. K. Inoue, Kobunshi Kako, 1990, 39, 171 (Chem. Abst., 1991, 114, 186098m). 214. S.T. Oh and W.J. Cho, Komu Hakhocchi, 1989, 24, 122 (Chem. Abst., 1991, 114 25590~). 215. R. Marchand and Y. Laurent, Eur. J. Solid State Inors. Chem, 1991, 28, 57. 216. J.H. Magill and R.L. Merker, US 4946938 (Chem. Abst., 1990, 113, 153319n). 217. H.R. Allcock, G.S. McDonnell and J.L. Desorcie, Macromolecules, 1990, 2 3 , 3873. 218. S.V. Burin, A.A. Volodin, A.S. Marsimov, G.M. Ragskaya and V.V. Kireen, Otkrvtiva Izobet., 1990, (35), 133 (Chem. Abst., 1991, 114, 165173~). 219. H.R. Allcock and J.S. Rutt, Macromolecules, 1991, 24, 2852. 220. R.A. Montague and K. Matyjaszewski, J. Am. Chem. SOC., 1990, 112, 6721. 221. R.A. Montague and K. Matyjaszewski, Polv. Prepr. (Am. Chem. SOC.. Div. Polvm. Chem.), 1990, (31(2), 679 (Chem. Abst., 1991, 114, 186125~). 222. M. Liang and I. Manners, J. Am. Chem. SOC., 1991, 113, 4044. 223. W. Schnick and J. Lucke, Z. Anora. Alls. Chem., 1990, 588, 19. 224. L. Boukbir, R. Marchand, Y. Laurent, Z.J. Chao, C. Parent and G.L. Flem, J. Solid State Chem., 1990, 8 7 , 423. 225. S.I. Golina, G.I. Rybasova and V.V. Kazantseva, Izv. Vvssh. Uchebn. Zaved., Khim. Khim, Tekhnol., 1990, 3 3 , 59 (Chem. Abst., 1991, 114, 8096d). 226. V.M. Chukova, G.I. Rybasova and S . I . Golina, Izv. Vvssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 1990, 3 3 , 99 (Chem. Abst., 1991, 114, 166048~). 227. H.R. Allcock and S.R. Pucher, Macromolecules, 1991, 2 4 , 23. 228. I. Maruyama, H. Fujiwara, Z. Ito and H. Shigenematsu, Jpn. Kokai Tokkyo Koho, JP02045534, (Chem. Abst., 1990, 113, 116130~). 229. A.J. Jagowski, Jr., R.E. Singler and A.D. Sullivan, Polvmer. Prepr. (Am. Chem. Soc.. Div. Polvm. Chem.), 1990, 31, 488. (Chem. Abst. 1990, 113, 172876h). 230. K V . D'yachenko, Ya. s'. Freidzon, V.P. Shibaev, D.R. Tur, Vvsokomol. Soedin. Ser.B., 1990, 32, 490 (Chem. Abst., 1990, 113, 232191t).

8: Phosphazenes

357

231. R.E. Singler, R.A. Willingham, C.Noel, C. Friedrich, L. Bosio and E. Alkins, Macromolecules, 1991, 2 4 , 510. 232. H.R. Allcock and C.Kim, Macromolecules, 1991, 24, 2841. 233. H.R. Allcock and C. Kim, Macromolecules, 1991, 24, 2846. 234. E. Schacht and J. Crommen, US 4965397 (Chem. Abst., 1991, 114, 186066b). 235. S . Cohen, M.C. Bano, K.B. Visscher, M. Chow, H. R. Allcock and R. Langer, J. Am. Chem. SOC., 1990, 112, 7832. 236. L.A. Dominey, T.J. Blakley and V.R. Koch, Proc. Intersoc. Eneruv Convers. Enq. Conf., 1990, 25th Vol. 3, 382 (Chem. Abst., 1991, 114, 105617g). 237. T. Nakanaga, Y. Tada and A. Insubushi, JDn. Kokai Tokkvo Koho, JP02169628 (Chem. Abst., 1990, 113,232301d). 238. Y. Kurachi and M. Kajiwara, J. Mater. Sci., 1991, 26, 1799. 239. Y. Kurachi, K. Shiomoto and M. Kajiwara, J. Mater. Sci., 1990, 2 5 , 2036. 240. H.R. Allcock, R.J. Fitzpatrick and L. Savati, Chem. Mater., 1991, 3 , 450. 241. C.H. Kolich, W.D. Klobucar and J.T. Books, US49413A (Chem. Abst. , 1990, 113, 154152q). 242. C.H. Kolick and W.D. Klobucar, US4945140 (Chem. Abst., 1990, 113, 1541333). 243. H.R. Allcock, J.S. Rutt and R.J. Fitzpartick, Chem. Mater., 1991, 3 , 442. 244. L.L. Fewell, J. ADD^. Polvm. Sci., 1990, 41, 391. 245. M. Kajiwawra and Y.Yamashita, J. Mater. SCi., 1991, 26, 2797. 246. K.B. Visscher, I. Manners and H.R. Allcock, Macromol., 1990, 23, 4885. 247. S.M. Risser and K.F. Ferris, Chem. Phvs. Lett., 1990, 170, 349. 248. G.J. Exarhos and W.D. Samuels, Mater. Res. SOC. SvmD. Proc., 1990, 175,95 (Chem. Abst., 1991, 114, 248193b). 249. V. Avotins, J. Sulga, A. Vitola and T.M. Moravshaya, Ltv. PSR Zinat. Akad. Vestis, Kim. Ser., 1990, 285 (Chem. Abst., 1990, 113, 223674a). 250. C.E. Hoyle, P. Wisian-Neilson, P.M. Chatterton and M.A. Trapp, Macromolecules, 1991, 2 4 , 2194. 251. G. Ellis, M.A. Gomez, C. Marco, J.G. Fatou and R.G. Haddon, Polvm. Bull. (Berlin), 1991, 2 5 , 351. 252. T. Kotaka and K. Adachi, US4933479 (Chem. Abst., 1990, 113, 2229352). 253. A.V. Semakov, E.K. Borisenkova, B.S. Khodyrev, D.R. Tur and V.G. Kulichikhin, Vvsolkomol. Soedin.. Ser. B., 1989, 3 l , 830 (Chem. Abst. , 1990, 113, 416383). 254. M.A. Gomez, C. Marco, J.G. Fatou, S.V. Chichester-Hicks and R.C. Haddon, Polvm. Commun., 1990, 31, 308. 255. A.T. Kalashnik, G. Ya. Rudinskaya, S.P. Papkov, L.K. Golova, N.P. Krachinin, N.V. Vasileva and D.R. Tur, Vvsolkomol. Soedin., Ser.A., 1990, 3 2 , 1053 (Chem. Abst., 1990, 113, 60307s). 256. L.K. Golova, G.Ya Rudinskaya, S.A. Kuptsov, N.V. Vasil'eva, A.T. Kalashnik, E.M. Antipov, D.R. Tur and S.P. Papkov, Vvsokomol. Soedin., Ser.B., 1990, 32, 605 (Chem. Abst., 1990, 113,232396~).

358

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257. M.M. Iovleva, N.A. Ivanova, S.I. Banduryan, G.A. Mikheleva, L.K. Golova and D . R . Turf Vvsokomol. Soedin. Ser. B., 1990, 32, 316 (Chem. Abst., 1990, 113, 60519n).

258. E.K. Borisenkova, D.R. Tur, I.A. Litvinov, E.M. Antipov, V.G. Kulichikhin and N.A. Plate, Vvsokomol. Soedin., Ser. A., 1990, 32, 1505 (Chem. Abst., 1990, 113, 116448h). 259. E.M. Antipov, E.K. Borisenkova, V.G. Kulichikhin and N.A. Plate, Makromol. Chem.. Macromol. SvmL)., 1990, 38, 275. 260. N.A. Plate, E.M. Antipov and V.G. Kulichikhin, Makromol. Chem., Macromol. Svmp., 1989, 33, 65. 261. M.A. Gomez, C. Marco, J.G. Fatou, T.N. Boner, R.C. Haddon and S.V. Chichester-Hicks, Macromolecules, 1991, 24, 3276. 262. K. Mizoguchi, Y. Kamiya and T. Hirose, J. Polvm. Sci., Part B: Polvm. Phvs., 1992, 29, 695. 263. M. Kajiwara. Sep. Sci. Technol., 1991, 24, 841. 264. R.A. Reed, T.T. Wooster, R.W. Murray, D . R . Yaniv, J. S. Tonge and D.F. Shriver, J. Electrochem. SOC., 1989, f36, 2565. 265. K.M. Abraham, M. Alamgir and R.D. Moulton, J. Electrochem. SOC., 1991, 138,921. 266. K.J. Adamic, S.G. Greenbaum, K.M. Abraham, M. Alamgir, M.C. Wintersgill and J.J. Fontanella, Chem. Mater., 1991, 3 , 534. 267. K.M. Abraham and M. Alamgir, Chem. Mater., 1991, 3 , 339. 268. H.R. Allcock, G.S. McDonnell, G.H. Riding and I. Manners, Chem. Mater., 1990, 2, 425. 269. G.J. Exarhos and K.M. Crosby, NIST SDec. Publ., 1990, 801, 324 (Chem. Abst., 1991, 114, 217403r). 270. J. Bravo, M. P. Tarazona, A. Roig and Y.E. Salz, Anal. Quim., 1991, 87, 27. 271. M.P. Tarazona, J. Bravo, M.M. Rodrigo and E. Salz., Polvm. Bull., 1991, &, 465. 272. E.I. Ryuntsev, I.N. Shtennikova, D.R. Tur, G.F. Kolbina, E.V. Korneeva and V.G. Kulichikhin, Vvsokomol. Soedin., Ser. B., 1990, 32, 648 (Chem. Abst., 1991, 114, 43921r). 273. V.N. Smirnova, L,K. Golova, N.V. Vasil'eva, D.R. Tur and M.M. Iovleva, Khim. Volokna, 1990, 20 (Chem. Abst., 1990, 113, 985252). 274. G. Eickhoff , G.G. Liversidge and R. Mutherarasan, J. Chromatoar., 1991, 536, 255. 275. Y. Nakacho, A. Inobushi and Y. Tada, W09010317 (Chem. Abst. , 1991, 114, 232035r). 276. Y. Nakacho, A . Inobushi and Y. Tada, S. Masuda and M. Taniguchi, W09010316 (Chem. Abst., 1991, 114, 189085t). 277. Y. Nakacho, A. Inobushi and Y. Tada, W09010315 (Chem. Abst., 1991, 114, 189084s). 278. A. Inobushi, Y. Nakacho and Y. Tada, W09007198 (Chem. Abst., 1991, 114, 105706k). 279. T. Nakanaga and Y. Tada, Jpn. Kokai Tokkyo Koho, JP020244660 (Chem. Abst., 1991, 114, 9619~). 280. S. Yasunami, Jpn. Kokai Tokkyo Koho, JP02252762 (Chem. Abst., 1991, 114, 124169d). 281. Y. Kuraki and S. Yasunami, Jpn. Kokai Tokkyo Koho, JP02304553 (Chem. Abst., 1991, 114, 196315~). 282. T. Kkubota and Y. Kuraki, Jpn. Kokai Tokkyo Koho, JP02293844 (Chem. Abst., 1991, 114, 256890s).

359

8: Phosphazenes 283. R. Matejec, R. Buescher and H. Langen, EP 377910 (Chem. Abst., 1991, 114, 196262b). 284. B.K. Coltrain, W.T. Ferrar and C.J.T. Landry, W090113223 (Chem. Abst., 1991, 114, 165903g). 285. K. Hashimoto, T. Koizumi, K. Kitagawa and N. Nomura, Jpn. Kokai Tokkyo Koho, JP02010357 (Chem. Abst., 1990, 113, 14832m). 286. M. Gleria, F. Minto and L. Flamigni, EP369398 (Chem. Abst., 1990, 113, 181450s). 287. P.B. Rolsma and J.N. Lee, ODt. Lett., 1990, 15, 721. 288. K. Ohkawa, T. Matsuki and N. Saki, US4959442 (Chem. Abst., 1991, 114, 8 3 6 8 3 ~ ) . 289. S.C. Chang, US4966937 (Chem. Abst., 1991, 114, 45169a). 290. Y. Hayashi and Y. Nomura, Jpn. Kokai Tokkyo Koho, JP02216267 (Chem. Abst., 1991, 114, 104309~). 291. H.R. Allcock, P.E. Austin and S.Kwon, US4880622 (Chem. Abst. , 1990, 113, 6 5 2 8 1 ~ ) 292. E. Schacht and J. Crommen, US4975280 (Chem. Abst., 1991, 114, 108973f). 293. K. Nanishi and H. Nakayama, US4908061 (Chem. Abst., 1990, 113, 174129r). . 294. A. Zinn, U. Patt-Siebel, U. Muller and K. Dehnicke, Z Anora. Allaem. Chem., 1990, 591, 137. 295. T. Hokelek and Z. Kilic, Acta Crvstallosr., Sect. C: Crvst. Struct. Commun., 1990, C46, 1519. 296. M. Parvez, S. Kwon and H.R. Allcock, Acta Crvstalloqr., Sect.C: Crvst. Struct. Commun., 1991, W, 466. 297. V.I. Sokol, L. Ya. Medvedeva, M.A. Porai-Koshits and I.A. Rozanov, Russ J. Inors. Chem. {Enal. Transl.), 1990, 35, 1618. 298. A.A. Dvonkin, V.A. Kalibabchuk, A.O. Gudima, V.L. Rudzevich and Yu. A. Simonov, Russ. J.Inors. Chem. (Enql. Transl.), 1990, 35, 1717.

.

Author Index

In this index the number given in parenthesis is the Chapter number of the citation and this is followed by the reference number or numbers of the relevant citations within that Chapter. Abbari, M. (1) 297 Abdelmalek, H.A. (7) 28 Abe, A. (1) 240, 241; (7) 8 Abell, A.D. (1) 236; (7) 11, 37 Abiyurov, B.D. (5) 152 About-Jaudet, E. (5) 127, 133, 225 Abraham, K.M. (8) 265-267 Abramkin, E.V. (5) 256, 259 Abramovitch, R.A. (5) 155 Absalon, M.J. (6) 247 Abunada, N.M. (8) 6 8 Abu-Ragabah, A. (8) 202, 203 Abu-Shgara, E. (8) 65 Achi, S . (5) 206 Achiwa, K. (1) 72, 90 Adachi, K. (8) 252 Adam, W. (5) 16 Adamic, K.J.(8) 266 Adamopoulos, S.G. (7) 27 Afanas’eva, A.N. (8) 183 Afarinkia, K. (4) 9; (5) 195, 196 Agback, P. (6) 244, 245 Agrawal, S. (6) 85, 203, 204 Ahlrichs, R. (1) 295 Ahmad, S. (6) 151 Ahmed, S. (8) 153 Ahuja, J.R. (1) 148 Aitken, R.A. (1) 254; (7) 12, 46 Ajo, D. (1) 59 Akacha, A.B. (5) 242 Akagi, M. (6) 303 Akashi, M. (6) 334 Akermark, B. (7) 57 Akkerman, M.A. (6) 257 Aksinenko, A.Yu. (5) 188, 303 Aksinenko, N.E. (4) 6 8 Aksoy, I.A. (5) 38, 39 Akutagawa, S. (1) I08

Aladzheva, I.M. (1) 265 Alajarin, M. (7) 102; (8) 7, 49 Alamgir, M. (8) 265-267 Alazard, J.P. (7) 103 Albericio, F. (6) 63, 196 Alberti, M. (8) 184 Alcaraz, J.M. (1) 403 Aldenhoven, H. (1) 60, 61 Aleksandrova, I.P. (8) 141 Alewood, P.F. (4) 40;(5) 21-23 Alexakis, A. (4) 28 Al’fonsov, V.A. (5) 235 Alias, A. (7) 110; (8) 47, 54 Alings, C. (6) 147 Al-Juaid, S.S. (1) 179, 373 Alkins, E. (8) 231 Allan, R.D. (5) 228 Allcock, H.R. (8) 80, 101, 118, 133, 135, 136, 139, 148, 149, 160, 198, 211, 212, 217, 219, 227, 232, 233, 235, 240, 243, 246, 268, 29 1, 296 Allen, C.W.(8) 100, 134, 159 Al-Madfa, H.A. (8) 143, 146 Al-Resayes, S.I. (3) 33 Altman, S. (6) 228 Altmeyer, 0. (1) 341 A M , R.H. (6) 62 Aly, A.A.M. ( I ) 229 Amrna, J.P. (4) 27; (5) 18 Anand, B.N. (2) 28 Anasako, Y. (8) 178 Anderson, C.B. (3) 20 Anderson, D.W. (5) 212 Anderson, R.A. (1) 174 Anderson, R.C. (1) 157 Ando, D.J. (7) 62 Ando, H. (8) 162, 168, 170, 171 Andraki, M.E. (6) 134

360

Andre, F. (6) 323 Andrus, A. (6) 66 Ang, H.G.(1) 221; (8) 93, 94 Angelov, Ch.M. (5) 261 Annan, T.A. (1) 29 Anslyn, E. (6) 8 Antipin, M.Yu. (1) 265 Antipov, E.M. (8) 256, 258-260 Antonovich, V.A. (1) 28 Anuradha, K. (5) 13 Anzai, S. (8) 176 Apperley, D.C. (2) 29 Arbuckle, B.W. (1) 110 Arbuzov, B.A. (1) 139, 287-290, 299-303 Archarlis, A. (7) 35 Arif, A.M. (1) 368; (2) 21; (5) 241, 302, 305 Arjunan, P. (6) 270 Armstrong, R.W. (7) 21 Arndt, V. (1) 45, 50 Arora, S.K. (6) 270 Arques, A. (1) 151; (7) 106, 109, 110; (8) 15, 43, 47, 54, 55 Arshinov, R.P. (5) 290 Artschwager-Perl, U. (7) 41 Artyushin, 0.1.(1) 182 Asensio, G. (1) 66 Ashley, G.W. (6) 220 Ashton, P.R. (5) 266 Asseline, U. (4) 60; (6) 110, 190 Athey, P.S. (5) 8 4 Atkins, E.D.T. (8) 210 Atoh, M. ( I ) 73 Atta, S.M.S. (5) 284 Attanasi, O.A. (7) 38 Atwood, J.L. (1) 52, 53. 320 Auhert. T. (7) 113

Author Index Auclair, C. (6) 291 Aumelas, A. (7) 123 Aurup, H. (6) 238 Austin, P.E. (8) 291 Au-Yeung, B. W. (1) 25 Avall, A.-K.C. (5) 131 Avotins, V. (8) 249 Awad, W.I. (1) 144 Ayed, N. (5) 242 Azzouzi, F. (7) 55 Baba, M. (6) 21, 29 Baboulene, M. (5) 63, 97 Babudri, F. (4) 8 Baccar, B. (5) 242 Baccolini, G. (1) 393 Baceiredo, A. (1) 192-195; (3) 32; (5) 286; (8) 117, 197 Bach, C. (6) 297 Bachrach, S.M. (1) 286, 372 Badawey, E.S.A.M. (8) 95 Badia, M.C. (5) I15 Badri, M. (5) 65, 246, 248 Badrudin, S.P. (5) 215 Baer, D.R. (8) 104 Baguley, B.C. (6) 283, 285, 309 Bailey, P.L. (5) 154 Bain, J.D. (6) 97 Bains, R. (2) 28 Baird, W.M. (6) 295 Bajwa, J.S. (1) 157 Baker, A.D. (6) 31 I Baker, C.H. (6) 45 Baker, G.R. (5) 50 Baker, M.J. (4) 21 Baker, R. (5) 36, 41 Baker, S.R. (1) 172 Balaban, A.T. (5) 121 Balakrishna, M.S. (4) 24 Balch, A.L. (1) 171 Baldus, H.-P. (4) 81 Ballou, C.E. (5) 42 Balogh-Hergovich, E. (8) 25 Balueva, A.S. (1) 139 Balzarini, J . (6) 12, 18, 21 Bancroft, D.P. (6) 301 Banduryan, S.I. (8) 257 Bankmann, M. (1) 325; (3) 18 Banks, M.A. (1) 87 Bannikova, O.B. (5) 108 Bannworth, W.( 5 ) 25 Bano, M.C. (8) 235 Bansal, R.K. (1) 390 Banzon, J. (6) 45 Baran, (3.0.(1) 216; (4) 26 Baraniak, J . (5) 95 Barbarella, G. (6) 324

361 Barbato, S. (6) 182 Bardos, T.J. (6) 33 Barendt, J.M. (4) 30 Barion, D. (1) 308 Barker, A.J. (7) 81 Barluenga, J. (1) 66, 237, 253; (7) 22, 49, 50; (8) 2, 61, 62, 70 Barrans, J. (1) 206, 344, 397, 398; (4) 76; (8) 191, 192 Barsegyan, S.K.(1) 140 Barta, T.A. (5) 184 Bartel, D. (6) 241 Barth, A. (1) 266 Barton, D.H.R. (5) 153 Barton, J.K. (6) 278, 313 Barton, S.D. (2) 5 Bartsch, R. (1) 388; (8) 87 Barvau, J . (5) 135 Ba-Saif, S.A. (5) 72 Bashkin, J.K.(4) 53; (6) 168, 169, 246 Basil, J.D. (1) 10 Bassett, M. (1) 128 Bastiaans, H.M.M. (1) 337 Bastian, H. (1) 271 Basu, A. (6) 183, 184 Bateson, J.H. (7) 79 Bats, J.W. (1) 415; (8) 193 Batyeva, E.S. (5) 235 Baudin, G. (5) 139 Baudler, M. (1) 44-51, 384-387 Baudry, D. (1) 383 Bauer, S. (1) 9, 304, 305 Baumann, K. (5) 20 Baumeister, U. (5) 298 Baures, P.W. (1) 16 Bawalda, P.L. (8) 151 Bayandina, E.V. ( 5 ) 236 Bayer, K. (5)223 Baze, M.E. (6) 60 Beachley, O.T. (1) 87 Beak, P. (5) 277 Beaton, G. (4) 61; (6) 121, 125 Beaucage, S.L.(6) 101, 142 Beaucourt, J.-P. (7) 85 Beaudry, W.T. (5) 91, 288 Bebendorf, J. (1) 243 Beche, G. (7) 51 Becker, G. (1) 3 1, 333 Bedel, C. ( I ) 412; (7) 10; (8) 195 Begley, T.P. (6) 177 Beijer, B. (6) 91, 143, 144 Bekiaris, G. (1) 21 1 Bekker, A.R. (4) 37 Bel, P. (5) 218 Belakhov, V.V. (5) 260

Bellamy, F. (3) 4; (7) 17, 88 Bellan, J . (1) 391; (4) 74 Bendayan, A. (1) 109 Benigni, D.A. (1) 172 Benkovic, S.J. (6) 81 Benmaamouf-Khallaayoun, Z. (5) 97 Benn, R. (1) 335 Bennani, Y.L. (5) 126, 207 Benner, S.A. (6) 133 Bennet, J.L. (8) 160 Bennett, M. (7) 117 Benseler, F. (6) 238 Bent, E.G. (4) 29 Bentrude, W.G. (2) 21; (5) 304, 305 Berchadsky, Y. (1) 12; (5) 215 Bergman, R.C. (1) 174 Bergstrasser, U. (1) 204 Berkin, D.M. (1) 376 Berlin, K.D. (5) 13 Berlin, W.K. (4) 43; (5) 29 Bermel, W. (6) 257 Bernadou, J. (6) 293 Bernaets, R. (6) 22 Bernal, 1. (5) 70 Bernotas, R.C. (1) 156 Berry, D.E. (6) 294 Bertrand, G. (1) 192-195; (3) 32; ( 5 ) 286; (8) 117, 197 Besnier, I. (5) 206 Bespal’ko, G.K. (2) 31; (8) 77 Bessho, K. (4) 10 Bestmann, H.J. (7) 15, 75 Betz, P. (1) 88, 335 Beveridge, D.L. (6) 260 Bevierre, M.-0. (1) 378 Bezoari, M.D. (8) 181 Bhalerao, U.T. ( I ) 189; (3) 9; (5) 85 Bhan, P. (6) 130 Bharadwaj, P.K. (1) 110 Bi, B.T. (7) 55 Bickelhaupt, F. (1) 337, 414 Biede-Charreton, C. (6) 292 Biedenbach, B. (1) 335 Bieher, K. (1) 402 Bielawska, H.(5) 104 Bildstein, B. (5) 237 Biller, S.A. (5) 115, 116, 186; (7) 54 Billington, D.C. ( 5 ) 36, 50 Bina, M. (6) 80 Binger, P. (1) 204, 334-336 Bin Shawkataly, 0. (1) 24 Bird, C.W. (1) 375; (8) 186 Birdsall, W.J. (8) 80 Birkel, M. (1) 331

362 Birrell, G.B. (6) 333 Birse, E.F. (3) 21 Bischofberger, N. (6) 74, 192 Bischoff, P. (6) 17 Bishop, J.M. (6) 117 Bissinger, P. (1) 81 Bitterer, F. (1) 208 Biyushkin, V.N. (5) 301 Bjergarde, K. (6) 73 Blachnik, R. (4) 81 Blackburn, G.M. (5) 266; (6) 53-55 Blakley, T.J. (8) 236 Blinn, D.A. (1) 100 Bloch, G. (6) 323 Bloch, W. (6) 79 Blbcker, H. (6) 147 Blommers, M.J.J. (6) 215 Blum, H. (5) 151, 214 Blum, J . (8) 65 Blum, 0. (1) 178 Boal, J. (6) 111 Bobst, A.M. (6) 199, 200 Boche, G. (5)276 Bochkov, V.N. (5) 32 Bock, H. (1) 274, 325; (3) 18 Bodalski, R. (4) 5; (5) 76, 77, 134 Bodepudi, V. (6) 68 Boder, N. (5) 5 Boeckman, R.K. (5) 184 Bbgge, H. (1) 135, 271, 272, 306, 416, 420 Boese, R. (1) 269, 374 Boganova, N.V. (4) 15; (5) 213 Boger, D.L. (6) 80, 271, 272 Bogusiak, J . (5) 49 Bohle, D.S. (1) 218, 351; (7) 31 Boiko, L.D. (8) 76 Boisdon, M . T . (1) 206, 344; (4) 76 Boldeskul, I.E. (1) 291 Bolelaya, N.K. (8) 76 Bolen, J.B. (5) 166 Bollens, E. (8) 37 Bollinger, J.M. (6) 45 Bolton, P.H.(6) 247 Bondarenko, N.A. (1) 129; (5) 143 Bonfils, E. (6) 201 Bongini, A. (7) 38 Bonnet, J.P. (8) 124 Bookham, J.L. (1) 95 Books, J.T. (8) 241 Bordieu, C. (1) 359, 409 Borisenko, A.A. (1) 68, 69, 280 Borisenko, V.P. (8) 97 Borisenkova, E.K.(8) 253, 258,

Organophosphorus Chemistry 259 Boritzki, T.J. (6) 283 Bornancini, E.R.N. (1) 63 Bortolus, P. (8) 105 Bose, N.K.(6) 64 Bose, R.N. (6) 306 Bosio, L. (8) 210, 231 Bosold, F. (5) 276 Bosyakov, Yu.G. (1) 102, 103 Bott, S.G. (1) 52, 53, 320 Boubia, B. (7) 17 Boukbir, L. (8) 224 Boulos, L.S. (7) 25, 26, 28 Bourdieu, C. (5)269 Bovermann, G. (5) 223 Bovin, A.N. (5) 295, 296 Bowmaker, G.A. (8) 16 Bowmer, T.N. (8) 261 Brandi, A. (3) 31 Brandsma, L. (1) 21 Brandt, K. (8) 112, 121, 129, 142 Brauer, D.J. (1) 208 Braun, R. (4) 80; (5) 231-233 Bravo, J. (8) 270, 271 Breiner, R.G. (6) 33 Breker, J. (1) 198; (5) 240 Brel’, V.K. (5) 256, 259 Bremer, M. (7) 15 Brennan, D.J. (8) 148 Brenton, A.G. (6) 327 Breslow, R. (6) 8 Breuer, E. (5) 176, 218, 273, 274 Brianese, N. (1) 59 Bridges, A. (8) 159 Brieden, W. (1) 18 Briki, F. (6) 332 Brill, W.K.-D. (4) 61; (6) 120, 121 Bringewski, F. (1) 114 Broder, S. (6) 112, 113 Brodtbehrer, P.R. (6) 27 Broeders, N.L.H.L. (6) 38 Bronson, J.J. (6) 27 Brovarets, V.S. (1) 260 Brown, D.E. (8) 134 Brown, J.M. (3) 3 Brown, M.L. (5) 302 Brown, P.S. (3) 19 Broxterman, H.J.G. (4) 45 Bruce, M.I. (1) 24 Bruche, L. (7) 104; (8) 57 Bruggink, A . ( 5 ) 79, 80 Bruins Slot, H.H. (5)80 Brunner, H. (1) 4, 14, 117; (4) 65 Brush, C.K. (6) 318

Bruzik, K.S.(6) 37 Bryce, M.R. (7) 62, 63 Buchko, G.W. (6) 167 Buck, H.M.(6) 4, 38, 226 Buckley, L. (6) 248 Budde, K. (8) 179 Budzelaar, P.H.M. (1) 22 Buechler, G. (7) 121 Buescher, R. (8) 283 Bujacz, G. (1) 227 Bull, E.O.J. (5) 12, 59 Bundel, Yu.D. (1) 150 Buono, G. (2) 25; (7) 35 Burangulova, R.N. (5) 17 Burdsall, D.C. (5) 130 Burford, N. (1) 364; (4) 72 Burgada, R. (5)297 Burgess, H . (4) 16 Burin, S.V. (8) 218 Burk, M.J. (1) 74, 75, 136 Burke, T . R . (5) 166 Burlini, N. (7) 59 Burmistrov, S.Y.(4) 38 Burnaeva, L.A. (2) 13; (5) 17 Burns, J.A. (1) 125 Burton, D.J. (5) 163; (7) 71 Burton, S.D. (2) 1 Busch, T. (1) 317, 340, 341 Bushnell, G.W. (1) 381 Busson, R. (6) 18 Butler, J.C. (1) 125 Button, R.S. (1) 100 Buttrey, L.A. (1) 87 Buzykin, B.I. (5) 264 Byistro, V.K. (1) 280 Cabal, M.P. (7) 118 Cadet, J. (6) 335 Cadogan, J.I.G. (4) 9; (5) 195, 196 Caesar, J.C. (7) 9 Cai, B. (1) 395, 396; (2) 34 Cai, M. (5) 106 Cai, X.M. (8) 93, 94 Cairns, M.S. (1) 249 Calabrese, J.C. (1) 136 Camaioni, N. (8) 105 Cambon, A. (8) 37 Camellini, M . T . (7) 31 Cameron, T.S.(8) 20 Caminade, A.-M. (1) 170, 349; (5) 65, 246-248 Camp, D. (1) 106; (3) 12 Campbell, A S . (5) 164 Campbell, M.M. (5) 174, 212; (7) 81 Campos, P.J. (1) 66

363

Author Index Canal, G. (1) 66 Candle, L.J. (3) 35 Cano, F.H. (8) 7 Cao, J.-H. (5) 141 Caoley, A.H. (5) 241 Caperelli, C.A. (6) 5 Capobianco, M.L. (6) 324 Capuano, L. (7) 36 Carbonnaux, C. (6) 326 Carey, J.V. (3) 3 Carite, C. (7) 103 Carrnichael, D . (1) 373, 401 Carr, S . (6) 294 Carreira, E.M. (7) 95 Carrera, G.M., jun. (7) 19 Carrick, C. (5) 41 Carrie, R. (1) 297 Carroll, S.S. (6) 81 Cartagena, I. (1) 151; (7) 106 Cart& B.K. (6) 294 Carter, B.J. (6) 249, 251-253 Caruthers, M.H. (4) 61; (6) 120, 121, 125 Casas, C. (6) 290 Casida, J.E. (5) 89, 90 Castagnino, E. (5) 153 Castedo, L. (3) 24, 25 Castellato, U. (1) 59; (3) 36 Castro-Pichel, J . (6) 34 Catalan, J . (8) 7 Cates, L.A. (5) 96 Cavell, R.G. (1) 247; (2) 32, 33; (8) 69, 84, 199 Cech, D . (6) 187 Cech, T.R. (6) 227, 239 Cedergren, R. (6) 237 Cereghetti, M. (1) 107 Cerny, J . (6) 23 Ceruzzi, M. (6) 119 Cetrullo, J . (5) 70 Cevasco, G. (5) 270 Chacon, S.T. (1) 24 Chadha, M.S. (1) 163 Chai, W. (5) 289 Chamberlin, A.R. (6) 97 Chan, S. (1) 109 Chandrasekhar, T.K. (8) 155 Chandrasekhar, V. (8) 155 Chang, J.Y.(8) 136 Chang, S.C. (8) 289 Chao, Z.J. (8) 224 Charubala, R. (6) 107, 137, 138 Chatterjee, M. (6) 191 Chatterton, P.M. (8) 250 Chattopadhyaya, J . (6) 244, 245 Chekhlov, A . N . (3) 14; (5) 188, 295, 296, 303 Chen, C. (7) 29

Chen, H. (1) 25 Chen, J . (5) 157; (6) 222 Chen, J.-D. (1) 13 Chen, R. (1) 395, 396; (2) 34; (5) 67, 210 Chen, W . (5) 47, 58, 8 Chenault, J . (1) 256 Cheney, D.L. (5) 78 Cheng, L.-T. (1) 126 Cheng, M.-C. (1) 83 Cheng, S.J. (8) 130 Cheng, T. (5) 106 Cheng, Y.C. (6) 114 Chen-Yang, Y . W . (8) 130, 132 Cheong, C. (6) 217 Cherches, G.Kh. (8) 119 Cherkasov, R.A. (2) 12; (5) 98, 100, 187, 202, 257, 258; (8) 38, 39 Chernega, A . N . (1) 346, 347; (4) 67-69; (8) 30 Chernov, P.P. (2) 8, 15 Chertanova, L.F. (1) 301 Chetcuti, P. (6) 279 Chichester-Hicks, S . V . (8) 254, 26 1 Chikashita, H. (6) 265 Chin, D.J. (6) 118 Chin, J . (6) 39 Chiorri, C. (5) 119 Chiquete, L.M. (2) 23 Chistokletov, V . N . (1) 181; (5) 17, 158, 159 Chivers, T. (8) 187 Chmielewski, J . (6) 219 Cho, W.J. (8) 214 Cho, Y. (4) 62; (6) 123 Choi, W . S . (5) 105 Chojnowski, J . ( I ) 200 Chordia, M . D . (7) 115 Chorev, M. (5) 176, 218, 274 Chou, W.-N. (3) 15; (7) 5; (8) 14 Choukroun, R. ( I ) 349 Chow, F.L. ( I ) 25 Chow, M. (8) 235 Christensen, J.W. (7) 18 Christner, D.F. (6) 258, 259 Chu, B.C.F. (6) 307 Chu, C.K. (6) 50 Chudakova, T.I. (5) 93 Chugunov, Y . V . (4) 11 Chukova, V.M. (8) 226 Chumakov, Yu.M. (5) 301 Chung, K.H. (1) 146 Chunming, Z. (7) 44 Churchill, M.R. (1) 87 Chuvashev, D . D . (1) 220

Cicchi, S. (3) 31 Ciosek, C.P. (5) 115, 186 Cirolo, M.R. (6) 250 Clararnunt, R.M. (8) 7 Clardy, J . (6) 263, 265 Clare, M. (7) 89 Clark, G.R. (1) 218 Classon, B. (1) 215 Clore, G.M. (6) 195 Cobb, J.E. (5) 28 Coe, D . M . (6) 49 Coe, P.L. (6) 12 Coggio, W . D . (8) 149 Cohen, J.S. (6) 106, 112, 113 Cohen, S. (8) 235 Cole-Hamilton, D.J. (1) 20 Coleman, R.S. (6) 176; (7) 118 Coley, S . M . (8) 198 Collet, A. (6) 194 Collier, D . A . (6) 209, 214 Collignon, N . (5) 127, 133, 225 Collin, J. (3) 10 Coltrain, B.K. (8) 284 Comber, M.F. (1) 225 Conary, G.S. (3) 35 Conda, L. (8) 158 Connolly, B.A. (6) 173-175 Contreras, R. (2) 23 Coogan, M.P. ( I ) 361; (5) 271 Corcoran, R.C. (5) 205 Cordi, A . A . (5) 119 Corey, E.J. (7) 47 Cormier, J.F. (6) 86 Corsano, S. (5) 153 Cosquer, P. (1) 297 Cosstick, R. (6) 161, 173-175 Costisella, B. (5) 124, 149 Cotton, F . A . (1) 13 Couladouros, E. (7) 119 Coull, J.M. (6) 189 Courbis, P. (4) 64 Courtois, G. (5) 194 Cowan, J . A . (6) 314, 315 Cowley, A.H. (1) 27, 52-54, 57, 200, 268, 276, 320, 354, 368 Cox, M.B. (6) 270 Craig, D.C. (1) 23; (5) 287 Cramer, C.J. (2) 3 Cregge, R.J. (7) 82 Crilley, M.M.L. (4) 3; (5) 120 Cristau, H.-J. ( 1 ) 116, 259; (3) 1; (7) 48; (8) 66, 67, 83 Cromrnen, J . (8) 234, 292 Crosby, K.M. (8) 269 Cross, S. (6) 290, 291 Cube, R.V. (1) 156 Culcasi, M. (1) 12 Cullen, W.R. (1) 24

364 Cummins, L. (6) 125 Cunningham, R.P. (6) 247 Cupertino, D.C. (1) 20 Curtin, M.L. (3) 28 Curtis, R.D. (1) 350; (8) 13 Cushman, C.D. (6) 130 Cypryk, M. (1) 209 Dabbagh, H.A. (1) 147 D’achenko, M.V. (8) 230 Dagle, J.M. (6) 134 Dahan, F. (1) 177 Dahl, B.H.(6) 73 Dahl, 0. (6) 73 Dahn, S.C. (6) 230 Dajaegree, A. (6) 330 Dake, L.S. (8) 104 Dalpozzo, R. (1) 393 Damerius, R. (8) 120 Damha, M.J. (6) 61, 141 Dan, S. (5) 210 Dange, V. (6) 252 D’Angelo, L.L. (6) 325 Daniel, L.W. (6) 14 Daniels, L.M. (4) 27; (5) 18 Danishefsky, S.J. (7) 118 Dannoue, Y. (6) 254 Danoff, S.K.(5) 34 Danopoulos, A.A. (1) 82 D’Anrea, S.V. (4) 14 Danzin, C. (6) 32 Dappen, M.S. (5) 119 Dargatz, M. (1) 32; (5) 298 D’Ari, R. (6) 185 Dartiguenave, M. (1) 232; (3) 32; (8) 36, 117 Dartiguenave, Y. (1) 232; (3) 32; (8) 36, 117 Dartmann, M. (1) 307 Darzynkiewicz, E. (6) 11 Das, S.K.(4) 27 Date, M. ( 5 ) 69 Daumas, M. (5) 198 Davidson, F. (1) 136 Davies, D.L. (1) 128 Davis, B.H. (1) 147 Davis, C.E. (8) 4 Davis, J.M. (5) 267 Davis, R.V. (4) 27; ( 5 ) 18 Davy, R.D. (8) 103 Day, R.O.(2) 1, 5, 6, 18, 20 Day, S . K . (5) 18 De, B. (7) 47 Debouzy, J.-C. (6) 13 Debrosse, C. (6) 294 DeCanio, E.C. (1) 13 De Clercq, E. (6) 12, 18, 21,

Organophosphorus Chemistry 24, 29, 30 Declercq, J.-P. (1) 284 Degenhardt, C.R. (5) 130 Dehmlow, E. (1) 264; (8) 18 Dehnicke, K. (8) 294 DeHoniesto, J. (5) 219 DeJaeger, R. (8) 206 De Kanter, F.J.J. (1) 414 Dekura, T. (8) 185 Delange, B. (5) 115 de Leon, E. (3) 6; (4) 6 Dellinger, D. (6) 125 Delmas, M. (5) 246 Delorme, D. (5) 126 de 10s Santos, C. (6) 184 Demassier, V. (6) 323 Dembek, A.A. (7) 61; (8) 135, 160 Dembowski, U. (1) 58 Denis, J.M. (1) 115, 324, 326; (5) 113 Denmark, S.E. (3) 27; (5) 250; (7) 52, 69 Dennis, T.J. (1) 323 Denny, W.A. (6) 279, 283-285, 309 dePaz, J.L.G. (8) 7 Depazay, J.C. (7) 84 De Ruiter, B. (8) 150 Dervan, P.B. (6) 212, 213 DeSolms, S.J. ( 5 ) 36 Desorcie, J.L. (8) 101, 159, 217 Despax, C. (4) 12; (5) 9, 48 Deutsch, T.F. (6) 248 Devaud, M. (7) 55 Devenyi, J. (7) 76 De Vine, R.J. (6) 134 Devine, R.L.S. (8) 135 De Voss, J.J. (6) 267 de Vroom, E. (6) 251 Dhawan, B. (5) 68, 203 Diallo, O.S. (1) 397, 398; (8) 191, 192 Dieck, H. (5) 263 Diefenback, U. (8) 120 Diel, P.J. ( 5 ) 191, 220 Diemert, K. (1) 86, 219, 362; (4) 78 Dillon, K.B. (2) 7 Dimmig, T. (5) 52 Ding, L. (6) 289-291 Ding, W.-D. (6) 267 Dipchand, A.I. (1) 364; (4) 72 Ditrich, K. (7) 93 Dixon, H.B.F. (5) 175, 183 Dixon, R.M. (6) 57 Dmitrichenko, M.Yu. (5) 109, 110; (8) 40, 196

Dmitriev, V.I. (1) 92 Dodge, J.A. (1) 153; (8) 101 Dorges, C. (1) 406-408 Doernhoefer, C. (8) 147 Doerrenbach, F. (1) 208 Doi, J.T. (1) 110 Dolgushin, G.V. (5) 110; (8) 40, 196 Dolgushina, T.S. (5) 245 Dolitzky, B.-Z. (5) 193 Dollase, W.A. (5) 214 Dominey, L.A. (8) 236 Donaghy, K.J. (1) 298 Dong, H. (6) 322 Donnely, J.A. (4) 16 Donskikh, V.I. (1) 220; (5) 110; (8) 40, 196 Dorbath, B . (1) 198 Dorow, R.L. (5) 250; (7) 69 Dostal, K. (8) 184 Dou, D. (1) 167 Douce, L. (1) 26 Doudna, J.A. (6) 240 Douglas, M.E. (6) 161 Doxsee, K.M. (1) 138 Doyle, T.W. (6) 260 Drach, B . S . (1) 260 Drapailo, A.B. (4) 69 Draper, K. (6) 119 Dreef, C.E. (5) 138; (6) 104 Dreef-Tromp, C.M. (6) 104, 193 Drescher, S . (7) 36 Driscoll, J.A. (1) 166 Drysdale, M.J. (7) 46 Dubourg, A. (1) 284 Duchamp, J.C. (1) 276 Duesler, E.N.(1) 167; (3) 35 Duster, D. (1) 387 Dufour, N. (1) 349 Duh, J.-L. (6) 199, 200 Dukescherer, D.R. (5) 221 Dumas, J. (7) 84 du Mont, W.-W. (1) 210 Dunaway-Mariano, D. (5)230 Dunn, B. (8) 148 Dunn, D.A. (6) 248 Dunn, J.A. (6) 33 Duplantier, A.J. (7) 92 Dupreez, J.G.H. (3) 36 Durand, T. (7)83 Durrant, I. (4) 48; (6) 198 Dutkiewicz, J. (8) 141 Dvonkin, A.A. (8) 298 Dvorakova, H. (6) 26 Dybkowski, P. (5) 156 Eaborn, C. (1) 179

Author Index Ealick, S. (5) 304 Ebel, J.P. (6) 223 Ebetino, F.H. (5) 130 Ecka, H.-L. (4) 7; (5) 125 Eckstein, F. (6) 5 1, 238 Edwards, M.L. (3) 5; (7) 60 Edwards, P.G. ( I ) 82 Efremov, D.A. (5) 62 Efremov, Yu.Ya. (1) 290, 299, 300; (5) 257

Egan, W. (6) 101, 111 Eggleston, D.S. (1) 16 Eguchi, S . (4) 13 Ehle, M. (1) 331 Ehresmann, B. (6) 223 Ehresmann, C. (6) 223 Ehrhard, A. (6) 32 Ehrig, M. (1) 295 Eickhoff, W.M. (8) 274 Einhorn, C. (I) 149 Einhorn, J. (1) 149 Einstein, F.W.B. (1) 24 Eisenberg, M. (6) 183 Eisenhaber, F. (6) 277 El-Batouti, M. (1) 251, 252 Elbaum, B. (8) 127 Eleftheriou, M.-E. (5) 285 El Essawi, M. (1) 244 El-Farargy, A.F. (5) 283 Elgamal, S . (8) 65 Elguero, J. (8) 7, 15 Elhaddadi, M. (5) 216, 217 Eliel, E.L. (5) 73 Elkatab, A.A. (7) 28 El Khalik, S.A. (1) 244 El-Khoshnieh, Y.O. (5) 284; (7) 25

Ella, C.J.J. (5) 138 Ellestad, G.A. (6) 267 Ellington, A.D. (6) 243, 299 Ellis, G. (8) 251 Ellman, J.A. (6) 95, 96 El Manouni, D. (5) 297 Elnaem, S.I. (7) 28 Elschenbroich, C. (1) 402 Elsevier, C.J. (8) 92, 200, 201 Elvahman, N.M.A. (7) 26 Embrey, K.J. (6) 274 Enchev, D.D. (5) 261 Endo, T. (6) 131 Engel, R. (1) 223, 224 Engelhardt, U . (8) 120 Engels, J.W. (4) 63; (6) 129, 145

English, U. (6) 100 Enjalbert, R. (8) 122, 124, 125 Ennis, M.D. (6) 60 Ephretikhine, M. (1) 383

365 Epishina, T.A. (5) 8 Erabi, T. (1) 255 Eritja, R. (6) 63, 166, 196 Erker, G . (7) 41 Erofeeva, M.R. (5) 158 Escale, R. (7) 83 Escarcella, M. (6) 196 Eschenmoser, A. (5) 20 Esipenko, A.N. (5) 53 Esker, J. (4) 42; (5) 19 Espenbetov, A.A. (1) 102 Essigmann, J. (6) 183, 184 Estevez, V.A. (5) 35 Etemad-Moghadam, G. (1) 284; (6) 289-291

Ethridge, V. (5) 305 Etzbach, T. (1) 384, 385 Evans, D.A. (7) 95 Evans, M.R. (4) 48; (6) 198 Evans, S.A. ( I ) 158 Exarhos, G.J. (8) 248, 269 Fackler, J.P. (1) 10 Fahmy, A.F. (5) 283; (8) 68 Falck, J.R. (7) 86 Falgueyret, J.-P.(7) 87 Falzone, C.J. (6) 322 Famulok, M. (5) 276 Fan, S. (8) 132 Fang, G. (7) 107 Farazi, V. (1) 100 Farina, V. (1) 172 Farnier, M. (7) 113 Farrell, N. (6) 308 Farschtschi, N. (4) 62; (6) 124 Fatou, J.G. (8) 251, 254, 261 Faucette, L.F. (1) 16 Fauq, A.H. (5) 38, 39 Fawcett, J. (3) 34 Fazakerley, G.V. (6) 326 Feaster, J.E. (1) 74 Feigon, J . (6) 319 Feng, K. (1) 392 Feng, R. (1) 76 Ferentz, A.E. (6) 160 Ferguson, G. (1) 254; (7) 12 Feringa, B.L. (1) 77 Fernandez-Forner, D. (6) 63, 166

Ferrar, W.T. (8) 284 Ferrara, L.M. (6) 27 Ferrero, M. (7) 49; (8) 61, 70 Ferris, C.D. (5) 34 Ferris, K.F. (8) 11, 12, 104, 247

Ferrond, D. (5) 206 Feshchenko, N.G. (2) 30

Fetisov, V.I. (5) 46 Fettinger, J.C. (1) 87 Feucht, G. (1) 37 Fewell, L.L. (8) 244 Fiandenese, V. (4) 8 Fife, T.H. (5) 71 Filali, A. (2) 27 Filbrich, R. (6) 206 Fild, M. (1) 113, 114 Filippone, P. (7) 38 Finnegan, P.M. (7) 89 Firth, S. (1) 323 Fitzpatrick, R.J. (8) 240, 243 Flamigni, L. (8) 105, 286 Fleischer, U. (1) 328; (4) 79 Flem, G.L. (8) 224 Floruss, A. (1) 51 Fluck, E. (1) 416-420; (4) 80; (5) 231-233; (8) 194

Foces-Foces, M.C. (8) 7, 54 Fokin, E.A. (5) 303 Fontanella, J.J. (8) 266 Ford, R.R. (8) 208 Foresti, E. (7) 38 Foricher, J. (1) 107 Forster, C. (5) 116, 186; (7) 54 Fortuniak, W. (1) 209 FOSS,V.L. (1) 68, 69, 280 Foster, A.L. (5) 144; (7) 68 Fotiadu, F. (7) 35 Foucaud, A. ( I ) 409, 410, 412; (5) 243; (7) 10; (8) 195 Fouquey, C. (5) 11 Francke, R. (1) 142 Francklyn, C. (6) 83, 300 Francois, P. (6) 152 Frank, B.L. (6) 258, 259 Frank, R. (6) 147 Franz, J.E. (5) 221 Franzus, B. (1) 147 Frebel, M. (1) 272 Freedman, J. (1) 155 Freeman, J.P. (4) 14 Freeman, S. (5) 182, 265 Freidzon, Ya.S. (8) 230 Freman, F. (6) 25 Frenking, G. (7) 51 Frenzel, M. (1) 377 Frick, W. (7) 73 Friedrich, C. (8) 210, 231 Friedrich, D.M. (8) 104 Frighetto, R.T.S. (7) 75 Frijns, J.H.G. (1) 22 Fritz, G. (1) 34-43, 203 Fritz, M. (1) 266, 322 Frolow, F. (1) 178 Froneman, M. (5) 14, 78 Froyen, P. (8) 45

366 Frerystein, N.A. (6) 316 Frye, J. (1) 199 Fujikawa, K. (6) 303 Fujimori, S. (6) 140 Fujimoto, T . (5) 33 Fujita, J . ( I ) 73 Fujiwara, H. (8) 154, 228 Fujiwara, M. ( I ) 255 Fukuda, N . (1) 17 Fukuda, R. (6) 281 Fulde, M . (1) 415; (8) 193 Fulop, V . (1) 400; (3) 13 Funaki, K. (8) 173 Furukawa, K. (6) 328 Furukawa, S . (5) 69 Furusawa, 0. ( I ) 263 Furuta, T. (7) 67 Furuya, S . (6) 266 Gabler, D. (8) 127, 128 Gaedcke, A . (5) 292 Gaffney, B.L. (6) 211 Gait, M.J. (4) 48; (6) 198, 234 Gajda, T. (5) 161, 162 Galishev, V . A . (5) 245 Gallazzi, M . C . (8) 161 Galy, J. (8) 122, 124, 125 Ganapathiappan, S. (8) 208 Gani, D. (5) 50 Gao, W.-Y. (6) 114 Gao, X. (6) 162 Gao, Z. (5) 140 Garanti, L. (7) 104; (8) 57 Garbers, H . V . (5) 86 Garcia, C. (8) 66 Garcia, R.G. (6) 144 Garcfa-Lbpez, T. (6) 34 Gard, G.L. (5) 150 Gard, J.K. (4) 53; (6) 168, 246 Garland, R.B. (7) 89 Garner, C . D . (5) 234 Gaset, A. (5) 246 Gasparutto, D. (4) 59; (6) 84 Gasparyan, G.Ts. ( I ) 140 Gastel, F. ( 5 ) 216 Gaudemer, A. (6) 292 Gaur, R.K. (6) 188 Gauss, D . H . (6) 100 Gazaliev, A.M. (5) 299 Gazizov, T.K. (4) 1 1 Ge, L. (6) 296 Geiser, T . (6) 108, 109 Genest, D. (6) 332 Genet, J.P. ( I ) 118; (4) 4, 36; (5) 206 Gentles, R.G. (6) 156 Geova, L.V.(8) 188

Organophosphorus Chemistry Geribaldi, S. (7) 66 Gerlach, B. (4) 44; (5) 27 Gerlt, J.A. (6) 247 Getman, K.M. (5) 221 Gheorghui, M . D . (5) 121 Ghosh, A . (4) 14 Ghosh, S.K. (1) 163 Giannaris, P.A. (6) 61, 141 Gibson, B.W. (6) 6 Gibson, D. (5) 176, 274 Gieske, T . H . (7) 82 Gigon, A. (7) 85 Gildea, B.D. (6) 189 Gill, G.B. (7) 117 Gillette, G.R. (1) 192, 193 Gillier, H . (5) 297 Gilyarov, V . A . (8) 78 Giralt, E. (6) 63, 196 Girard, G.R. (I) 16 Girard, J.-P. (7) 83 Givens, R.S. (5) 84 Glaser, R. (2) 4 Glegg, W . (5) 234 Glenmarec, C. (6) 244, 245 Gleria, M. (8) 105, 161, 286 Glowacki, Z. (5) 170 Gmeiner, W.H. (6) 170 Goesmann, H. (1) 43 Gohsh, D . (6) 327 Gold, L. (6) 298 Goldberg, I.H.(6) 258, 259 Gol’dfarb, E.I. (2) 14, IS Golding, B.T. (4) 3; (5) 120 Goldschmidt, B. (5) 26 Golina, S.I. (8) 225, 226 Golinski, M. (7) 91 Golokhov, D.B. (4) 20 Gololobov, Y.G. (5)45 Golova, L.K. (8) 255-257, 273 Gornez, M.A. (8) 251, 254, 261 Gonbeau, D . ( I ) 285 Gonce, F. ( I ) 170; (5)247 Gong, B. (5) 81 Gordillo, B. (5) 73 Gordon, E.M. (5) 115, 186 Gorenstein, D.G. (4) 62; (6) 123, 124, 320 Goreva, T . V . (5) 8 Gorgues, A. (5) 65; (7) 64, 65 Gosink, H.J. (8) 204 Gosovami, B. (6) 164 Goti, A . (3) 31 Gott, J.M. (6) 172 Gottikh, M. (6) 190 Goubitz, K. (8) 200 Goudetsidis, S. (5) 151 Gougoutas, J.Z. (7) 53 Gourdie, T.A. (6) 283, 284

Gouyette, C. (6) 13 Gouygou, M. ( I ) 284, 285 Graber, P. (6) 195 Grachev, M.K. (4) 37, 38 Graczyk, P. (1) 227 Grblund, A . (6) 312 Graff, D. (6) 125 Grajkowski, A . (6) 37 Grandas, A . (4) 61 Grandos, A. (6) 121 Granger, J.N. (4) 62; (6) 123 Granier, M. (1) 194, 195; (3) 32; (5) 286; (8) 117, 197 Graulich, J . (1) 402 Gravatt, G.L. (6) 283, 285 Gravier-Pelletier, C . (7) 84 Graziani, R. (1) 59; (3) 36 Grew, M . N . (5) 121 Gree, R. (7) 85 Green, G.A. (6) 118 Green, J.M. (5) 205 Green, R. (6) 241, 243 Greenbaum, S.G. (8) 266 Greeves, N. (3) 19 Griffith, O . H . (5) 137; (6) 333 Griffiths, D . V . (7) 9 Griffiths, P.A. (7) 9 Grigoryan, N.Yu. (1) 235 Grimaldo-Moron, J.T. (1) 228; (3) 11 Grobe, J. ( I ) 101, 307, 327 Gronchi, G. ( I ) 12 Gronenborn, A . M . (6) 195 Gross, H . (5) 122, 124, 149 Grubb, R.H. (7) 32 Griitzmacher, H . (1) 242, 296, 328, 343; (4) 79; (5) 239; (7) 14; (8) 32 Grunberg-Manago, M. (6) 223 Grushin, V . V . (1) 175 Gu, Q. (5) 106 Gubnitskaya, E.S. (5) 226 Gudat, D. (1) 339; (4) I; (8) 5 Gudima, A . (1) 281; (4) 73; (8) 205, 298 Gudrun, U . ( I ) 31 Gueck, J . (5) 20 Guenot, P. (1) 326 Guerk, G. (8) 113 Gughaev, A . V . (5) 62 Gug-Kim, S . (4) 54, 55; (6) 70 Guilard, R. (7) 113 Guillemin, J.C. ( I ) 115, 324, 326; (5) 113 Gumus, F. (6) 15 Guo, F. (8) 44 Guo, M. (7) 77 GUO,M . 4 . (5) 266; (6) 53-55

367

Author Index Gupta, A. (1) 390 Gupta, K.C. (6) 64,202 Guranowski, A. (5) 266; (6) 5 4 Gusar, N.I. (7) 100 Gusarova, N.K. (1) 92, 93, 159 Guy, A. (6) 151 Gvozdetskii, A.N. (2) 26 Gyor, M. (1) 190 Ha, T.-K. (1) 363 Haas, J. (1) 336 Habhadi, N. (1) 232 Haber, S. (1) 374 Habliston, D.L. (6) 333 Hacker, M.P. (6) 308 Haddon, R.C. (8) 251, 254, 261 Hadjiarapoglou, L. (5) 16 Hadzic, P.A. ( 5 ) 293 Haegele, G. (5) 151, 214, 292 Haenel, M.W. (1) 88 Hanssgen, D. ( I ) 60, 61 Hafez, T.S. (5) 283, 284 Hagiwara, S. (4) 13 Hahn, J. (1) 44 Hahn, M. (1) 386 Hahn, T. (1) 86 Halazy, S. (6) 33 Haller, F. (7) 51 Haller, S. (8) 36 Haltiwanger, R.C. (4) 29, 30 Hamad, M.M. (5) 283 Hamada, Y. (5) 300 Hamanaka, N. (1) 222 Hamano, M. (6) 275 Hambley, T.W. (3) 26; (5) 228 Hammerschmidt, F. (5) 171-173, 223, 224 Hammond, P.S. ( 5 ) 268 Hampp, A. (1) 71 Han, F.S. (6) 114 Handel. H. (2) 27 Handlon, A.L. (6) 5 8 Hanessian, S. (5) 126, 207 Hani, R. (8) 4 Hanke, D. (1) 43 Hanker, I. (6) 52 Hanna, M. (6) 241 Hanna, M.T. (1) 251, 252 Hanrahan, J.R. (5) 228 Hanson, A.K. (8) 11 Hanson, B.E. (1) 89 Harada, K. (6) 135 Harangi, J. ( 5 ) 293 Harayama, T. (4) 10 Hardee, J.R. (1) 199 Harger, M.J.P. (1) 361; (5) 265, 271, 275

Harlow, R.L. (1) 74, 75, 136 Harms, K. (7) 51 Harris, C.M. (6) 157, 318 Harris, F.M. (6) 327 Harris, P.A. (6) 181 Harris, P.R. (1) 54 Harris, R.K. (2) 29 Harris, T.M. (6) 157, 318 Harrison, K.N. (4)21 Harrity, T.W. (5) 115, 186 Hartung, H. (5) 298 Hartwig, J.F. (1) 174 Harusawa, S. (5) 107; (8) 56 Harvey, R.G.(6) 155 Hasegawa, Y. (5) 94 Haseltine, J.N. (7) 118 Hasenbach, J. (1) 51 Hashimoto, K. (8) 285 Hashimoto, M. (8) 99 Hashimoto, S. (1) 382; (8) 74, 75 Hasimoto, Y. (6) 140 Hassaneen, H.M. (8) 6 8 Hassanein, M. (1) 245 Hasselbring, R. (8) 33 Hassler, K. (1) 33 Hata, T. (4) 56-58; (5) 60;(6) 71, 72, 122 Hatano, K. (5) 300 Hau, J.F. (4) 60;(6) 110 Hauck, S.I. ( I ) 172 Haug, W. (1) 294, 317 Haught, J. (6) 80 Haupt, E.T.K. (5) 263 Hausel, R. (1) 134 Hausheer, F.H. (6) 128 Havelka, K.O. (7) 61 Haw, J.F. (8) 107, 108, 127, 128 Hayashi, Y. (8) 290 Haynes, R.K. (3) 26 He, L. (1) 395 Healy, P.C. (1) 106; (3) 12 Hehert, N. (4) 47 Hecht, S.M. (6) 249, 251-253 Heckmann, G. (1) 416-420; (8) 194 Hedden, D. (1) 127 Heelis, P.F. (6) 177 Heesche, K. (1) 96 Hefetz, Y. (6) 248 Hefferman, G.D. (5) 174 Hegemann, M. (1) 327 Heikens, W. (6) 147 Hein, G. (1) 362; (4) 78 Hein, J. (1) 319, 348, 365 Heine, M. (7) 91 Heineke, D. (7) 31

Heinemann, U. (6) 147 Heinicke, J. (1) 278 Heitz, A. (7) 124 Helbing, J. (6) 146 Helene, C. (6) 209, 214 Helinski, J. (6) 105 Hellwinkel, D. (1) 169 Helquist, P. (7) 57 Hemling, M.E. (6) 294 Hendrickson, J.B. (1) 261 Henin, Y.(6) 13 Henkel, T. (8) 21 Hennawy, I.T. (7) 28 Hennet, S. (7) 121 Henriksen, L. (6) 73 Hepburn, T.W. ( 5 ) 230 Herberhold, M. (8) 147 Herbst-Irmer, R. (8) 202 Herdan, J.M.(5) 121 Herdewijn, P. (6) 18, 19, 21, 136 Herdtweck, E. (1) 165 Herranz, R. (6) 34 Herrmann, A.T. (1) 336 Herrmann, E. (1) 32 Herschlag, D. (6) 239 Herve, M.-J. (1) 285 Hesse, D. (7) 30; (8) 90 Heuer, L. (1) 202 Heus, H.A. (6) 216, 229, 232, 233 Higgins, K.M. (5) 292 Highcock, R. (6) 48 Higuchi, H. (6) 131 Hikosaka, T. (1) 120 Hilbers, C.W. (6) 215, 257 Hilbers, M.P. (6) 226 Hilderbrandt, W. (1) 101 Hill, D.T. (1) 16 Hill, M.N.S. (5) 293 Hillenkamp, F. (6) 248 Hilpert, H. (6) 48, 49 Hines, W. (6) 6 Hinkle, R.J. (1) 234 Him, A. (1) 219 Him, M. (6) 155 Hiort, C. (6) 310, 312 Hirai, K. (5) 272 Hirakawa, K. (7) 70 Hirama, M. (7) 96 Hirata, Y. (6) 177 Hiratake, J. (2) 1 1 Hiroaki, H. (6) 218, 231 Hirose, T. (8) 262 Hirota, K. (6) 50 Hirotsu, K. (1) 277, 310, 313, 3 15 Hirschbein, B.L. (4) 18; (6) 103

Organophosphorus Chemistry

368 Hirschowitz, W. (6) 67 Hitchcock, P.B. (1) 179, 332, 373, 388; (3) 33 Hoang, H. (7) 24 Hochberg, R. (7) 99 Hock, R. (7) 41 Hocking, M.B. (1) 381 Hodge, R.P. (6) 318 Hoenle, W. (1) 42 Hoffman, M. (5) 169, 170 Hoffmann, J. (1) 204, 331 Hogarth, G. (1) 176 Hohenwarter, K. ( I ) 405 Hokelek, T. (8) 295 Holand, S. (I) 399, 403 Holley, W.K. (8) 91 Holrnes, C.E. (6) 252 Holmes, J.M. (2) 1, 5, 6, 20 Holmes, R.R. (2) 1, 5, 6, 18, 20 Holy, A. (6) 21-24, 26, 31 Hon, Y.4.(7) 40 Honda, T. (8) 74, 75 Hoogmartens, J. (6) 18 Hope, H. ( I ) 55, 56 Hopkins, P.B. (6) 286, 287 Hori, T. (5) 69 Hormi, O.E.O.(5) 131 Horn, H. (1) 295 Hornbuckle, S.F. (7) 1 Hosaka, H. (4) 54, 55; (6) 70, 92 Hosmane, N.S. (1) 27; (4) 24 Hosoda, A. (5) 280 Hosoda, M. (6) 273 Hosona, H. (6) 50 Hostetler, K.Y.(6) 16 Howell, H.G. (6) 27 Hoyle, C.E. (8) 250 Hrebabecky, H. (6) 22 Hruska, F.E. (6) 167 Hu, B.-F. ( 5 ) 58, 81 Huang, D.-L.(6) 8 Huang, L.M. (8) 209 Huang, N.Z. (7) 80 Huang, T.T.-S. ( I ) 147 Huang, Y .-2. (7) 29 Huang, Z. (6) 133 Huber, E.W. ( I ) 155 Huch, V. (1) 195; (7) 36 Hudson, H.R. (5) 88 Huff, J.R. (5) 36 Hughes, A.N. (1) 404 Hughes, N.A. (5) 293 Hund, H. (8) 41 Hund, R.D. (8) 34, 35 Hursthouse, M.B. (7) 62 Husek, A. (5) 7 4 Huskens, J. (6) 65, 132

Hussoin, M.S. (1) 261 Huszthy, P. (1) 190 Huttner, H. ( I ) 266 Huy, N.H.T. (1) 389 Huynh-Dinh, T. (6) 13 Hwang, C.-K. (6) 264; (7) 119 Hyatt, E.M. (4) 27; (5) 18 Iden, C.R. (6) 68, 69, 156 Igau, A. (1) 192 Ignat’eva, S.N. (1) 289, 299, 300, 302 Igolen, J. (6) 205 Iguchi, S. (1) 222 Ihara, T. (6) 275, 282 Iimura, S. (6) 3 Iino, Y. (7) 105; (8) 58, 60 Iishikawa, K. (6) 72 Ikegami, S . (8) 74, 75 Ikehara, M. (6) 218 Ikuta, S. (6) 166, 321 Imada, T.(6) 87, 88 Imai, S. (6) 36 Imamoto, T. (1) 119, 120; (3) 17 Iman, M. ( I ) 256 Imbach, J.-L. (6) 102, 148, 149 Imhoff, P. (8) 92, 200, 201 Inamoto, N. (1) 180, 310, 312; ( 5 ) 294 Indzhikyan, M.G. ( I ) 65, 94, 140, 141, 235; (5) 87 Inobushi, A. (8) 275-278 Inoguchi, K. (1) 72, 90 Inoue, K. (8) 137, 157, 213 Insubushi, A. (8) 237 Ionin, B.I. (5) 256, 260 Ionkin, A.S. ( I ) 287-290, 299-303; (5) 257 Iorish, V.Y.(4) 37 Iovleva, M.M. (8) 257, 273 Iribarren, A. (6) 143, 144 Ironside, M.D. (3) 21 Irwin, W.J. (5) 182 Ishigami, K. (1) 161 Ishikawa, N. (8) 114-1 16, 180 Ishizaki, T. (6) 80, 271 Ishmaeva, E.A. (1) 342; (8) 17 Ishmuratov, A S . (5) 46 Islam, M.S. (8) 208 Islamov, R.G. (5) 202 Ismagilov, R.K. (5) 123 Issleib, K. (1) 97 Ito, S. (7) 96 Ito, Z. (8) 154, 228 Ivanchenko, V.I. (1) 292 Ivanov, A.N. (5) 8

Ivanova, N.A. (8) 257 Iverson, P.L. (6) 106 Ivonin, S.P. (1) 130 iwai, S. (6) 89 Iwasaki, F. (7) 16 Iwasawa, N. (7) 118 Iyer, N. (6) 14, 15 Iyer, R.P. (6) 101, 111 Izso, G. (1) 190 Jaarsveld, K. (3) 29 Jachow, H. (1) 49, 51 Jackson, R.F.W. (5) 154 Jacob, P. (4) 31; (5) 103 Jacobson, K. (6) 66 Jacobson, R.A. (4) 27; (5) 18 Jacquier, R. (5) 216, 217 Jaeger, G. (5) 52 Jaeger, L. (8) 153 Jaeggi, K.A. (5) 253 Jagowski, A.J., jun. (8) 229 Jakubik, D. (1) 88 Jamieson, L.A. (5) 130 Janakiraman, M.N. (4) 27; (5) 18 Janati, T. (1) 326 Jand, J. (1) 369; (8) 113 Janecki, T.(4) 5; (5) 134 Jankowski, S. (5) 77 Jansen, J.F.G.A. ( I ) 77 Jansen, M. (7) 99 Janssen, A. (4) 7 8 Janssen, G. (6) 18 Jaques, J. (5) 11 Jarmer, M. (1) 35, 36, 38, 39, 203 Jarvi, E.T. (3) 5; (6) 45; (7) 60 Jaseja, M. (6) 245 Jastorff, B. (4) 44;(5) 27 Jaud, J . (1) 284 Jaworska, D. (5) 197 Jedlinski, Z. (8) 142 Jekel, A.P. (8) 129 Jenkins, I.D. (1) 106; (3) 12 Jenkins, M.J. (7) 81 Jhurani, P. (6) 7 4 Ji, Y. (6) 17 Jia, X. (6) 305 Jiaqi, P. (7) 44 Jie, L. (6) 19 Jin, G. (1) 392 Jina, A.N. (5) 42 Jinkerson, D.L.(8) 4 Johns, D.G. (6) 21 Johns, R.B. (4) 39-41; (5) 21-23, 75 Johnson, F. (6) 68, 69, 153, 156

369

Author Index Johnson, J.W. (5) 1 18 Johnson, L.K. (7) 32 Johnson. M.P. (4) 23, 25 Johnson, M.R. (5) 28 Johnson, P. (6) 309 Johnson, R.K. (1) 16 Johnson, R.L. (5) 227 Johnston, G.A. (5) 228 Jones, A.S. (6) 12 Jones, P.G. (1) 202; (2) 9 , 19 Jones, R.A. (1) 52-54, 57; (6) 162-164, 21 1 Jones, R.C.F. (7) 58 Jones, R.H. (1) 24 Jones, S. (1) 95 Jordan, S. (6) 146 Joseph-Nathan, P. (2) 2 3 Joyce, G.F. (6) 242 Jubault, M. (7) 65 JugC, S. (1) 1 1 8; (4) 4, 36; (5) 206 Jung, K.-Y. (2) 16, 17; (5) 185; (7) 122 Jung, M. (1) 73 Jurkschat, K. (5) 298 Just, G. (4) 47; (6) 39 Jutzi, P. (1) 135, 371 Kabachnik, M.1. (1) 265; (8) 78 Kabata, H. (6) 35 Kabela, J . (8) 184 Kadoura, J. (8) 66 Kaehlig, H. (5) 171, 224 Kagan, H.B. (3) 10 Kahne. D. (6) 268 Kaji, A. (6) 131 Kajihara, K. (1) 255 Kajiwara, M. (8) 140, 238, 239, 245, 263 Kakiuchi, H. (8) 63 Kalabina, A.V. (8) 196 Kalashnik, A.T. (8) 255, 256 Kalchauser, H. (5) 291 Kalibabchuk, V.A. (8) 205, 298 Kalish, V.J. (7) 80 Kalman, A. (1) 400; (3) 13 Kamalov, R.M. (5) 202 Kameda, M. (1) 166 Kamenecka, T.M. ( 5 ) 184 Kamiya, Y. (8) 262 Kamokari, M. (8) 9 8 Kan, L. (5) 289 Kan, L . 4 . (6) 208 Kanamathareddy, S. (5) 155 Kanaoka, Y. (6) 207 Kanavarioti, A. (6) 7 Kandile, N.G. (1) 144

Kaneko, C. (5) 262 Kaneko, M. (8) 9 8 Kann, N. (7) 57 Kanomata, N. (8) 59 Kanzaki, M. ( I ) 255 Kapoor, P.N. (1) 179 Kappe, T. (8) 95 Kappen, L.S. (6) 258, 259 Karaghiosoff, N. (1) 390 Karanewsky, D.S.(5) 115; (7) 53 Karasik, A.A. (1) 197 Kardos, N. (5) 206 Karelson, M. (6) 181 Karev, V.N. (1) 11 1 Karim, S. (7) 97 Karkozov, V.G. (8) 183 Karpacheva, S.N. (1) 124 Karplus, M. (6) 329, 330 Karpunina, L.B. (2) 26 Karsch, H.H. (1) 62; (7) 34 Karthikeyan, S. (8) 152 Kashemirov, B.A. (5) 252 Kasheva, T.N. (5) 208, 209 Kashiwabara, K. ( I ) 73 Kaska, W.C. ( I ) 80 Kasparek, F. (5) 74 Kasukhin, L.F. (5) 45 Katagiri, N. (5) 262 Kataoka, S. (6) 36 Kato, H . (8) 6 3 Kato, M. (6) 36 Kato, R. (4) 56; (6) 71 Katritzky, A.R. (5) 118; (6) 181; (7) 114 Katti, K.V. (1) 247; (8) 69, 84, 199, 202, 203 Katzenbeisser, U . (1) 33 Kaukorat, T. (2) 9 Kaur, T. (8) 31 Kawada, T . (6) 36 Kawade, T. (6) 35 Kawai, S.H. (6) 39 Kawai, Y. (1) 330 Kawanishi, K. (5) 69 Kawasaki, M. (7) 6 Kawashima, M. (6) 92 Kawashima, T. (1) 180; (5) 294 Kawate, H. (8) 63 Kazakov, P.V. (5) 128, 129 Kazankova, M.A. (1) 182 Kazantseva, M.V.( I ) 220 Kazantseva, V.V. (8) 225 Kean, J.M.(6) 130 Keana, J.F.W. (5) 137 Keck, H. ( I ) 352; (4) 66 Keenan, R.W. (5) 37 Keglevich, G. (1) 400: (3) 13

Kellner, K. (1) 133 Kemmitt, R.D.W. (3) 34 Kempener, Y. (6) 152 Kemper, B. (6) 221 Kenan, W.R. (1) 158 Kennepohl, D.K. (2) 32, 33 Kennewell, P.D. (7) 101; (8) 53 Kenyon, G.L. (6) 6 Kerdel, K. (5) 63 Kergaye, A.A. (5) 305 Khachatryan, R.A. (1) 65, 94, 235 Khalil, F.Y. (1) 251, 252 Khalil, K.M. (7) 28 Khan, M. (5) 304 Khanous, A. (7) 64,65 Kharchenko, A.V. (1) 130 Khaskin, B.A. (5) 46 Khistich, A.I. (8) 76 Khodyrev, B.S. (8) 253 Khokhlov, P.S. (5) 252 Khorana, H.G. (7) 7 8 Khusainova, N.G. (5) 257, 258 Kibardin, A.M. (1) 41 1; (4) 35 Kierzek, R. (6) 179, 180 Kikuchi, T. (7) 16 Kikuoka, M. (1) 184 Kilic, A. (8) 126, 145 Kilic, Z. (8) 126, 295 Kim, C. (8) 135, 139, 232, 233 Kim, C.U. (6) 20, 2 8 Kim, J.N. (1) 146 Kim, S. (4) 23 Kim, S.K. (6) 312 Kim, T.C. (1) 369, 370; (4) 70, 71 Kim, T.V. (5) 93, 147, 148, 254 Kimura, Y. (1) 238, 263 Kirchner, J.J. (6) 286, 287 Kirchner, M.B. (5) 268 Kireen, V.V. (8) 218 Kisalus, J.C. (1) 413 Kiseleva, E.I. (5) 93, 147, 148, 254 Kishida, E. (8) 73 Kitade, Y. (6) 50 Kitagawa, K. (8) 285 Kitani, A. (6) 44 Kitas, E.A. (5) 25 Kitayama, M. (8) 172 Klarner, F.-G. (1) 407; (3) 8; (7) 41 Klein, H.-F. (8) 36 Klepa, T.I. (1) 112 Klicic, J. (5) 16 Kline, P.C. (6) 150 Klingebiel, U . (1) 30 Klobucar, W.D. (8) 241, 242

370 Knight, D.A. (1) 20 Knobler, C.B. (1) 138 Knorr, R. ( 5 ) 25 Knudsen, K.L. (1) 404 KO, Y.Y.C.Y.L. (1) 297 Kobayashi, N. (5) 272 Kobayashi, T. (8) 63, 9 8 Koch, T.H. (6) 172 Koch, V.R. (8) 236 Kochendorfer, F. (7) 99 Kochevar, I.E. (6) 248 Kodaka, M. (1) 162 Kodama, G. (1) 166 Kodama, H. (6) 231 Koehler, H. (8) 153 Kollemann, C. (1) 246 Koenig, H. (8) 36 Koenig, M. (1) 284, 285 Koerner, J.F. (5) 227 Koster, H. (6) 187 Koev, I.G. (8) 141 Koga, M. (6) 142 Kohda, K. (6) 288 Kohn, H. (6) 269 Koidan, G.N. (1) 216, 291; (4) 26; (8) 82 Koizumi, M. (6) 235 Koizumi, T. (5) 229; (8) 285 Kokubo, I. (5) 279 Kolbina, G.F. (8) 272 Kolesnik, N.P. (1) 67; (5) 112 Kolich, C.H. (8) 241, 242 Koll, 8. (1) 45 Kolmel, C. (1) 295 Kolodka, T.V. (4) 33 Kolodyazhnyi, 0.1. (1) 137; (4) 19, 20; (5) 251; (7) 2 Kolomnikova, G.D. (5) 45 Komarov, V.Ya. (5) 245 Korniyama, M. (6) 9, 35 Komori, T. (8) 115 Kondo, S. (1) 239 Konieczny, M. (5) 155 Konovalova, I.V. (2) 8, 13-15; ( 5 ) 17 Kook, L.H. (6) 38, 132, 226, 244, 245 Kooreman, P.A. (4) 45 Kopylova, L.Yu. (5) 123 Korenchenko, O.V. (5) 188, 303 Korf, U. (6) 43 Korkin, A.A. (4) 68; (8) 9, 10, 78 Korneeva, E.V. (8) 272 Kornilov, M.Yu. (5) 147 Kostka, K. (5) 165 Kosuge, S. ( I ) 222 Kotaka, T. (8) 252

Organophosphorus Chemistry Kouchakdjian, M. (6) 183, 184 Kouril, M. (8) 184 Kovacs, I. (1) 278 Kovalenko, L.V. (5) 128, 129 Kovaleva, T.V. (5) 111 Kowalski, M.H. (1) 234 Koyanagi, S. (7) 70 Kozarich, J.W. (6) 256, 258, 259 Kozawa, H. (1) 250 Kozikowski, A.P. ( 5 ) 38, 39 Kozlov, E.S. (1) 130 Kozlova, E.V. (5) 208 Krachinin, N.P. (8) 255 Kramer, B. (1) 273 Krannich, L.K. (1) 11 Krawchik, E. (5) 261 Krawiecka, B. (5) 92 Krebs, B. (1) 307 Krech, F. (1) 97 Kreitmeier, P. (1) 316, 318 Kren, R.M. (1) 368; (5) 241 Kretschmer, U. (6) 126, 127 Kriger, U. (7) 14 Krishnamurthy, S.S. (2) 18; (4) 24; (8) 20, 152 Krishnan, B.R. (5) 5 Krol, E.S. (5) 267 Kroona, H.B. (5) 227 Kroos, R. (1) 135, 371 Kross, M. (8) 156 Kroto, H.W. (1) 323 Kruger, C. ( I ) 88, 335, 336; (7) 41 Kriiger, U. (1) 328, 343; (4) 79; (8) 32 Kruger, T.L. (1) 100 Krulle, T. (7) 73 Krylova, V.N. (5) 32 Krzyzanowska, B. (5)61 Kuhiniok, S. (1) 210 Kuho, A. (8) 106 Kubota, T. (8) 282 Kubota, Y. (6) 280 Kucera, L.S. (6) 14, 15 Kuchen, W. (1) 86, 219, 352, 362; (4) 66, 78 Kucherova, M.N.(8) 96 Kudryavtsev, A.A. (4) 26 Kudryavtseva, L.I. (5) 142 Kuhn, A. (1) 201 Kuhn, N. (1) 201 Kuijpers, W.H.A. (6) 65, 132 Kukhar, V.P. ( I ) 137; ( 5 ) 190, 208, 209 Kukubo, I. (5) 278 Kukushkin, V.Yu. (1) 248; (8) 44

Kulagowski, J.J. (5) 36 Kulichikhin, V.G. (8) 253, 258-260, 272 Kulishov, Y.G. (3) 14 Kulkarni, D.G. (1) 148 Kumagawa, Y. (7) 112 Kumar, A. (6) 12 Kumar, D. (8) 131 Kumar, P. (6) 64,202 Kumar, R. (1) 29 Kumaravel, S.S. (2) 18; (8) 20, 187 Kumberger, 0. (8) 16 Kung, P.-P. (6) 21 1 Kunisada, H. (1) 239 Kunugi, S. (6) 35 Kuo, E.E. (6) 97 Kuptsov, S.A. (8) 256 Kurachi, Y. (8) 238, 239 Kurahashi, A. (8) 163, 166, 168, 172 Kurakake, T. ( I ) 267 Kuraki, Y. (8) 281, 282 Kurchenko, L.P. (8) 11 1 Kureno, Y. (5) 300 Kurg, V.V. (1) 260 Kurihara, T. (5) 107; (8) 56 Kurts, A.L. (1) 150 Kurtz, S.K. ( I ) 126 Kusano, T . (5) 10 Kushlan, D.M. (6) 220 Kusumoto, T. (3) 17 Kuz’mina, N.Yu. (1) 103 Kuznetsova. A.A. (1) 220 Kuznetsova, N.A. (8) 96 Kuznetsova, S.A. (5)4 5 Kwazoe, Y. (6) 288 Kwik, W.L. (8) 93, 9 4 Kwok, T.J. (4) 22 Kwon, S. (8) 212, 291, 296 Labarre, J.F. (8) 113, 122-125, 156 Labelle, M. (7) 87 Labuda, D. (6) 237 Lachkova, V. ( 5 ) 249 Lacombe, S . (1) 324 Lafitte, J.A. (1) 118; (4) 36 Lahti, M. (6) I 1 Lamandk, L. (1) 367 Lamm, G.M. (4) 51; (6) 197 Lammertsma, K. (7) 3; (8) 8 Larnond, A.I. (6) 91, 143 Lampe, D. (5) 51 Landini, D. (8) 158 Landry, C.J.T. (8) 284 Lang, H.(1) 321, 322

37 1

Author Index Lang, S . (1) 41 Lange, L. (1) 210 Langen, H. (8) 283 Langer, R. (8) 235 Langhauser, F. (1) 336 Langley, D.R. (6) 260 Lanssen, A. (1) 362 Laretina, A.P. (8) 78 Larpent, C. (1) 191, 230, 231 (3) 2 Laszkiewicz, B. (8) 141 Latscha, H.P. (7) 13 Lattes, A. (5) 63, 97 Lauchmann, J. (1) 164 Laurent, C. (1) 206 Laurent, Y. (8) 215, 224 Lavery, R. (6) 332 Lavetina, A.P. (5) 129 Lavilla, R. (7) 77 Layher, E. (1) 43 Lazanova, R.A. (8) 141 Lazhko, E.I. (1) 182 Leader, H. (5) 274 Leake, E. (6) 14 Lecomte, L. (1) 186 Lee, A.L. (1) 162 Lee, F.K.(1) 221 Lee, H. (6) 155, 309 Lee, J.N. (8) 287 Lee, K. (5) 181 Lee, S. ( 5 ) 230 Lee, Y.F. (2) 33 Lee, Y.H. (5) 105 Leeson, P.D. (5) 41 Lefeber, A.W.M. (5) 138 Lefkaditis, D.A. (7) 27 Le Floch, P. (1) 9, 282, 283, 401

Le Goffic, F. (5) 198 Leichtweis, I. (8) 88 Leise, M. (1) 321, 322 Lellouche, J.-P. (7) 85 Le Merrer, Y. (7) 84 Lemmen, P. (4) 46; (5) 43 Lemos, M.A.N.D.A. (1) 332 Lempert, K. (1) 190 Lemon, I.C. (5) 41 Lenting, H.B.M. (6) 16 Lenz, R.W. (8) 210 Leonardo, C.L. (8) 7 Leong, W.R. (8) 94 Leont’eva, I.V. (1) 265 Lepre, C.A. (6) 301 Lekontov, S.A. (5) 2, 3; (8) 86 Leroux, Y. (5) 297 Leserman, L. (6) 138 Leslie, D.R. (5) 91 Lesnikowski, Z.J. (6) 37

L’Esperance, R.P. (1) 122 Letsinger, R.L. (6) 62 Leung, P.H. (1) 187 Leusen, F.J.J. (5) 79, 80 Le Van, D. (1) 307, 327 Levina, A.Ya. (1) 41 1; (4) 35 Levine, J.A. (5) 70 Levis, J.T. (6) 130 Lewis, T. (5) 174 Lho, D.S. (5) 105 Li, C. (5) 106 Li, G. (1) 395; ( 5 ) 106 Li, J. ( 5 ) 277 Li, S.-Y. (7) 40 Li, V . 4 . (5) 96; (6) 269 Li, X. (6) 174 Li, Y.-G. (5) 141 Li, Y.F.(6) 178 Li, Z.-H. (5) 166 Liang, M. (8) 222 Liao, Q. (1) 258 Liao, X. (5) 140 Liao, Y. (7) 29 Lidon, M.J. (8) 51 Lie, L. (6) 18 Lieberknecht, A. (7) 74 Lieberman, J. (8) 33, 204 Lieske, C.N. (5) 268 Lim, C. (6) 329, 330 Lindeman, S.V. (5) 299 Linden, A. (8) 20 Lino, Y. (8) 3 Linti, G. (1) 357 Lippard, S.J. (6) 301 Lippert, B. (6) 45 Lipshutz, B.H. (1) 154 Litinas, K.E. (7) 27 Litkei, G. (8) 52 Litten, J.C. (1) 236; (7) 37 Litvinov, 1.A. ( I ) 291; (8) 258 Liu, H.-J. (7) 116 Liu, K. (2) 11 Liu, L. (1) 395 Liu, M. (1) 286 Liu, P.-K. (7) 61 Liu, S.-T. (1) 83 Liu, Y.-S. (5) 141 Liu, Z. (1) 215; (5)47 Liu, 2.-P. (7) 4 Livantsov, M.V. (1) 183, 214; (2) 22; (4) 15; (5) 213 Live, D.H. (6) 210 Liversidge, G.G. (8) 274 Liverton, N.J. (5) 41; (7) 98 Llamas-Saiz, A.L. (8) 54 Lochschmidt, S . (1) 366 Lodwig, C. (1) 407; (3) 8 Liinnherg, H. (6) 10, 11

Liinnecke, P. (4) 81 Loginova, I.V. (2) 13 Logunov, A.P. (1) 102, 103 Logusch, E.W. (5) 221 Long, E.C. (6) 251, 278 Lopez, L. (1) 344, 397, 398; (4) 76; (8) 191, 192 Lopusinski, A. (5) 4 Lorenzen, D. (1) 219 Loschner, T. (6) 129 Losse, G. (6) 94 Low, D. (7) 15 Lowe, G. (6) 56, 57 Lown, J.W. (6) 170, 276 Lu, K.-J. (1) 27 Lu, L. (7) 40 Lu, P. (6) 67 Luche, J.L. (1) 149 Ludwig, J. (6) 51 Lucke, E. (1) 306 Lucke, J. (8) 223 Liiking, S. (4) 63; (6) 145 Luth, B. (1) 327 Luetkens, M.L. (1) 10 Luh, B.Y. (6) 20, 28 Luheshi, A.-B.N. (7) 101; (8) 53 Lukashev, N.V. (1) 182 Luk’yanenko, S.N. (4) 34; (5) 255 Lumbroso, H. (1) 376 Lumin, S. (7) 86 Lutsenko, I.F. (4) 15; (5) 213 Luu, B. (6) 17 Luu, R.P.T. (4) 64 Luzikova, E.V. (1) 182 Lyashenko, Yu.E. (1) 212, 213 Lynch, V.P. (5) 88 Ma, X.-B. (1) 394 Ma, Y . - X . (4) 61; (6) 121, 125 Maas, G. (1) 204 Maasa, W. (1) 402 McBeath, R.J. (6) 169 McCarthy, J.R. (3) 5; (7) 60 Maccioni, A . (8) 158 McClard, R.W. (5) 117 McClure, C.K. (2) 16, 17; (5) 185; (7) 122 McCollum, C. (6) 66 MacDairmid, J.E. (6) 33 MacDonald, H.R. (6) 195 McDonnell, G.S. (8) 101, 217, 268 McElroy, A.B. (3) 19 McEwen, W.E. (1) 249 McFadyen, W.D. (6) 309 McFarlane, H.C.E. (1) 85

372 McFarlane, W. (1) 85, 95 McGall, G.H. (6) 256 McGrath, J.E. (3) 16 McInally, T. (4) 3; (5) 120 McKellar, R.B. (6) 5 McLennan, A.G. (6) 54 MacMillan, A.M. (6) 158, 159 McNemar, L. (6) 6 McQuaid, L.A. (5) 219 McQuire, L. (3) 21 Maeda, H. (1) 184; (6) 328 Maeno, N. (5) 229 Maerker, A. (1) 18 Markl, G. (1) 316, 318, 405-408; (3) 8 Maestro, M.M. (3) 24 Mag, M. (4) 63; (6) 145 Magill, J.H. (8) 216 Magliozzo, R.S. (6) 250 Magnusson, E. (2) 2 Mague, J.T. (4) 25 Mahajna, M. (5) 273 Mahran, M.R. (5) 284 Mai, G. (7) 111 Maia, A. (8) 158 Maib, P. (7) 11 1 Maidanovich, N.K. (8) 97 Maier, L. (5) 114, 189, 191, 192, 200, 201, 220 Majewski, P. (1) 145 Majoral, J.-P. ( I ) 170, 349; (5) 65, 246, 247, 248 Majumdar, C. (6) 112 Mak, T.C.W. (1) 25 Makarov, G.M. (5) 202 Makenzie, L. (6) 294 Makhaeva, G.F. (5) 46 Maki, T. (1) 184 Maki, Y. (6) 50 Malavaud, C. ( 1 ) 344; (4) 76 Malenko, D.M. (4) 34; (5) 145, 146, 255 Maligres, P. (3) 6; (4) 6 Malik, M. (5) 212 Malik, P. (8) 159 Malinovskii, T.I. (5) 301 Malkova, G.Sh. (5) 187 Malley, M.F. (7) 53 Malygin, V.V. (5) 46 Malysheva, S.F. (1) 92, 93, 159 Malyutina, I.V. (1) 112 Marndapur, V.R. (1) 163 Manchilova, S. (5) 263 Mangeney, P. (4) 28 Manginot, E. (7) 48; (8) 67, 83 Mann, A. (7) 17 Manners, 1. (8) 101, 160, 198, 222, 246, 268

Organophosphorus Chemistry Mannik, J.H. (6) 277 Mantlo, N.B. (7) 118 Marasco, C.J., jun. (6) 15 Marchand, R. (8) 215, 224 Marchenko, A.P. (1) 216, 291; (2) 31; (4) 26; (8) 77, 82 Marco, C. (8) 251, 254, 261 Marder, T.B. (1) 126 Mardones, M.A. (1) 27, 52, 53, 57 Marecek, A. (8) 81 Marecek, J.F. (5) 34, 35, 40 Marfey, P. (6) 141 Mariano, P.S. (5) 230 Marinelli, E.R. (6) 69 Marinetti, A. (1) 9, 283, 304, 305, 373 Markovskii, L.N. (1) 67, 279, 281, 292, 342, 345-347; (4) 67, 69, 73, 75; (5) 112, 301; (8) 17, 30 Markowska, A. (5) 44 Marlin, J.E. (3) 27 Marquez, V.E. (5) I66 Marretta, J. (5) 186 Marsch, M. (7) 51 Marshall, W.S. (6) 125 Marsimov, A.S. (8) 218 Marsters, J.C. (6) 74, 192 Martin, J.C. (6) 20, 27, 28 Martin, R. (1) 101 Martin, S.F. (1) 153 Martinez, J. (7) 123, 124 Martynov, I.V. (1) 212, 213; (5) 2, 3, 8, 46, 188, 256, 303; (8) 86 Martynyuk, E.G.(5) 1 1 1 Marumoto, R. (6) 254 Maruyama, I. (8) 154, 228 Marzilli, L.G. (6) 304, 305 Masarnune, S. (7) 92 Mascerenas, J.L. (3) 25 Mashima, K. (1) 17 Mason, S. (3) 34 Masotti, H. (4) 64 Mastalia, A. (5) 153 Mastryukova, T.A. (1) 265; (5) 128, 129, 178 Masuda, S. (8) 276 Masui, M. (1) 184, 241 Mataga, N. (6) 177 Matejec, R. (8) 283 Matern, E. (1) 34, 36, 38, 203 Mathey, F. (1) 7-9, 282, 283, 304, 305, 373, 378, 380, 383, 389, 399, 401, 403 Mathieu, R . (1) 177 Matos, R. (1) 308

Matoshko, G.V. (8) 96 Matsui, M. (5) 229 Matsuki, T. (8) 288 Matsukura, M. (6) 111, 113, I15 Matsumoto, J . (8) 6 4 Matsurnoto, K. (1) 382 Matsurnoto, Y. (6) 9 Matsurnura, Y. (1) 17 Matsuura, T. (6) 255; (7) 90 Matt, D. ( I ) 26 Matthews, D.P. (3) 5 ; (7) 60 Matuszewski, B. (5) 84 Matveeva, E.D. (1) 150 Matyjaszewski, K. (8) 207, 220, 22 1 Matzen, M. (6) 146 Mawer, I.M. (5) 36 Mayer, H.A. ( I ) 80 Maynard, S.J. (8) 107, 108 Mazerolles, P. (1) 206 Mazibres, M.-R. ( I ) 281, 369, 370, 391; (4) 70, 71, 73, 74 Mazumder, A. (6) 247 Mazzah, A. (8) 204 Meares, C.F. (6) 9 8 Mebel, A.M. (8) 9 Medvedeva, L.Ya. (8) 188, 297 Meehan, E.J. (5) 304 Meetsma, A. (8) 129, 187 Mehrotra, R.C. (5) 55 Meidine, M.F. ( I ) 308, 332, 348 Meier, H. (4) 7; (5) 125 Meignan, G. (1) 191, 230, 231; (3) 2 Meirovich, R. (5) 193 Meline, R.L. (3) 35 Mencl, J. (8) 184 Mendel, D. (6) 96 Menger, F.M. (6) 325 Menu, H.-J. (3) 32 Menu, M.-J. (8) 36, 117 Mercier, A. (5) 215 Mercier, F. (1) 378, 380 Mergny, J.-L. (6) 214 Merino, I. ( I ) 237, 253; (7) 22, 50; (8) 62 Merka, A. (6) 22 Merker, R.L. (8) 216 Merrirnan, M.C. (4) 53; (6) 246 Merwin, L.H. (5) 214 Metschies, T. (4) 44;(5) 27 Metternich, H.J. (1) 358 Metz, B. ( I ) 402 Meunier, B. (6) 289-29 1, 293 Mewett, K.N. ( 5 ) 228 Meyer, A. (6) 148 Meyer, K.L. (6) 15

Author Index Meyer, M. (1) 30 Meyer, W . E . (8) 27 Miao, X.-L. (5) 141 Michalska, M. (5) 104 Michalski, J . (5) 261; (6) 105 Michel, F. (6) 241 Miginiac, L. (5) 194 Mikhailov, S.N. (6) 137 Mikheleva, G . A . (8) 257 Mikhno, I.L. (8) 76 Mikohjczyk, M. ( I ) 227; (7) 120 Mikroyannis, J . (5) 292 Milder, S.J. (6) 289 Miljkovic, D . A . (5) 293 Millard, J.T. (6) 287 Miller, M.J. (7) 8 0 Miller, P.C. (7) 52 Miller, P.S. (6) 130 Miller, R.W. (1) 298 Miller, T . A . (1) 154 Millet, J. (7) 88 Milstein, D. (1) 178 Minami, T . (3) 7; (7) 70 Minasyan, G . G . ( I ) 141 Minbaev, B . U . (5) 152 Minic, D.J. (5) 293 Minouni, N. (5) 133 Minto, F. (8) 105, 286 Mio, S. (7) 112 Mioskowski, C. (3) 4; (7) 17, 88 Mirkin, C . A . (8) 79 Mironenko, D . A . (5) 208 Mironov, V.F. (2) 8, 13-15 Miroshnichenko, V.V. (8) 82 Mirskova, A.N. (5) 108 Misco, P.F. (6) 28 Misiura, K. (4) 48; (6) 198 Misra, V. (6) 210 Mitchell, M.J. (6) 67 Mitchell, T.N. (1) 96 Mitlsuya, H. (6) 113 Mitovic, A . D . (5) 228 Mitsuda, N. (1) 180 Miyamoto, T. (8) 6 4 Miyano, M. (7) 89 Miyano, S. (5) 83 Miyasaka, T. (6) 29 Miyauchi, N. (6) 334 Miyazawa, M. (1) 79 Mizakh, L.I. (2) 26 Mizoguchi, K. (8) 262 Mlotowska, B. (5) 44 Mocerino, M. (1) 152 Modak, A.S. (4) 53; (6) 168, 169, 246 Modest, E.J. (6) 14, 15 Modranka, R. (5) 165

373 Modro, T . A . (5) 14, 78, 86 Miiller, U . (6) 187 Moezzi, A. (1) 355 Mohammad, T. (6) 295 Moiseev, A.I. (1) 248; (8) 42 Mok, C.-Y. (1) 323 Mokhov, V.M. (8) 183 Molina, P. (1) 151; (7) 102, 106, 108-1 10; (8) 7, 15, 43, 46,47, 49-5 1, 54, 55 Molko, D. (4) 59; (6) 84 Mollin, J . (5) 74 Momose, S. (1) 79 Moni, S. (8) 166 Monohan, J.B. (5) 119 Montague, R.A. (8) 220, 221 Montenay-Garestier, T . (6) 2 14 Montforts, F.-P. (7) 111 Montlo, D . (1) 177 Montoneri, E. (5) 136, 160; (8) 161 Moore, A.J. (7) 62, 63 Moore, M.F. (6) 142 Moore, M.R. (3) 34 Moran, J . (1) 125 Moravshaya, T.M. (8) 249 Morgan, R.J. (6) 31 1 Mori, T. (1) 239; (6) 255, 313 Motiarty, R.M. (2) 11 Morimoto, T. (1) 90 Morise, X. (5) 113 Moriya, K. (8) 140 Morr, M. (6) 147 Morris, K.B. (1) 236; (7) 37 Morris-Natschke, S.L. (6) 15 Morrison, H. (6) 295 Morton, G.O. (6) 267 Morvan, F. (6) 102 Moskva, V.V. (1) 217; (5) 123; (8) 190 Mougel, M. (6) 223 Moulton, K.M. (8) 265 Mourey, R.J. (5) 34 Mourino, A . (3) 24, 25 Mousa, H . A . H . (8) 6 8 Mouyssou, P. ( I ) 256 Mugge, C. (1) 97 Muller, A . (1) 135, 271, 272, 306, 416, 420 Muller, G. (1) 62; (8) 16 Mueller, J.E. (6) 221 Mueller, N. (5) 224 Muller, U . (1) 243; (8) 294 Muller, W . E . G . (6) 138 Muir, A.S. (1) 85 Mukaiyama, T. (1) 262 Mukundan, S., jun. (6) 304 Mulder, G.J. (6) 59

Mulekar, S.V. (5) 13 Muller, G. (1) 164; (7) 34 Mullis, K.B. (6) 77 Mundt, C. (8) 24 Munk, S . A . (6) 80, 271, 272 Munoz, A. (1) 367 Murafuji, T . (7) 16 Murahashi, E. (3) 2 3 Murayama, M. (1) 277 Murillo, A . (2) 23 Murkerjec, P. (8) 4 Murray, A . W . (3) 21 Murray, H.H.(1) 10 Murray, M. (5) 151, 292 Murray, R.W. (8) 264 Murty, V.S. (6) 249 Musin, R.Z. (5) 235 Musio, R. (4) 8 Musker, W.K. (1) 110 Muth, H.-P. (6) 47 Mutherarasan, R. (8) 274 Mutti, S. (4) 28 Muzyka, P.V. (8) 30 Myers, P.L. (6) 48 Mynott, R. (1) 335 Nadzan, A.M. (7) 19 Naesens, L. (6) 21 Naganova, E . G . (1) 280 Nagao, F. (1) 250 Nagaraju, C. (5) 12, 59 Nagase, S. (1) 267, 277 Nagata, R. (3) 23 Nagato, Y. (5) 9 4 Naidu, M.S.R. (5) 12, 59 Nai-jue, 2. (7) 107 Nakacho, Y . (8) 275-278 Nakamura, H. (6) 280 Nakamura, S. (7) 70 Nakamura, Y. (8) 56 Nakanaga, T . (8) 138, 237, 279 Nakane, H. (6) 50 Nakanishi, T. (6) 3, 93 Nakashima, H . (6) 29 Nakatsuka, M. (7) 9 4 Nakayama, H. (8) 293 Nakayama, K. (5) 15 Nakayama, T . A . (7) 7 8 Nam, T.T. (1) 32 Narnestnikov, V.I. (5) 159 Namura, A . (6) 35 Nanishi, K. (8) 293 Nanjundiah, B.S. (1) 148 Narasimhan, N.S. (7) 115 Narisada, M. (7) 90 Narula, C.K. (1) 167 Nasman, J.H. (5) 131

Organophosphorus Chemistry

374 Naso, F . (4) 8 Nasser, J . (5) 127, 225 Natalinio, B. (5) 119 Natchev, I.A. (5) 21 1 Navech, J. (4) 12; (5) 9, 48 Nazamov, I.S. (5) 235 Neeb, M.K.(1) 100 Nefkens, S.C.A. (8) 200 Neganova, E.G. (I) 68, 69 Negoita, N. (5) 121 Negrebetskii, V.V. (1) 124, 292; (8) 30 Neidlein, R. (5) 193 Neijman, E.W.J.F. (6) 257 Neild, J. ( I ) 128 Neilson, R.H. (8) 4 Nekhoroshkov, V.M. (1) 290, 299, 300; (5) 257 Nelson, J. (6) 124 Nelson, S.G.(5) 184 Nesterova, L.I. (4) 34; (5) 255 Neuman, A. (5) 297 Neuman, J.-M. (6) 13, 323 Neumann, B. (1) 31 1 Neumann, J.-M. (6) 205 Neuner, P. (6) 91 Newman, P.C. (6) 173-175 Newton, M.G. (5) 304 Newton, R.P. (6) 327 Ng, P. (6) 74 Ngo, D.C. (8) 80, 133 Nguyen, M.T.(1) 329, 363 Nicolaides, D.N. (7) 27 Nicolaou, D.C. (6) 266 Nicolaou, K.C. (3) 6; (4) 6; (6) 262, 264, 266; (7) 119 Nicotra, F. (7) 59 Niecke, E. (1) 207, 273, 308, 319, 339-341, 348, 358, 360, 365; (4) 1, 17; (8) 5, 28, 29 Niedermann, H.-P. (4) 7; (5) 125 Nief, F. (1) 383 Nieger, M. (1) 61, 70, 194, 273, 319, 341, 360; (4) 17; (5) 286; (8) 29, 197 Nielsen, J. (4) 61; (6) 120, 121 Niemann, J . (1) 294 Nietzschmann, E. (5) 298 Nifant’ev, E.E. (4) 37, 38 Niimi, T. (8) 99 Niitsu, T. ( I ) 312 Nikolaeva, N.V. (1) 290, 303 Nikonov, G.N. ( I ) 139, 197 Ninader, M.V. (7) 109 Nishikawa, S. (6) 331 Nishio, S. (5) 94 Nisikawa, Y. (8) 157

Nitta, H. (8) 137 Nitta, I . (6) 29 Nitta, M. (7) 105; (8) 3, 58-60 Nixon, J.F. (1) 308, 332, 348, 373, 388; (3) 33 No, B.I. (1) 1 1 1 Noble, S.A. (6) 49 Noda, I. (7) 98 Noda, N. (5) 37 Noda, T. (7) 96 Noel, C. (8) 210, 231 Noth, H. (1) 167, 316, 318, 357, 408 Nolte, U . ( I ) 311 Noltemeyer, M. (1) 58; (7) 30; (8) 33, 85, 88-90, 202, 203 Nomura, N. (8) 285 Nomura, Y,(8) 290 Noordik, J.H. (5) 80 Noort, D.(6) 59 Norden, B. (6) 310, 312 Norman, A.D. (4) 29, 30 Norman, N.C. (1) 200, 268 Normant, J.F. (4) 28 Novak, L. (7) 76 Novosad, J . (5) 285 Nowotny, M. (1) 402 Noyori, R. (1) 5, 108 Nuber, B. (1) 169, 405 Nugiel, D.A.(7) 119 Nunn, C.M. (1) 54, 57 Nurenkov, O.A. (5) 299 Nuretdinov, LA. (5) 236 Nuyken, 0. (8) 179, 198 Nwosu, V.U. (6) 173 Nyulaszi, L. (1) 278 Oae, S. (1) 168, 250 Ohon, R. (1) 151; (7) 106 Oda, Y. (6) 218 Odinets, I.L. (5) 128, 129 Oehler, E. (5) 167, 168, 291 Oehmigen, T. (1) 113, 114 Offen, P. (6) 294 Otitserov, E.N. (2) 8, 14 Oganesyan, A.S. (5) 45 Ogawa, T. (6) 92; (7) 16 Ogilvie, K.K. (6) 82 Ogino, K. (7) 103 Oh, D.Y. (5) 181 Oh, S.T. (8) 214 Ohkawa, K. (8) 288 Ohmori, H. (1) 184, 240, 241; (7) 8 Ohnama, M. (8) 60 Ohno, A. (1) 188 Ohnuma, M. (7) 105

Ohta, H. (1) 233 Ohtani, M. (7) 90 Ohtsuka, E. (6) 89, 235 Oivanen, M. (6) 10 Okada, Y. (3) 7 Okamo, T. (8) 102 Okamoto, A. (1) 277, 313 Okamoto, Y. (5) 10, 278-282 Okamura, T. (6) 177 Okamura, W . H . (3) 28 Okuma, K. (1) 233 Okuno, H. (1) 162 Olah, G.A. (4) 77; (5) 180; (7) 72 Oleinik, V.A. (1) 291 Olinski, R. (6) 302 Olsen, D.B. (6) 238 Ol’shevskaya, V.A. (1) 28, 279 Ono, A. (6) 208 Ono, K. (6) 50 Onoue, K. (1) 250 Onozawa, T. (3) 17 Onys’ko, P.P. (5) 93, 147, 148, 254 Oosting, G.E. (8) 151 Oppenheimer, N.J. (6) 58 Orgel, L.E. (6) 135, 307 Orpen, A.G. (1) 22, 173; (4) 21 Osankina, E . I . (5) 236 Oshikawa, T. (5) 177 Oshiki, T. (1) 119, 120; (3) 17 Osowska-Pacewicka, K. (8) 72 Ossola, F. (1) 59 Otrnar, M. (6) 22, 23 Oudai, 0. (6) 231 Ouzouris, D. (I) 387 Ovakimyan, M.Zh. (1) 65, 140, 141 Ovchinnikov, V.V. (2) 12; (5) 187 Ozaki, S. (5) 33 Ozaki, T. (4) 13 Ozegowski, S. (5) 122, 124 Paasch, J. (8) 44,48 Paasch, S . (7) 107 Padwa, A. (7) 1 Paetzold, P. (1) 207; (8) 28 Page, P. (1) 391; (4) 74 Pai, N.R. (5) 66, 99 Paiaro, G. (1) 143 Paillous, N. (6) 289 Paine, R.T. (1) 167, 357; (3) 35 Pajunen, E.O. (5) 131 Pakrysh, E.F. (8) 76 Pakulski, M. (1) 200, 268, 276 Palacios, F. (1) 237, 253; (7)

375

Author Index 22, 49, 50; (8) 2, 61, 62, 70 Palacios, S.M. (1) 63, 64 Palmer, B.D. (6) 309 Palmer, T.C. (6) 128 Palom, Y. (6) 166 Pandey, G. (1) 189; (3) 9 Pandey, S.K. (5) 55 Pandolfo, L. ( I ) 143 Panza, L. (5) 139; (7) 59 Papkov, S.P. (8) 255, 256 Pardi, A. (6) 216, 229, 232, 233 Parent, C. (8) 224 Park, J . (3) 22 Parkin, S. (1) 55 Parmee, E.R. (7) 97 Parvez, M. (8) 80, 118, 148, 149, 160, 296 Pascal, J . (1) 116; (3) 1 Pascal, R.A. (1) 121, 122 Paschal, J.W. (5) 219 Pasternack, R.F. (6) 292 Pasternak, A. (1) 91; (8) 19 Patel, D.J. (6) 183, 184, 210 Patel, D . V . (5) 222 Patel, N . (6) 312 Patin, H. (1) 191, 230, 231; (3) 2 Patois, C.(5) 132, 244; (7) 56 Patonay, T. (8) 52 Patonay-Peli, E. (8) 52 Patsanovskii, 1.1. (1) 342; (8) 17 Pattenden, G. (7) 117 Patt-Siebel, U. (8) 294 Pautard-Cooper, A. ( I ) 158 Pauwels, R. (6) 21 Pavel, G.V. ( I ) 104 Pavlov, P.A. (5) 264 Pederson, R.L. (4) 42; (5) 19 Pederson, S.F. (3) 22 Pedroso, E. (6) 63, 166 Peel, M.R. (6) 49 Pegram, J.T. (3) 20 Peiffer, G. (1) 109 Peisach, J . (6) 250 Pel, R.A. (8) 142 Pellerin, B. (1) 320 Pellieciari, R. (5) 119 Pellon, B. (8) 159 Peneory, A.B. (1) 63 Peng, S.-M. (1) 83 Penk, M. (1) 135 Pen’kovskii, V . V . (1) 275, 293 Pennanen, P. (5) 131 Pennington, W. (5) 155 Pbc’h, D. (6) 148, 149 Perera, S.D. ( I ) 19 Peresypkina, L.P. (5) 226 PCrez, C. (6) 34

Perez, J. (7) 108; (8) 46 Perez-Sestelo, J . (3) 25 Perich, J.W. (4) 39-41; (5) 21-24, 75 Perilleux, D. (6) 152 Perischetti, R.A. (6) 200 Perreault, J.-P. (6) 237 PerrCe-Fauvet, M. (6) 292 Persau, C. (1) 43 Pervukhina, I.N. ( I ) 124 Peshkov, A.F. ( I ) 181 Pestana, D.C. (1) 55, 56, 355, 356 Peters, K. (1) 71 Peterson, N.L. (5) 227 Petrie, M.A. (1) 355 Petrosyan, V.S. (1) 183, 214; (2) 22 Petrov, A . A . (5) 245 Petrov, G. (5) 249 Petrova, J . (5) 263 Petrovskii, P.V. (1) 28; (5) 129 Petrus, C. (5) 216, 217 Petrus, F. (5) 216, 217 Ptister-Guillouzo, G. (1) 285, 324 Pfleiderer, W. (6) 10, 107, 136-138 Philippe, C. (6) 223 Phillips, L.R. (6) 101 Pianka, M. (5) 88 Piantadosi, C. (6) 14, 15 Piantadosi, S. (6) 15 Piccialli, G. (6) 182 Piccirilli, J.A. (6) 239 Pieken, W . A . (6) 238 Pieles, U . (4) 51; (6) 143, 197 Pieper, U . ( I ) 30 Pietrusiewicz, K.M. (3) 31 Pilarski, B. (5) 1 1 8 Pinchuk, A.M. ( I ) 112, 216; (2) 30, 31; (4) 26; (8) 77, 82 Pine, S.H. (7) 24 Pinkerton, A.A. (1) 247; (2) 33; (8) 69 Piotto, M.E. (4) 62; (6) 123, 124, 320 Pipko, S.E. (4) 33 Pireh, D. (7) 89 Pisarnitskii, D.A. (1) 183; (2) 22 PitiC, M. (6) 293 Pitt, C.G. (2) 10 Plass, W . (1) 416, 418-420 Plate, N . A . (8) 258-260 Plenat, F. (1) 116, 259; (3) 1 Plotnikov, V.F. (5) 245 Pliickthun, A . (6) 296 Plvshevskii. S . V . 18) 119

Pochet, S. (6) 185, 205 Podda, G. (8) 158 Pogosyan, A . S . (5) 87 Pohl, S. (1) 210 Polborn, K. ( I ) 316, 318, 357,

408

Polniaszek, R.P. (5) 144; (7) 68 Polonskaya, L.Yu. (2) 26 Polubentsev, A . V . (1) 93 Polumbrik, O . M . (5) 301 Polyakov, A . V . (1) 28 Pombeiro, A.J.L. (1) 332 Pomerantz, M. (3) 15; (7) 5; (8) 14 Pon, R.T. (4) 52; (6) 170, 186 Pons, A. (6) 196 Pooranchand, D. ( I ) 189; (3) 9 Popov, A . V . (5) 2 Poppe, L. (7) 76 Porai-Koshits, M.A. (8) 297 Porchia, M. (1) 59 Porco, J.A., jun. (6) 263, 265 Porter, B. (7) 77 Portier, C. (6) 223 Potin, P. (8) 206 Potter, B.V.L. (5) 51 Povolotskii, M.I. (1) 112, 292, 346; (4) 33, 67, 69; (8) 30 Povsic, T.J. (6) 212 Power, P.P. (1) 55, 56, 353, 355, 356 Powis, G. (5) 38, 39 Prakash, A . S . (6) 284 Prakasha, T.K. (4) 24 Prashed, M. (5) 212 Pratviel, G. (6) 293 Prestwich, G.D.(5) 34, 35, 40 Prikhod’ko, Yu.V. (1) 104 Pringle, P.G. (1) 98; (4) 21 Priol, J . ( I ) 191 Prishchenko, A . A . (1) 183, 214; (2) 22; ( 4 ) 15; (5) 213 Pritzkow, H. (1) 242, 296, 343; (7) 13, 14; (8) 32 Prouse, L.J.S. (1) 128 Priitz, W.A. (6) 317 Pruitt, J.R. (5) 184 Pucher, S.R. (8) 212, 227 Pudovik, A . N . (1) 105, 41 1; (2) 8, 13-15, 24; (4) 35; (5) 17, 202, 235, 257, 258 Pudovik, M.A. (5) 202 Pudovik, N . A . (2) 24 Puglisi, J.D. (6) 224, 225 Pujari, M.P. (5) 71 Purdy, A.P. (2) 10 Pushin, A . N . (5) 2 Pvle. A.M. (6) 313

376 Pyykko, P. (8) 6 Qing, B. (5) 58 Qu, Y. (6) 308 Quella, F. (8) 179 Quin, G.S. (1) 359; (5) 77, 269 Quin, L.D. (1) 359, 413; (5) 76, 77, 269, 273 Raben, A. (6) 14 Rachon, J . (5) 199 Radhakrishnan, 1. (6) 210 Ragan, J.A. (7) 94 Ragskaya, G.M. (8) 218 Raguveer, K.S.(8) 208 Rahrnan, M.F. (5) 85 Rakhrnatulina, T.N. ( I ) 92, 93, 159 Rakov, I.M. (5) 3 Ralitsch, M. (7) 116 Ralph, J . (5) 42 Rarnachandran, K. (7) 77 Rarnli, E. (5) 304 Rarnstein, J . (6) 332 Randina, L.V. (5) 145, 146 Rani, B.R. (5) 85 Rao, K.E.(6) 276 Rao, M.V. (6) 90 Rao, N.S. (1)413 Rao, R.J. (5) 54 Ratovskii, G.V. (1) 220 Raucher, S. (6) 287 Raut, S.V. (1) 254; (7) 12 Rauzy, K. (1) 391; (4) 74 Rayner, B. (6) 102, 148, 149 Raytarskaya, M.V. (5) 143 Razhabov, A. (5) 101 Reddy, C.D. (5) 13 Reddy, D. (8) 155 Reddy, K.S.(6) 249, 253 Redrnore, D. (5) 68, 203 Reed, A.E. (2) 4 Reed, R.A. (8)264 Rees, C.W. (4) 9; (5) 195, 196 Reese, C.B. (6) 4, 90 Regan, W . (6) 101 Regitz, M. (1) 6, 204, 331, 334, 374 Reid, L.S. (6) 141 Reid, S.S. (6) 314 Reidalova, L.1. (8) 97 Reilly-Gauvin, K. (5) 222 Rein, T. (7) 57 Reitel, G.V. (1) 345-347; (4) 67, 69, 75 Rerniszewsk, S.W. (7) 98

0rganoph osph orus Chemistry Rengen, K. (1) 223, 224 Renhowe, P.A. ( I ) 226; (7) 20 Renneberg, H. (1) 352; (4) 66 Renner, G. (8) 198 Resvick, R. (6) 45 Reuter, J. (1) 41 Revenko, G.P.(1) 103 Rhee, Y . 4 . (6) 163 Rheingold, A.L. (8) 93 Ricard, L. (1) 304, 305, 378, 383, 399, 401, 403 Ricca, G. (5) 136; (8) 161 Rich, A . (6) 240 Rich, L.C. (5) 186 Richman, D.D. (6) 16 Richter, W . (4) 31, 32; (5) 102, 103 Rickard, C.E.F. (1) 218, 351 Rida, S.M. (8) 95 Rideout, D. (3) 6; (4) 6 Rider, P. (6) 91 Riding, G.H.(8) 101, 268 Ried, W . (1) 415; (8) 193 Riedl, T. (1) 407 Riendeau, D. (7) 87 Riesel, L. (8) 24 Rietzel, M. (8) 85, 202, 203 Rima, G. (5) 135 Risser, S.M. (8) 11, 12, 247 Robert-Guroff, M. (6) 113 Roberts, N.K. (1) 23; (5) 287 Roberts, S.M. (6) 48, 49 Robertson, D.L. (6) 242 Robertson, S.A. (6) 95 Robic, N. (6) 292 Robins, A.M. (7) 79 Robins, M.J. (6) 45 Robinson, D.H. (4) 3; (5) 120 Robinson, W.T.(7) 11 Robl, J.A. (5) 115 Robles, J . (6) 63 Rockenbauer, A. ( I ) 190 Rockensuss, W . (1) 58 Roder, T. (7) 15 Rodger, A.J. (6) 310 Rodi, Y.K. ( I ) 344, 397; (4) 76; (8) 191 Rodrigo, M.M. (8) 271 Rodriguez, M. (7) 123, 124 Roe, D.C. (1) 136 Roelen, H.C.P.F. (4) 45 Riiling, A. (6) 47 Riischenthaler, G.-V. (1) 142, 21 1; (5) 150; (8) 34, 35, 41 Roesky, H.W. (7) 30; (8) 21, 33, 85, 88-90, 189, 202-204 Roesky, M. (1) 58 Rogers, K.L.(5) 183

Rogers, M. (5) 266 Rohrbaugh, D.K. (5) 91, 288 Rohse, S. (5) 57, 238 Rohwer, H.E. (3) 36 Roig, A. (8) 270 Rokach, J. (7) 87 Rokita, S.E. (6) 191 Rolsrna, P.B. (8) 287 Rornanenko, E.A. (1) 216 Rornanenko, V.D. (1) 279, 281, 292, 342, 345-347; (4) 67-69, 73, 75; (8) 17, 30 Rornanov, G.V. (1) 105 Roobeek, C.F. (1) 173 Roper, W.R. (1) 218, 351 Rose, W.C. (6) 33 Roserneyer, H. (6) 139 Rosenbach, M.T. (6) 7 Rosenberg, I. (6) 21-23, 26 Rossetto, G. (1) 59 Rossi, J.-C. (7) 83 Rossi, R.A. (1) 63, 64 Rostinejad, F. (6) 67 Rougee, M. (6) 214 Rouillard, M. (7) 66 Roundhill, D.M. (4) 23 Roundhill, M.D. (1) 127 Rowley, S.P. (1) 171 Royan, B.W. (1) 364; (4) 72 Rozanov, I.A. (8) 188, 297 Rozinov, V.G. (5) 109, 110; (8) 40, 196 Ruban, A.V. (1) 279, 345-347; (4) 67-69, 75; (8) 17, 30 Rudavskii, V.P. (8) 76, 96 Rudinskaya, G.Ya. (8) 256 Rudolph, L.N. (6) 147 Rudornino, M.V. (1) 129; (5) 143 Rudzevich, V.L. (8) 205, 298 Ruf, K. (6) 136 Ruffner, D.E. (6) 230, 236 Rufinska, A. (1) 335 Ruiz, J. (1) 53 Ruiz-Montez, J. (5) 206 Runova, O.B. (5) 32 Rusinskaya, G.Ya. (8) 255 Russell, D.R. (1) 128; (3) 34 Russell, M.J.H. (3) 3 Russo, G. (7) 59 Rutkovskii, E.K. (2) 30 Rutt, J.S. (8) 118, 133, 219, 243 Rybasova, G.I. (8) 225, 226 Ryono, D.E. (5) 222 Ryschkewitsch, G.E. (8) 91 Ryu, E.K. (1) 146 Ryurntsev, E.I. (8) 272 Ryzhikova, T.Ya. (1) 105

377

Author Index Saadein, M.R. (5) 305 Saak, W. (1) 210 Saasaki, J. (8) 56 Sabol, J.S. (7) 82 Sadana, K.L. (6) 167 Sadanani, N.D. (5) 77 Sadkova, D.N. (5) 236 Sadovskaya, N.P. (8) 96 Safadi, M. (5) 176, 218, 274 Safina, Yu.G. (2) 12; (5) 187 Safsaf, A. (5) 297 St.Clair, T.L. (8) 131 Saito, 1. (3) 23; (6) 171, 254, 255, 273 Saito, M. (1) 161 Saito, R. ( 5 ) 60 Saito, S . (6) 29 Sakata, T. (6) 218, 231 Sakatsume, 0. (6) 92 Saki, N. (8) 288 Salamonczyk, G.M. (6) 37 Salem, S.M. (7) 101; (8) 53 Salim, A. (1) 160 Sal’keeva, L.K. (4) 1 1 Salmon, L. (6) 292 Salz, E. (8) 270, 271 Samano, V. (6) 45 Samarai, L.I. (5) 226 Sammakia, T. (7) 94 Sample, K.R. (6) 169 Samuels, W.D. (8) 248 Samuelsson, B. (1) 215 Sancar, A. (6) 177, 178 Sanchez, M. (1) 281, 369, 370, 391; (4) 70, 71, 73, 74 Sanders, M. (5) 89 Sandstrom, A. (6) 245 Sano, H. (8) 106 Santa, H. (6) 11 Santacroce, C. (6) 182 SantaLucia, J., jun. (6) 179, 180 Santarsiero, B.D. (2) 32 Santo, K. (8) 56 Sapino, C. (1) 172 Sardina, F.J. (3) 24 Sarfati, S.R. (6) 205 Sargent, M.V. (1) 225 Sarina, T.V. (1) 279 Sarvarova, N.N. (1) 139 Sasagawa, K. (8) 98 Sasaki, K. (6) 44 Sasaki, M. (3) 10 Sasaki, T. (6) 89 Sasaki, Y. (3) 7 Sasakurd, T. (8) 177, 178 Sasmor, H. (6) 125 Satge, J. ( 5 ) 135 Sathyanarayana, S . (6) 202

Sato, E. (6) 207 Sato, H. (4) 54 Sato, R. (1) 161 Sam, T. (1) 310 Sattelberger, A.P. (1) 10 Sattler, G. (1) 169 Sauer, W. (1) 402 Savage, G.P. (7) 114 Savati, L. (8) 240 Savenkov, N.F. (5) 252 Savignac, P. (1) 115, 326; (5) 113, 132, 244; (7) 56, 83 Sawada, N. (6) 288 Saxe, J.D.(6) 128 Sayadyan, S.V. (1) 65, 94 Scaringe, S.A. (6) 83 Scarlato, G.R. (7) 21 Schabtach, E. (6) 333 Schacht, E. (8) 234, 292 Schadler, H.D. ( I ) 32, 377 Schaefer, H.F., 111 (8) 103 Schaefer, M.A. (8) 208 Scheer, M. (1) 32 Scheide, G.M. (8) 4 Schell, R. (6) 10 Schilz, J. (5) 7 Schimmel, P. (6) 300 Schinazi, R.F. (6) 50 Schippel, 0. (7) 33 Schlewer, G. ( 5 ) 32 Schleyer, P.von R. (2) 4 Schlosser, M. (7) 4 Schlossman, A. (5) 274 Schmid, B. (1) 133 Schmid, R. (1) 107 Schmidbaur, H . (1) 81, 164, 165, 229; (8) 16 Schmidpeter, A. (1) 366, 379, 390; (7) 7 Schmidt, G . (6) 17 Schmidt, H. (1) 31, 333, 377 Schmidt, H.G. (8) 88, 202 Schmidt, J. (7) 74 Schmidt, K.R. (7) 73 Schmutzler, R. (1) 198, 202; (2) 9, 19; (5) 240; (8) 87 Schnalke, M. (1) 46, 47 Schneider, H.-W. (1) 40, 42 Schneider, K.C. (6) 133 Schneider, R. (1) 204 Schnell, M. (5) 149 Schnick, W. (8) 223 Schoeller, W.W. (1) 294, 317, 340, 341 Schoenen, F.J. (6) 263 Schonholzer, P. (1) 107 Scholz, G . (1) 48 Schrader, S. (1) 264; (8) 18

Schrader, T. (5) 204 Schreiber, S.L. (6) 76, 263, 265, 267; (7) 94 Schriver, M.J. ( I ) 350; (8) 13 Schroder, H.C.(6) 138 Schrumpf, F. (8) 89 Schubert, F. (6) 187 Schulte, G.K. (7) 118 Schulten, M. (1) 201 Schultz, C. (4) 44; (5) 27 Schultz, P. (6) 219 Schultz, P.G.(6) 95, 96 Schulz, J. (5) 6 Schulz, M. (7) 33 Schumann, H.(1) 269, 270 Schuster, H. (1) 338 Schwalbe, C.H.(5) 182; (6) 25 Schwartz, J . (6) 119 Schwartz, 0. (6) 13 Schwartz, U.M. (7) 1 1 1 Schwartzman, M.L. (7) 86 Schwerdtfeger, P. (1) 351 Sciavovelli, 0. (4) 8 Scilimati, A . (4) 8 Scott, L.T. (1) 15 Scott, S.A. (6) 213 Searle, M.S. (6) 274 Sebastian, M. (1) 113 Seega, J . (5) 151 Seela, F. (6) 47, 126, 127, 139, 173, 175 Seernan, N.C. (6) 221, 222 Seewald, M.J. (5) 38, 39 Segall, Y. (5) 89 Sekine, M. (6) 3, 93 Sekine, S. (8) 106 Sekiya, K. (6) 29 Selvaraj, 1.1. (8) 155 Semakov, A.V. (8) 253 Semenenko, N.M. (1) 280 Semenii, V.Ya. (5) 111 Senaldi, A. (7) 59 Senyukh, S.M. (5) 159 Sepulchre, C. (3) 4; (7) 88 Sera, T. (6) 254 Seratinowska, H.T. (6) 90 Seredkina, S.G. ( 5 ) 108 Sergent, M. (4) 64 Serianni, A.S. (6) 150 Setzer, W.N. (5) 302, 304, 305 Shablovskaya, E.A. (8) 76, 96 Shagidullin, R.R. (5) 290 Shagi-Mukhametova, N.M. (2) 22 Shagvaleev, F.Sh. (1) 217 Shaikhudinova, S.I. (1) 92 Shakirov, I.Kh. (5) 290 Shamselvaleev, F.M. (5) 98; (8)

378 39 Shankland, P . (6) 125 Shapiro, G. (7) 121 Sharma, P. (6) 202 Sharp, T . R . (8) 107, 108 Shashidhar, M . S . (5) 137 Shatzmiller, S. (5) 193 Shaw, A . A . (6) 335 Shaw, A.R. (6) 195 Shaw, B . L . ( I ) 19 Shaw, G. (4) 21 Shaw, L . S . (8) 146 Shaw, R . A . (8) 126, 143-146 Shawali, A . S . (8) 68 Shcherhina, T . M . (5) 129; (8) 78 Shea, R.G. (6) 192 Sheidecker, S. (8) 123 Sheldrick, G . M . (7) 30; (8) 21, 90, 202 Shen, G.S. (1) 138; (7) 24 Shen, T . Y . (4) 43; (5) 29 Shen, Y. ( I ) 257, 258; (7) 23, 42, 43, 45 Shenoy, S.J. (5) 66, 99 Shephard, W . B . (1) 218 Sherman, A . S . (8) 17 Shermolovich, Yu.G. (1) 67; (5) 112 Sheu, J.-H. (7) 77 Shevchenko, I . V . ( I ) 137 Shi, G. (8) 26 Shi, M. (5) 281, 282 Shi, Y. (8) 135 Shihaev, V . P . (8) 230 Shihutani, S. (6) 156 Shiganakova, O . V . (1) 102 Shigematsu, H. (8) 154 Shigenematsu, H. (8) 228 Shimada, T. (6) 113 Shin, J . (3) 6; (4) 6 Shinde, B.R. (5) 66, 99 Shinohara, T. (5) 33 Shinozuka, Z. (6) I13 Shiornoto, K. (8) 239 Shiozawa, N. (8) 71 Shiro, M. (5) 229 Shoner, S . C . ( I ) 355 Shriver, D . F . (8) 264 Shtennikova, I . N . (8) 272 Shudo, K. (6) 140 Shue, Y.-K. (7) 19 Shuker, A.J. (7) 117 Shumeiko, A . E . (8) 1 1 1 Shvets, V.I. (5) 32 Sibi, M.P. ( I ) 226; (7) 18, 20 Siedlecki, J.M. (6) 176 Sigurdsson, S.T. (6) 287 Silherzahn, J . (7) 13

Organophosphorus Chemistry Simonov, Yu.A. (8) 298 Simpkins, L.M. (5) 115 Simurova, N.V. (5) 145, 146 Sinden, R.R. (6) 200 Sinegovskaya, L.M. ( I ) 159 Singh. C . (6) 128 Singh, J.D. (5) 56 Singh, U . ( I ) 163 Singler, R.E. (8) 210, 229, 231 Singman, C . N . (6) 62 Sinitsa, A . D . (2) 31; (4) 33, 34; (5) 93, 145-148, 254, 255; (8) 77, 97 Sinou, D . ( I ) 186 Sinyashina, T . N . (2) 14 Siriwardane, U. (4) 24 Sitdikova, T.Sh. ( I ) 217 Siv, P.G.C. (4) 64 Sivolobova, O.A. (5) 152 Skelton, B.W. (1) 106; (3) 12 Sklenar, V . (6) 319 Skoblikova, L.I. (5) 252 Skokotas, G. (6) 266 Skolimowski, J . J . ( I ) 413 Skowronska, A . (5) 156, 261 Skowronski, R. ( I ) 259 Skrzypczynski, Z. (6) 105 Skuratovich, L.G. (8) 119 Skvorcov, S. ( I ) 97 Sladky, F. (1) 246; (5) 237 Slata, J.M. (5) 234 Slavin, L.L. (6) 306 Sleath, P.R. (6) 58 Slim, G . (6) 234 Smalley, R.K. (7) 101; (8) 53 Smeets, W.J.J. (1) 414 Smirnova, L.V. (5) 257 Smirnova, V . N . (8) 273 Smith, A , (5) 275 Smith, A . B . , 111 (7) 98 Smith, A . L . (6) 262, 264 Smith, C . A . (6) 154 Smith, C . D . (3) 16 Smith, D . B . (7) 94 Smith, E.C.R. (5) 219 Smith, J . D . (1) 179 Smith, M.B. (1) 98 Snyder, J.R. (6) 150 Snyder, S.H.(5) 34 Soares, V . M . (5) 88 Sohol, R.W. (6) 107, 138 Sofia, M.J. (5) 115 Sokol, V.I. (8) 297 Sokolov, M.P. (5) 264 Sokolov, V.B. (1) 212, 213; (5) 8, 188, 303 Soliman, F.M. (7) 28 Soliman, F.S.G. (8) 95

Solodenko, V . A . (5) 190, 208, 209 Solov’ev, A . V . (1) 67 Solov’eva, L . D . (1) 150 Sonawane, H . R . ( I ) 148 Sonveaux, E . (6) 152 Sood, M. (8) 31 Soroka, M . (5) 197 Soto, K. (3) 17 Sournies, F. (8) 113, 122-125 Southgate, R . (7) 79 Sowers, L . C . (6) 326 Spahn, M. (1) 417; (8) 194 Spangler, C . W . (7) 61; (8) 135 Sparkes, M.J. (5) 175, 183 Speier, G. (8) 25 Spek, A . L . (1) 414 Spencer, J.T. (1) 298 Spiess, B. (5) 32 Spiess, E. (6) 66 Spindler, C . ( I ) 390 Sproat, B.S. (4) 51; (6) 91, 143, 144, 197 Squier, C . A . (4) 30 Srivastava, D . K . (1) 11 Srivastava, G. (5) 55 Srivastava, P . C . (8) 23 Srivastava, S . K . (5) 56 Srivastava, T.N. (5) 56 Stadler, B . (4) 44 Stadler, C. (5) 27 Stalke, D. ( I ) 30, 341; (8) 21 Stam, C . H . (8) 92, 200 Stamrnler, H.-G.( I ) 31 1 Stand, E . A . (6) 157 Stang, P.J. ( I ) 234 Stangier, P. (6) 42 Stapleton, A . (7) 117 Stec, W.J. (5) 61, 95; (6) 37, 106, 1 1 1 Steenhergen, A . (8) 151 Steglich, W. (5) 204 Steier, W.H.(8) 135 Steigelmann, 0. ( I ) 81 Stein, C . A . (6) 106, 112, 113 Stelzer, 0. (1) 208; (8) 87 Stemerick, D . M . (3) 5; (7) 60 Stepanchuk, V . A . (8) 96 Stepanov, A . E . (5) 32 Stepanov. B.I. ( I ) 124 Stepanova, Yu.Z. ( I ) 342 Stephan. M. ( I ) 118; (4) 4, 36 Stepura, G.S. (8) 97 Stern, M.K. (4) 53; (6) 246 Stetten, E. (6) 316 Stezowski, J . J . (6) 155; (7) 74 Stille, J.K. (1) 199 Stiller, R. (6) 41

Author Index Stoelben, S. (7) 107; (8) 44 Stokes, J.P. (3) 26 Stoll, K. (1) 34 Stoller, A. (3) 4; (7) 88 Stone, F.G.A. (1) 307 Stoner, M.R. (5) 84 Storer, R. (6) 48, 49 Storhoff, B.N. (1) 100 Storm, C. (6) 11 1 Stout, T.J. (6) 263, 265 Stowell, M.H.B. (5) I17 Straubinger, R. (6) 118 Straw, T.A. (2) 7 Streitwieser, A. (2) 4 Strekas, T.C. (6) 31 1 Streubel, R. (1) 207; (8) 28 Stroehl, D. (5) 52 Struchkov, Yu.T. (1) 28, 102, 175, 265; (5) 299 Struszczyk, H. (8) 141, 182 Stubhe, J. (6) 45, 46, 247, 256, 258, 259 Studnicka, A . (8) 184 Stutzer, A . (1) 165 Stuhmiller, L.M. (6) 16 Stuke, M. (1) 58 Sturnpf, R. (4) 46; (5) 43 Suades, J. (1) 177 Subasinghe, C. (6) 106 Suda, K. (1) 240, 241; (7) 8 Suda, S. (1) 262 Sudhakar, P.V. (7) 3; (8) 8 Suetke, T. (8) 179 Suehiro, N. (6) 334 Suemune, H. (6) 266 Sueptitz, G. (6) 94 Sugai, S. (7) 112 Sugiyarna, H. (6) 171, 254, 273 Suhadolnik, R.J. (6) 107, 138 Sukhozhenko, 1.1. (5) 2 Sulga. J. (8) 249 Sullivan, A.D. (8) 229 Sulston, I. (6) 91 Sundell, M. (5) 131 Sunthankar, P.S. (5) 13 Suppel’, 1.Ya. (5) 258 Surpina, M.Ya. (8) 183 Sutton, B.M. (1) 16 Suvalova, E . A . (5) 93 Suzuki, H. ( I ) 263; (7) 16 Suzuki, S. (1) 267 Suzuki, Y. (4) 54, 55; (6) 70 Svedas, V . K . (5) 208 Swarny, K.C.K. (2) 1, 5, 6, 20 Swann, P.F. (6) 165 Swenton, L. (7) 89 Symons, M.C.R. (8) 202, 203 Szafraniec, L.L. (5) 91, 288

379 Szameitat, J. (1) 307 Szantay, C.S. (7) 76 Szczesny, Z. ( 5 ) 197 Szeja, W. (5) 49 Szrnuszkovic, J. (4) 14 Szoelloesy, A. (1) 400; (3) 13 Szoka, F.C., jun. (6) 118 Szostak, J.W. (6) 240, 241, 243, 299 Tabor, A.B. (6) 267 Tachon, C. (1) 284 Tada, M. (8) 59 Tada, N. (1) 250 Tada, Y. (8) 138, 237, 275-279 Taira, K. (6) 328, 331 Takagi, M. (6) 275, 281, 282 Takahashi, K. (8) 114-116, 180 Takahashi, T. (5) 229 Takaka, H. (6) 70 Takaki, M. (6) 92 Takaku, H. (4) 54, 55; (6) 92 Takarnuku, S. (5) 10, 278-282 Takanarni, T. (1) 240, 241; (7) 8 Takashirna, H. (6) 29 Takaya, H. (1) 5, 17, 108 Takaya, Y. (1) 168 Takeishi, M. (8) 71 Takenaka, S. (6) 275, 281, 282 Tdkeuchi, H. (1) 233; (4) 13 Takeuchi, 1. (5) 300 Tamai, Y. (5) 83 Tamura, M. (6) 303 Tan, W.H.W. (5) 243 Tanabe, K. (6) 331 Tanaka, H. (6) 29 Tanaka, T. (6) 218, 231 Tanaka, Y. (1) 233 Tang, J.-S. (5) 67 Tang, J.-Y. (6) 85, 204 Tanigaki, T. (8) 137, 157 Taniguchi, M . (8) 276 Tanimura, H. (6) 87, 88 Tankard, M. (7) 58 Tanswell, J.L. (1) 23; (5) 287 Tapley, C.L. (1) 100 Taran, V . V . (8) 76 Tarasova, R.I. (1) 217; (8) 190 Tarazona, M.P. (8) 270, 271 Tarraga, A. (8) 51 Tasz, M.K. (1) 259 Tatdrinova, A . A . ( I ) 159 Tattershall, B.W. (4) 81 Taylor, G. ( 5 ) 266; (6) 53, 54 Taylor, N.J. (1) 126 Tebbe, K.-F. (1) 49 Tebby, J.C.(7) 9

Teichmann, H. (5) 6, 7 ten Wolde, A. (3) 30 Thule, R. (4) 59; (6) 84, 151 Terent’eva, S.A. (2) 24 Terlouw, J.K. (1) 352; (4) 66 Teulade, M.-P. (5) 132 Texier, F . (7) 64 Thal, C. (7) 103 Thatcher, G.R.J. (5) 164, 267 Thea, S. (5) 270 Theisen, P. (6) 66 Thelnalt, U. (8) 147 Thenappan, A. (7) 71 Therbert, A.B. (5) 34 Thiele, M. (1) 379; (7) 7 Thiele, R. (1) 294 Thiern, J. (6) 41, 42, 43 Thiesen, H.J. (6) 297 Thimm, J. (6) 43 Thomas, E.J. (7) 97 Thompson, E.A. (6) 90 Thompson, W.J. (5) 15 Thomson, W. (6) 25 Thorimhen, S. (5) 206 Thornton, J.J. (6) 78 Thornton-Pett, M. (1) 95 Thuong, N.T. (4) 60; (6) 110, 190, 201, 209 Tilichenko, M.N. (1) 104 Tillett, J.G. (1) 160 Timokhin, B.V. (1) 220 Tinker, A. (4) 3; (5) 120 Tinoco, I., jun. (6) 217, 224, 225 Tiripicchio, A. (7) 31 Titskii, G.D. (8) 11 1 Tkachenko, S.E. (3) 14 Tocher, D . A . (8) 94 Toeke, L. (1) 400 Togni, A. (1) 134 Tohamy, F.A. (1) 144 Toia, R.F. (5) 89, 90 Toke, L. (3) 13 Tolrnachev, A.A. (1) 130 Tomcufcik, A.S. (8) 27 Tomioka, H. ( 5 ) 272 Tomohiro, T. (1) 162 Tomoi, M. (1) 238 Tondelli, L. (6) 324 Tonge, J.S. (8) 264 Tonnard, F. (1) 297 Topolski, M. (5) 199 Tordo, P. (1) 12; (5) 215 Torgasheva, N.A. (5) 46 Torgomyan, A . M . (5) 87 Torreilles, E. (7) 48; (8) 66, 67, 83 Tortora, P. (7) 59

Organophosphorus Chemistry

380 Toth, 1. ( I ) 89 Toto, S.D. (1) 110 Townsend, C.A. (6) 267 Toyota, K. (1) 277, 309, 310, 3 12-315 Trabelsi, H. (8) 37 Trapp, M.A. (8) 250 Trehearne, T.E. (1) 100 Trent, J. (7) 11 Trigo Passos, B.F. (1) 308, 348 Trishin, Yu.G. (1) 181; (5) 17, 158, 159 Trivedi, A. (8) 23 Trofimov, B.A. ( I ) 92, 93, 159 True, S. (8) 143, 144 Truesdale, L.K. (5) 82 Trzeciak, A. (5) 25 Tsai, B.D.(8) 130, 132 Tsao, C.-L. (1) 83 Ts’O, P.O.P. (6) 208 Tsunetsugu, S. (6) 44 Tsutsarin, V.V. (8) 76 Tsutsumi, Y. (6) 171 Tsvetkov, E.N.(1) 129; (3) 14; (5) 143, 295, 296 Tuck, D.G. ( I ) 29 Tuerk, C. (6) 298 Tufano, M.D. (7) 19 Tugnolli, V. (6) 324 Tuinman, R.J. (5) 138 Tuli, D.K. (6) 174 Tumanyan, V.G. (6) 277 Tunney, S.E. (1) 199 Tupchienko, S.K. (2) 31; (8) 77 Tur, D.R. (8) 230, 253, 255-258, 272, 273 Turdybekov, K.M. (5) 299 Turner, D.H. (6) 179, 180 Turner, M.L. (8) 149 Tuzhikov, 0.1. (1) 112 Tzschach, A. (5) 298 Ubusawa, M. (6) 29 Uchida, T. (1) 382 Uchida, Y. (1) 168, 250 Uchimaru, T. (6) 331 Uebayasi, M. (6) 328 Uehling, D.E. (7) 94 Ueland, J.M. (5) 117 Ueno, Y. (5) 60 Uesugi, S. (6) 218, 231 Ugi, 1. (4) 31, 32; (5) 102, 103 Uhl, G. (1) 333 Uhl, W. (1) 333 Uhlenbeck, O.C. (6) 172, 229, 230, 236 Uhlig, F. ( I ) 32

Uhlig, W. (1) 131 Ulbrich, R. (5) 276 Umeda, M. (8) 99 Umezu, Y. (3) 7 Unno, M. (1) 15 Urata, H. (6) 303 Usha, K. (2) 28; (8) 31 Usman, N. (6) 83, 237, 240 Ustenko, S.N.(4) 20 Uzanski, B. (6) 111 Uziel, J. (5) 206 Vaahs, T. (1) 35, 39 Vaal, M.J. (1) 155 Vacca, J.P. (5) 36 Vahldiek, M. (1) 113 Vahrenkamp, H. (7) 31 Valentine, K.G.(6) 268 Valerig, R.M. (5) 23 Valitskii, Y.V. (4) 33 Valu, K.K. (6) 283 Van Aerschot, A. (6) 18, 19 van Atta, R.B. (6) 252 van Boeckel, C.A.A. (5) 30, 31; (6) 65, 132 van Bolhuis, F. (8) 150 van Boom, J.H. (4) 45; (5) 138; (6) 59, 104, 193, 215, 251 Vanbrecht, B.J.A.M. (3) 36 Van Dam, E.M.A. (6) 193 van de Grampel, J.C. (8) 129, 150, 151, 187 van den Elst, H. (4) 45; (6) 193 van den Winkel, Y. (1) 337, 414 van der Bosch, H. (6) 16 van der Does, T. (1) 414 van der Gen, A. (3) 29, 30; (6) 59 Van der Haest, A.D. (5) 79, 80 Van der Heijden, H. (1) 185 van der Laarse, J. (1) 414 van der Lee, A. (8) 187 van der Marel, G.A. (4) 45; (5) 138; (6) 59, 104, 193, 215, 25 1 Vanderveer, D.G. (5) 302 van de Ven, F.J.M. (6) 215 Van Doorn, J.A. (1) 185 Van Engen, D. (1) 121, 122 van Es, J.J.G.S. (3) 29, 30 van Genderen, M.H.P. (6) 226 van Leeuwen, P.W.N.M. (1) 173 Vannoorenberghe, Y. (2) 25 van Oort, A.B. ( I ) 22 Vanquickenborne, L.G. ( I ) 363 Vansweevelt, H. (1) 363

Vapirov, V.V. (8) 111 Varani, G. (6) 217 Varmus, H.E. (6) 116 Vasella, A. (5) 139 Vasil’eva, N.V. (8) 255, 273 Vasisht, S.K. (8) 31 Vasser, M. (6) 74 Vasseur, J.-J. (6) 149 Vasyanina, L.K. (4) 38 Vavcikova, K. (5) 74 Vedachalam, M. (5) 155 Veith, M. (1) 195; (8) 156 Veits, Yu.A. (1) 68, 69, 280 Velikokhat’ko, T.N. (8) 86 Verchkre-Bkaur, C. (6) 292 Verdine, A.M. (6) 158 Verdine, G.L. (6) 76, 159, 160 Verkade, J.G. (4) 27; (5) 18 Verkruijsse, H.D. (1) 21 Verma, P.K. (8) 31 Vidal, A. (7) 102; (8) 49 Vidal, M. (1) 228; (3) 11 Viktorov-Nabokov, O.V. (8) 96 Vilaplana, M.J. (7) 108; (8) 46, 50 Villafranca, J.J. (6) 6 Vina, S. (1) 253 Vinader, M.V. (8) 15, 43, 55 Vinayak, R. (6) 66 Vincens, M. (1) 228; (3) 11 Vincze, A. (5) 218 Virgil, S.C. (7) 32 Visscher, K.B. (8) 235, 246 Visser, H.C. (1) 352; (4) 66 Vitola, A. (8) 249 Vittadini, A. (1) 59 Vogtle, F. (7) 99 Volkmann, M. (7) 99 Volodin, A.A. (8) 218 Volpin, M.E. (1) 175 Volwerk, J.J. (5) 137 von der Gtinna, V. (1) 360; (8) 29 von Itzstein, M. (I) 152 Vonka, V. (6) 23 von Kiedrowski, G. (6) 146 Von Schneering, H.G. (1) 42, 71 Vo-Quang, L. (5) 198 Voronkov, M.G. (1) 92, 93, 159 Vostrowsky, 0. (7) 75 Votruba, I. (6) 22, 23, 24 Vu, C.B. (7) 39 Vu, H. (4) 18; (6) 66, 103 Vukojevic, N.S. (5) 293 Vul’fson, S.G.(1) 139 Vymenits, A.B. (1) 175 Vysotskii, V.I. (1) 104

Author index Wada, M. (1) 255 Wada, T . (4) 56-58; (6) 71, 72, 122 Waegell, B. (1) 109 Waggoner, K.M. (1) 55, 355 Wagner, E. (5) 20 Wagner, I. (1) 210 Wagner, 0. (1) 331 WaiTan, W.H.-L. (1) 409, 410 Wakelin, L . P . G . (6) 279, 283, 284, 309 Wakselman, M. (4) 4 Walder, J . A . (6) 134 Walker, D . A . (6) 97 Walker, R.T. (6) 12, 29 Walker, S. (6) 268 Wallen, C . A . (6) 15 Walter, A. (1) 101 Walton, D . R . M . (I) 323 Walton, T.J. (6) 327 Walz, L. (1) 71 Wamhoff, H . (7) 107; (8) 44, 48 Wang. C. ( 5 ) 106; (6) 162 Wang, C.-K.(6) 262 Wang, M.F.(4) 3; (5) 120 Wang, M.L. (8) 109, 110 Wang, P. (2) 4 Wang, R.-J. (1) 25 Wang. S.N. (6) 249 Wang, T. (7) 42, 43; (8) 208 Wang, W. (4) 14 Wang, Y. (6) 221 Wang, Y.-S. (6) 321 Waring, M.A. (5) 72 Warren, S. (3) 19 Wasiak, J. (6) 105 Wassef, N.W. (1) 144 Wassermann, H . H . (7) 39 Wasylishen, R.E. (1) 350; (8) 13 Watanahe, F. (7) 90 Watanahe, M . (5) 69, 272 Watanabe, Y. (5) 33 Watkins, C.L. (1) 11 Watt, D . S . (7) 91 Watts, D . (5) 266 Wawer, A. (1) 196 Wawer, 1. (1) 196 Weber, L. (1) 269-272, 306, 31 1 Webster, H.F. (3) 16 Weidner, M.F. (6) 287 Weiguo, C. (7) 44 Weik, C. (5) 193 Weiler, B.E. (6) 138 Weintraub, P.M. (7) 82 Weiyu, D . (7) 44 Welch, S.C. (5) 70 Wells, R.L. (2) 10 Welz, U . (1) 317

381 Wen, M.-X. (5) 141 Wendehorn, S . V . (6) 262, 264 Wender, P . A . (6) 261 Wenkert, E. (7) 77 Werner, H. (1) 71; (7) 33 Werner, S. (7) 41 Werner, W. (8) 22 Wessolowski, H. (5) 150 West, A.P. (1) 121, 122 West, S . D . (1) 100 Westerduin, P. (5) 30, 31 Westermann, H. ( I ) 70; (4) I 7 Westmoreland, D . L . (1) 368; (5) 24 1 Westwood, R. (7) 101; (8) 53 Wettling, T. (1) 204, 334 White, A.H. (1) 106; (3) 12 White, J.D. (7) 6 White, P.S. (1) 364; (4) 72 Whitesides, G.M. (1) 125 Whittle, R.R. (8) 80 Wiaterek, C. (1) 46 Wiberg, N. (1) 338 Wickham, G. (6) 309 Widhalm, M. (1) 78 Wieber, M. (1) 198; (5) 57, 238 Wieczorek, M.W. (1) 227 Wiel, A. ( I ) 169 Wightman, J.P. (3) I 6 Wightman, R.H. (5) 212 Wijata, A. (5) 64 Wijmenga, S.S. (6) 257 Wilbrandt, D. (5) 6 Wild, S.B. (1) 123, 187 Wilke, E. (5) 151 Willens, H . A . M . (5) 30, 31 Williams, A. (5) 72 Williams, D.J. (5) 285 Williams, D . M . (6) 173-175 Williams, I.D. (1) 126 Willingham, R.A. (8) 210, 231 Willis, A.C. (1) 24 Willis, M.C. (6) 172 Wills, A.R. (1) 82 Wilson, G.E. (6) 322 Wilson, S . H . (6) 112 Wilson, S.R. (1) 91; (7) 52; (8) 19 Wilson, W.R. (6) 283, 285 Wimmer, T. (1) 164 Windscheif, P.-M. (7) 99 Wingfield, P. (6) 195 Wink, D.J. (4) 22 Winkeler, K.A. (4) 53; (6) 246 Winkler, T. (5) 253 Winter, R. (5) 150 Wintergrass, D.J. (4) 27; (5) 18 Wintersgill, M.C.(8) 266

Wintersohl, H. (7) 107; (8) 44 Winwood, D . (5) 5 Wise, W.B. (6) 169 Wisian-Nielson, P. (8) 208, 209, 250 Wisniewski, W. (3) 31 Withka, J . (6) 247 Witt, M. (8) 21 Wlotzka, B. (6) 146 Woenckhaus, C. (6) 206 Wojna-Tadeusiak, E. (5) 92 Wolf, J . (7) 33 Wolf, R. (1) 369, 370; (4) 70, 71 Wolfsberger, W. (1) 3, 84, 99, 132, 205; (8) 16 Wolmershauser, G. (1) 334 Wong, C.-H.(4) 42; (5) 19 Wong-Staal, F. (6) 113 Woo, J . (6) 287 Wood, C . E . (8) 4 Wood, G.L. (1) 167 Woodgate, P . D . (6) 283, 284 Woolins, J.D. (5) 285 Wooster, T.T. (8) 264 Worth, L., jun. (6) 258, 259 Wright, W.B., jun. (8) 27 Wrighton, M.S. (8) 7 9 Wrobel, L. (7) 114 Wroblewski, A . (4) 27; (5) 18 WU, A.-H. (4) 77; (5) 180; (7) 72 Wu, H.S.(8) 109, 110 Wu, J.V. (6) 125 Wu, S.Y. (5) 89, 90 Wu, T. (6) 82 WU, X.-P. (5) 77, 273 Wyatt, J.R. (6) 224, 225 Wynberg, H. (5) 79, 80 Xiang, Y. (1) 257; (7) 45 Xiang, Y.-B. ( 5 ) 20 Xie, Y. (8) 103 Xu, Y. (6) 304 XU, Y.-Z. (6) 165 Yaguchi, A . (8) 164, 165, 167, 169, 173-175 Yamaguchi, K. (3) 2 3 Yamaguchi, M. (3) 7; (7) 70 Yamaji, N. (6) 36 Yamamoto, H. (5) 94 Yamamoto, K. (1) 79 Yamamoto, M. ( 5 ) 262 Yamamoto, S. (1) 233 Yamamoto, Y. (7) 67

382 Yamashita, D.S. (7) 118 Yamashita, M. (5) 177 Yamashita, Y. (8) 245 Yamovskaya, V.L. (5) 46 Yan, S. (5) 289 Yanada, R. (4) 10 Yanagida, S. (4) 13 Yang, J.-H. (6) 237 Yang, Y.-C. (5)288 Yang, Z.-Y. (5) 163 Yaniv, D.R.(8) 264 Yano, S. (8) 140 Yanovskii, A.I. (1) 28, 102, 175 Yaolvskaya, A.J. (1) 150 Yaouanc, J.-J. (2) 27 Yarerna, K. (6) 183, 184 Yashirna, E. (6) 334 Yashiro, T. (5) 300 Yasuda, S. (7) 96 Yasui, M. (7) 16 Yasui, S. (1) 188 Yasunami, M. (1) 330 Yasunami, S. (8) 280, 281 Yau, E. (4) 61; (6) 121, 125 Yazawa, N. (1) 263 Ye, M. (5) 289 Yee, A . (4) 22 Yoneda, F. (4) 10 Yoneda, R. (5) 107; (8) 56 Yoon, H.S. (8) 114-116, 180 Yoshida, Y. (1) 238, 263 Yoshifuji, M. (1) 277, 309, 310, 312-315, 330 Yoshikawa, K. (1) 90 Yoshikawa, M. (6) 207 Yoshirnura, H. (1) 277, 309, 313, 314 Yu, J.H. (2) 21 Yu, P.L. (6) 69

Organophosphorus Chemistry Yu, P.S. (6) 90 Yu, Y. (8) 26 Yu, Z. (6) 6 Yuan, Z. (1) 126 Yuki, Y. (1) 239 Yurchenko, R.I. (1) 112; (5) 53 Yurchenko, V.G. (5) 53 Yusupov, M.M. (5) 101 Zaharylo, S.V. (6) 61 Zabirov, N.G. (5) 98, 100; (8) 38, 39 Zagnibida, D.M. (8) 96 Zahra, J.-P. (1) 109 Zakharkin, L.I. (1) 28, 279 Zal’tsman, I.S. (2) 30, 31; (8) 77 Zarnecnik, P.C. (6) 203 Zanella, P. (1) 59 Zanin, B. (8) 123-125 Zanotto, L. (1) 179 Zarges, W. (7) 51 Zarrinrnayeh, H. (6) 80, 272 Zatorski, A. (7) 120 Zavlin, P.M. (5) 62 Zawadzki, S. (5) 64 Zayed, M.F. (7) 25 Zhigniew, J. (8) 121 Zbiral, E. (5) 167, 168 Zecchi, G. (7) 104; (8) 57 Zeelie, B. (3) 36 Zein, M. (6) 267 Zeiss, H.-J. (5) 179 Zellner, K. (1) 62; (7) 34 Zercher, C.K. (6) 261 Zettlmeier, W. (1) 117; (4) 65 Zhang, D. (1) 392 Zhang, G. (6) 62

Zhang, J. (5) 106 Zhang, J.-L. (1) 394 Zhang, L. (5) 106; (6) 40 Zhang, L.-J. (7) 29 Zhang, R. (5) 140, 157 Zhang, S. (1) 76 Zhang, W. (5) 29 Zhang, W.-S. (4) 43 Zhang, Y. (2) 4 Zhao, M. (5) 106 Zhao, Y. (5) 289; (8) 6 Zhao, Z. (7) 21 Zheng, J. (1) 392 Zherebtsov, A.A. (5) 109 Zhigareva, C.G. (1) 28 Zhou, L. (6) 157 Zhou, W. (5) 141 Zhou, X.-X. (6) 244 Zhou, Y. (7) 23 Zhu, N.J. (8) 44 Zhurinov, M.Kh. (5) 299 Zhut-skii, P.V. (2) 22; (5) 213 Zibuk, R. (7) 98 Ziegler, J. (1) 14 Ziegler, M.L. (1) 405 Ziller, J.W. (7) 32 Zilm, K.W. (1) 276 Zirnrnerling, R. (5) 52 Zimrnerrnan, J . (6) 276 Zinchenko, S.V. (5) 109 Zinn, A. (8) 294 Zon, G. (6) 75, 99, 106, 108, 113, 115, 118, 304, 305 Zotov, Yu.L. (1) 111 Zschunke, A . (1) 97 Zsolnai, L. (1) 266, 322 Zurmuhlen, F. (1) 204 Zwierzak, A. (8) 72 Zykova, T . V . (1) 217