Organophosphorus Chemistry

Organophosphorus Chemistry Volume 13

A Specialist Periodical Report

Organophosphorus Chemistry Volume 13

A Review of the Literature published between July 1980 and June 1981

Senior Reporters

D. W. Hutchinson Department of Chemistry and Molecular Sciences, University of Warwick J. A. Miller Chemistry Department, University of Dundee Reporters

D. W. Allen Sheffield City Polytechnic R. S. Edmundson University of Bradford C.

D. Hall King's College, London

J. B. Hobbs The City University, London W. J. Stec Polish Academy of Sciences,*ddi

J. C . Tebby North Staffordshire Polytechnic, Stoke-on- Trent B. J. Walker Queen's University of Belfast

The Royal Society of Chemistry Burlington House, London W1 V OBN

British Library Cataloguing in Publication Data Organophosphorus chemistry.-Vol. 13.(Specialist periodical report/Royal Society of Chemistry) 1. Organophosphorus compounds - Periodicals I. Royal Society of Chemistry 11. Series 547’.07’05 QD412.Pl ISBN 0-85186-1 16-4 ISSN 0306-0713

Copyright 01982 The Royal Society of Chemistry All Rights Reserved

No 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 - withour written permission from The Royal Society of Chemistry

Printed in Great Britain by Adlard and Son Ltd Bartholomew Press, Dorking

Introduction

One of the major events of 1981 was the International Conference on Phosphorus Chemistry held at Duke University, Durham, NC, and which included sessions recognizing the contributions of Professors Wittig and Westheimer to phosphorus chemistry. The manuscripts provided by those lecturing at this Conference have been published by the American Chemical Society, and give an idea of the ‘state of the art’ in phosphorus chemistry. In this volume, the occasional review concerns the important anti-cancer drug cyclophosphamide and has been contributed by Professor W. J. Stec of the Polish Academy of Sciences, Centre of Molecular and Macromolecular Studies, in €hdi, Poland. Despite many trials and tribulations, Professor Stec has completed his voluminous review with very little delay, and must be congratulated for the production of an interesting, up-to-date review. Next year, the occasional review will be devoted to the mass spectrometry of organophosphorus compounds, a field which has become increasinglyimportant with the advent of such techniques as field desorption and fast-atom bombardment, which allow the mass spectra of involatile compounds to be studied. During the past year, the use of nucleoside polyphosphates that are specifically labelled with oxygen isotopes for the investigation of enzyme mechanisms has continued to provoke considerable interest and elegant experimentation, and has afforded many new results. Significant progress has been made in the development of novel reagents and methods for use in the phosphotriester strategy of oligonucleotide synthesis, and in particular the description of increasingly, efficient solid-phase methods for this process. Reports on the simple, large-scale preparation of nicotinamide coenzymes and sugar phosphates, using immobilized enzymes, should be of considerable commercial importance, as the starting materials are cheap and the products require little or no purification. Interest in the new field of two-co-ordinate phosphorus compounds continues to grow. Monomeric trimetaphosphate, for so long an elusive species, has been prepared, and it can attack acetophenone at the carbonyl oxygen atom to give an enol phosphate. New synthetic developments include the use of palladium complexes in the synthesis of phosphonic acids and the formation of mixed phosphate esters by the stepwise replacement of triazole groups from phosphoryl tris(triazo1ide). In keeping with one of the themes of the 1981 ICPC meeting, there has been much exciting progress on several aspects of the Wittig reaction. Particularly pleasing is the degree of agreement (albeit not complete!) between MO studies, and perhaps the most thorough general experimental study of the Wittig reaction

vi

Introduction

mechanism yet published. These studies clearly indicate that betaine intermediates, so favoured for many years, must now be regarded as unlikely, at least in salt-free systems. For the more practically orientated there have also been valuable additions to our options for control of the geometry of alkenes in Wittig reaction products. Another old faithful in which some mechanistic progress has been made is the Conant reaction, between phosphorus(II1) halides and simple carbonyl compounds. Much of the new synthetic work with phosphines and derived oxides or sulphides has been devoted to new heterocyclic phosphorus compounds. Perhaps the most novel is in the medium-ring field, where, for example, the first synthesis of a phosphonin has appeared. Once again, the synthesis of new chiral di- and tri-phosphine ligands for asymmetric homogeneous hydrogenation continues to attract much attention. The phospha-alkenes are becoming increasing recognized as interesting reactive intermediates, as are the phospha-alkynes. There should be exciting times ahead as the properties of these n-bonded structures are investigated. Various aspects of the equilibria between phosphorus(Iv), phosphorus(v), and phosphorus(v1) species remain a focal point for research. Overall, one has the impression that organophosphorus chemistry remains an active field, in which there is much new fundamental work being done, and several interesting and potentially valuable applications are being examined. This provides its enthusiasts with a nice blend of consolidation in some areas, and of completely new horizons in others. April 1982

D.W.H. J.A.M.

Contents Chapter 1 Phosphines and Phosphonium Salts By D. W. Allen

1

1 Phosphines Preparation From Halogenophosphines and Organometallic Reagents From Metallated Phosphines By Addition of P-H to Unsaturated Compounds By Reduction Miscellaneous Methods of Preparation Reactions Nucleophilic Attack at Carbon Nucleophilic Attack at Halogen Nucleophilic Attack at Other Atoms Miscellaneous Reactions

1 1 1 3 6 7 9 13 13 14 17 19

2 Phosphonium Salts Preparation Reactions Alkaline Hydrolysis Additions to Unsaturated Phosphonium Salts Miscellaneous Reactions

21 21 24 24 26 27

3 Phospholes and Phosphorins

29

Chapter 2 Quinquecovalent Phosphorus Compounds By C. D. Hall

33

1 Introduction

33

2 Structure and Bonding

34

3 Phosphoranes containing a P-H Bond

34

4 Acyclic Phosphoranes

36

5 Four-membered-ring Phosphoranes

39

6 Five-membered-ring Phosphoranes

39

7 Hexaco-ordinated Phosphorus Compounds

47

vii

viii

Contents

Chapter 3 Halogenophosphines and Related Compounds By J. A. Miller

49

1 Introduction

49

2 Halogenophosphines

49 49

Preparation Reactions with Carbonyl Compounds and Related Compounds Reactions with Group V Donors Reactions with Carbanions, Alkenes, and Aromatic Compounds Insertion Reactions of Silylphosphines Physical and Structural Aspects 3 Halogenophosphoranes Structural Preparation Reactions with Nitrogen Compounds Reactions Relevant to Organic Synthesis

Chapter 4 Phosphine Oxides and Related Compounds By J. A. Miller

51 55 55

57 57 58 58 58 59 59

62

1 Introduction

62

2 Preparation of Acyclic Oxides

62

3 Preparation of Cyclic Oxides

66

4 Structural and Physical Aspects

69

5 Reactions at Phosphorus

71

6 Reactions of the Side-Chain

72

7 Phosphine Oxide Donor-Acceptor Complexes, and Extractants

75

Chapter 5 Tervalent Phosphorus Acids By B. J. Walker

77

1 Introduction

77

2 Phosphorous Acid and its Derivatives Nucleophilic Reactions Attack on Saturated Carbon Attack on Unsaturated Carbon Attack on Nitrogen

77

77 77 79 85

Contents

ix Attack on Oxygen Attack on Halogen Electrophilic Reactions Cyclic Esters of Phosphorous Acid Miscellaneous Reactions 3 Phosphonous and Phosphinous Acids and their Derivatives

Chapter 6 Quinquevalent Phosphorus Acids By R. S. Edmundson

86 88 88 94 95 96

98 98

1 Synthetic Methods General Phosphoric Acid and its Derivatives Phosphonic and Phosphinic Acids and their Derivatives

98 100 103

2 Reactions General Phosphoric Acid and its Derivatives Phosphonic and Phosphinic Acids and their Derivatives

111 111 113 121

Chapter 7 Phosphates and Phosphonates of Biochemical Interest 131 By D. W. Hutchinson 1 Introduction

131

2 Coenzymes and Cofactors

132

3 Sugar Phosphates

134

4 Phospholipids

135

5 Phosphonates

137

6 Enzyme Mechanisms

139

7 Phosphorylated Proteins

141

8 Other Compounds of Biochemical Interest

142

Chapter 8 Cyclophosphamide and its Congeners By W. J. Stec

145

1 Introduction

145

2 The Rationale for the Synthesis of Cyclophosphamide

146

3 The Current Status of Knowledge of the Metabolism of Cyclophosphamide

146

Contents

X

4 The Synthesis of Analogues of Cyclophosphamide and their Metabolites

153

5 Biological Properties of Newly Synthesized Analogues of Cyclophosphamide

170

6 Concluding Remarks

172

Chapter 9 Nucleotides and Nucleic Acids B y J . B. Hobbs

175

1 Introduction

175

2 Mononucleotides Chemical Synthesis Cyclic Nucleotides Affinity Chromatography

175 175 182 185

3 Nucleoside Polyphosphates Chemical Synthesis Affinity Labelling

187 187 197

4 Oligo- and Poly-nucleotides Chemical Synthesis Enzymatic Synthesis Sequencing 0ther Studies

201 20 1 212 213 214

5 Analytical Techniques and Physical Methods

219

Chapter 10 Ylides and Related Compounds By B. J. Walker 1 Methylenephosphoranes

Preparation and Structure Reactions Aldehydes Ketones Miscellaneous

222 222 222 226 226 230 233

2 Reactions of Phosphonate Anions

240

3 Selected Applications in Synthesis

247 247 249

Pheromones Prostaglandins

xi

Contents Carbohydrates Carotenoids and Related Compounds /3-Lactam Antibiotics Non-benzenoid Aromatic Compounds Miscellaneous Applications

Chapter 11 Physical Methods By J. C. Tebby

249 249 25 1 252 254

259

1 Nuclear Magnetic Resonance Spectroscopy Biological Applications and Instrumental Techniques Chemical Shifts and Shielding Effects Phosphorus-31 BP of n2 compounds BP of n3 compounds BP of n4 compounds BP of n6 compounds Carbon-13 Nitrogen-15 Chlorine-35 Studies of Equilibria, Shift Reagents, and Liquid Crystals Variable-temperature Studies Pseudorotation Restricted Rotation Studies of Configuration Spin-Spin Coupling J(PP) and J(PM) J(PC) J(PH) J(PCnH) and J(PXCnH) Studies of Relaxation, CIDNP, and N.Q.R.

259 259 259 259 260 260 26 1 262 262 262 262 262 263 263 264 265 265 265 266 267 267 268

2 Electron Spin Resonance Spectroscopy

268

3 Vibrational and Rotational Spectroscopy Band Assignments and Absorptivity Bonding Stereochemistry Rotational Data

269 269 270 27 1 272

4 Electronic Spectroscopy Absorption Spectroscopy Photoelectron Spectroscopy X-Ray Fluorescence Spectroscopy

272 272 272 273

5 Diffraction X-Ray Diffraction Electron Diffraction

273 273 276

xii

Contents

6 Dipole Moments and the Kerr Effect

277

7 Mass Spectrometry

278

8 pKa and Thermochemical and Kinetic Studies

278

9 Chromatography Gas-Liquid Chromatography Thin-layer Chromatography and Paper Chromatography High-performance Liquid Chromatography Column Chromatography

280 280 280 280 280

Author Index

281

Abbreviations* AIBN CIDNP CNDO CP DAD DBN DBU DCC DIOP DMF DMSO DMTr EDTA E.H.T. ENU FID g.1.c.-m.s. HMPT HN2 h.p.1.c. 1.r. L.F.E.R. MIND0 MO MS-Cl MS-nt MS-tet NBS n.q.r. p.e. PPA SCF TBDMS TDAP TFAA Tf2O

bisazoisobutyronitrile Chemically Induced Dynamic Nuclear Polarization Complete Neglect of Differential Overlap cyclopentadienyl diethyl azodicarboxylate 1,5-diazabicyclo[4.3.O]non-5-ene 1,5-diazabicyclo[5.4.O]undec-5-ene dicyclohexylcarbodi-imide [(2,2-dimethyl-1,3-dioxolan-4,5-diyl)bis(methy1ene)lbis( diphenylphosphine) dimethylformamide dimethyl sulphoxide 4,4’-dimethoxytrityl ethylenediaminetetra-aceticacid Extended Hiickel Treatment N-ethyl-N-nitrosourea Free Induction Decay gas-liquid chromatography-mass spectrometry hexamethylphosphortriamide methylbis-(2-chloroethyl)amine high-performance liquid chromatography infrared Linear Free-Energy Relationship Modified Intermediate Neglect of Differential Overlap Molecular Orbital mesitylenesulphonyl chloride mesitylenesulphonyl-3-nitro1,2,4-triazole mesit ylenesulphonyltetrazole N- bromosuccinimide nuclear quadrupole resonance photoelectron polyphosphoric acid Self-Consistent Field t-butyldimethylsilyl tris(diethy1amino)phosphine trifluoroacetic acid trifluoromethanesulphonic anhydride

* Abbreviations used in Chapters 7-9 and 1978,171, 1.

are detailed in Biochem. J., 1970,120, 449 xiii

xiv THF t.1.c. TPS-C1 TPS-nt TPS-tet TsOH U.V.

Abbreviatiort

tetrahydrofuran thin-layer chromatography tri-isopropylbenzenesulphonylchloride tri-isopropylbenzenesulphonyl-3-nitro1,2,4-triazole tri-isopropylbenzenesulphonyltetrazole toluene-p-sulphonic acid ultraviolet

1 Phosphines and Phosphonium Salts BY D. W. ALLEN

1 Phosphines Preparation.-From Hulogenophosphines and Orgunometallic Reagents. Interest in the availability of tertiary phosphines which may form hydrocarbon-soluble transition-metal complexes (of possible importance in homogeneous catalysis) has prompted the synthesis of a series of arylphosphines (l), bearing straightchain alkyl substituents in the para-position of the benzene ring, via the reaction of phosphorus trichloride with Grignard reagents derived from the appropriate p-bromo(alky1)benzene. These phosphines are more sensitive to atmospheric oxidation than is triphenylphosphine.' The reactions of bis(dich1orophosphino)methane with Grignard reagents (or equimolar mixtures of Grignard reagents) have given the diphosphines (2), which on treatment with hydrogen chloride are converted into the corresponding bisphosphonium salts. The reaction of the bis(dich1orophosphine) with t-butylmagnesium chloride unexpectedly gives the cyclic tetraphosphine The Grignard procedure has also been used in the synthesis of the chelating diphosphine (4), which undergoes dehydration in the presence of certain rhodium(1) complexes to give (5).4 ( 3 ) . 2 9 3

(1) TI = 2-9

(2) R',Rz= alkyl or Ph

Organolithium reagents continue to be widely employed in the synthesis of tertiary phosphines. Improved routes to the (2-pyridy1)phosphines(6), involving the reactions of halogenophosphines with 2-lithiopyridine, have been de~cribed.~ S . Franks and F. R. Hartley, J . Chem. SOC.,Perkin Trans, I , 1980, 2233. A. A. Prishchenko, N. E. Nifant'ev, Z . S. Novikova and I. F. Lutsenko, Zh. Obshch. Khim., 1980, 50, 1881 (Chrm. Abstr., 1980, 93, 239 536). A. A. Prishchenko, Z . S. Novikova, and 1. F. Lutsenko, Zh. Obshch. Khim., 1980, 50, 687 (Chem Abstr., 1980, 93, 186 460). M. A. Bennett and H. Neumann, Aust. J . Chrm., 1980, 33, 1251 H. Schmidbaur and Y . Inoguchi, 2. Nuturforsch., Tril. B , 1980, 35, 1329.

1

2

Organophosphorus Chemistry

Me

( 6 ) n = 0,1, o r 2

(7) R’ = H, Me, or Pri;R2 = CH(OR),

(8)

Q\

[I”/;.;;lr..

Fe

PPh

(9) R = Me, But, o r Ph

The reactions of N-protected 2-lithio-imidazoles with phosphorus trichloride have given the (imidazoly1)phosphines(7), from which the N-protecting group can be removed on treatment with aqueous acetone.6 The potentially chelating ligand (8) is formed in the reaction of di-t-butylchlorophosphinewith a 2-lithiomethylquinoline reagent.’ The synthesis of (0-hydroxyaryljphosphines, e.g. (9), in good yield has been achieved from the reactions of halogenophosphines with the lithium reagent that is obtained on treatment of o-bromophenol with two moles of butyl-lithium.* The atropisomeric, chelating diphosphine (10) (which has been resolved via chiral palladium complexes) has been prepared from the reaction of chlorodiphenylphosphine with the dilithium reagent obtained from metallation of 2,2’-dibromo-l,l’-binaphthylwith t-butyl-lithi~m.~ A second report of the synthesis of the phosphino-[ Ilferrocenophane (1 1) has appeared.1° A wide range of chiral ferrocenyl-phosphines and -diphosphines, e.g. (12), has been prepared by previously established routes involving lithiation of the ferrocenyl nucleus ortho to the chiral aminoalkyl function, followed by reaction with

Fe

(HOOC CH,),P

n

P(CH,COOH),

PR, (12) R = Me or Ph N. J. Curtis and R. S . Brown, J . Org. Chem., 1980, 45, 4038. A. J . Deeming, 1. P. Rothwell, M. B. Hursthouse, and K. M. A. Malik, J . Chem. Soc., Dalton Trans., 1980, 1974. 8 A. Tzschach and E. Nietzschmann, Z. Cfzem., 1980, 20, 341. 9 A. Miyashita, A. Yasuda, H . Takaya, K . Toriumi, T. Ito, T. Souchi, and R. Noyori,J. Am. Chem. SOC.,1980, 102, 7932. l o A. G . Osborne, R. H. Whiteley, and R. E. Meads, J . Organonlet. Cfiem., 1980, 193, 345. 6

Phosphines and Phosphonium Salts

3

an appropriate halogenophosphine.ll9 l2 Similarly, ortho-lithiation of (hydroxymethyl)cymantrene, followed by treatment with chlorodiphenylphosphine,gives (13).13 Further studies of the synthesis of chiral phosphines via the reactions of organometallic reagents with phosphinous esters that are derived from cinchonine have been reported.14The phosphorus analogue (14) of EDTA has been prepared by alkylation of 1,2-bis(dich1orophosphino)ethane with ethyl(bromozinc)acetate, followed by hydrolysis of the resulting tetraester, and isolated as the tetrasodium ~ a 1 t . lThe ~ dimethoxyethane solvate of bis(trifluoromethy1)cadmium has been used to alkylate phosphorus tri-iodide, giving tris(trifluoromethyl)phosphine, but only in 20% yield.16 Preparation from Metallated Phosphines. The reactions of metallophosphide reagents with alkyl halides or tosylates (and related sulphonate esters) continue to be widely employed in the synthesis of phosphines, and a considerable number of new systems, many of which are chiral, have been described. This area continues to be stimulated by the great interest in the use of chiral phosphines as ligands in transition-metal complexes that are used as catalysts for asymmetric hydrogenation and related reactions; a timely review of this field has appeared.17 The reactions of sulphonate esters with lithiophosphide reagents have been employed in the synthesis of the chiral unidentate phosphines (15)'* and (16),19 and of a range of chiral bidentate phosphines,20-22e.g. (17)20 and (18).21 In the CH,PPh,

I

l1

l2

13

l4 15 l6 1' 18 l9 2O 22

K. Yamamoto, J. Wakatsuki, and R. Sugimoto, Bull. Chem. SOC. Jpn., 1980,53,1132 T. Hayashi, T. Mise, M. Ftlkushima, M. Kagotani, N. Nagashima, Y. Hamada, A. Matsumoto, S. Kawakami, M. &onishi, K. Yamamoto, and M. Kumada, Bull. Chem. SOC.Jpn., I 1980,53, 1138. N. M. Lim, P. V. Kondrar'ev, N. P. Solov'eva, V. A. Antonovjch, P. V. Petrovskii, Z. N. Parnes, and D. N. Kursaqov, J. Organomet. Chem., 1981, 209, 233. W. Chodkiewicz, J. Organomet. Chem., 1980, 194, C25. J. Podlahova and J. Podlaha, Collect. Czech. Chem. Commun., 1980, 45, 2049. L. J. Krause and J. A. Morrison, J. Chem. SOC.,Chem. Commun., 1980, 671. V. Caplar, G. Comisso, and V. SunjiC, Synthesis, 1981, 85. G. Comisso, A. Sega, and V. h n j i c , Croat. Chem. Acta, 1980, 53, 445. D. Valentine, Jr., K. K. Johnson, W. Priester, R. C. Sun, K. Toth, and G. Saucy, J . Org. Chem., 1980,45, 3698. D. P. Riley and R. E. Shumate, J. Org. Chem., 1981, 45, 5187. P. A. MacNeil, N. K. Roberts, and B. Bosnich, J. Am. Chem. SOC.,1981, 103, 2273. J. Benes and J. Hetflejs, Czech. P. 178 228 (Chem. Abstr., 1981, 94, 121 713).

4

Organophosphorus Chemistry

synthesis of (18), the (d)-10-camphorsulphonate esters were employed, these having the advantage of being readily separated into internal diastereoisomers by crystallization. The reactions of alkyl halides with lithiophosphide reagents have been employed in the synthesis of a range of DIOP systems (19). Purification of these phosphines is facilitated by the preparation of the copper(1) complexes, which, following recrystallization, are decomposed with ammonia to give the free ligand.23The reactions of lithiophosphide reagents with halides or tosylates have also been used in the preparation of polymer-supported p h o s p h i n e ~ , ~ ~ - ~ ~ e.g. (20).24 Interest continues in the synthesis of macrocyclic phosphines from the reactions of lithiophosphide reagents that are derived from bis(secondary alky1)phosphines with appropriate alkyl halides, under high-dilution conditions. Among the systems reported in the past year are (21)-(23).28-30

Ph

Lithiophosphide reagents have also been used for the synthesis of a range of other systems. (Dimethylaminomethy1)ferrocene undergoes asymmetric cyclopalladiation to give the chiral complex (24), which, on treatment with lithium diphenylphosphide, gives the chiral ligand (25).31 The reaction of lithium phosphide with benzoyl chloride in dimethoxyethane has given the lithium complex (26) of the enol form of dibenz~ylphosphine.~~ The dichloro-lactone (27) is converted into the diphosphine (28) on treatment with lithium diphenylphosphide, but, in the related reaction with diphenyl(trimethylsilyl)phosphine, only one chlorine is replaced, to give (29).33 Syntheses involving reagents obtained from metallation at a carbon atom that is alpha to phosphorus have also been reported. Thus lithiomethyl(dipheny1)23 2.1 25

26 27 28 29

30 31 32 33

J. M. Townsend, J. F. Blount, R. C. Sun, S. Zawoiski, and D. Valentine, Jr., J. Org. Chem., 1980, 45, 2995. T. Hayashi, N. Nagashima, and M. Kumada, Tetrahedron Lett., 1980, 21, 4623. J. K. Stille, S. J. Fritschel, N. Takaishi, T. Masuda, H. Imai, and C. A. Bertelo, Ann. N . Y. Acacl. Sci., 1980, 333, 35 (Chenz. Abstr., 1980, 93, 185 407). V. Kavan and M. Capka, Collect. Czech. Cliem. Commun., 1980, 45, 2100. J. I. Schulman, U.S. P. 4 209 468 (Clwm. Abstr., 1980, 93, 239 644). M. Ciampolini, P. Dapporto, N. Nardi, and F. Zanobini, Znorg. Chim. Acta, 1980, 45, L239. E. P. Kyba and S-S. P. Chou, J . Org. Chetn., 1981, 46, 860. E. P. Kyba and S - S . P. Chou, J . Am. Chem. SOC.,1980, 102, 7012. V. 1. Sokolov, L. L. Troitskaya, and 0. A. Reutov, J . Organomet. Chem., 1980,202, C58. G. Becker, M. Birkhahn, W. Massa, and W. Uhl, Angew. Chem., I n t . Ed. Engl., 1980. 19, 741. D. Fenske, H. Prokscha, P. Stock, and H. J. Becher,Z. Naturforsch., Ted. B, 1980,35, 1075.

5

Phosphines and Phosphonium Salts Ph

\

phosphine has been used to prepare a range of phosphines that are based on the zirconocene nucleus, e.g. (30).34The related reagent (31), obtained from the metallation of methoxymethyl(diphenyl)phosphine, has found application for the hydroformylation of sterically hindered, enolizable Sodium diethylphosphide and potassium diphenylphosphide have been used to prepare new polydentate, tripod-like phosphines, e.g. (32).36937 The reactions of sodiophosphide reagents with chloromethyltrimethylsilanehave given a range of a-trimethylsilyl-substituted methylphosphines (33).3s The new ligand (34) is formed in the reaction of potassium diphenylphosphide with chloromethyl phenyl t h i ~ e t h e rA. ~route ~ to ethylmethylphosphine, starting from phosphine, via stepwise metallation with sodium and subsequent alkylation has also been described.40

PhP( R)CH, SiMe,

PhSCH,PPh,

(33) R = Me, Et, Pri, Ph, or CH,SiMe,

(34)

A considerable number of new heterocyclic systems have been prepared via the use of metallophosphide reagents. The reaction of dilithium methylphosphide with a,o-dichloro-polysilanes has given the permethyl-phosphacyclopolysilanes (35),41 and the addition of t-butoxyl radicals to some of these systems, giving phosphoranyl radicals, has been studied by e.s.r. spectros~opy.~~ Amongst new N . E. Schore and H. Hope, J . Am. Chem. SOC., 1980, 102,4251. E. J. Corey and M. A . Tius, Tetrahedron Lett., 1980, 21, 3535. 3 6 C. Bianchini, C. Mealli, A. Meli, and L. Sacconi, Znorg. Cliim. Acta, 1980, 43, 223. 37 C. Bianchini, A . Meli, A. Orlandini, and L. Sacconi, J . Organomet. Chem., 1981, 209, 219. 38 R. Appel, J. Peters, and R. Schmitz, Z . Anorg. Allg. Chem., 1981, 475, 18. 39 A . R. Sanger, C. G . Lobe, and J. E. Weiner-Fedorak, Inorg. Cliim. Actn, 1981, 53, L123. 4 0 J . G. Morse, Znorg. Chim. Acta, 1980, 41, 161. 41 T. H. Newman, R. West, and R . T. Oakley, J . Organomet. Chem., 1980, 197, 159. 4 2 T. H. Newman and R. West, J . Organomet. Chem., 1980, 199, C39. 34

35

Organophosphorus Chemistry

6 (SiMe,), Me,Si’ ‘SiMe,

I

PhP-PPh

I

Me,SiySiMe, Me (35) n = 0, 1, or 2

I

ButP --But B ‘’ NR* (36) R = alkyl or Ph

PhP\

\

/PPh N C6Hl I (37)

But P

/ \

ButP -PBu‘

(39) R = Prior But

(38)

(40) R = Prior But

systems that have been reported in the past by Baudler’s group are (36)43 and (37),44Of particular interest is the cyclopropane-like ring-closure with lithium hydride, giving reaction of 1,3-di-iod0-1,2,3-tri-t-butyltriphosphane (38).4sThe related reactions of bis(monoha1ogenophosphino)methanes with alkali metals have given the diphosphacyclopropanes (39), which dimerize readily to give (40).49 Preparation of Phosphines by Addition of P-H to Unsaturated Compounds. A procedure for the continuous production of (secondary alky1)phosphines by the free-radical-catalysed addition of phosphine to alkenes at high temperature and pressure, in an inert solvent, has been described. The bicyclic secondary phosphines (41) have also been prepared by this method.50 Free-radical-catalysed procedures continue to be, employed in the synthesis of polydentate phosphine ligands. Thus, e.g., the addition of cyclohexylphosphine to vinyldiphenylphosphine has given (42), and addition of dicyclohexylphosphine to phenyldivinylphosphine gives (43).51Secondary phosphines also undergo free-radical-catalysed

rr\

Cy P(CH,CH,PPh,),

(R’HC) PH(CHR2),

QJ

(41) n , m = 1 - 3 (n + rn R’, R2= H or alkyl

< 5)

R10SO2NHCH(Ph)PR2,

(42)

CyP [ C( X)NHPh ] ,

(45) X = 0 or S (44) R’ = H or Me R 2 = P h o r Cy

PhP(CH,CH,PC y 3,

(43)

k k Ph

(46)

50

Baudler and A. Marx, Z. Anorg. Allg. Chem., 1981, 474, 18. Baudler and P. Lutkecosmann, Z . Anorg. Allg. Chem., 1981, 472, 38. Baudler, Y . Aktalay, J. Hahn, and E. Di rr, Z . Anorg. AIIg. Chem., 1981, 473, ?.0. Baudler, W. Fa5er, and J. Hahn, Z . Anorg. Allg. Chem., 1980, 469, 15. Baudler and S. Klautke, Z . Nuturforsch., Teil. B , 1981, 36, 527. Baudler and J. Hellmann, Z . Nrrturforsch., Teil. B , 1981, 36, 266. A. A. Prishchenko, Z . S. Novikova, and 1. F . Lutsenko, Zh. Obshch. Khirn., 1980, 50, 689 (Chem. Ahstr., 1980, 93, 168 342). G. Elmer, G . Heymer, and H . W. Stephan, Br. P . 1 5 6 1 874 (Cham. Abstr., 1981, 94, 8 4

51

294). G. Miihlbach, B. Rausch, and D. Rehder, J . Organornet. Chem., 1981, 205, 343.

43 4-1 45

46 47

-18 49

M. M. M. M. M. M.

7

Phosphines and Phosphonium Salts

addition to N-(arylsulphony1)benzaldimines to give the a-(arylsu1phonamido)benzylphosphines (44).52 Further studies have been made of the addition of primary and secondary phosphines to hetero-allenes. Amongst new products of such reactions are the phosphino-amides (43, which arise from the addition of cyclohexylphosphine to phenyl isocyanate and phenyl is~thiocyanate.~~ Various substituted 4-phosphorinanones, e.g. (46), have been prepared by the addition of phenylphosphine to appropriately substituted penta-l,4-dien-355

Preparation qf Phosphines by Reduction. The reduction of phosphine oxides and phosphine sulphides continues to be a major route to phosphines, and the past year has seen the use of a wide range of reagents. The complex that is formed when titanium tetrachloride is reduced with four equivalents of lithium hydride in THF is capable of reducing phosphine oxides in high yield.56The most commonly used reagent has been trichlorosilane, which has been employed for the reduction of phosphine oxides to give both chiral forms of the chelating diphosphine (47),57 the substituted phospholans (48) and (49), and the bicyclic system (50), as a mixture of It has also found use in the synthesis of the novel bicyclic heterocyclic phosphines (51) and (52), designed to explore the possibility of forcing the lone pair on phosphorus into n-p, conjugation with the aromatic ring as a result of the steric constraints that are imposed by the ring system. Alas, electrochemical and spectroscopic data suggest that in neither of these compounds does this interaction occur to any significant extent, and both systems behave normally in reactions with oxygen and i ~ d o m e t h a n e . ~ ~

0:

QPPh2

d3 s

PPh,

Me (49)

(47)

(50) 52 53 54 55 56 57

58 59

(51)

( 5 2)

K. Kellner, H-J. Schultz, and A. Tzschach, Z . Chem., 1980, 20, 152. D. H. M. W. Thewissen and H. P. M. M. Ambrosius, R e d . Trar. Cliiiii. Puys-Bas, 1980,99, 344. J. B. Rampal, G. C . Macdonnell, J. P. Edasery, K. D. Berlin, A. Rahman, D. van der Helm, and K. M. Pietrusiewicz, J. Org. Chem., 1981, 46, 1156. J. B. Rampal, K. D. Berlin, J. P. Edasery, N. Satyamurthy, and D. van der Helm, J . Org. Chem., 198 1,46, 1166. U. M. Dzhemilev, L. Yu. Gubaidullin, G . A. Tolstikov, and L. M. Zelenova, Izzo. Akutl. Nauk SSSR, Ser. Khim., 1980, 734 (Chem. Abstr., 1980, 93, 25 841). H. Brunner, W. Pieronczyk, B. Schonhammer, K . Streng, I. Bernal, and J. Korp, Chem. Ber., 1981, 114, 1137. J. E. MacDiarmid and L. D. Quin, J . Orp. Chem., 1981, 46, 1451. C . H. Chen, K. E. Brighty, and F. M. Michaels,J. Org. Chem., 1981, 46, 361.

8

Organophosphorus Chemistry R' \P

R' = M e or Ph

( 5 3)

(54)

( RZ,R3 = H or Me)

(55)

Trichlorosilane in the presence of pyridine, in benzene solution, has been used in the reduction of the phosphine oxide of the first dibenzophosphonin system (53). This potentially aromatic lor-electron system is found to be highly puckered and non-aromatic as a result of the unfavourable orientation of p-orbitals, preventing extended pn-p,, overlap.6o A combination of trichlorosilane with triethylamine in benzene solution is effective for the reduction of phosphole oxide dimers (54) to the syn-7-phosphanorbornenes (55), which have the most deshielded 31Pn.m.r. shifts ever reported for tertiary phosphines. Attempted reduction of (54) with trichlorosilane in the absence of triethylamine leads to a retro-McCormack cycloaddition, with loss of the phosphorus bridge.s1 The 7-phosphanorbornene system (56) has been obtained by reduction of the corresponding phosphine sulphide, using the nickelocene-ally1 iodide reagent that has been developed by Mathey's group in the past few yearss2 This reagent has also found application in the synthesis of the (E)-l,3-butadienyl-phosphines (57).63Reduction of phosphine sulphides has also been achieved, using sodium, in the preparation of chiral diphosphines, e.g. (58),64 and by the use of hexachlorodisilane in the preparation of chelating diphosphinomethanes, e.g. (59).65-67 Ph

Ph,PCH,PBu',

Ph,P(CH,).CN

(5 9)

(60) n = 3 or 4

0 'Me

(61) 60

61 62

63 64

65 66 67

E. D. Middlemas and L. D. Quin, J . Am. Chem. SOC.,1980, 102, 4838. L. D. Quin and K. A. Mesch, J . Chem. SOC.,Chem. Commun., 1980, 959. F. Mathey and F. Mercier, Tetrahedron Lett., 1981, 22, 319. F. Mathey, F. Mercier, and C. Santini, Inorg. Chem., 1980, 19, 1813. 0. Samuel, R. Couffignal, M. Lauer, S . Y. Zhang, and H. B. Kagan, Nouu. J . Chim., 1981, 5 , 15. S. 0. Grim, P. H. Smith, I. J. Colquhoun, and W. McFarlane, Inorg. Chem., 1980,19, 3195. S. 0. Grim, L. C. Satek, and J. D. Mitchell, Z. Naturforsch., Teif. B, 1980, 35, 832. S. 0. Grim and E. D. Walton, Phosphorus Sulfur, 1980, 9, 123.

Phosphines and Phosphonium Salts

9

Diphenylsilane has found use for the selective reduction of (w-cyanoalky1)phosphine oxides to give (60).ss Full details have now appeared of the use of phenylsilane in the selective reduction (with retention of configuration at phosphorus) of epoxyphosphine oxides to give, e.g., (61).s9 Several patents have appeared, describing conditions for the reduction of dichlorophosphoranes to phosphines by hydrogen under pressure, either in the presence or absence of a transition-metal c a t a l y ~ t . ~ ~ - ~ ~ Miscellaneous Methods of Preparation of Phosphines. The synthesis of the diphospheten system (62) by the reactions of substituted acetylenes with cyclopolyphosphines has been re-investigated, and improved routes have been d e ~ e l o p e d . ~ ~ Treatment of the phosphonium salt (63) with butyl-lithium generates an ylide which rearranges over the course of 2-3 days to form the bicyclic phosphine (64), the structure of which was proved by X-ray Tris(trimethylsiloxymethy1)phosphine is converted into the bicyclic phosphine (65) on treatment with trimethyl orthoacetate in the presence of toluene-p-sulphonic An interesting ring-contraction occurs, on treatment of the perhydrodiazaphosphorine(66) with p-toluidine, to give the azaphosphetidine (67).76 A number of other (aminomethyl)phosphines, some of them chiral, have been prepared by the reactions of (hydroxymethy1)phosphines with amines or with

I

I

RZC=CR2 RIP-PR'

[a<;I-l! p

(62) R1= Ph RZ= Et , But, or Ph

/

(63)

68 69

70

71

72

73 74 75 76

(R = But or Ph)

(64)

B. N. Storhoff, D. P. Harper, I. H. Saval, and J. H. Worstell, . I . Orgunomet. Chem., 1981, 205, 161. L. D. Quin, C. Symmes, Jr., E. D. Middlemas, and H. F. Lawson, J. Org. Chem., 1980,45, 4688. E. A. Broger, Eur. Pat. Appl. 5746, 5747 (Chem. Abstr., 1980, 93, 114 703, 114 702). Ube Industries Ltd., Jpn. Kokai Tokkyo Koho 80 149294 (Chem. Abstr., 1981, 94, 175 258). Ube Industries Ltd., Jpn. Kokai Tokkyo Koho 80 149293 (Chem. Absrr., 1981, 94, 175 259). C. Charrier, J. Guilhem, and F. Mathey, J. Org. Chem., 1981, 46, 3 . D. Hellwinkel, W. Krapp, and W. S. Sheldrick, Chem. Ber., 1981, 114, 1786. E. S. Koslov and V. I. Tovstenko, Zh. Obshch. Khim., 1980, 50, 1499 (Chem. Abstr., 1980, 93, 220 850). B. A. Arbuzov, 0. A. Erastov, and G . N. Nikonov, Izo, Akad. Nuuk S S S R , Ser. Khim., 1980, 2129 (Chem. Abstr., 1981, 94, 30 620).

Organophosphorus Chemistry

10

R~N-NR’

0 R’

(68) R = Me or aryl

(70) R’ =Cy or Ph R2= Me or Pri

(69) R = H or CH,PPh,

RW’

‘NR’

Ph,PCH

/
Ph,PCH,

(72) R’ =Me, Et, Cy, or Ph R2 = CH(Me)Ph

(73) R = Pri

hydrazines. Thus the reactions of (hydroxymethy1)phosphines with ammonia and with hydrazine have given the polydentate ligands (68) and (69), re~pectively.~~ The related reactions of bis(hydroxymethy1)phosphines have given heterocyclic systems, e.g. (70) and (71).78 Similarly, the reactions of ethylenediamines with bis(hydroxymethy1)phosphines also lead to heterocyclic systems, e.g. (72).79Two groups have reported the extension of these reactions to oc-amino-acid esters, giving rise to chiral NN-bis(phosphinomethy1)amino-acidesters, e.g. (73).80181 The reactions of diphenylphosphine with various substituted benzylamines have given a range of substituted benzyldiphenylphosphines (74). This reaction can also be applied to 3-(aminomethy1)indoles to give the related 3-diphenylphosphinomethyl derivative.sz Pyrolysis of the heterocycle (75) gives the phosphiran (76).83

(74) X = 2-OH, 2-NH2, 4-NH2, or 4-NHEt

(75) R’= But, R2= Me,Si

The long-chain olefinic diphosphines (77) have been prepared by a previously established route, involving the reaction of the a,w-dihalogenoalkene with di-tbutylphosphine followed by deprotonation of the intermediate phosphonium The condensation of ethylenediamine with o-(diphenylphosphin0)77

78 79 80

82

83 84

G . Markl and G . Yu Jin, Tetrahedron Lett., 1981, 22, 1105. G . Markl and G . Yu Jin, Tetrahedron Lett., 1981, 22, 229. G . Markl and G . Yu Jin, Tetrahedron Lett., 1980, 21, 3467. G . Markl and G . Yu Jin, Tetrahedron Lett., 1981, 22, 223. K. Kellner, A. Tzschach, Z. Nagy-Magos, and L. Marko, J. Organomet. Chem., 1980, 193, 307. K. Kellner, S. Rothe, E. M. Steyer, and A. Tzschach, Phosphorus Sulfur, 1980, 8, 269. E. Niecke, W. W. Schoeller, and D-A. Wildbredt, Angew. Chem., Int. Ed. Engl., 1981, 20, 131. C. Crocker, R. J. Errington, R. Markham, C. J. Moulton, K. J. Odell, and B. L. Shaw, J . Am. Chem. SOC.,1980, 102,4373.

11

Phosphines and Phosphonium Salts

Q p p h

But, P(CH,),CH=CH(CHJ,PBut,

CH

N It

(77) n = 1 or 2

c” J -N

PhyJ HC

II

Ph/’Up\Ph

\ / ”

benzaldehyde gives the polydentate ligand (78),85 and a related Schiffs-base condensation of (paminoalky1)phosphines in the presence of a nickel(@ ion ‘template’ has given the macrocyclic ligand (79) as the nickel(@ complex.86 The past year has seen considerable activity in the preparation and characterization of p,-bonded phosphorus compounds. The ‘phospha-alkene’ H,C=PH, prepared by the pyrolysis of (trimethylsilylmethyl)phosphine,has been fully characterized by microwave spectros~opy.~~ The highly substituted analogue (80) has been shown to form transition-metal complexes which are thought to involve the lone-pair on phosphorus in co-ordination to the metal.** Amongst new (82),91the heterocyclic compounds systems that have been prepared are ( 8 1 ) , 8 9 9 ,OSiMe, G P = C P h 2

Me\

/

Me

(80)

R-P-C ‘But

(81) R’ = H or But

R

\

P=C

/SiMe3 ‘SiMe,

(82) R = alkyl or aryl

(85) R = Me or Et 85

86

87

J. C. Jeffery, T. B. Rauchfuss, and P. A. Tucker, Znorg. Chem., 1980, 19, 3306. L. G. Scanlon, Y.-Y. Tsao, S. C. Cummings, K. Toman, and D. W. Meek, J . Am. Chem. SOC.,1980, 102, 6849. H. W. Kroto, J. F. Nixon, K. Ohno, and N. P. C. Simmons, J. Chem. SOC.,Chem. Commun.,

1980, 709. 88 89

90

91

H. Eshtiagh-Hosseini, H. W. Kroto, J. F. Nixon, M. J. Maah, and M. J. Taylor, J. Chem. SOC.,Chem. Commun., 1981, 199. G . Becker, M. Rossler, and W. Uhl, Z. Anorg. Allg. Chem., 1981, 473, 7 . G. Becker and W. Uhl, 2. Anorg. Allg. Chem., 1981, 475, 3 5 . K. Issleib, H. Schmidt, and C. Wirkner, Z. Anorg. Allg. Chem., 1981, 473, 85.

12

Organophosphorus Chemistry

(83) and (84),92 and the p-phosphatrimethinecyanine dyes (85), the latter involving two-co-ordinate phosphorus in the (+ 3) oxidation Base-induced elimination of hydrogen chloride from alkyldichlorophosphines has given the first P-halogenofunctional phospha-alkenes, e.g. (86);94 on pyrolysis at -700 "C,in uacuo, these undergo further elimination to give the phospha-alkynes (87) in almost quantitative ~ i e l d . ~96 ~Ag similar base-promoted elimination of hexamethyldisiloxane from (88) gives (87; R = But), which is stable at room temperat~re.~' The synthesis and reactivity of other compounds of this type, e.g. (87; R = N H 2 or AcO), have also been ~ t u d i e d . ~ ~ - l ~ ~

R p - C l

*

RC-P (87)

Me,Si

(86) R = Ph or Me,Si Me,Sn=PPh

(89)

-

Me,SiO P-

SiMe

BU'

(88) Pri,N-P=NBu'

(90)

Pri2N-P-0

(91)

In extension of their work on p,-p,-bonded silicon- or germanium-phosphorus systems, the French group has now reported the characterization of (89), which is the first example of a compound containing sp2-hybridized tin and two-co-ordinate The chemistry of the iminophosphines, e g . (90), continues to develop,lo49lo5and the first example of a p,-p,-bonded phosphorusoxygen compound, i.e. (91), has been characterized as a metal carbonyl complex in which the lone-pair at phosphorus is co-ordinated to the metal.los The reaction of phenylpivaloylphosphine with mercury bis(trimethylsily1amide) gives the diphosphine (92) in which the distance between phosphorus and carbonyl-carbon is long compared with those usually found in acyl-phosphines, 92A. Schmidpeter, W. Gebler, F. Zwaschka, and W. S. Sheldrick, Angew. Chem., Int. Ed. Engl., 1980, 19, 722. 93N.Gamon and C. Reichardt, Liebigs Ann. Chem., 1980, 2072. 9 4 R . Appel and A. Westerhaus, Angew. Chem., Int. Ed. Engl., 1980, 19, 556. 95R. Appel, G . Maier, H. P. Reisenauer, and A. Westerhaus, Angew. Chem., Int. Ed. Engl.. 1981, 20, 197. 96R. Appel and A. Westerhaus, Tetrahedron Lett., 1981, 22, 21 59. 97 G. Becker, G. Gresser, and W. Uhl, 2. Naturforsch., Ted. B, 1981, 36, 16. 981. S. Matveev, Khim. Prom-st., Ser.: Reakt. Osobo. Chist. Veshchestoa. 1979, 6 (Chem. Abstr., 1980, 93. 168 341). 991. S. Matveev, Khim. Prom-st., Ser.: Reakt. Osobo. Chist. Veshchestua, 1979, 33 (Chem. Abstr., 1980, 93, 95 347). 100 I. S . Matveev, Khim. Prom-st., Ser.: Reakt. Osobo. Chist. Veshchestua, 1980, 7 (Chem. Abstr., 1981, 94, 121 641). 101 I . S . Matveev, Khim. Prom-st., Ser.: Reakt. Osobo. Chist. Veshchestva, 1980, 29 (Chem. Abstr., 1981, 94, 121 642). 1 0 2 I. S . Matveev, Khim. Prom-st., Ser.: Reakt. Osobo. Chist. Veshchestoa, 1980, 44 (Chem. Abstr., 1981, 94, 121 643). 103 C. Couret, J. D. Andriamizaka, J. EscudiC, and J. SatgC, J. Organornet. Chem., 1981, 208, c3. 104 E. Niecke, H. Zorn, B. Krebs, and G. Henkel, Angew. Chem., Int. Ed. Engl., 1980,19,709. lo5 E. Niecke, A. Nickloweit-Luke, and R. Ruger, Angew. Chem., Int. Ed. Engl., 1981,20,385. 106 E. Niecke, M. Engelmann, H. Zorn, B. Krebs, and G. Henkel, Angew. Chem., Int. Ed. Engl., 1980, 19, 710.

Phosphines and Phosphonium Salts But CO

\

Me,Si

P-P

Ph/'

7OBu' 'Ph

(92)

Ph

13

\ /

N-C-P

/

I1

NPh

SiMe, MeOH)

KP-C

\R

I1

-NHPh

NPh (94)

(93) R = H or SiMe,

indicating that there is little P=C 'enol' Silylphosphines react with diphenylcarbodi-imide to give the phosphaguanidines (93) ; on treatment with methanol, these give the primary phosphaguanidine (94).loS Reactions of Phosphines.-Nucleophilic Attack at Carbon. A very timely and extensive review has appeared of the reactions of a wide range of tertiary phosphines (e.g. acyclic, heterocyclic, and vinyl-phosphines, as well as bis-phosphines) with dimethyl acetylenedicarboxylate, which lead to the formation of heterocyclic systems that contain The reactions between triethylphosphine and a number of aliphatic and aromatic 0-alkyl selenoesters under oxygenfree conditions appear to involve nucleophilic attack by the phosphine at the carbon atom of the selenocarbonyl group, almost certainly leading to the initial formation of the zwitterions (93, which are of limited stability, undergoing elimination of selenium to form ylides. However, quenching the reaction mixtures with iodomethane leads to the formation of dimethyl selenide and the very unstable (iodoalky1)phosphonium salts (96); on treatment with methanol, these are converted into the more stable salts (97) (Scheme 1).llo

Se(95)

PeoH

TiEt3

R' -C -0R2

'PEt, R' = Me, Pri, or Ph R2= Me, Et, or Pri

I

R'-CH-OR2

I-

(97)

Scheme 1

The nucleophilic addition of primary and secondary phosphines to the carbony1 group of aromatic aldehydes in the presence of an alcohol leads to the formation of (a-alkoxybenzy1)phosphines.Thus, e.g., the reaction of diphenylphosphine with benzaldehyde in the presence of various alcohols gives (98),ll1 G. Becker, 0. Mundt, and M. Rossler, Z . Anorg. Allg. Chem., 1980,468, 5 5 . K. Issleib, H. Schmidt, and Ch. Wirkner, Synth. React. Inorg. Met.-Org. Chem., 1981, 11, 279. log A. N. Hughes, Heterocycles, 1981, 15, 637. 110 P-E. Hansen, J. Chem. SOC., Perkin Trans. I , 1980, 1627. H. Oehme and E. Leissring, Tetrahedron, 1981, 37, 7 5 3 . lo7 108

0rganophosphorus Chemistry

14

R'

(yf%

PbPCH (Ph)OR

HO

HO

PH,

&p$h 0

(98) R = Me, Et, Pri, or But

(99)

R2

H or Me (R'RZ== Me or Pri

0

and the primary phosphines (99), bearing two primary alcohol functions, combine with aromatic aldehydes to give the bicyclic system (100).112 Patents have appeared which describe the reaction between tributylphosphine and p-hydroquinone in the presence of acids, giving the salts (101).l13911* Two groups have reported instances of the nucleophilic attack of phosphines at carbon atoms that are co-ordinated to a transition metal, leading to the formation of co-ordinated ylides.ll6*116 Thus, e.g., the reaction of the (iodomethy1)rhodium complex (102) with trimethylphosphine leads to the ylide complex (103).ll6Reports of the demethylation of stabilized dimethylselenonium ylides by phosphines continue to appear.l17 2+

21-

(101) X = BF,, H,PO,, C1, or RCO, But ,P(X)=CHR

Ph ,P=CCl,

(104) R = H or alkyl X = C1 or Br

Nucfeophific Attack at Halogen. Alkyl-di-t-butylphosphines react with carbon tetrachloride or tetrabromide to give the P-halogeno-ylides (1O4).ll8 The ylide (lOS), known to arise in the triphenylphosphine-carbon tetrachloride system, appears to be involved in the use of this combined reagent for the dichloromethylenation of esters, lac tone^,^^^ and cc-keto-y-lactones.12*However, on the basis of a number of experiments, it has been suggested that more than one reaction 112 113 114 115 116 117 118 119 120

H.Oehme, E. Leissring, and H. Meyer, 2. Anorg. Allg. Chem., 1980, 471,155. Dow Chemical Co., Neth. Appl. 78 05 509 (Chern. Abstr., 1980, 93, 71 947). G. A. Doorakian and L. G. Duquette, Fr. Demande 2 428 048 (Chern. Abstr., 1980, 93, 150 375). R.A. Pickering, R. A. Jacobson, and R. J. Angelici, J . Am. Chem. SOC..1981,103, 817. R. Feser and H. Werner, Angew. Chem., Int. Ed. Engl., 1980, 19, 940. Yu. V. Belkin, N. A. Polezhaeva, N. N. Magdesieva, and R. A. Kyand'zhetsian, Zh. Obshch. Khim., 1980,50, 1294 (Chern. Absfr., 1980,93, 186 477). 0.I. Kolodiazhnyi, Tetrahedron Lett., 1980, 21, 3983. M. Suda and A. Fuliushima, Tetrahedron Lett., 1981, 22, 759. M. Suda and A. Fukushima, Chem. Left., 1981, 103.

Phosphines and Phosphonium Salts

15

pathway is involved, including the reaction of the salt (106) (formed initially from the combined reagents) with the carbonyl group to give the alkoxyphosphonium salt (107), which, in the presence of the trihalogenomethanide ion, subsequently eliminates triphenylphosphine oxide to give the dichloro-alkene (Scheme 2).120 R-CH-CX, P h y X CX;

(1 06)

,,

I

O-$Ph,

X-

RCH=CX, +

+cx,

Ph ,PO

(107) Reagents: i, RCHO ; ii, CXa- (X= C1 or Br)

Scheme 2

The reactions of bis(dipheny1phosphino)methane with carbon tetrachloride in the presence of primary or secondary amines give rise to the phosphonium salts (108), which, on treatment with sodium hydride, are converted into the bisphosphoranes (1O9)lz1and (1

Applications of phosphinexarbon tetrachloride reagents in synthesis continue to appear. The triphenylphosphine-carbon tetrachloride combination has been used for the dehydration of and also for regioselective dehydrations in the 14~-hydroxy-steroidseries.124It has also found use as a dehydrating agent in a biomimetic synthesis of /?-lactams from substituted /3-hydroxyhydroxamic and in the stereospecific synthesis of 2-azetidinones from 3-aminopropanoic acids.126The reaction of diphenylketimine with this reagent leads to a mixture of the salt (111) and the phosphinimine (112).12’ The advantages and disadvantages of the repetitive use of polymer-bound phosphines in such combined reagents have been considered. The formation of the polymer-bound 121

lZ2 lZ3 lZ4

lZ5

lZ7

R. Appel and K. Waid, Z . Naturjorsch., Teil.B, 1981, 36, 131. R. Appel and K. Waid, Z . Naturforsch., Teil. B, 1981, 36, 127. T. U. Qazi, Curr. Sci., 1980, 49, 860 (Chem. Abstr., 1981, 94, 121 148). F. Theil, C. Lindig, and K. Repke, 2. Chem., 1980, 20, 312. M. J. Miller, P. C. Mattingly, M. A. Morrison, and J. F. Kerwin, Jr., J. Am. Chem. SOC., 1980, 102, 7026. L. S . Trifonov and A. S. Orahovats, Moncrrsh. Chem., 1980, 111, 1117. I. N. Zhmurova and V. G. Yurchenko, Zh. Obshch. Khim., 1980, 50, 52 (Chem. Abstr.. 1980, 93, 46 774).

16

0rganophosphorus Chemistry

0

xyy:

0

OiPh, C1-

X

Qcl

phosphonium salt (1 13) causes partial consumption of the reagent and creates difficultiesin subsequent regeneration of the phosphine.12* Halogenation of cyclohexanone in carbon tetrachloride that contains triphenylphosphine leads to the tetrahalogeno-derivatives (1 14).129The advantages of the use of phosphine-halogen reagents for the preparation of alicyclic halogeno-compounds, e.g. (115), from alcohol precursors have been noted, and a number of intermediate alkoxyphosphonium salts, e.g. (1 16), have been characterized, enabling their mode of thermal decomposition to be studied under a variety of conditions.130The combination of tris(dimethy1amino)phosphine and hexachloroethane affords an excellent reagent for the preparation of activated esters of N-protected a r n i n o - a c i d ~Improvements .~~~ in the use of the triphenylphosphine-hexachloroacetone reagent for the conversion of allylic alcohols into chlorides have been reported. It is now found that sulpholane is a superior solvent for this system, the reaction taking place rapidly, under mild conditions, to give high yields, with an easy separation of the product. A further advantage is that the use of sulpholane much reduces the degree of rearrangement that occurs when tertiary allylic alcohols undergo the reaction if hexachloroacetone is used as the solvent, as well as one of the components of the reagent.132The combination of triphenylphosphine with hexachlorocyclopentadiene also gives a reagent that is capable of the conversion of alcohols into alkyl chlorides. Phosphorus-31 n.m.r. studies indicate the involvement of the chlorotriphenylphosphonium This cation has also been characterized in the form of a polyhalide salt, arising from the reactions of triphenylphosphine with interhalogens in acetonitrile Nucleophilic attack by triphenylphosphine at the bromine atom of the 6bromodihydrodiazepinium salts (1 17) occurs, on heating in methanol, to give the salts (1 18) (involving a heterocyclic ‘onium-anion’); in the protic solvent, these 128 149

130

131 132

133 13*

R. Appel and W. Lothar, Chem. Ber., 1981, 114, 858. J. Miller and B. J. Needham, U . S . P. 4 219 505 (Chem. Abstr., 1981, 94, 3792). D. B. Denney, B. H. Garth, J. W. Hanifin, Jr., and H. M. Relles, PhosphorusSulfur, 1980, 8, 275. R. Appel and U. Glasel, Chem. Ber., 1980, 113, 3511. R . M. Magid, B. G. Talley, and S. K. Souther, J. Org. Chem., 1981, 46, 824. B. V. Timokhin, V. A. Kron, and V. N. Dudnikova, Zh. Obshch. Khim., 1980, 50, 1415 (Chem. Abstr., 1980, 93, 186 478). M. F. Ali and G. S. Harris, J. Chem. SOC., Dalton Trans., 1980, 1545.

17

Phosphines and Phosphonium Salts H

(117) R = H or Me

(1 18)

Reagents: i, PPh3, MeOH; ii, MeOH

Scheme 3

salts are converted into the dihydrodiazepinium system (119), as shown in Scheme 3. In a similar manner, the salts (117) undergo photodebromination on treatment with triphenylphosphine in protic Full details have now appeared of the use of the combination triphenylphosphine-iodine-imidazole for the transformation of primary and secondary alcohol groups in carbohydrates into the corresponding iodo-derivatives, with inversion of configuration. It is supposed that the above combination leads to the formation of an N-imidazolyltriphenylphosphoniumsalt ; this, in the presence of the alcohol, is converted into an alkoxyphosphonium iodide, which decomposes in the usual way.136This reagent has also been used in carbohydrate chemistry for the conversion of vicinal diols into the corresponding alkene.13' The combination of triphenylphosphine and iodine effects the quantitative reduction of arenesulphonic acids to thiophenols;138 in contrast, aliphatic sulphonic acids (together with a wide range of other alkyl-sulphur derivatives) are converted smoothly and quantitatively into the corresponding alkyl iodides by this reagent .13 Nucleophilic Attack at Other Atoms. Recent developments in the chemistry of phosphine-borane adducts have been reviewed.140 Tributylphosphine has been used to deoxygenate 1,2,4-benzothiadiazine 1 and the reactions of amino-phosphines with sulphur dioxide, leading to a complex mixture of products, have been in~estigated.'~~ Further examples of the reactions of phosphines with azido-compounds, ~ - l ~this ~ leading to the formation of phosphinimines, have been r e p ~ r f e d , l ~ and topic has been reviewed.14' The use of the combined reagent triphenylphosphinediethyl azodicarboxylate in the synthesis and transformation of natural products D. Lloyd, R. K. Mackie, G. Richardson, and D. R. Marshall, Angew. Chem., Int. Ed. Engl., 198 1, 20, 190. 136 P. J. Garegg and B. Samuelsson, J . Chem. SOC.,Perkin Trans. 1, 1980, 2866. 13' M. Bessodes, E. Abushanab, and R. P. Panzica, J . Chem. Soc., Chem. Commun., 1981, 26. 138 K. Fujimori, H. Togo, and S. Oae, Tetrahedron Lett., 1980, 21, 4921. 139 S. Oae and H. Togo, Synthesis, 1981, 371. 1 4 0 H. Schmidbaur, J . Organomet. Chem., 1980, 200, 287. 141 N. Finch, S. Ricca, Jr., L. H. Werner, and R. Rodebaugh, J. Org. Chem., 1980, 45, 3416. 1 4 2 R. W. Light and R. T. Paine, Phosphorus Sulfur, 1980, 8, 255. 143 R. E. Banks, A. Prakash, and N. D. Venayak, J. FIuorine Chem., 1980, 16, 325. 144 J. Kovacs, I. Pinter, F. Szego, G. Toth, and A. Messmer, Magy. Kem. Foly., 1981, 87, 49. 145 L. F. Kusukhin, M. P. Ponomarchuk, Z . I. Kuplennik, and A. M. Pinchuk,Zh. Obshch. Khim., 1980, 50, 1032 (Chem. Abstr., 1980, 93, 167 278). 146 M. M. Sidky, F. M. Soliman, and R. Shabana, Egypt. J . Chem., 1978 (publ. 1980), 21,29 (Chem. Abstr., 1980, 93, 204 759). 14' Yu. G. Gololobov, I. N. Zhmurova, and L. F. Kasukhin, Tetrahedron, 1981, 37, 437.

135

18

Organophosphorus Chemistry

has also been reviewed,14* and a number of new applications in carbohydrate chemistry have been r e p ~ r t e d . ~ ~ Nucleophilic ~-'~l attack at the azo-group of the heterocycle (120) occurs in the reaction with triphenylphosphine to give the dipolar adduct (121), which is then able to undergo a further reaction with cyclopropenyl ketones to give the heterocyclic system (1 22).152

E

N

Ph,P

R"vfi 0

(122) R * = C F ,

(120)R'=MeorPh

Applications of the triphenylphosphine-thiocyanogen combination continue to be developed. A number of epoxides have been converted into a-thiocyanatovinyl ketones, vic-dithiocyanates, or uic-thiocyanatohydrins by this reagent, depending on the structure of the starting epoxide. The reactions proceed siteand stereo-~pecifically.~~~ Treatment of the thietan-3-ones (123) with tertiary phosphines in methanol results in ring-opening to give the zwitterion (124), which, in the protic solvent, subsequently undergoes further t r a n ~ f o r n i a t i o n ~ . ~ ~ ~ Tris(dialky1amino)phosphines readily desulphurize trisulphides to disulphides under mild conditions. Radiolabelling experiments show that the central sulphur atom of a diary1 trisulphide is removed, whereas a dialkyl trisulphide loses a terminal sulphur atom.155Removal of one sulphur atom from penicillin-related disulphides, using triphenylphosphine, has also been R'

(123) R ' = H or M e R2= Bu or p-MeOC,H,

Following many applications of the triphenylphosphine-2,2'-dipyridyl disulphide reagent in peptide synthesis, it has now been found that the combination of triphenylphosphine with 2,2'-dibenzothiazolyl disulphide (which is both inexpensive and easy to handle) affords an effective reagent for the preparation of 148 149 150 151 152

0.Mitsunobu, Synthesis, 1981, 1. R. D.Guthrie, I. D. Jenkins, and R. Yamasaki, Curbohydr. Res., 1980, 85, C5. R. D. Guthrie, 1. D. Jenkins, and R. Yamasaki, J. Chem. Soc., Chem. Commun., 1980,784. E. Mark and E. Zbiral, Monutsh. Chem., 1981, 112, 215. Y. Kobayashi, T.Nakano, K. Shirahashi, A. Takeda, and I. Kumadaki, Tetrahedron Lett., 1980,21, 4615.

153 154 155 156

Y. Tamura, T. Kawasaki, H. Yasuda, N. Gohda, and Y. Kita, J. Chem. SOC.,Perkin Trans. I , 1981, 1577. B. Fohlisch and W. Gottstein, J. Chem. Res., 1981, (S)94; ( M ) 1132. D.N. Harpp, D. K. Ash, and R. A. Smith, J. Org. Chem., 1980, 45, 5155. K. Prasad, H. Hamberger, P. Stutz, and G. Schulz, Helu. Chim. Actu, 1981, 64, 279.

Phosphines and Phosphonium Salts

19

amides from primary amines and carboxylic The use of triphenylphosphine-2,2’-dipyridyl disulphide in acetonitrile solution has been found to be effective for the formation of P-lactams from @-amino-a~ids.~~* The related combination of triphenylphosphine and 2,2’-dipyridyl diselenide has been used in the synthesis of oligoribonucleotides.15gA tributylphosphine-phenyl selenocyanate reagent has been employed in a stereoselective conversion of secondary alcohols into the corresponding alkyl bromides, with retention of configuration.lao Spectroscopic studies have shown that the reaction of bis(diphenylphosphin0)methane with the selenocyanate ion results in the formation of the monoselenide of the diphosphine, whereas the diselenide is formed in the related reaction of 1,2-bis(diphenylphosp hino)ethane.lal Miscellaneous Reactions qf Phosphines. The syn-7-phosphanorbornene (125) is completely destroyed if warmed in methanol for 15 minutes, with the formation of cyclo-octatetraene, phenylphosphine, and dimethyl phenylphosphonite. Each of these is a secondary product, and they are thought to arise via an unprecedented biphilic attack of the strained tertiary phosphine on methanol to give the phosphorane (126), which then degrades by a reverse McCormack cycloaddition to give the diene (127) and the phosphinite (128), both of which undergo further transformations to form the final products.ls2

The kinetics of the reactions of a series of triarylphosphines with tetramethyl1,2-dioxetan in benzene solution, giving the phosphoranes (129), are not consistent with nucleophilic attack at oxygen by phosphorus but rather with a concerted, biphilic insertion of the phosphine into the peroxo-bond of the dioxetan.ls3 The stannylenes (130), involving intramolecular phosphorus +tin co-ordination, are formed in the reactions of tin(r1) alkoxides with alkylbis(2-sulphydryl158

159 160

162 163

K. Ito, T. Iida, T. Fujita, and S. Tsuji, Synthesis, 1981, 287. S. Kobayashi, T. Iimori, T. Izawa, and M. Ohno, J. Am. Chem. SOC.,1981, 103, 2406. H. Takaku, M. Kato, M. Yoshida, and R. Yamaguchi, J. Org. Chem., 1980, 45, 3347. M. Sevrin and A. Krief, J. Chem. SOC., Chem. Commun., 1980, 656. S. W. Carr and R. Colton, Ausr. J. Chem., 1981, 34, 35 K. A. Mesch and L. D. Quin, Tetrahedron Lett., 1980, 21, 4791. A. L. Baumstark, C. J. McCloskey, T. E. Williams, and D. R. Chrisope, J. Org. Chern., 1980,45, 3593.

2

Organophosphorus Chemistry

20

ethyl)ph~sphines.~~* The cleavage of the phosphorus-phosphorus bond of tetraalkyldiphosphines by organo-hydrides of silicon, germanium, and tin has been Phenylphosphinidene (from the thermolysis of pentaphenylcyclopentaphosphane) inserts into the germanium-germanium bond of hexa(pentafluoropheny1)digermane to give the germylphosphine (1 3 1).166The steric course of displacement of the diethylphosphino-group from the geometrical isomers of (132) by a range of reagents has been investigated, as also have insertion reactions into the silicon-(or germanium-)phosphorus bond.167

(130)

(132) M = Si or Ge

Several papers have appeared in which the cleavage of P-phenyl bonds of triphenylphosphines and related ligands in the course of reactions of transitionthat is metal complexes is d e ~ c r i b e d . l ~ *Bis(dipheny1phosphino)methane -~~~ co-ordinated to platinum(I1) is deprotonated, on treatment with sodium hydride, to give a complex of the bis(dipheny1phosphino)methanide ligand.172Complexes of the carbanion derived from (ethoxycarbonylmethy1)diphenylphosphine have also been Dicyclohexylphosphine has been used as a free-radical trap in an estimation of electron-transfer contributions in the reactions of alkyl bromides with trimethylstannyl~odium.~~~ Stable radical cations are formed as the first step of the electrochemical oxidation of trime~ity1phosphine.l~~ Radical cations are also involved in the controlled-potential electrolysis of triphenylphosphine in acetonitrile that contains oximes and related compounds, resulting in the formation of the cations (1 33), which subsequently undergo the Beckmann rearrangement 1 CIDNP experiments have shown under very mild ~ 0 n d i t i o n s . lPhosphorus-3 ~~ that photochemically induced homolysis of triphenylphosphine proceeds from the triplet state and involves a hitherto unknown type of disproportionation 164 165

166 167

A. Tzschach and W. Uhlig, 2.Anorg. Allg. Chem., 1981, 475, 251. P. Dehnert, J. Grobe, and D. Le Van, Z. Naturforsch., Teil. B, 1981, 36, 48. A. Castel, J. Escudit, P. Riviere, J. Satgt, M. N. Bochkarev, L. P. Maiorova, and G. A. Razuvaev, J. Organomet. Chem., 1981,210, 37. J. Dubac, J. EscudiC, C. Couret, J. Cavezzan, J. Satge, and P. Mazerolles, Tetrahedron, 1981, 37, 1141.

168 169 170 171 172

173 174 175 176

G. Gregorio, G. Montrasi, M. Tampieri, P. Cavalieri d’Oro, G. Pagani, and A. Andreetta, Chim. Ind. (Milan),1980, 62, 389. T. Nishiguchi, K. Tanaka, and K. Fukuzumi, J. Organomet. Chem., 1980,193, 37. W. Beck, M. Keubler, E. Leidl, U. Nagel, M. Schaal, S. Cenini, P. D. Buttero, E. Licandro, S. Maiorana, and A. C. Villa, J. Chem. SOC.,Chem. Commun., 1981, 446. A. S. Berenblyum, T. V. Turkova, and I. I. Moiseev, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 2153 (Chem. Abstr., 1981,94, 29 864). J. Browning, G. W. Bushnell, and K. R. Dixon, J. Organomet. Chem., 1980, 198, C11. P. Braunstein, D. Matt, J. Fischer, L. Ricard, and A. Mitschler, Nouo. J. Chim., 1980, 4, 493. H. G. Kuivila and G. F. Smith, J. Org. Chem., 1980, 45, 2918. A. V. Il’yasov, Yu. M. Kargin, E. V. Nikitin, A. A. Vafina, G. V. Romanov, 0. V. Parakin, A. A. Kazakova, and A. N. Pudovik, Phosphorus Sulfur, 1980,8,259. H. Ohmori, S. Nakai, and M. Masui, Chem. Pharm. Bull., 1980, 28, 2247.

Phosphines and Phosphonium Salts

21 0

II +

Ph ,P -O-N=

C R'R2

(133)

0

I/

Me,C(OH)PPh, (1 35)

reaction, involving cleavage of an ortho-hydrogen from a phenyl radical to form b e n ~ y n e .Studies ~ ~ ~ of the photolysis of (ortho-substituted benzoy1)diphenylphosphines continue; among the products of photolysis of (o-methoxybenzoy1)diphenylphosphine (1 34) is the (a-hydroxyalky1)phosphine oxide (1 35).178 (Acetoxymethy1)phosphines undergo a pseudo-allylic rearrangement into methylphosphine oxides on treatment with acids in glacial acetic acid.17

2 Phosphonium Salts Preparation.-Bis-dimethyland bis-diphenyl-phosphinomethanes undergo quaternization, on heating with o-xylylene dibromide, to give the cyclic diphosphonium salts (136).180The reaction of l-methylphosphorinan with an equimolar amount of 1,6dibromobutane gives the salt (137), which, on treatment with potassium hydride followed by an acid, gives the spirobicyclic phosphonium salt (1 38).la1 Heating the bromo-ketone (139) with triphenylphosphine gives the salt ( l a ) , which, on heating at its melting point for 30 minutes, is converted into (141).la2

177

Ya. A. Levin, E. I. Gol'dfarb, and E. I. Vorkunova, Zh. Obshch. Khim., 1980,50, 1981 (Chem. Abstr., 1981, 94, 29 812).

178

179 lSo

182

M. Dankowski, K. Praefcke, J . 4 . Lee, and S. C. Nyburg, Phosphorus Sulfur, 1980,8, 359. E. N. Tsvetkov, T. E. Kron, Z . N. Mironova, and M. I. Kabachnik, Bull. Acad. Sci. USSR,Div. Chem. Sci.,1979, 28, 1722. H. Schmidbaur, T. Costa, and B. Milewski-Mahrla, Chem. Ber., 1981, 114, 1428. H. Schmidbaur and A. Mortl, Z . Naturforsch., Ted. B, 1980, 35, 990. F. Toda and K. Tanaka, Tetrahedron Lett., 1980, 21, 4869.

22

Organophosphorus Chemistry

Conventional quaternization procedures have also been used in the preparation of the ketophosphonium salts ( 142),183the (ammonioalky1)phosphonium salts (1 43),lS4and the [poly(oxyethylene)]phosphonium salts (144).185The secondary phosphine (145), on treatment with an excess of iodomethane, gives the salt ( 1 4 6 ) y and the reaction of tertiary phosphines with l-chlorobuta-2,3-diene gives rise to the buta-l,3-dienylphosphoniumsalts ( 147).187

'-

n

Ph,kH,CO(CH,), N

W0

(142) X = C1 or Br n = 0, 1, or 2

Ph,;(CH,),

hHZR 2Br-

(143) R = H, E t , Pr, Bu, or Cy n = 3-6

Ri3kHZcH,O),,RZ X(144) R'=Ph or CH,OH RZ= alkyl . n = 3 , 6 , 9 , 12, or 15

Me

H

H

H

H

(145)

(147) R = Ph or Bu

H

(146)

Continuing their studies of the cyclization of alkenylphosphonium salts, Berlin's group has now described the conversion of the salt (148) into the tetracyclic system (149) on heating with polyphosphoric acid.188 Synthetic routes to the (o-acylaminobenzy1)phosphonium salts (150) have been developed [involving either the reduction of (o-nitrobenzy1)triphenylphosphonium bromide or the reaction of triphenylphosphine hydrobromide with ortho-amino-substituted

(i) PPA (ii) KPF,

a ' r P h ,

Br-

~

@0

CHQPh, Br-

+PPh, PF;

\

(149)

--..N(R')COR*

(150) R ' = H or Ph R2= Me, H,C=C(Me), or aryl

CH,0bPh3 OTf-

CH,OH (i) Tf,O (ii) PPh,

CH,OH 183 184 185

186

187 188

CH,ObPh,

[Sstbw,

BF;

OTf-

R. Houssin, J.-P. Henichart, M. Foulon, and F. Baert, J . Pharm. Sci., 1980, 69, 888. P. R. McAllister, M. J. Dotson, S. 0. Grim, and G . R. Hillman, J. Med. Chem., 1980, 23, 862. R. Vilceanu and A . Venczel, Rev. Chim.(Bucharest), 1980, 31, 1062 (Chem. Abstr., 1981, 94, 157 025). B. A. Arbuzov, 0. A . Erastov, S. N. Ignat'eva, T. A. Zyablikova, and R. P. Arshinova, Bull. Acad. Sci. USSR, Div. Chem. Sci.,1979, 28, 1726. M. Zh. Ovakimyan, R. K . Lulukyan, and M. G . Indzhikyan, USSR P. 763 353 (Chem. Abstr., 1981, 94, 84 302). A . S. Radhakrishna, K. D. Berlin, and D . van der Helm, Pol. J. Chem., 1980, 54, 495.

Phosphines and Phosphonium Salts

23

benzyl alcohols] ; such salts undergo intramolecular Wittig reactions to form ind01es.l~~ The diol (151), on treatment with triflic anhydride and a nine-fold excess of triphenylphosphine, is converted into the bistriphenylalkoxyphosphonium salt (152), which reacts with halide ions with displacement of triphenylphosphine oxide.lgoTreatment of 2-ethoxy-l,3-dithiolan with triphenylphosphine and fluoroboric acid in T H F gives the salt (153); the ylide that is derived from this is useful for the synthesis of keten SS-a~eta1s.l~~ A derivative of phosphatidylcholine has been prepared in which the trimethylammonium group has been replaced by a triphenylphosphonium group.1g2 Studies of the nickel-catalysed arylation of amino-phosphines [giving, e.g., (154)] have continued.lg3 Further instances of the formation of aryl- and heteroarylphosphonium salts, e.g. (155),lg4simply by heating a halogeno-arene with triphenylphosphine to temperatures in excess of 200 "C,have appeared.lg4$lg5 (Heteroary1)phosphonium salts have also been prepared by the electrochemical oxidation of phosphines in the presence of a heteroarene,lgs and anodic oxidation of methylbis-(2,4,6-trimethoxyphenyl)amine in the presence of triphenylphosphine gives the salt (156).lg7

(156) R = OMe

In the presence of Wilkinson's catalyst, ccp-unsaturated acid chlorides undergo The decarbonylation to give (substituted viny1)triphenylphosphonium reaction of tributylphosphine with butoxyacetylene, followed by treatment with iodomethane, gives the vinylphosphonium salt (157).ls9 The (p-cyanoviny1)phosphonium salt (158) is formed in the reaction of a chlorodicyanoethylene with triphenylphosphine.200 The reactions of isomeric p-bromovinyl aryl sulphones with amino-phosphines have given the respective isomeric salts (159),201and the 189

190 191 192

193

194 195

196 197 198

199 200

201

M. Le Corre, A. Hercouet, and H. Le Baron, J. Chem. Suc., Chem. Commun., 198 1, 14. S. Ramos and W. Rosen, Tetrahedron Lett., 1981, 22, 35. S. Tanimoto, S. Jo, and T. Sugimoto, Synthesis, 1981, 53. P. Kertscher, H. J. Rueger, and P. Nuhn, Pharmazie, 1979, 34, 845 (Chem. Abstr., 1980, 93, 25 842). H. J. Cristau, A. Ch&ne,and H. Christol, Synthesis, 1980, 551. 0. M. Bukachuk, I. V. Megera, and M. I. Shevchuk, Zh. Obshch. Khim., 1980, 50. 1730 (Chem. Abstr., 1981, 94, 4067). M. I. Shevchuk, I. N. Chernyuk, E. M. Volynskaya, V. V. Shelest, and P. I. Yagodinets, Zh. Obshch. Khim., 1980, 50, 1978 (Chem. Abstr., 1981, 94, 30 852). E. V. Nikitin, Yu. M. Kargin, 0. V. Parakin, A. N . Pudovik, G . V. Romanov, T. Ya. Stepanova, and A. S. Romakhin, USSR P. 755 795 (Chem. Abstr., 1980, 93, 220 937). D. Serve, Nuuv. J. Chim., 1980, 4, 497. J. A. Kampmeier, S. H. Harris, and R. M. Rodehorst, J. Am. Chem. Suc., 1981,103, 1478. A. M. Torgomyan, A. S. Pogosyan, M. Zh. Ovakimyan, and M. G. Indzhikyan, Arm. Khim. Zh., 1980, 33. 408 (Chem. Abstr., 1980,93, 186 471). N. G . Pavlenko, E. I. Sagina, and V. P. Kukhar, Zh. Obshch. Khim., 1980,50,2379 (Chem. Abstr., 1981, 94, 192 409). E. A. Berdnikov, V. L. Polushina, F. R. Tantasheva, and E. G. Kataev, Zh. Obshch. Khim., 1980, 50, 993 (Chem. Abstr., 1980, 93, 168 343).

24

Organophosphorus Chemistry +

Bu,PC (0Bu) =C HMe

I-

(157)

R'S0,CH=CH6(NR2,),

(NC),C=CH$Ph,

C1-

(158)

X-

(159) R 1 = a r y l , R 2 = M e o rEt X = Br, I, ClO,, BF,, or BPh,

R1R2NC(CHClJ=NhAr, C1(160) R' = H, Me, Et,or Pr R2= Me, Et, Pr, But, Ph, or PhCH,

salts (160) are formed in the reactions of triarylphosphines with amidines of halogeno-acetic acids.202 The chemistry of phosphenium ions, containing two-co-ordinate cationic phosphorus which also has a lone pair, continues to develop. Treatment of bis(ferroceny1)chlorophosphine with aluminium trichloride in dichloromethane at - 78 "C leads to the formation of the bis(ferroceny1)phosphenium Reactions of Phosphonium Salts.--A fkaZine Hydrolysis. In order to shed more light on the detailed operation of steric and ring-strain effects in determining the stereochemical course of alkaline hydrolysis of cyclic phosphonium salts that contain five- and six-membered rings, which has been much investigated by Marsi's group in recent years, X-ray structural studies of representative members of each series, i.e. (161)-(163), have been carried O U ~ . The ~ ~ X-ray ~ , ~co~ ordinates have been used to develop a molecular-mechanics approach that is Me

designed to simulate alkaline hydrolysis. For the systems that contain fivemembered rings, the stereochemical course of alkaline cleavage is dependent on the direction of ring pucker, which alters the steric encounter between the methyl group on the ring and the approaching hydroxide A similar for the alkaline hydrolysis of the cis- and trans-isomers of 1-benzyl-1phenyl-4-methylphosphorinanium bromide requires less inversion of configuration for the trans-isomer compared to that for the cis-isomer, in accord with experimental results. The bicyclic phosphonium salt (164) undergoes alkaline hydrolysis to give a mixture of the isomeric oxides (165) and (166). Isomer (165) has been reduced to the parent phosphine (using phenylsilane) and converted into the related ( p nitrobenzy1)phosphonium salt, the X-ray structure of which has been determined, 202

203 204

205

A. D. Sinitsa, V. S. Krishtal, V. I. Kal'chenko, and L. N. Markovskii, Zh. Obshch. Khim., 1980, 50, 2413 (Chem. Absfr., 1981, 94, 121 646). S . G . Baxter, R. L. Collins, A. H. Cowley, and S. F. Sena, J. Am. Chem. SOC., 1981, 103, 714. R. 0. Day, S. Husebye, J. A. Deiters, and R. R. Holmes, J . Am. Chem. SOC., 1980, 102, 4381. J. C. Gallucci and R. R. Holmes, J. Am. Chem. SOC.,1980, 102, 4379.

~

Phosphines and Phosphonium Salts

25

in order to establish the conformation of the ring system before studies are made of the stereochemistry of alkaline hydrolysis of such bicyclic salts.206 Alkaline hydrolysis of phosphonium salts has found use in a potentially general synthesis of phosphines that have chiral organic groups bound to chiral phosphorus, few examples of which are known, presumably because of a lack of adequate synthetic methods. Quaternization of neomenthyldiphenylphosphine with iodomethane gives the salt (1 67), which undergoes alkaline hydrolysis to give a 1:1 mixture of ( R ) and (S) phosphorus epimers of menthylmethylphenylphosphine oxides (168); these are separated by fractional crystallization and then reduced to the chiral phosphines, using hexachlor~disilane.~~~ 0

Me

I+ PbP-(neoMen) (167)

I-

II

Ph- ..

(168a)

0

Me,

.,II

Ph/ P-M

(168b)

+

Ph,PCH,-C-CH

I

I

(169) X = 0 or NR

Ph,$(CH,), CO,H X-

(170) X = H, C1, or Br Y=OorS

( 1 7 1 ) n = 2 , 3 , 5 , 1 0 , o r 11 X = C1 or Br

Alkaline hydrolyses have also been used in other synthetic sequences. Thus, e.g., the (heteroarylmethy1)phosphonium salts (169), obtained in regiospecific

reactions of (2,4-dioxoalkyl)triphenylphosphoniumsalts with hydroxylamine or hydrazines, undergo alkaline hydrolysis, with cleavage of the heteroarylmethyl group, to form the methyl-substituted isoxazole or pyrazole respectively, together with triphenylphosphine oxide.208Similarly, the salts (170) undergo hydrolysis to form an N-methylated heterocyclic lactone Phosphonium salts that bear fluoro-alkenyl substituents undergo extremely facile cleavage of the fluoroalkenyl group on treatment with dilute base, or even, in some cases, when dissolved in water, and this reaction has found use in the synthesis of fluoroalkenes.210v211 On treatment of the salts (171) with sodium hydride in DMSOTHF, cleavage of a phenyl group occurs, with the formation of a series of 206 207

208 209

210 211

Mazhar-ul-Haque, W. Horne, S. E. Cremer, P. W. Kremer, and J. T. Most, J . Chem. SOC., Perkin Trans. 2, 1980, 1467. D. Valentine, Jr., J. F. Blount, and K. Toth, J. Org. Chem., 1980, 45, 3691. E. 6hler and E. Zbiral, Chem. Ber., 1980, 113, 2852. K. Giyasov, N . A. Aliev, and Ch. Sh. Kadyrov, Khim. Prir. Soedin., 1980, 553 (Chem. Abstr., 1981, 94, 30 61 1). D. J. Burton, S. Shin-Ya, and R. D. Howells, J. Fluorine Chem., 1980, 15, 543. D. J. Burton, Y.Inouye, and J. A. Headley, J. Am. Chem. SOC., 1980,102, 3980.

0rganophosphor us Chemistry

26

(w-diphenylphosphiny1)carboxylicacids. This reaction presumably involves the DMSO-/DMSO base-solvent system, and is an example of a non-aqueous ‘alkaline hydrolysis’.212 Additions to Unsaturated Phosphonium Salts. The allylic phosphonium salt (172) couples in a stereospecific manner with the related ylide (173) to give the ylide salt (174), which is easily protonated to give the related diphosphonium salt (175).213 ,CO,Et

\

C0,Et

The alkynylphosphonium salts (176), on treatment with acetic acid in the presence of ammonium acetate, add one mole of water to give the phosphoniapyran salts (177). The former salts (176) are much more stable to alkaline hydrolysis than are the related salts derived from phenylacetylene, which decompose even in moist air.214 Ph,+/R PhR;(CZCBu‘),

X-

(176) R = Me o r PhCH, X = C10, o r Br

H,O, HOAc NH,OAc +

But

LLx(177)

Addition of bromine to the allenylphosphonium salts (178) occurs at thedoublebond that is adjacent to In the reactions of the (alkoxyviny1)phosphonium salts (179) with hydrogen bromide or dipropylborane, the electrophilic attack occurs at the fl-position of the vinyl group to give (180), implying that the influence of the alkoxy-group is greater than that of the phosphonium group.216 212

213 214

215

216

K. S. Narayanan and K. D. Berlin, J. Org. Chem., 1980, 45, 2240. M. W. Bredenkarnp, J. S. Lesch, J. S. Malherbe, E. M. Molnar, and D. F. Schneider, Tetrahedron Lett., 1980, 21, 4199. J. Skolimowski and M. Sirnalty, Tetrahedron Lett., 1980, 21, 3037. Zh. A . Aklayan, R. A. Khachatryan, and M. G. Indzhikyan, Arm. Khim. Zh., 1979, 32, 645 (Chem. Abstr., 1980, 93, 71 865). A. M. Torgomyan, A. S. Pogosyan, M. Zh. Ovakimyan, and M. G. Indzhikyan, Arm. Khim. Zh., 1980,33, 501 (Chem. Abstr., 1980,93, 220 860).

Phosphines and Phosphonium Salts

27 HX

Ph,hCH=C=CHR Br(178) R = Ph or C(Me)=CH,

Ph,k(OR)=CH, Br(179) R = Et or Bu

Ph,h -C (0R) Me B r-

+

n

_I

(1 80) X

=

Br or BPr,

Miscellaneous Reactions of Phosphonium Salts. It has been established previously that the salt (181), on treatment with nucleophiles, undergoes opening of the cyclopropyl ring to form ylides, which can then be used in subsequent synthetic schemes. Continuing this theme, the generation of ylides from (181) on treatment with imide anions has facilitated a three-step synthesis of the alkaloid (+)-isoretronecan01.~~~ In a similar vein, full details are now available of the use of the salts (182) as reagents for the synthesis of ring-fused cyclopentanones.218The aminophosphonium salt (183) has now found use in the organocuprate-induced coupling of propargyl or enyne alcohols, giving a regio-controlled synthesis of allenes and conjugated e n y n e ~ . ~ ~ ~

(181)

(182) R = Me, Pr', or Ph

Interest in the catalytic properties of phosphonium salts, particularly under phase-transfer conditions, continues. Vapour-pressure osmometry studies reveal that phosphonium salts are associated in solution in benzene or chloroform, the degree of association being greater in the former solvent. The higher the degree of association, then the greater is the catalytic effect of the salt.220Polymer-bound phosphonium salts have also been investigated,221$ 222 and it has been shown that the catalytic activity of tetra-alkylphosphonium salts that are supported on polystyrene depends on the length of the alkyl chain that separates the phosphonium centre from the polymer backbone.222A solid-phase catalyst, consisting of a mixture of alumina and a tetra-alkylphosphonium salt, is effective for the gas-phase exchange of halogen between alkyl halides.223 Electrolytic reduction of dimethyldiphenylphosphonium bromide at a mercury cathode gives a mixture of methyldiphenylphosphine and dimethylphenylphosphine, the proportions of which vary with the applied The electrolysis of allyltriphenylphosphonium nitrate at an aluminium cathode, in DMF solution, yields triphenylphosphine, the biallyl dimer hexa-l$-diene, and propene. The diene is only formed in appreciable amounts under anhydrous conditions, implying that the ally1 carbanion is inv01ved.~~~ 217 z18

2l9 220 221 222 223 224

225

J. M. Muchowski and P. H. Nelson, Tetrahedron Lett., 1980, 21, 4585. J. P. Marino and M. P. Ferro, J. Org. Chem., 1981, 46, 1828. Y. Tanigawa and S.-I.Murahashi, J. Org. Chem., 1980, 45, 4536. L. Horner and J. Gerhard, Liebigs Apn. Chem., 1980, 838. P. Tundo and P. Venturello, J. Am. Chem. SOC.,1981, 103, 856. M. S. Chiles, D. D. Jackson, and P. C. Reeves, J. Org. Chem., 1980, 45, 2915. E. Angeletti, P. Tundo, and P. Venturello, J. Chem. SOC.,Chem. Commun., 1980, 1127. E. A. H. Hall and L. Horner, Phosphorus Sulfur, 1980, 9, 231. R. N. Gedye, Y. N. Sadana, and R. Eng, J. Org. Chem., 1980, 45, 3721.

28

Organophosphorus Chemistry RCONHC-bPh,

C1-

II

*ISH

+ RCONHC-$Ph,

II C(SAr),

cc4 (1 84) R = M e or aryl

C1-

(1 85)

The reactions of the (dichloroviny1)phosphonium salt (184) with nucleophiles have been studied. Thus, e.g., on treatment of (184) with thiophenols, the salts (1 8 5 ) are formed.226

?I PhCH,+(OPh),

C1-

(1 86)

MeEt6(OBui), I-

O V 0

(187)

(188)

The salt (186) has been used to convert acetylenic alcohols into the corresponding acetylenic alkyl The kinetics of decomposition, in acetonitrile, of the Arbuzov intermediate (187) have been studied, confirming a two-step decomposition mechanism at low concentrations of the intermediate.228Thermolysis of tris(hydroxymethy1)phenylphosphonium chloride gives the heterocyclic phosphine (188).229The thermal decomposition of phosphonium salts that bear l-alkoxy-2-bromoethy1-, 1-alkoxyvinyl-, or 1-alkoxyalkyl-substitutents has also been Ring-strained ‘cyclen’ phosphonium salts, e.g. (189), are found to dimerize in solution, with the formation of structures of the type (190) that involve quinque-

+/R LN-P-NEt, ‘NEt,

I-

(191) R = M e or Et 226

227

228 229

230

heat

(Et,N),$(R)-N

AN-f’(R)(NEt,), W

21-

(192)

0. P. Lobanov, A . P. Martyn’yuk, and B. S. Drach, Zh. Obshch. Khim., 1980, 50,2248 (Chem. Abstr., 1981, 94, 84 229). A. N. Patel, Zh. Org. Khim., 1980, 16, 2621 (Chem. Abstr., 1981, 94, 174 187). L. V. Nesterov and N. A. Aleksandrova, Zh. Obshch. Khim., 1980, 50, 36 (Chem. Abstr., 1980,92, 214 648). B. A. Arbuzov, 0. A. Erastov, S. Sh. Khetagurova, T. A. Zyablikova, R. P. Arshinova, and R. A. Kadyrov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1626 (Chem. Abstr., 1980, 93, 220 857). A . M. Torgomyan, M. Zh. Ovakimyan, and M. G . Tndzhikyan, Arm. Khim. Zh., 1980,33, 63 (Chem. Abstr., 1980, 93, 114 639).

Phosphines and Phosphonium Salts

29

covalent On heating, the aziridinylphosphonium salts (191) undergo some degree of conversion into the salts (192).232Various amino-phosphonium salts have been shown to form adducts with thiourea, some of which decompose, on heating, to form phosphonium t h i o c y a n a t e ~ . ~ ~ ~ 3 Phospholes and Phosphorins Recent structural and spectroscopic studies of phosphole complexes of palladium(@ have indicated that the phosphorus-palladium bond is stronger than of phosphorusin related complexes of acyclic p h o s p h i n e ~ .235 ~ ~A~consideration * selenium coupling constants in comparable series of dibenzophosphole selenides and acyclic phosphine selenides reveals that the s-character of the electron-pair that is donated from phosphorus is greater in the phosphole system, requiring a shorter (and, presumably, a stronger) bond to selenium. Consistent with this, it is also found that p(P-Se) occurs at higher wavenumber in the dibenzophosphole ~elenides.~~~ Irradiation of 3,4-dimethylphospholes with U.V. light, in the presence of carbonyls of the Group VI metals, leads to the formation of complexes (193), involving Diels-Alder [4 + 21 phosphole dimers; these have the exo configuration and act as chelating ligands. At 50 "C, these complexes react with sulphur to form the related [4+2] exo dimeric sulphides (194), which, contrary to the related endo dimers, collapse on heating in boiling toluene to give a phosphindole derivative (195). On the other hand, similar treatment of l-phenylphosphole results in the formation of a complex of a [2 + 21 head-to-head dimer, which, on heating with sulphur in xylene at 150 "C for 24 hours, is also converted into a phosphindole s ~ l p h i d e . ~ ~ '

R (193)R = Me,But, or Ph M=Cr,Mo,orW

(194)

(195)

Further studies of the reactivity of ,the 1,l'-diphosphaferrocene system, using the readily available 3,3',4,4'-tetramethyl derivative (196; X = H), have been In general, the phosphaferrocene system is, as expected, less reactive towards electrophiles than is ferrocene. The reaction of the phosphaferrocene 231

232

233 234 235 236

237

238

J. E. Richman, 0. D. Gupta, and R. B. Flay, J. Am. Chem. SOC.,1981, 103, 1291. G. K. Bezpal'ko, V. V. Miroshnichenko, A. P. Marchenko, and A. M. Pinchuk, Zh. Obshch. Khim., 1980, 50, 956 (Chem. Absrr., 1980, 93, 95 345). L. I. Mizrakh, L. Yu. Polonskaya, T. A. Babushkina, N. V. Ulanovskaya, and T. M. Ivanova, Zh. Obshch. Khim., 1980,50,2242 (Chem. Abstr., 1981,94, 103 481). J. J. MacDougall, F. Mathey, and J. H. Nelson, Inorg. Chem., 1980, 19, 1400. J. J. MacDougall, J. H. Nelson, F. Mathey, and J. J. Mayerle, Inorg. Chem., 1980,19, 709. D. W. Allen and B. F. Taylor, J. Chem. Res. ( S ) , 1981, 220. C. C. Santini, J. Fischer, F. Mathey, and A. Mitschler, J. Am. Chem. SOC.,1980, 102, 5809. G. de Lauzon, B. Deschamps, and F. Mathey, Nouu. J. Chim., 1980, 4, 683.

Organophosphorus Chemistry

30

(196; X = H) with ethyl chloroformate under Friedel-Crafts conditions gives the ester (196; X = C02Et). Usually, alkyl chloroformates are decarboxylated under such conditions, giving alkyl-substituted aromatic systems. The reactivity at phosphorus of the phospholyl anion ligands in (196; X = H ) has also been explored. It is possible to form a o-complex with either or both of the phosphorus atoms, on heating with a metal carbonyl in THF, and such complexes still undergo electrophilic substitution reactions at the rings, to give, e.g., uncomplexed ring-acetylated derivatives. An X-ray study of one such o-complex shows that the phospholyl ring remains fully aromatic after complexation to a metal carbonyl Infrared spectroscopic studies of phosphacymantrene (197) show that the phospholyl anion ligand is more electrophilic and a weaker n-donor than the cyclopentadienyl ion, in accordance with the general chemical properties of this

The chemistry of azaphospholes continues to develop. The reaction of tris(dimethy1amino)phosphine with NN-dimethyl-N’-aminoguanidinium iodide Unlike other triazaphospholes, this compound gives the triazaphosphole (198).241 forms a tetrameric complex, involving an eight-membered P-N ring system, on treatment with molybdenum h e ~ a c a r b o n y l Both . ~ ~ ~possible modes of co-ordination (i.e. involving nitrogen or phosphorus) have been observed in a range of complexes of di- and tri-azaphospholes with gold The crystal structure of the triazaphosphole (199) has been determined, the bond lengths being consistent with a delocalized r - ~ y s t e m . ~ ~ ~

(200) R = Me or CF,

As an extension of earlier work on acyl-phosphines, the P-acyldibenzophospholes (200) have now been prepared from the reactions of the parent 5Hdibenzophosphole with acid anhydrides.246 A number of new phosphole systems have been prepared. Thus the reaction of (o-sulphydrylpheny1)phosphine (201 ; X = SH) with carbonyl compounds has 23Q

J. Fischer, A. Mitschler, L. Ricard, and F. Mathey, J. Chem. SOC.,Dalton Trans., 1980, 2522.

240 241

242

0. Poizat and C. Sourisseau, J. Organornet. Chem., 1981, 213, 461. A. Schmidpeter and H. Tautz, Z . Naturforsch., Teil. B, 1980, 35, 1222. A. Schmidpeter, H. Tautz, J. von Seyerl, and G. Huttner, Angew. Chem., Znt. Ed. Engl., 1981, 20, 408.

243

244

K. C. Dash, H. Schmidbaur, and A. Schmidpeter, Znorg. Chim. Acta, 1980, 46, 167. J.-P. Lejgos, Y.Charbonnel, and J. Barrans, C. R. Hebd. Seances Acad. Sci., Ser. C, 1980, 291, 271.

245

E. Lindner and G. Frey, Z . Naturforsch., Teil. B, 1980,35, 1150.

Phosphines and Phosphonium Salts

31

given the 1,3-benzothiaphosphole system (202).246Similarly, the reaction of (o-hydroxypheny1)phosphine(201 ; X = OH) with pivaloyl p-tolylimide chloride gives the related 1,3-benzoxaphosphole (203), which is reported to be only moderately rapidly oxidized in air, and stable to water and dilute alkali.247

(202) R = H , Me, or Ph

(201) X = OH or SH

(203)

Routes to the phosphindole system from (204) have been developed.248A cyclic phosphinic acid has been converted, in three stages, into the P-benzylphosphindole (205), which has been subjected to the established phospholephosphorin ring-expansion sequence of treatment with benzoyl chloride, followed by reduction, to give the benzophosphorin (206). It has been concluded that benzoannelation does not affect the delocalization of the phosphorin ring or its ability to form rr-complexes with metal c a r b o n y l ~ . ~ ~ ~ Et,N (iii) Ni, 2 2 5 ° C

~

CH2Ph

Ph

R’ ,OMe

0H

Rz’

‘OMe

(208)

(j

ap 0

Li.414

~

$

R2

(209)

(207) R’=Me, Et, Bu, Cy, or Ph R2 = e.g. BuO, But, or Ph

The 1,4-dihydrophosphorins (207) rearrange, in the presence of acids, to form the A5-phosphorins (208). A1ternatively, reduction of (207) with lithium aluminium hydride yields the A3-phosphorins (209).2509251 Previously established synthetic routes have been used to prepare a series of A5-phosphorins that bear heteroaryl or ferrocenyl groups bound to A5-Phosphorins that bear functional groups as substituents on the phosphorin ring have also been prepared.253 246 247

248

z49 250 251 252

253

K. Issleib and R. Vollmer, Tetrahedron Lett., 1980, 21, 3483. J. Heinicke and A. Tzschach, 2. Chem., 1980, 20, 342. T. M. Balthazor, J. Org. Chem., 1980, 45, 2519. F. Nief, C. Charrier, F. Mathey, and M. Simalty, Nouv. J. Chim., 1981, 5, 187. G. Markl, H. Baier, and R. Liebl, Liebigs Ann. Chem., 1981, 919. G. Markl, H. Baier, R. Liebl, and D. S. Stephenson, Liebigs Ann. Chem., 1981, 870. G. Markl, C. Martin, and W. Weber, Tetrahedron Lett., 1981, 22, 1207. K. Dimroth and M. Luckoff, Chem. Ber., 1980, 113, 3313.

32

0rganophosphor us Chemistry

Full details have now appeared of reactions of diphosphabarrelenes that lead to the diphosphorin (210), and of the photochemical transformations undergone by the latter.254The diphosphorin has also been shown to react with sulphur to give the thiadiphosphanorbornadiene system (211); among the products of the reaction of the latter with the diphosphorin (210) is the thiadiphosphole (212).255

254

255

Y. Kobayashi, S. Fujino, H. Hamana, Y.Hanzawa, S. Morita, and I. Kumadaki, J o r g . Chem., 1980,45,4683. Y.Kobayashi, S.Fujino, and I. Kumadaki, J. Am. Chem. SOC.,1981, 103, 2465.

2 Quinquecovalent Phosphorus Compounds BY C. D. HALL

1 Introduction The year has again seen a diminution in the volume of published information in this area, and much of the work has involved the utilization of existing methods or principles and the extension of earlier findings. Thus on the theoretical side, ab initio calculations have revealed some unexpectedly small energy differences in the pseudorotational isomers of oxaphosphetan intermediates in the Wittig reaction,l e.g. AE= 19.3 kJ mol-l (4.6 kcal mol-l) for (1) and (2). In

co: (ROLP + MeO,CC=CCO,Me

(RO)(

---+

Me0,C

(RO),P =C-CC02Me (RO),P=O

+

I

II

~

(Ro),P

MeO$

(4)

/c=c\

COzMe

0 'C=O

/w

(RO),P'

0-CC0,Me

'\f=O

C0,Me

(3)

contrast, on a strictly empirical note, a pentaco-ordinated intermediate (3) has been detected en route to the ylide (4) - a reaction which is, in effect, a fixation of carbon dioxide by the trialkyl phosphite-dimethyl acetylenedicarboxylate system.2 It is interesting to note that the synthetic methods and the techniques of H. J. Bestmann, J. Chandrasekhar, W. G. Downey, and P. von R. Schleyer, J. Chem. SOC., Chem. Commun., 1980, 978. D. V. Griffiths and J. C. Tebby, J. Chem. SOC.,Chem. Commun.,1981,607.

33

Organophosphorus Chemistry

34

structure determination that are now so well established in phosphorus chemistry are proving useful in the fields of sulphurane~,~ ~elenuranes,~ and telluranes.* 2 Structure and Bonding Various structures (5),5 (6),s (7),7 and have been determined by X-ray analysis, and all show some degree (%) of distortion from the trigonal bipyramid along the Berry co-ordinate towards the rectangular or square-pyramidal configuration. Steric crowding in (6) is alleviated by a 70" rotation about the P-P bond away from the eclipsed conformation,6 and the P-P bond length is 226.4 pm, compared to 221.6 pm for the bond of (7),7 in which, incidentally, the methyl groups are trans. The fused five-membered rings of ( 6 ) are, as expected, in the meridional (aea) configuration, but the inclusion of a third five-membered ring within the phosphorane structure (8) results in the facial (eae) configuration of the bicyclus becoming energetically more favourable.8

( 6 ) [ 33%'] 0

Me

N'

), ,Me N

3 Phosphoranes containing a P-H Bond N.m.r. provides convincing evidence for the formation of aminodifluorophosphorane (9) from the reaction of difluorophosphine with ammonia, and at 21 5 K there is no indication of fluxional behaviour or rotation about the P-N bond.g

5

'Organic Compounds of Sulphur, Selenium and Tellurium' (Specialist Periodical Reports), ed. D. R. Hogg, The Chemical Society, London, 1979, Vol. 5. D. B. Denney, D. Z. Denney, P. J. Hammond, and Y.F. Hsu, J. Am. Chem. SOC.,1981, 103,2340. H. W. Roesky, H. Djarrah, D. Armizadeh-Asl, and W. S . Sheldrick, Chem. Ber., 1981,114, 1554.

6 7

* 9

J. E. Richman, R. 0. Day, and R. R. Holmes, J. Am. Chem. Soc., 1980, 102, 3955. D. Schomberg, N. Weferling, and R. Schmutzler, J. Chem. SOC.,Chem. Commun., 1981,609. W. S. Sheldrick, D. Schomburg, and A. Schmidpeter, Acta Crystallogr., Sect. B, 1980, 36, 2316. D. W. H. Rankin and J. G. Wright, J. Chem. SOC.,Dalton Trans., 1980, 2049.

Quinquecovalent Phosphorus Compounds

35 F

H

The reaction of (10) with diphenylphosphinouschloride led to the isolation of the monocyclic phosphorane (12), which was readily re-converted into (1 1).lo A combination of n.m.r. (lH, l9F, 31P, and 13C),i.r., and X-ray evidence shows the hydrogen atom of (12) to be apical, and there is an exceptionally low value of l J p= ~ 266 Hz.

Addition of alcohols or amines to derivatives of tetramethyldioxaphospholan (13) leads to monocyclic phosphoranes (14), each containing a P-H bond, which H from 539 are in equilibrium with the starting materials.ll The values of ~ J Prange to 667 Hz for X = 0, but are much lower (460 to 478) for X = NH; on this basis, it has been postulated that the P-H bond is equatorial for the alkoxyphosphoranes but apical for the aminophosphoranes. The molecular rotation of optically active spirophosphoranes containing ephedrine, a P-H bond, and other optically active ligands [generalized in (15)] has been analysed to afford separation of the rotational contributions from the ligands and the helix structure.12 This has allowed the assignment of absolute configuration to a large number of pentacoordinated phosphorus compounds.

The reactions of spirophosphoranes that contain a P-H bond with dialkyl acetylenedicarboxylates have been studied l3 and, whereas tetraoxyphosphoranes (X = 0)give new vinyl-spirophosphoranes (16), the oxazaspirophosphoranes give rise to enamine phosphites (17), presumably by the mechanism outlined in 10 11 l2 13

M. R. Ross and J. C. Martin, J. Am. Chem. SOC.,1981, 103, 1234. M. T. Boisdon, C. Malavaud, B. Tangour, and J. Barrans, Phosphorus Sulfur, 1980, 8, 305. A. Klaebe, J. F. Brazier, B. Garrigues, and R. Wolf, Phosphorus Sulfur, 1981, 10, 5 3 . R. Burgada and A. Mohri, Phosphorus Sulfur, 1981, 9, 285.

0rganophosphorus Chemistry

36

R1C=CHC02R2

H

+ R1C-CC02R2

o x

--+

(R' = H or C02R3) (16)

( X = 0, NH, or NMe) = N H or NMe]

C02R2

(17)

Scheme 1

Scheme 1. It is also of interest to note that water and alcohol react with spirophosphoranes, e.g. (1 S), that contain the P-H bond to displace the a-amino-acid and form phosphites (19; R = alkyl) or phosphonates (20; R = H).14

(19) R

(18)

=

alkyl

l+ (20) R = H

4 Acyclic Phosphoranes A series of pyrrole-substituted fluorophosphoranes, (23a) or (23b), has been prepared by the reaction of N-trimethylsilyl-pyrroles(21) with alkyl- or arylfluorophosphoranes (22).15The products contain P-N (23a) or P-C (23b) bonds, depending on the nature of the starting silyl-pyrrole, and although (23a; R1=R2=H, n=0) was shown to be present by n.m.r., it disproportionated to form (24) in high yield. R 3, R 0 R 2 SiMe, (211 R', R 2 = H or Me

+

R3,PP5_,, + R 1 N0 R 2 and/or R1&Al:ipn

(22) R 3 = M e , Et, or Ph =O

Or

I I

H

R',,, PF4 (23a)

l4 15

B. Garrigues, A. Munoz, and M. Mulliez, Phosphorus Sulfur, 1980, 9, 183. M. J. C . Hewson and R. Schmutzler, Phosphorus Sulfur, 1980, 8, 9.

(23b)

Quinquecoualent Phosphorus Compounds

37

The major impact in this area, however, has been to emphasize the fact that halogen-substituted alkoxy-groups afford a range of very stable phosphoranes. Thus (25) and (26) are formed from phosphorus halides and perfluoro-t-butyl hypochlorite by displacement and oxidative-addition reactions, respectively.l6 In a versatile synthesis, a wide range of trico-ordinated phosphorus compounds (27) react with trifluoroethyl benzenesulphenate (28) to give (29) in high yie1d.l' All of these compounds were obtained analytically pure, and in one instance a pure

[ a t 0"Cl

5 (CI,),COCl+ PC1,

[at

P[ OC(CF,),]

+ 5C1,

(25)

O"c]

* F,P[OC(CF,),I ,+ ci,

~(cF,),coc~ + PI:,

(26)

( 2 7 ; n = 0) + (28) -+

PhSP(OCH,CI:$,

(30)

sample of the intermediate thiophenylphosphorane (30) was also isolated. Likewise, 2,2,2-trichloroethoxy-groupsstabilize aminophosphoranes (31) and (32), so that pure samples may be isolated.l* Compound (3 1) required heating at 180 "C for 1 hour before the Arbusov rearrangement to phosphoramidate (33) occurred.

A X U

(Cl,CCH,O),P + C1N

X

=

+ (CI,CCH,O),P

// '0

CH, or 0

(Jt

180°C.t o r 1 h ]

';" n CI,CCH,OH

0

II

Cl,CCH,Cl + (Cl,CCH,O),P-N

(33) l6 17

nx U

(C1,CCHI,O),P-N

WX

(32)

Q.-C. Mir, R. W. Shreeve, and J. M. Shreeve, Phosphorus Suwur, 1980, 8, 331. D. B. Denney, D. Z . Denney, P. J . Hammond, and Y.-P. Wang, J . Am. Chem. SOC.,1981, 103, 1785.

18

L. N. Markovskii, A. V. Solov'ev, and Yu. G. Shermolovich. J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 1757.

38

Organophosphorus Chemistry

The equilibria between the pentaco-ordinate and tetraco-ordinate structures in halogenophosphoranes has also attracted further attention. A combination of U.V. and 31Pn.m.r. data has shown that aryltetrachlorophosphoranes are in the molecular form (34) in benzene or cyclohexane whereas solvents of higher polarity promote ionization to (35) except when Ar=p-FC,H,, in which case the compound exists in the molecular form in all solvents used.lg Similarly, compounds ArPC1,

(34)

(ArPCl,]' C1-

r

A r k l , C1-

(35)

(PhO),PCCl,

(37)

(36) and (37), which, according to the 35Cln.q.r. spectra, have the CC13 group in an apical position, are quinquecovalent in benzene and nitromethane.20Michalski has shown, however, that triphenyl phosphite and halogen give adducts in which the equilibrium is strongly in favour of the tetraco-ordinated structure (39), with no evidence for the pentaco-ordinated species (38).21 A study of the nucleophilic

attack of amines on methylphosphonic difluoride has provided convincing evidence for the intermediacy of acyclic hydroxyphosphoranes (40),22 and hydroxyphosphoranes naturally feature as intermediates in the hydrolysis of pentaphenoxyphosphorane in aqueous d i o ~ a n The . ~ ~ high negative entropy of activation (- 188 kJ mol-l) and low enthalpy of activation (22.5 kJ mol-l) for this reaction are consistent with a multi-step process involving an exothermic pre-equilibrium. l9 2o

21 22 23

L. M. Sergienko, G. V. Ratovskii, V. I. Dmitriev, and B. V. Timokhin, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 1578. V. I. Dmitriev, E. S. Kozlov, B. V. Timokhin, L. G . Dubenko, and A. V. Kalabina, J . Gen. Chem. USSR (Engl. Transl.), 1980, 50, 1799. J. Michalski, M. Pakulski, A. Skowronska, J . Gloede, and H. Gross, J . Org. Chem., 1980, 45, 3122. I. Granoth, Y. Segall, D. Waysbort, E. Shirin, and H. Leader, J . Am. Chem. SOC., 1980,102, 4523. A. Queen, A. E. Lemire, and A. F. Janzen, Int. J . Chem. Kinet., 1981, 13, 411.

39

Quinquecovalent Phosphorus Compounds

5 Four-membered-ring Phosphoranes Cryoscopic measurements have shown that triphenyl phosphite ozonide (41) is essentially monomeric, and its direct reaction with a number of olefins has been The use of pyridine in methanol as solvent permits the controlled generation of singlet oxygen from (41) at temperatures as low as 173 K.25

In an extension of earlier work,26a number of P-fluorophosphadiazetidinones

(44), unsymmetrically substituted on nitrogen, have been prepared from the appropriate unsymmetrically substituted disilyl-ureas (42) and fluorophosphoranes (43).27The partial equilibration of these compounds to the symmetrical species, e.g. (46), is thought to involve catalytic amounts of isocyanate and to occur via a six-membered-ringintermediate (45). RZ

\

o=c

/

NSiMe,

‘NSiMe,

/

R3

+

R’PF,

-

R2

\

N

O=C ,-” ‘PR’I:,

(43) R’ = alkyl or aryl

(42) RZ= Me, R 3 =Et

N ‘’ R’

/ (44)

C-N

R2

(44) + R 2 N C 0

(45)

6 Five-membered-ring Phosphoranes The reaction of (47)with alkyl or aralkyl halides gives stable compounds (48a, b), which, despite the low-field 31Pn.m.r. shifts, appear to be borderline cases between halogeno-phosphoranes and phosphonium halides.28The argument is based on the downfield shift of protons that are ortho to phosphorus in the aromatic ring of the benzoxaphosphole structure in pentaco-ordinatedcompounds 24

P. D. Bartlett and H.-K. Chu, J. Org. Chem., 1980, 45, 3000.

z5 P. D. Bartlett, G. D. Mendenhall, and D. L. Durham, J. Org. Chem., 1980, 45, 4269.

s6 S. C. Peake, M. J. C. Hewson, 0.Schlak, R. Schmutzler, R. K. Harris, and M. I. M. Wazeer, Phosphorus Sulfur, 1978,4, 67. 27 0. Schlak, R. Schmutzler, R. K. Harris, E. M. McVicker, and M. I. M. Wazeer, Phosphorus Sulfur, 1981, 10, 87. 28 1. Granoth and J. C. Martin, J. Am. Chem. SOC.,1981, 103, 2711.

OrganophosphorusChemistry

40

@O

+ RX

\

'

-

~

,

,

\

,

p

h

I

R' X (48) a ; R = Me, X = I [ b ( 3 1 P ) = +87.2 p.p.m.1 b ; R = Bz, X = Br [6(3'P)= +86.6 p.p.m.1

Ph

(47)

of the type (48). Stable aryloxy(ha1ogeno)phosphoranes have also been claimed from the reaction of (49) with thionyl chloride to generate (50), followed by antimony trifluoride to obtain (51).29 In both cases, the 31Pn.m.r. shifts are at high field. Anisotropic effects on the methylene protons (HA and HB) have been used to support the proposal of pentaco-ordinated zwitterionic structures (52) from the reaction of lithium chloride (or bromide) with acyclic phosph~nates.~~

c-0-so-c1 " f-4

aL0 -

(49)

c1-

P

I

$.

0

0

I1

(51)

( 50) [S ("P) = - 30.4 p.p.m.1

[6("P) = -50.7 p.p.m.1

x(52) X = C1 or Br

Trialkyl phosphites react with 1,l ,l-trifluoroacetone to give (53),31 which, contrary to previous experience with activated ketones, contains the 1,4,2dioxaphospholan ring; (53) isomerizes slowly to the acyclic fluorophosphorane 29

30 3l

I. Granoth, R. Alkabets, and Y. Segall, J . Chem. SOC.,Chem. Commun., 1981, 622. M. M. C. F. Castelijns, D. van Aken, P. Schipper, J. J . C. van Lier, and H. M. Buck, R e d . Trau. Chim. Pays-Bas, 1980, 99, 380. A. M. Kibardin, T. Kh. Gazizov, Yu. Ya. Efremov, V. H. Zinin, R. 2. Musin, and A. N. Pudovik, Bull. Acad. Sci. USSR, Diu. Chem. Sci., 1980, 656.

Quinquecovalent Phosphorus Compounds

(RO),P+ CH,COCI:,

-

?+ (R0)3pk0 H,C CF, (5 3 )

41

r

--+

CH,

I I (RO),P-O--C-O-C=-CF2 I c r:,

CH,

I

(54)

+

(54). Conventional methods lead to phosphoranes (55) and (56) [ P I I I sulphenate ester], (57) and (58) [ P I I I + biacetyl], and (59) [ P I I I dithieten], and a modification using a bisulphenate (60) gives (61).32N.m.r. data (lH, 13C,and 31P)indicate the structures shown for (55) and (56), without revealing whether or not the molecules are rigid or fluxional, but variable-temperature n.m.r. indicates reorganization of the ligands in (58), (59), and (61) through structures in which the five-membered ring that contains two oxygen atoms [as in (58) and (61)] or two sulphur atoms, i.e. (59), goes diequatorial. In (57) a rapid reorganization of the ligands was detected at room temperature, involving the ring nitrogen as the equatorial ‘pivot’.

+

(55)

(61)

Condensation of (62) with biacetyl or benzil gave the mixed oxazaphosphoranes (63a, b), and variable-temperature 13Cn.m.r. studies showed that the phosphoranes did not undergo rapid intra- or inter-molecular reorganization of the ligands. In fact, (63b) was rigid up to 368 K but the six-membered-ring analogue 32

D. B. Denney, D. Z. Denney, P. J. Hammond, C. Huang, and K.-S. Tseng, J . Am. Chem. SOC.,1980, 102, 5073.

Organophosphorus Chemistry

42

(63) a ; R = Me b;R=Ph

(64) showed rapid reorganization of ligands at room temperature (AG*z 4 5 kJ mol-l), probably via (65) rather than (66).33In a sequel to this paper, Denney has shown, by detailed n.m.r. studies and in particular the retention of carbonphosphorus spin-spin coupling, that the condensation products of tris(dimethy1amino)phosphine and benzil or phenanthraquinone, e.g. (67) for benzil, are penta~o-ordinated.~~ The change in chemical shift of 31Pfrom hexane (- 30) to methylene chloride (- 13) has been explained as resulting from an increased contribution by (67b) to the resunance hybrid as the polarity of the medium 8o increases. In view of the earlier results reported for halogeno-phosphorane~,~~~ this interpretation seems very reasonable.

In an extension of the a-dicarbonyl synthesis, phenanthraquinone monoxime has been shown to react with trialkyl phosphites to give 1,3,Zoxazaphospholines (68).35A detailed kinetic study of the stereospecific fragmentation of spirophosphoranes (69) [8(31P) = + 4 to + 30 p.p.m.]12 to t,t-hexa-2,4-diene and (70) shows that steric compression within each phosphorane dictates the rate of 33 34 35

D . B. Denney, D . Z . Denney, D. M. Gavrilovic, P. J. Hammond, C. Huang, and K . 4 . Tseng, J . Am. Chem. SOC.,1980, 102, 7072. D. B. Denney, D . Z. Denney, P. J. Hammond, and K.-S. Tseng, J. Am. Chem. Soc., 1981, 103, 2054. M. M. Sidky, M. F. Zayed, A. A. El-Kateb, and I. T. Hennawy, Phosphorus Sulfur, 1981, 9, 343.

Quinquecovalent Phosphorus Compounds

+

(RO),P

43

(68)

[R = Et, 6 ("P)

= - 5 1.4 p.p.m.1

RP

<+

v (69) R = Me or Ph

fragmentati~n.~~ The same A3-phospholensreact with sulphenate esters to give a range of products involving rearrangement of the double-bond, dealkylation to phospholen oxides, and fragmentation of the ring, the last of which must occur through pentaco-ordinated intermediate^.^' In an analogous reaction between sulphenamides (7 1) and A3-phospholens, stereochemical evidence indicates the intermediacy of pentaco-ordinated species (72) en route to the ylide product (73). The P-chloro-spirophosphorane (76) [d(31P)= - 20.7 p.p.m.1 is obtained via (75) from the condensation of o-aminophenol with (74),3*and the equilibria Me

Me

1

I

+ Et,NSMe

+

(7 1) (7 2)

-

c1

t

(74) 36

s7 38

P. J. Hammond, J. R. Lloyd, and C. D. Hall, Phosphorus Sulfur, 1981, 10, 47. P. J. Hammond, J. R. Lloyd, and C. D. Hall, Phosphorus Sulfur, 1981, 10, 67. V. P. Kukhar', E. V. Grishkun, and V. P. Rudavskii, J . Gen. Chem. U S S R (Engl. Transl.), 1980, 50, 812.

Orgamphosphorus Chemistry

44

Ph

Ph

&

R’

But

(77) R’, R2= alkyl or aralkyl R

between (2-hydroxypheny1)iminophosphoranes (77) and 1,3,2-benzoxazaphospholines (78) have been studied carefully by 31Pn.m.r. s p e c t r o s ~ o p yThe . ~ ~ latter often show two 31Pn.m.r. signals at 220 K, indicating that there are two pseudorotamers, which interconvert at room temperature (AG* % 55 kJ mol-l). Spirophosphoranes (79) are also obtained by the ‘head-to-tail’ condensation of two moles of o-hydroxybenzaldehyde or o-hydroxybenzophenone with phenylphosphonous dichloride40and by redox reactions involving catechylphosphorus

tribromide (80) and either cyclic or acyclic aryl phosphites, to give (81).41 The dilithiation of hexafluorocumyl alcohol gives a very versatile reagent (82) which is capable of generating a range of stable hypervalent spiro-compounds with phosphorus, sulphur, silicon, or iodine as the central h e t e r ~ a t o r nThe . ~ ~ resultant spirophosphorane (83) may be readily converted into a stable hydroxyphosphorane (84). 39 40 41

42

K. Scheffler, A. Burrnester, R. Haller, and H. B. Stegmann, Chem. Ber., 1981, 114, 23. S. D. Harper and A. J. Arduengo, Tetrahedron Lett., 1980, 21, 4331. J. Gloede and B. Costisella, 2. Anorg. Allg. Chem., 1980, 471, 147. E. F. Perozzi, R. S. Michalak, G . D. Figuly, W. H. Stevenson, 111, D. B. Dess, M. R. ROSS, and J. C. Martin, J. Org. Chem., 1981, 46, 1049.

Quinquecovalent Phosphorus Compounds

45

(i) POCI, . OH

2

I

II

(iii) KOH

Azodicarboxylic esters behave as hetero-dienes in the oxidative [4 + 11 cycloaddition to triazaphospholes (85) to generate a pentacyclic diphosphorane (87) via (86),43 and another double cycloaddition, involving aldehydes and methyleneaminophosphites [e.g. ( S S ) ] , yields (90) via the [3 + 21 cycloaddition product (89).44The latter may be trapped with methanol to give (91).

N ,T MeN

\pH

N

/ \ (85)

Ph

A

N MeN. \

OR

I

“P-N RO,CN‘/

l

+

RO,CN=NCO,R

N-P’

N+/

o

I

/ <,NCO,R

(”Me

\

kN

OR

(86)

43 44

H. Tautz and A. Schmidpeter, Chem. Ber., 1981, 114, 825. A. Schmidpeter, W. Zeiss, D. Schomburg, and W. S. Sheldrick, Angew. Chem., Int. Ed. Engl., 1980, 19, 825.

Organophosphorus Chemistry

46

The fluorine atom in the benzoxazaphosphoranes (92) is displaced by a variety of nucleophiles, including water [to give (93)], sodium alkoxide [to (94)], and lithium alkyl [to (95)] and, if R4= H, treatment of (92) with lithium diethylamide leads to elimination of HF and dimerization of the product (96) to the tricyclic bisphosphorane (97).45946

&)<:=

R3

Ph

R3

R4 (92)

(95 ) t b R . = H1

R3&OH

N=PPh,R'

Ph

R3&OH NP(O)Ph, (93) R4

1

[ R" = HI LiNR,

[

R3&,PPh] /

N

[x21*

N-PPh, Ph,P-N I 1

(96)

(97)

Several spirophosphoranes with a P--OH bond, e.g. (99), have been prepared by the oxidation of the corresponding P-H phosphoranes (98) with DMSO or with DMSO and N204,and the tautomeric equilibrium between (99) and the phosphate (100) has been examined by 31Pn.m.r. s p e c t r o s ~ o p y . ~ ~

45

H. B. Stegmann, H. V. Dumm, A. Burmester, and K. Schemer, Phosphorus Sulfur, 1980,8, 59.

H. B. Stegmann, H. V. Dumm, A. Burmester, and K. Schemer, Phosphorus Sulfur, 1980.9, 99. 47 A. Munoz, B. Garrigues, and M. Koenig, Tetrahedron, 1980, 36, 2467. 46

47

Quinquecovalent Phosphorus Compounds

The facile displacement of phenol or of 2,2,2-trihalogenoethanolfrom spiro(acy1oxy)phosphoranes (101) by alcohols ('transphosphorylation') is notable for the fact that the oxygen nucleophile (R30H) attacks phosphorus rather than the carbonyl group of the mixed anhydride.48The mechanism may involve hexacoordinated intermediates (102), but an ionization mechanism via (103) and (104) has not yet been ruled out.

n

0

\lo

R~OH

R30'-P-OR'

___)

0

(101) R' = Ph or CX,CH,O ( X = I: or C1)

(102)

\

A

R' 0-P+-

0

RQH

O+R2 O - 30

7 Hexaco-ordinated Phosphorus Compounds Hexaco-ordinated species have been proposed as intermediates in nucleophilic displacement reactions at the phosphorus of pho~phoranes,~~. 48 but information on isolable hexaco-ordinated phosphorus compounds has been sparse this year. Tris(trifluoroethoxy)diphenylphosphorane (105) reacts with trifluoroethoxide ion

Ph JYO R) (105)

NaOR

Ph.. Ph

OR ,,OR

I

' /'P \

I

OR OR (106a)

-2=-

OR ,'OR

I / \ RO I Ph

Ph.,

'P'

OR (106b)

(R = CH,CI:,) 48

S. Kobayashi, Y.Narukawa, T. Hashimoto, and T. Saegusa, Chem. Lett., 1980, 1599.

48

Organophosphorus Chemistry

to give (106a), in which the phenyl groups are initially cis but which equilibrates rapidly to a mixture of the cis-compound (106a) (18%) and the trans-isomer (106b) (8279." In the same paper it is reported that the spirophosphorane (107) reacts with trifluoroethoxide ion to give an equilibrium mixture of cis- [(lO8a),

n X

(CHF,CF,O),P + 2 HN (109)

W

(X = 0 or CH,)

(CHF,CF,O),P-N

n

A

WX ( 1 10)

67 %] and trans- [(108b), 33 %] hexaco-ordinated species, in agreement with earlier finding^.^^^ 5 0 In a system that is again stabilized by fluoroalkoxy-groups, (109) has been shown to react with secondary amines (piperidine or morpholine) to give organoammonium (amino)penta-alkoxyphosphoranides (1 10) ; these are thermally labile, and hydrolyse very readily.61

49

50 S1

R. Sarma, F . Ramirez, B. McKeever, J. F. Marecek, and V. A. Prasad, Phosphorus Sulfur, 1979, 5, 323. J. J. H. M. Font Freide and S. Trippett, J . Chem. SOC.,Chem. Commun., 1980, 157. L. N. Markovskii, N. P. Kolesnik, and Yu. G. Shermolovich, J . Gen. Chem. USSR. (Engl. Transl.), 1980, 50, 662.

Halogenophosphines and Related Compounds BY J. A. MILLER

1 Introduction There has been a reduction by about 30% in the volume of publication in this area over the year to July 1981. Much of the work in the field of phosphorus(II1) halides is an offshoot of the expanding interest in other areas, such as chiral phosphines and phospha-alkenes, although some longstanding problems related to Conant’s reaction have been resolved. In the field of phosphorus(v) halides, theoretical and structural studies have almost ceased, whilst synthetic applications continue to be discovered. 2 Halogenophosphines Preparation.-( - )-Menthol has been converted into chloro(dimenthy1)phosphine (l), which is of potential value in the preparation of chiral tertiary phosphines,l as shown in Scheme 1. The industrial synthesis of dichloro(methy1)-

A

( 1 ) Men = menthyl

(-)-menthol Reagents: i, ZnClz, HCI; ii, Mg, THF; iii, PC13

Scheme 1

phosphine (2) has been described and its commercially useful chemistry outlined.2 A summary is given in Scheme 2. Trimethylsilyl iodide (3) has been added to the list of reagents which convert chlorophosphines into iodopho~phines.~ The preparation and donor-acceptor properties of the phosphines (4a) have been r e p ~ r t e d In . ~ the related series (4b) it was not possible to prepare the mixed phosphines (4b; n = 1 or 2), owing to the facility with which exchange of ligands O C C U ~ S . ~ 1 2

3 4

H. W. Krause and A. Kinting, J. Prakt. Chem.: 1980, 322,485. K. Weissermel, H.-J. Kleiner, M. Finke, and U.-H. Felcht, Angew. Chem., Int. Ed. Engf., 1981, 20, 223. W. D. Romanenko, V. 1. Tovstenko, and L. N. Markovskii, Synthesis, 1980, 823. C. A. Wilkie and R. W. Parry, Znorg. Chem., 1980, 19, 1499.

49

0rganophosphorus Chemistry

50 0

0

I1

I1 MePCH,Cl I

M ePO R‘

I

/

ii+

0 CH, + PC1,

MePC1,

0

””

*

II

M#CH(NH,)R

OH 0

II I II MeP-C-PMe I Rl OH l HO Reagents: i, 600 “ C ;ii, 1,3,5-trioxan; iii, RIOH, base; iv, R2X; v, RCHO, HzNCOOCHzPh; vi, H30+; vii, buta-1,3-diene; viii, HzO; ix, RCOzH, heat

Scheme 2 Rn P(CN)3 - n

Me,SiI (3)

R,PCl3-,,

---+

(4) a ; R = Ph b; R = C1

R,,P13-n

A number of recent syntheses of halogenophosphines have a bearing on the current interest in the generation and properties of phospha-alkenes and phosphaalkynes. Thus Issleib’s group have reported the preparation of tris(trimethylsily1)methyl(ch1oro)phosphines although the dichlorophosphine ( 5 ; R = C1) turned out not to be a suitable precursor of the corresponding phospha-alkene.5 Meanwhile, Appel and co-workers have reported a base-catalysed route to the phospha-alkenes (6), of which ( 6 ; R1=Ph, R2=SiM%) was the only one to be analytically handleable.’ A new and very efficient synthesis of phenylmethyiidynephosphine (7) has been reported.8 Stepwise addition of hydrogen chloride to ( 5 ) , 5 9

/R

RPC1,

(Me,Si),CLi

+

heat

(Me,Si),CP \CI

+ + [R=CI]

(Me,Si),C=PCI

( 5 ) R = C1 or Ph

R2 >CHPCl, R’

Et3N

+

‘)== PCI

R’

(6) 5 7 8

K. Issleib, H. Schmidt, and C. Wirkner, Z. Chem., 1980, 20, 153. K.Issleib, H. Schmidt, and C. Wirkner, Z. Chem., 1980, 20, 419. R. Appel and A. Westerhaus, Angew. Chem., I n t . Ed. Engl., 1980, 19, 556. R. Appel, G. Maier, H.-P. Reisenauer, and A. Westerhaus, Angew. Chem., Int. Ed. Engl., 1981, 20, 197.

Halogenophosphines and Related Compounds

-

phppc, [at700"CIw

ZHCl

PhCEP

Me,Si

51 PhCH,PCl,

(7)

[

(8)

- loo%]

(7) gives benzyldichlorophosphine (8), but base-catalysed reversal of this sequence was not successful.s For related work, see Section 1 of Chapter 1. Tetrakis(trimethylsily1)cyclotetraphosphine (9) has been made as shown, and analysis of its n.m.r. spectra reveals an all-trans geometry for the silicon-containing l i g a n d ~ . ~

Me,SiPH, + Bu',Hg

-

Me$!

,SiMc,

P-P

I 1

Me,SidP-\.

SiMe,

(9) [63';/(1

Reactions with Carbonyl Compounds and Related Compounds.-A number of recurrent themes in this area have reappeared in this year's literature. Thus a further investigation of the reactions of chlorodiethylphosphine (10) or of chlorodiphenylphosphine (1 1) with simple carbonyl compounds shows that oxides and phosphinic acid derivatives are formed l o - as shown for cyclohexanone. The relationship between this work and earlier studies11,12with acetone is not clear, since the oxides (12) and (1 3) were originally reported," but these are not mentioned in the recent paper.I0 The related reactions of (11) with aldehydes appear to have been tamed at last. Under thermal conditions, a-chloroalkyl(dipheny1)phosphine oxides, e.g. (14), 0 IR = Ph]

(10) R = Et (1 1) R = Ph

9 10

11 12

P h z ! a

0

0

+ Ph;"10

+

II

Ph,POH

HO

M. Baudler, G. Hofmann, and M. Hallab, Z. Anorg. Allg. Chem., 1980, 466, 71. M. Kashirskaya, N. M. Ismagilova, R. Sh. Gubaidullinova, T. V. Zykova, R. A. Salakhutdinov, and V. S. Tsivunin, J . Gen. Chem. USSR (Engl. Transl.), S. Kh. Nurtdinov, I.

1980,50, 1049. S. Kh. Nurtdinov, R. S. Khairullin, R. V. Zykova, V. S. Tsivunin, and G. Kh. Kamai, J . Gen. Chem. USSR (Engl. Transl.), 1971,41, 2158. J. A. Miller, in 'Organophosphorus Chemistry' (Specialist Periodical Reports), ed. S. Trippett, The Chemical Society, London, 1973, Vol. 4, p. 58.

3

52

Organophosphorus Chemistry 0 Ph,PCI + 2PhCHO

--+

I/

Ph,PCHPhOCH(CI)Ph

(1 1)

il

$0

(14) Reagents: i, PhzPCI, H 2 0 ; ii, heat, HCl

Scheme 3

have been confirmed as the major products, and the nature of two isolable intermediates has now been established,13as shown in Scheme 3. The main significance of this sequence is that it relates this type of chemistry to that already established14 for a range of phosphorus(u1) compounds (e.g. phosphites, phosphoramidites, and phosphines). Moreover, the mechanistic differences between reactions of monochlorophosphines and those of phosphorus trihaIide~*~* l6 now become apparent, since the former clearly involve nucleophilic phosphorus in the initial steps, whereas the latter do not. No evidence for oxaphosphiran intermediates, so favoured in earlier literature and in current Russian work, appears in the present r e ~ 0 r t s .l5 l~~ PhCHO + Ac,O i ,PhCH(OAc),

+

0

PhCH(C1)OAc

“\\L,OVPh

ii(

(15) Reagents: i , Pc13, catalyst; ii, PC13

Scheme 4

The sequence shown in Scheme 4 has been dern~nstratedl~ for the reaction of phosphorus trichloride with benzaldehyde in the presence of acetic anhydride. The product is the dimeric phosphonic acid derivative (15), recognized many years ago18 as the true intermediate in Conant’s work of the 1920’s - work which provided the first serious evidence compatible with an oxaphosphiran intermediate. l3

N. J. De’ath, J. A. Miller, M. J. Nunn, and D. Stewart, J . Chem. Soc., Perkin Trans. I , 1981, 776.

For a review, see F. Ramirez, Acc. Chem. Res., 1968, 1 , 168. l5 J . K. Michie, J . A. Miller, M. J. Nunn, and D. Stewart, J. Chrm. Soc., Perkin Trans. I ,

l4

1981, 1744. l6 l7

1s

J. A. Miller and M. J. Nunn, J . Chem. SOC.,Perkin Trans. I , 1976, 535. J. K. Michie and J . A. Miller, J. Chem. SOC.,Perkin Trans. I , 1981, 785. F. R. Atherton, V. M. Clark, and A. R . Todd, R e d . Trav. Chim. Pays-Bas, 1950, 69, 295.

Halogenophosphines and Related Compounds

53 0

0

R + PhPCll

d

'

OH

Et,N

~

'

(17)

OP(C1)Ph

P

(16) R [R

P

1

= H, 807% = Ph, 80%

Scheme 5

There are resemblances between the intermediates of Scheme 3 and those that have been suggested to lie on the pathway (see Scheme 5 ) to the trioxaphosphoranes (16), which were isolated in good yield from reactions of dichloro(pheny1)phosphine(17) with o-acyl-phen~ls.~~ The importance of the type of base in these reactions is indicated by the fact that an apparently similar reaction of salicylaldehyde (as its sodium salt) with (17) gives only substitution products that contain phosphorus(r~~).~* 0

0

ll Ph,POCAr

Ph,PC1

(18)

(1 1)

+ RCOOH

Fl: *

II

Ph,PCH,K (19) [ R = Ph, 88%]

The simple substitution products (18) have been obtained from reactions between chlorodiphenylphosphine (1 1) and various benzoate Salk2' By contrast, the thermal reaction of (1 1) with benzoic acid in the presence of water produces a minor surprise.22 Benzyldiphenylphosphine oxide (19) is the major product (yield up to 8879, and the reaction has been extended preparatively to other carboxylic acids. This sequence thus surpasses those of acetic23and trifluoroacetic acids,24in that the original carbonyl has become doubly reduced in (19) - some mechanistic fun clearly lies ahead in this area. 19 20

S. D. Harper and A. J . Arduengo, Tetrahedron Lett., 1980, 21, 4331. P. A . Awasarkar, S. Gopinathan, and C. Gopinathan, Indian J. Chem., Sect. A , 1980, 19, 596.

Z1 22

23 a4

E. Lindner and J. C. Wuhrmann, Z . Naturforsch., Ted. B, 1981, 36, 297. P. Sartori and G. Mosler, Phosphorus SulJirr, 1980, 9, 115. J. A. Miller and D. Stewart, Tetrahedron Lett., 1977, 1065. D. J. H. Smith and S. Trippett, J. Chem. SOC.,Perkin Trans. I, 1975, 963; P. Sartori and R. H. Hochleitner, Z . Naturforsch., Teil. B, 1976, 31, 76.

54

Organophosphorus Chemistry

A huge compilation of the reactions of a-amino-ketones with phosphorus(II1) chlorides has appeared.25The products are A4-l ,3,2-oxazaphospholines, e.g. (20), and full spectral and chemical characterization is included in this work. New examples of synthetic reactions that have been achieved by using iodophosphines have appeared; they include the reduction of a-halogeno-ketones (21 ; X=Br or I),26 deprotection of the acetal (22),27 the synthesis of the benzyl sulphides (23),28and the dehydration of carboxamides to nit rile^.^^

0

R1 OMe

II

ArCH,OH

R1CR2

p:i\p,,*

ArCH,SPh

(23) [6-95V]

Acetals are known to react with phosphorus trichloride, and a new study has shown how the nature of the alkyl acetal ligand, and the reactant ratio, control the yield of the usual product, the phosphonate (24).30The reaction of acetals of ap-unsaturated aldehydes with chlorodiphenylphosphine(1 1) leads to good yields of the allylic oxides (25).31 A further study of the reaction of epichlorohydrin with phosphorus trichloride has appeared.32

(RO),CH, + PC1,

heat or catalyst

0

I1

ROCH2PC1,

(24)

hRz R'

Ph,PCl + (MeO),CH

25 26

27 28

29

30

0 OMe R3

+ P h 2 ! V R 2

Yu. V. Balitskii, Yu. G. Gololobov, V. M. Yurchenko, M. Yu. Antipin, Yu. T. Struchkov, and I. E. Boldeskul, J . Gen. Chem. USSR (Engl. Transl.), 1980, 50, 231. J. N. Denis and A. Krief, Tetrahedron Lett., 1981, 22, 1431. J. N. Denis and A. Krief, Angew. Chem., Znt. Ed. Engl., 1980, 19, 1006. H. Suzuki and N. Sato, Chem. Lett., 1981, 267. H. Suzuki and N. Sato, Nippon Kagaku Kaishi, 1981, 392. K. A. Petrov, V. A. Chauzov, and S. V. Agafonov, J . Gen Chem. USSR (Engl. Transl.), 1980, 50, 628.

31 92

M. Maleki, J. A. Miller, and 0. W. Lever, Tetrahedron Lett., 1981,22, 365. P. Atanasov and L. Yankov, Dokl. Bolg. Akad. Nauk, 1981, 34, 59.

Halogenophosphines and Related Compounds K K

I I

[at

B~ASASBU' +

BU'ASC~,

-78"Cl

55

y, B~~AS-ASBU'

(26)

Reactions with Group V Donors.-The first monocyclic, homonuclear threemembered ring structure, the cyclotriarsine (26), has been prepared as Detailed n.m.r. evidence has been presented in support of the new phosphines (27), although none was stable enough to be isolated.34The same comments apply to aminodifluorophosphorane (28), prepared from difluorophosphine and ammonia.35 BrPF,

+

Me3_,P(MMe3),, = 1 or 3 M = Si or Sn

,Me?-,, F,PP (M ' Me, ),,

iz

( 2 7 ) i z = 2 or 0

Reactions with Carbanions, Alkenes, and Aromatic Compounds.-Two paperss6 37 have described the unusual phosphoranes (29)36and (30),37each made from a halogeno-phosphine and a bis-organometallic compound. Further discussion of these interesting compounds appears in Chapter 2. 9

33 34

35 36 '3

M. Baudler and P. Bachmann, Angew. Chem., Int. Ed. Engl., 1981, 20, 123. E. A. V. Ebsworth, D. J. Hutchison, E. K. MacDonald, and D. W. H. Rankin, Inorg. Nucl. Chem. Lett., 1981, 17, 19. D. W. H. Rankin and J. G . Wright, J . Chem. SOC.,Dalton Trans., 1980, 2049. M. R. Ross and J. C. Martin, J. Am. Chem. SOC.,1981, 103, 1234. I. Granoth and J. C. Martin, J . Am. Chem. SOC.,1981, 103, 2711.

56

Organophosphorus Chemistry

Malonate displacements on a series of chlorophosphines lead either to phosphines (31) or to phosphinites (32), depending upon the bulk of the phosphorus substit~ents.~~ R’ ‘PCI

/ R2

RI

R’

+ CH(COOR3) +

/ ‘PCH(COOR3),

OR

\ I ,POC=CHCOOR3

or

R2

R2

(31)

(32)

Various aspects of the chemistry of halogenophosphine-aluminium chloride complexes have been presented. For example, it is now apparent that a one-pot route to tertiary phosphines (33)39does not require that the final alkyl group be derived from an a-halogeno-ether or -sulphide. The effects of various additives on these reactions are nicely rationalized in the same paper.39

PCI,

AIC‘I,

+ PhH

*

Ph,PCI-AlCI,

RX

0

II

Ph,PR

(33)

(34) [ 30%]

(35) [2570]

A new phosphine oxide, (34), and the phosphinoyl chloride (35) are formed as shown from ~ a m p h e n e . ~ The * lack of chirality in the latter product suggests a pathway involving an addition of a proton, by analogy with previous systems discussed by Quin et al. in recent years.41 Finally, the treatment of chloro(diferroceny1)phosphine with aluminium chloride dimer at a low temperature leads to a red cation, (36), believed to be two-co-ordinate at phosphorus; i.e., dp= + 182 ~ . p . m . ~ ~

+

Fc-P-Fc

(36) Fc = ferrocenyl (37)M = Si or Ge 38 39 40 41 42

0. I. Kolodyazhnyi, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 1198. K. A. Petrov, V. A. Chauzov, and S. V. Agafonov, J . G m . Chem. USSR (Engl. Transl.), 1980,50, 1227. E. Vilkas, M. Vilkas, J. Saiton, B. Meunier, and C. Pascard, J. Chem. Soc., Perkin Trans. I, 1980,2136. C . Symmes and L. D. Quin, J. Org. Chem., 1978,43, 1250. S . G . Baxter, R. L. Collins, A. H. Cowley, and S. F. Sena, J. Am. Chem. Soc., 1981, 103, 714.

Halogenophosphines and Related Compounds

57

Insertion Reactions of Sily1phosphines.-Further studies of the stereochemical aspects of insertions into phosphorus-silicon or phosphorus-germanium bonds have been reported, using the cyclic derivatives (37).43A very complex pattern is emerging, as shown by retention (LiAlH,, R,CO, or metal alkyls), inversion (LiBH 4), or racemization (ROH) being observed with different reagents. Ph,PSiMe, + X=C=Y

+

S==C

,PPh,

'

7 h 2

or X=C

SSiMe,

(38)

N'

(SiMe,)R

(X = 0 or S)

(X = Y = S)

Diphenyl(trimethylsily1)phosphine (38) undergoes insertion with a series of heteroallene~.~~ Tellurium inserts readily into di-t-butyl(trimethylsily1)phosphine to give (39).45The same product is formed from the telluride (40), a sequence i n t e r ~ r e t e das ~ ~indicating that phosphine tellurides behave almost like weak complexes of phosphorus(iI1) with tellurium(0). Ru',PSiMe,

+ TeO

+ But2P-Te-SiMe,

(39) a I I a nge

Te

II

Bun,P==Te + But, PSiMe, -+ But ,P-SiMe,

+ Bun,P

(40)

Physical and Structural Aspects.-The most interesting structural work of the year centres on a U.V. photoelectron spectroscopic study of a series of arylphosphorus(Ir1) compounds (41) and (42),46and of various 1-alkynes (43) bearing a phosphorus(u1) s~bstituent.~'The data on (41a) have been interpreted in terms of a favourable interaction of the lone-pair with the aromatic ring (i.e. PhPH, is like PhNH,), whereas in (41b) there is C,,symmetry, as a result of poor overlap of orbitals of the ring with the lone-pair of p h o ~ p h o r u sA . ~qualitatively ~ similar effect is observed in (43b), where the lone-pair does not conjugate, whereas in (43a) it

(41)a; R = H b;R=Cl

c; R 43 44 45 46

47

= NEt,

(43) a ; R = H b;R=Cl c ; R = NEt,

J. Dubac, J. Escudik, C. Couret, J. Cavezzan, J . Satge, and P. Mazerolles, Tetrahedron, 1981,37, 1141. U. Kunze and A . Antoniadis, 2. Anorg. Allg. Chem., 1979, 456, 155. W.-W. Du Mont, Angew. Chem., Int. Ed. Engl., 1980, 19, 554. D. E. Cabelli, A. H. Cowley, and M. J. S. Dewar, J . Am. Chem. Soc., 1981, 103, 3286. D . E. Cabelli, A. H. Cowley, and M. J. S. Dewar, J . Am. Chem. SOC.,1981, 103, 3290.

Organophosphorus Chemistry

58 w*p),lN(SiHJ3

Ar,PX3

-I?

( 4 5 ) ~= 1, 2 , o r 3 X = C1 or Rr

(44) n = 1 or 2

The phosphines (44) are each planar at nitrogen, and the directions of the lone-pairs of phosphorus and of nitrogen are approximately o r t h o g ~ n a l . ~ ~ Complexation of tin(1v) chloride with various arylphosphine derivatives (45) has been studied in detail by i.r. and Mossbauer s p e c t r o s ~ o p y . ~ ~ 3 Halogenophosphoranes Structural.-A thorough study, by n.m.r., of the unstable phosphorane (28) has revealed that the fluorines are axial, and that the plane of the amino-group is orthogonal to the equatorial plane of the trigonal b i ~ y r a m i dEven . ~ ~ at - 177 “C, the phosphoranes (46) show no coalescence in their n.m.r. spectra, and this observation has been related to possible tunnelling modes for rearrangement.50

(28)

Preparation.-Several styrylfluorophosphoranes, e.g. (47) and (48), have been prepared from chlorophosphoranes, using arsenic trifl~oride.~’Antimony trifluoride has been used to prepare heterocyclic phosphoranes (49)from the corresponding phosphorus(Ir1) d e r i v a t i v e ~ . ~ ~ PhCH=CHPCI,

As].,

*

PhCH=CHPF,

(47) [ 82961 PhC(Cl)=CHPCl,

As1

PhC(Cl)=CHPF, (48) [58%]

(30) a; R = Me, X = I b ; R = CH,Ph, X = Br ‘8 49

50

51

G . S. Laurenson and D. W. Rankin, J . Chem. SOC.,Dalton Trans., 1981, 425. A. A. Muratov, 0. B. Sobanova, E. G. Yarkova, N. B. Gilfanova, A . S. Khramov, and A. N. Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50,579. D. Fastenakel and J. Brocas, Mot. Phys., 1980, 40, 361. S. V. Fridland, N. V. Dmitrieva, and I. S. Salakhov, J . Gcn. Chrm. USSR (Engl. Transl.), 1980, 50,624.

Halogenophosphines and Related Compounds

59

The dichloroarsorane (50) is prepared in good yield from triphenylarsine oxide, provided solvent is Trimethylsilyl iodide will exchange iodine for chlorine, as in the general case shown for (51).3 The halogenophosphoranes (30a) and (30b) have been prepared by addition to a phosphinite intermediate.37 Reactions with Nitrogen Compounds.-The full complexities of the reactions of N-trimethylsilylated pyrroles (52) with a range of aryl-polyfluorophosphoranes have been These reactions can lead to substitution at N or at (2-2, as shown in the general equation, and very detailed spectral evidence has been presented for each

I

1

R I Q R z + PhnPF5-n

I

-

I

1

R ' g R '

I

I

I

and/or R ' Q p p h H n

4-n

PhnPF4-n

SiMe, (52) R', R 2 = H or Me

A related sequence has also been used to convert phosphorus pentafluoride into the phosphorane (53),54although its instability leads to a series of subsequent complexities, as shown in Scheme 6. PF, + Me,Si(Bu')NPF,

+

F,PN(Bu')PF,

+ Bu'F

+ F,P=NPF,

(53) Me,C--CH,

+ HF

Scheme 6

Chlorotetrafluorophosphorane has been converted into the donor-acceptor complex (54),55and n.m.r. data reveal that the chlorine and amine moieties are trans to each other. Reactions of the phosphoranes ( 5 5 ) and (56) with iminium respectively, have been reported. chlorides56 and with ben~ylideneacetamides,~~

Reactions Relevant to Organic Synthesis.-Fluorophosphoranes continue to be used to convert various organic functions into fluorides. Thus a series of alcohols are converted into fluorides (57) by phenyltetrafluorophosphoranein methylene whilst the phosphorane (58) converts a-halogeno-ketones and epox52 53

54

V. S. Gamayurova, V. K. Gordeev, and B. D. Chernokalskii, J. Gen. Chem. USSR (Engl. Transl.), 1979, 49, 2464. M. J. C. Hewson and R. Schmutzler, Phosphorus Su(fur, 1980,8,9. G.-V. Roschenthaler, W. Stoner, and R. Schmutzler, 2. Nurut-forsch., Ted. B, 1980, 35, 1125.

55 58

57 58

R. M. Kren, A. H. Cowley, and M. V. Smalley, Inorg. Chim. Acta, 1980,43, 191. K. D. Gallicano, R. T. Oakley, and N. L. Paddock, J . Inorg. Nucl. Chem., 1980,42, 923. M. El-Deek, M. A. Hassan, and S. El-Hamshary, J . Indian Chem. Soc., 1980, 57, 1104. A. I. Ayi, M. Remli, R. Guedj, and R. Pastor, J. Fluorine Chem., 1981, 17, 127.

60

Orgartophosphorus Chemistry

OSiMe, I

0 II

CHO I

OSiMe, I

ides into fluorides at low t e m p e r a t u r e ~ The . ~ ~ same phosphorane (58) can also promote aldol condensation, as in the formation of (59) from a silyl enol ether.59 Treatment of epoxides with phosphine dichlorides leads to crystalline salts (60); on heating, these give 1,2-di~hloroalkanes.~~ The thermal stability of the salts (60) depends largely upon the other ligands on phosphorus, and falls across the series Ph, < Ph,Pr < PhEt, < Bu, < Et3.60

wR5

R3 0 RI,R2PCI,

+

la'20"c1

R4

R6

R2 R 3 R'

0

I I I R',POC-CCl + I I C1- R4 R6

[at

R3 R5

II I I * R',PR2 + ClC-CCI

35- 14oocj

I R6I

R4

(60) [ 65 -95701

Details have appeareds1 of the reactions of epoxides with the bisthiocyanate (61). The product mixtures can be complex,61depending upon the nature of the epoxide, as shown in Scheme 7 (major trends only!). Conversions of hydroxyl

CH*

Rl$

R'

Ph,P(SCN),

(61)

0

R2 +CH,SCN R' OH

SCN

Scheme 7 59

J. Leroy, J. Bensoam, M. Humiliere, C. Wakselman, and F. Mathey, Tetrahedron, 1980,36,

60

R. Appel and V. I. Glasel, 2. Nuturforsch., Teil. B, 1981, 36, 447. Y. Tamura, T. Kawasaki, H. Yasuda, N. Gohda, and Y. Kita, J. Chem. Soc., Perkin Trans. 1, 1981, 1577.

1931. 61

61

Halogenophosphines and Related Compounds

groups of sugars into iodide, using triphenylphosphine, iodine, and imidazole, have been shown to give high yields, and proceed with inversion.sz Deyhdration of a series of 14~-hydroxy-~teroids (62) with triphenylphosphinecarbon tetrachloride gives A14-steroidsin 50-92 % yield.63 The same reagent reacts with the oxolan-2,3-dione (63) to give Wittig products from either carbonyl When the ylide (64) is pre-formed, its reaction with (63) occurs at the ketone predominantly, and the authors speculate as to how the product that is obtained from attack at the lactone carbonyl group arises in the main reaction.

Ph,P=CCl,

(64)

A further study of reactions of lactones with triphenylphosphineand carbon tetrachloride shows that the formation of enol ethers (65) is restricted; e.g., y-lactones fail, as do ag-unsaturated lac tone^.^^ Other synthetic applications of these reactions are discussed in Section 1 of Chapter 1.

Ph,P,CCI,

62

63

64 e5

P. J. Garegg and B. Samuelsson, J. Chem. SOC.,Perkin Trans. I , 1980, 2866. F. Theil, C. Lindig, and K. Repke, 2. Chem., 1980, 20, 372. M. Suda and A. Fukushima, Chem. Lett., 1981, 103. M. Suda and A. Fukushima, Tetrahedron Lett., 1981, 22, 759.

4 Phosphine Oxides and Related Compounds BY J. A. MILLER

1 Introduction This has been a busy year for the synthetic chemistry of phosphine oxides, notably in the field of cyclic oxides. As in recent years, much of this effort has clearly been directed at general synthetic methods. Maybe next year's literature will justify all this activity! Another area of increased interest is that of X-ray structural analysis of phosphine oxides, although the field would benefit from efforts to relate different studies, and to develop useful structural guidelines.

2 Preparation of Acyclic Oxides Chiral tertiary phosphine oxides are not common, and therefore two new approaches to their synthesis are especially welcome. In the first of these, shown in Scheme 1, (-)-menthy1 bromoacetate is used to control the formation of the oxide (1) as one diastereoisomer only.' Subsequent hydrogenation and decarboxylation allowed the correlation of the configuration of (1) with that of ethyl(methy1)phenylphosphine oxide.

in

PhPCL,

PhPOBu"

Ph \p/

ROOC

0 zPh\p/o

/k

Mk'Et

(1) R = (-)-menthy1 Reagents: i, BunOH, Et3N; ii, HzC=CHMgBr; iii, BrCHzCOOR [R =( -)-menthyl]; iv, [Hz]; v, LiCl, aq. DMSO

Scheme 1

A menthyl unit is also used to control stereochemistry in the second method,e as outlined in Scheme 2. The key here is a fractional crystallization to give pure samples of the diastereoisomers of menthyl(methy1)phenylphosphine oxide (2). Diphenylphosphine oxide handles continue to be valued in the design of functionalized oxides for synthetic reactions. For example, the p-keto-phosphine oxide (3) undergoes Wittig-Horner reactionswith a range of carbonyl compounds3 to give unsaturated #I-keto-esters (4) (Nazarov reagents), which are potentially 1 8

R. Bodalski, E. Rutkowska-Olma, and K. M. Pietrusiewicz, Tetrahedron, 1980, 36, 2353. D. Valentine, J. F. Blount, and K. Toth, J. Org. Chern., 1980, 45, 3691. J. A. M. Van Den Goorbergh and A. Van Der Gen, Tetrahedron Lett., 1980, 21, 3621.

62

63

Phosphine Oxides and Related Compounds

(Neo = neomenthyl)

Me

Ph‘

( R1-(2)

(S)-(2)

(Men = menthyl) Reagents: i, Me1 [ 9 5 % yield]; ii, NaOH, heat [88% yield]; iii, fractional crystallization

Scheme 2

Ph,POEt + Br X

O

E

t

-

0

IJ

Ph,P

OEt

+ e n d ester

(Perkow)

(3)

(4) [52-90%]

Reagents: i, 2 equivalents of NaH, THF-HMPA; ii, R1R2CO

Scheme 3

useful in alicyclic synthesis. This sequence, and the preparation of (3), are outlined in Scheme 3. A related purpose has recently been achieved by using analogous phosphonates.* The functionalized allylphosphine oxides ( 5 ) have been prepared as ~ h o w n . ~ Tertiary phosphine oxides (6), available after alkylation of the aluminium chloride-chloro(dipheny1)phosphine complex, are no longer restricted to those derivable from a-halogeno-ethers or a-halogeno-sulphides.6A neat Diels-Alder route has been used to prepare the bis-phosphine oxide (7) in good overall Ph,PCI + (MeO),CHCH=CR1R2

*

0

II

+

ph2pm Me0

R1

( 5 ) [50-98%]

0 Ph,PCI*AICI,

(i) R X

I1

Ph,PR

(6) R. Bodalski, K. M. Pietrusiewicz, J. Monkiewicz, and J. Koszuk, Tetrahedron Lett., 1980, 21, 2287. M. Maleki, J. A. Miller, and 0. W. Lever, Tetrahedron Lett., 1981, 22, 365. K. A. Petrov, V. A. Chauzov, and S. V. Agafonov, J. Gen. Chem. USSR(Eng1. Transl.), 1980,50, 1227.

64

0rganophosphorus Chemistry

app 0

0

ClC--CCl

+

II

iiii

II Ph,PC--CCl

A Ph:PC=CPPh,

Ph,POLt

5

(8)

PPh,

I1

0 (7) [60'i;] Reagents: i, EtzO, at -20°C; ii, PhzPOEt; iii, 2H-pyran-2-one, at 180°C

Scheme 4

yield.7 The precursor (8) is available from di~hloroethyne,~ by a reaction which can easily be stopped at the stage of one displacement, as shown in Scheme 4. Alkyldiphenylphosphine oxides (9) may be prepared from carboxylic acids as shown. (a-Ha1ogenoalkyl)phosphine oxides (10) are available from a range of aldehyde^,^ as shown in Scheme 5 , and a 2 :1 oxide adduct has been found to be a readily isolated intermediate, at low temperatures, in the case of ben~aldehyde.~ When (10; X = Br) is formed, a subsequent dehalogenation occurs readily to give benzyldiphenylphosphine oxide. O The oxides (1 1) and (12) have been isolated from the analogous reactions of 0 PhzPCl

+ RCOOH

3

II

Ph2PCH,R ( 9 ) [ 35 - - S S X ]

0 PhZPX

+ 2RCH0

[at

II

20"c'l

Ph2PCHROCH(X)R [ R = Ph, X = C1; l O O V ]

( X = C1 o r Br)

1

IsO'cl

0

0

II

I1

Ph,PCHIPh

Ph,PCHXR 110)

Scheme 5 0

(1 1 ) 7 8

9 10

(1 2)

E. P. Kyba, S. P. Rines, P. W. Owens, and S.-S. P. Chou, Tetrahedron Lett., 1981,22, 1875. P. Sartori and G. Mosler, Phosphorus Sulfur, 1980, 9, 115. N. J. De'ath, J. A. Miller, M. J. Nunn, and D. Stewart, J. Chem. SOC., Perkin Trans. 1, 1981, 776. J. K. Michie, J. A. Miller, M. J. Nunn, and D. Stewart, J. Chem. SOC., Perkin Trans. 1, 1981, 1744.

Phosphine Oxides and Related Compounds

65

cyclohexanone with ch1orodiphenylphosphine.ll (p-Chloroalky1)phosphine oxides (13) are formed from aldehydes in an aberrant Wittig reaction.12 Treatment of the phosphorane (14) with t-butyl hypochlorite leads to a quantitative yield of the oxide (15). This somewhat surprising reaction can be reversed by using trich10rosilane.l~Photolytic cleavage of the acyl-phosphorus bond of acylphosphines leads to low yields of the oxides (16)14and (17).15 0

But

\

c1’

P=CHR2

+ RTHO

+ RFHCHR’P’

I

1

c1

R1

II

But

‘R1

(13) [28-80%]

0

-

II

ArCPPh,

rv

ButOCl

benzene

HO 0

I II

(15) [ l O O % ]

(14) [80%1

0

Bis(trimethylsilyloxymethyl)methylphosphine oxide (18) is formed in nearly quantitative yield when tris(trimethylsilyloxymethy1)phosphine is allowed to react with hydrogen chloride.16 This is a very interesting reaction to add to the growing list of those in which a-functionalized phosphorus(II1) compounds undergo redox reactions: see Chapter 4 of Volume 12 of this series for other examples.

HCI

(Me,SiOCH,),P

0

I1

MeP(CH,0SiMe3),

(18) [98%]

S. Kh. Nurtdinov, I. M. Kashirskaya, N. M. Ismagilova, R. Sh. Gubaidullinova, T. V. Zykova, R. A. Salakhutdinov, and V. S. Tsivunin, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 1049. 12 0. I. Kolodiazhnyi, Tetrahedron Lett., 198 1,22, 123 1. l3 M. R. Ross and J. C. Martin, J. Am. Chem. SOC.,1981, 103, 1234. l4 M. Dankowski and K. Praefcke, Phosphorus Sulfur, 1980, 8, 105. l5 M. Dankowski, K. Praefcke, J . 4 . Lee, and S. C. Nyburg, Phosphorus Sulfur, 1980, 8, 359. l 6 V. D. Romanenko, V. I. Tovstenko, E. S. Kozlov, and L. N. Markovskii, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 802. l1

Organophosphorus Chemistry

66

Halogen exchange in the oxide (19) is achieved by trimethylsilyl i0dide.l' Synthetic routes to oxides of general structure (20) have been reviewed.l* The formation of the monoselenide (21) and of the diselenide (22) from the corresponding diphosphines and selenocyanate ion has been described, and detailed n.m.r. evidence for structures (21) and (22) has been presented.le A 0

I/ (ClCH,),PPh (19)

Se

Se

-

I1 Ph ,PCH2CH2PPh, II

(22)

Me,SiI

0

0

II (ICHJ,PPh

I1

[ 60%1

0

I1 R',PP

,R2

-

L

C1CH2PR,

Ph2PCH2PPh,

(20)

(21)

R',POP,

/R2

-

OR^

' 0 ~ 3

0

llp2

R',PP

'OR3

(23)

further study of the relative stabilities of diphosphine mono-oxides and the isomeric phosphinous anhydrides (23) has been described.20 3 Preparation of Cyclic Oxides Work in this area is presented below, in order of increasing size of the heterocyclic ring. Camphene has been converted into the tricyclic phosphetan oxide (24),2fwhich is formed as only one isomer, under fairly standard conditions.

(24) [ 30%]

The phosphine sulphide (25) forms the 2-phospholen oxide (26) on treatment with methanesulphonic acid and phosphorus pentoxide.22Scheme 6 summarizes a very plausible interpretation of this reaction. Careful control of work-up conditions in a McCormack addition allows isolation of the 3-phospholen 1-oxides (27), where R represents a protected ketone or alcohol, from which the protecting group may also be removed without isomerization of the 3-phospholen l7 18

V. D. Romanenko, V. I. Tovstenko, and L. N. Markovskii, Synthesis, 1980, 823. E. N. Tsvetkov, T. E. Kron, and M. I. Kabachnik, Bull. Acad. Sci. USSR, Diu. Chem. Sci., 1980, 491.

19 20

S . W. Carr and R. Colton, Aust. J . Chem., 1981, 34, 35. V. L. FOSS,V. V. Kudinova, and I. F. Lutsenko, J. Gen. Chem. USSR (Engl. Transl.), 1979, 49, 2462.

21

E. Vilkas, M. Vilkas, J. Saiton, B. Meunier, and C. Pascard, J. Chem. SOC.,Perkin Trans. I ,

22

C . H. Chen and K. E. Brightly, Tetrahedron Lett., 1980,21,4421. L. D. Quin and J. E. Macdiarmid, J. Org. Chem., 1981, 46, 461.

1980, 2136. 23

Phosphine Oxides and Related Compounds S

67

S Me

(25)

0 Me-P

0

II

\

\

(26)

MeSocOH,

Reagents: i, H + ; ii, MeSOsH

Scheme 6

(27)

The phosphole oxide dimers (28) have been cleanly deoxygenated by triThe 7-phosphanorbornene products chlorosilane in the presence of ~yridine.~* are clearly very unusual compounds, on account of their abnormally deshielded 31Pn.m.r. shifts: see Section 1 of Chapter 1 and Chapter 11 for other details.

R

(28)

Further ring-expansions of phospholes to phosphorin oxides have been reported. That leading to the phosphorin oxide (29) proceeds via a 1,Zaryl shift,

07

-_ qp /CH,Ph

OH \CH,Ph

Ph

O\ OH

(29) Reagents: i, HSiC13; ii, PhCOCl, EtsN; iii, HzO

Scheme 7 24

L. D. Quin and K. A. Mesch, J. Chem. SOC.,Chem. Commun., 1980,959.

0rganophosphorus Chemistry

68

dF'h

HCI, dioxan heat

+ R*PH,

(30) [ RZ= Ph or H , 4-50761

and not a 1,2-vinyl shift (Scheme 7).25The oxides (30) have been prepared in low yield, as 27 The phosphine oxide (31) has been converted into the phosphorus analogues of lilolidine (32) and of julolidine (33),28as outlined in Scheme 8. Each ringconstruction rests on the facile metallation of the methyl groups of (31), in turn. In one of the steps, the oxide (34) is a major by-product, and its formation is explained in terms of a very unusual ipso-ring-closure.2s

if

\I,

iii, iv

(33)

(32)

Reagents: i, BunLi; ii, MezCHCHO; iii, H+, heat; iv, HSiCl3; v, MezCO

Scheme 8

Phosphacannabinoid derivatives have been made29 by taking advantage of the known3(' phosphorinan l-oxide (35). Stereoelectronic factors would seem to 26

F. Nief, C. Charrier, F. Mathey, and M. Simalty, Nouu. J. Chirn., 1981,5, 187. V. I. Vysotskii, S. M. Kalinov, and M. N. Tilichenko, J . Gen. Chem. USSR (Engl. Transl.),

27

V. I. Vysotskii, S. M . Kalinov, and M. N. Tilichenko, J. Gen. Chem. USSR (Engl. Transl.),

25

1979,49, 2463. 28 29

30

1980, 50, 1383. C. H. Chen, K. E. Brightly, and F. M. Michaels, J. Org. Chem., 1981, 46, 361. J. B. Rampal, K. D. Berlin, N. S. Pantaleo, A. McGuffy, and D. Van Der Helm, J. Am. Chem. SOC., 1981, 103, 2032. B. A. Arbuzov, 0. A. Erastov, S. N. Ignateva, T. A. Zyablikova, and E. I. Goldfarb, Bull. Acad. Sci. USSR, Diu. Chem. Sci., 1978, 27, 1339.

69

Phosphine Oxides and Related Compounds 0

0

(R = Me or C,H, ,) [ 37-43%]

(35)

control the alkaline cleavage of the dibenzorb,flphosphepin 1-oxide (36), since diphenyl(o-toly1)phosphine oxide cleaves its different P-C bonds in a statistical 2 : 1 ratio.31 The best available route to (36) is that shown in Scheme 9.31

(36) Reagents: i, 2 equivalents of BunLi; ii, PhPClz; iii, H202; iv, NaOH, heat; v, Hi

Scheme 9

One of the highlights of the year has been the synthesis32of the phosphonin 1-oxide (37), using a McCormack cycloaddition-ozonolysis sequence,33as shown in Scheme 10. The intermediate diketone (38) has been found to exist as two non-interconverting isomers, and the oxide (37) has double-bonds of different geometries. For strangers to the field of phosphorus heterocycles, an expert, yet thoroughly readable, account of the subject has now been published,34and it should facilitate chemical appreciation of the new work described in this section.

4 Structural and Physical Aspects Following recent activity in the synthesis of phosphine oxides, there is now a rush of X-ray structural work, notably on cyclic phosphine oxides. The work of Galdecki and Glowka is prominent in this field, and has included studies of the oxides (39),35(40),36(41),37 (42),38(43),39(44),40and (45).41 It will be apparent that a number of these oxides are of interest because of their relationship to natural systems, e.g. sugars and terpenoids. 31

32 33 34 95

36 37 38 39 40

41

Y. Segall, E. Shirin, and I. Granoth, Phosphorus Sulfur, 1980, 8, 243. E. D. Middlemass and L. D. Quin, J. Am. Chem. SOC.,1980, 102, 4838. L. D. Quin and E. D. Middlemas, J. Am. Chem. SOC.,1977,99, 8370. L. D. Quin, ‘The Heterocyclic Chemistry of Phosphorus’, John Wiley, New York, 1981. Z. Galdecki and M. L. Glowka, Acta Crystallogr., Sect. B, 1980, 36, 1495. M. L. Glowka and Z. Galdecki, Acta Crystallogr., Sect. B., 1980, 36, 2312. Z. Galdecki and M. Glowka, Acta Crystallogr., Sect. B., 1980, 36, 2809. Z. Galdecki and M. L. Glowka, Acta Crystallogr., Sect. B, 1980, 36, 2191. Z. Galdecki and M. L. Glowka, Acta Crystallogr., Sect. B., 1981, 37, 459. Z. Galdecki and M. L. Glowka, Acta Crystallogr., Sect. B., 1980,35, 2191. Z. Galdecki, M.L. Glowka, and B. Golinski, Acta Crystallogr., Sect. B., 1981, 37, 461.

70

,XPh -

Organophosphorus Chemistry

i-iii

0HL‘Ph

v

iv, v i

vi, vii

0/ \ Ph

ON ‘Ph

(37) (58761

(38) [58%]

Reagents: i, PhPBrz; ii, HzO; iii, hv, 12, 0 vi, NaBH4; vii, Poc13, pyridine

[ 5 6 % yield]; iv,

2

0 3 ,

MeOH; v, KI, AcOH;

Scheme 10

Hob OH b h

(39)

(42) R = Me (43) R = H

(44)

(45 1

0

h:

Ph

SH ’Ph

(46) R = H (47) R = Me

II

MeQ::OR SN ‘Ph

(48) R

=

Me

(49) R = H

71

Phosphine Oxides and Related Compounds

Other cyclic compounds to be subjected to X-ray structure analysis include the sulphides (46),42(47),43(48),44 and (49).45The oxide (50)46has been found to exist as a hydrogen-bonded dimer. Structures have also been reported for the bisphosphine oxide (5 1) 47 and for the triphenylphosphine oxide-zinc chloride complex (52).48 Chapter 1 1 contains other comments on X-ray work. Dipole moments and Kerr constants have been measured for the phosphorinanones (53).49 Various conformational and vibrational spectral data on tetraallyldiphosphine disulphide (54;R = allyl) have been published.50 Other studies on disulphides include photoelectron spectra of (54; R = Me)51 and n.m.r. in 1,Zdiphosphine d i ~ u l p h i d e s . ~ ~ coupling constants

1s

Zn(OPPh,),Cl,

R,P -PR,

( 5 2)

(5 4)

5 Reactions at Phosphorus

The phosphole sulphide ( 5 5 ) has been converted into a Diels-Alder adduct, and this, in turn, has been used to prepare the 7-phosphanorbornene (56).53Chromatography of (56) on silica gel causes partial inversion at phosphorus, and uncovers another i l l ~ s t r a t i o nof~ ~the remarkable deshielding that is associated with SP in the compound (56), with its syn geometry: see Scheme 1 1 . Details have appeared of the trapping of phosphinidene sulphide or oxide, which are extrusion products from the photolysis of (57).54 The most successful system is illustrated (other attempts were less successful).

43

J. B. Ramdal, G. D. MacDonell, J. P. Edasery, K. D. Berlin, A. Rahman, D. Van Der Helm, and K. M. Pietrusiewicz, J. Org. Chem., 1981, 46, 1156. J. B. Ramdal, K. D. Berlin, J. P. Edasery, N. Satyamurthy, and D. Van Der Helm, J. Org.

44

R. B. Knott, H. Honneger, A. D. Rae, F. Mathey, and G. de Lauzon, Cryst. Strucr.

45

D. C . Craig, M. J. Gallagher, F. Mathey, and G. de Lauzon, Cryst. Struct. Commun., 1980,

42

Chem., 1981,46, 1166. Commun., 1980, 9 , 905. 9, 901. 46 47

48

V. V. Tkachev, N. A. Bondarenko, E. I. Matrosov, E. N. Tsvetkov, L. 0. Atovmyan, and M. I. Kabachnik, Izu. Akad. Nauk. SSSR, Ser. Khim., 1981, 211. M. Yu. Antipin, Yu. T. Struchkov, S. A. Pisareva, T. Ya. Medved, and M. I. Kabachnik, Zh. Strukr. Khim., 1980, 21, No. 5, p. 101. J. P. Rose, R. A. Lalancette, J. A. Potenza, and H. J. Schugar, Acta Crystallogr., Sect. B, 1980,36, 2409.

49 50

51

I. I. Patsanovskii, E. A. Ishmaeva, A. P. Logunov, Yu. G. Bosyakov, B. M. Butin, S. K. Shishkin, and A. N. Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1980,50,417. A. J. Blake, G. P. McQuillan, and I. A. Oxton, Spectrochim. Acta, Part A, 1980, 36, 501. L. Alagna, C. Cauletti, A. Marco, C. Furlani, and G. Haegele, Z . Naturforsch., Ted. A , 1981, 36, 68.

52 53 54

R. Couffignal, H. B. Kagan, F. Mathey, 0. Samuel, and C. Santini, C . R. Hebd. Seances Acad. Sci., Ser. C., 1980, 291, 29. F. Mathey and F. Mercier, TetrahedronLett., 1981,22, 319. H. Tomioka, S. Takata, Y. Kato, and Y. Izawa, J. Chem. SOC., Perkin Trans. 2, 1980, 1017.

Organophosphorus Chemistry

72

+ 0

0

(55)

)

-iv

[ a p = 64 p.p.m.1

( 5 6 ) [ S p = 118.4 p.p.m.1

Reagents: i, MeOH; ii, NiCpz; iii, HzC=CHCHzI; iv, N-methylimidazole

Scheme 11 S

Me - M e

LJ x//

hu, MeOH

+ [PhP=S]

[X = S]

MeOH hv h

II

PhP(OMe),

[ 27%]

'Ph

(57) X = S o r O

Deoxygenation of triphenylarsine oxide ( 5 8 ) , using arsenic trichloride, has been described.55 Differential thermal analyses of rearrangements of arsine sulphides, e.g. (59), have been Transfer of tellurium from tri-n-butylphosphine telluride leads to the telluride (60),and this, in turn, has been found to rearrange to a phosphorus(II1) ester.57 R,As=X ( 5 8 ) R = Ph, X = 0 (59) R = PI, X = S

Bu ",P =Te

+ But,PSiMe,

Te

II

--+ Bu',PSiMe,

+ But,P-Te-SSiMe,

(60)

6 Reactions of the Side-Chain The problem of geometric control in the synthesis of alkenes via Wittig-Homer reactions has been successfully tackled,5s as shown in Scheme 12. The synthesis 55

V. S. Gamayurova, V. K. Gordeev, and B. D. Chernokalskii, J. Gen. Chem. USSR (Engl.

56

Yu. F. Gatilov, and V. A. Perov, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 309. W.-W. Du Mont, Angew. Chem., Znt. Ed. Engl., 1980, 19, 554. A. D. Buss and S . Warren, J. Chew. Soc., Chem. Commun., 1981, 100.

Transl.), 1979, 49, 2464. 57

58

73

Phosphine Oxides and Related Compounds 0

0

OH

(61) [ 90%erythro]

0

II Ph,PCHR'COR2

0

OH

II I PbPCHR'CHR2

A

(61)

R'k 'R2

[ 85% rhreo] Reagents: i, R2CHO; ii, HzO; iii, NaH, DMF; iv, RZCOOEt; v, NaBH4; vi, NaH, DMF

Scheme 12

of each pure alkene isomer relies upon different diastereoisomeric compositions of the oxides (61), depending upon their origins. In each case, the final step involves an elimination, using sodium h ~ d r i d e . ~ ~ or-Diazomethyl(dipheny1)phosphine oxide (62) has been photolysed in the presence of keten dimer, to give both geometric isomers of the adduct (63).59The analogous phosphonates have been used in a synthesis of cycl~pentanedione.~~ 0

More chemistry of carbenes with diphenylphosphinoyl handles has come from Regitz and co-workers.60~61 Details of this trapping work on the carbene (64), using carbonyl compoundsso or using chalcones,61are given in Scheme 13. An expectedly simple Friedel-Crafts alkylation of benzenes, using 3-phospholen oxides, has been reported.62The conditions require aluminium chloride as catalyst, and the limitations on structure of reactants are quite stringent, although in favourable cases, e.g. (65) and (66), the yields of product can be good.62 A detailed description of the products from various epoxidations of 2-phospholen 1-oxides and 3-phospholen 1-oxides has appeared.g3 Some examples appear in Scheme 14, along with an example of how stereo- and regio-selective the subsequent opening of the epoxide ring can be. 59 60 61 62

63

T. Kato, N. Katagiri, and R. Sato, J. Org. Chem., 1980,45, 2587. M. Regitz and H. Eckes, Chem. Ber., 1980, 113, 3303. M. Regitz and H. Eckes, Tetrahedron, 1981, 37, 1039. J. E. MacDiarmid and L. D . Quin, J. Org. Chem., 1981, 46, 1451. L. D . Quin, C. Symmes, E. D. Middlemass, and H. F. Lawson, J . Org. Chem., 1980, 45, 4688.

Organophosphorus Chemistry

74 Ph @

r

Ph

0

2

\

P h0 /fPh

H

R ivf

0

(64)

Reagents: i, TsN3; ii, PhLi; iii, h v ; iv, RCHO; v, ArCOCH=CHAr; vi, heat

Scheme 13

KJ ’0

- i, I

p,

’ 0

‘Me

“Me

[81%]

[63%]

[ 74%]

Reagents: i, m-ClPBA; ii, RNH2

Scheme 14

Phosphine Oxides and Related Compounds

75 Ph

ZAICI, benzene

dMe oH'\Me

OH \Me

( 6 5 ) [2 isomers, 75%)

Me AICI, [at 85'Cj

(66) [ 1 isomer, 30%]

20R

(67) R = Me or CF,

Further examples have demonstrated the extremely high reactivity of the as shown for the oxide (67).65 carbonyl group of acylphosphine 7 Phosphine Oxide Donor-Acceptor Complexes, and Extractants An infrared study of complexes between aryl(dimethy1)phosphineoxides (68) and phenol has been reported, and details of the preparation of (68) have also been given.66 The diphosphine derivatives (69) have been studied as participants in host-guest inclusion complexes with various pure Hydrogen-bonding in 2 : l complexes of triphenylphosphine oxide with perchloric acid has been described.68 Complexes of tertiary phosphine oxides or sulphides with various metal salts continue to be isolated. Thus complexes of triphenylphosphine oxide with copper(I1) a l k a n o a t e ~ ,with ~ ~ nickel(I1) chloroa~etates,~~ and with rare-earth acetylacetonates 71 have been reported, as have complexes of tertiary arylphos64

65

66

67 68 69

70

1'

E. Lindner and G. Frey, Chem. Ber., 1980, 113, 3268. E. Lindner and G. Frey, Z. Naturforsch., Ted. B, 1980, 35, 1150. L. V. Goncharova, A. A. Shvets, Yu. I. Sukhorukov, 0. A. Osipov, and L. N. Talanova, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 258. D. H. Brown, R. J. Cross, P. R. Mallinson, and D. D. MacNicol, J. Chem. SOC., Perkin Trans. 2, 1980, 993. M. Yu. Antipin, A. E. Kalinin, Yu. T. Struchkov, E. I. Matrosov, and M. I. Kabachnik, Krystallografiya, 1980, 25, 514. N. Kumar, P. L. Kachroo, and R. Kant, J. Indian Chem. SOC.,1980. 57, 98. N. Kumar, P. L. Kachroo, and R. Kant, Bull. Chem. SOC.Jpn., 1980, 53, 1787. B. T. Khan and S . F. Ali, Indian J. Chem., Sect, A , 1980, 19, 701.

Organophosphorus Chemistry

76

x

x

I/ II Ph,P(CH,) PPh, (68) X = H, OMe, or NMe,; Y = H X=H,Y=NO,

0

0

(69) n = 2 or 3 , X = S or Se

0

ll ll II Ph,PCH, PCH,PPh, I

Ph

(70)

phine sulphides with HgT1,PdII, and PdIV,72and with ZnII and Hg11.73Complexes of the trioxide (70) with halides of CuII and CoII have been de~cribed.'~ Other efforts have concentrated on 31Pand other n.m.r. aspects of complexes, e.g. those of tributylphosphine sulphide or selenide with halides of CdII or HgII.75-77The last of these studies'' also involved the use of selenium-77 and mercury-119 n.m.r. Tri-n-octylphosphine oxide (71) still remains a popular subject for investigation of extractant properties, having been used for sodium uranium(v~),~ chromium(vI),81 neptunium(1v) and plutonium(Iv),82 zinc(^^),^^ europium,84and various metal perch lor ate^.^^ Other extractant systems that have been studied include bis(dipheny1phosphinoy1)methane (51), for americium86 and for rare-earth element^.^^ Physicochemical properties of complexes of tributylphosphine oxide with uranium(1v) and uranium(v1) have been described.88 99

72

R. K. Singh, S . K. Singh, and E. B. Singh, Indian J. Chem. Sect. A , 1981, 19,1212.

73

T.S. Lobana, S . S . Sandhu, and T. R. Gupta, J. Indian Chem. SOC.,1981, 58, 80. E. 1. Sinyavskaya, S. A. Pisareva, N. I. Tsokur, T. I. Ignateva, and M. P. Komarova, Zh.

74

75 76

77 78 79

8o

81 82

83 85 86

87

88

Neorg. Khim., 1981, 26, 1274. S. 0. Grim, E. D. Walton, and L. C. Satek, Can. J. Chem., 1980,58, 1476. P. A. Dean and L. Polensek, Can. J. Chem., 1980,58, 16. I. J. Colquhoun and W. McFarlane, J. Chem. SOC.,Dalton Trans., 1981, 658. S. Kusakabe and T. Sekine, Bull. Chem. SOC.Jpn., 1980, 53, 1759. M. Konstantinova and S . Mareva, Dokl. Bolg. Akad. Nauk, 1980,33, 515. Y. Shigetomi, T. Kojima, and H. Kamba, Talanta, 1980, 27, 1079. M. V. Murty, V. M. Rao, and M. N. Sastri, J. Indian Chem. SOC.,1980, 57, 688. S. K. Patil, V. V. Ramakrishna, P. K. Kartha, and N. M. Gudi, J. Radioanal. Chem., 1980, 59, 331. S. M. Pushparaja, Indian. J. Chem., Sect. A , 1980, 19, 998. K. Akiba, M. Wada, and T. Kanno, J. Znorg. Nucl. Chem., 1981, 43, 1031. S. Kusakabe and T. Sekine, Bull. Chem. SOC.Jpn., 1980, 53, 2087. M. N. Litvina, M. S. Milyukova, and B. F. Myasoedov, Radiokhimiya, 1980, 22, 374. M. K. Chmutova, M. P. Novikov, 0. E. Koiro, and B. F. Myasoedov, Radiokhimiya, 1981, 23, 192. I. A. Volodin, L. V. Kotova, T. V. Kolyvanova, M. A. Kovalenko, and E. A. Filippov, Radiokhimiya, 1980, 22, 414.

5 Te rvaIe nt Ph0 s phorus Acids BY B. J. WALKER

1 Introduction Some of the most interesting results this year are in the area of compounds that contain two co-ordinate phosphorus; however, almost all of this work is still being carried out by two or three, albeit prolific, research groups.

2 Phosphorous Acid and its Derivatives Nucleophilic Reactions.-Attack on Saturated Carbon. Examples of the use of the Arbusov reaction include the synthesis of a new series of antiviral agents (l),l phosphonyl vinyl isocyanate derivatives (2),2 and 4-oxoazetidin-2-yl-phosphonates (3) and -phosphinates (4).3On further reaction, the last examples provide routes to #?-phosphono-(5) and #?-phosphino-derivatives ( 6 ) of p-alanine. 0

0

11 //N-N (HO),PCH,C \N,N R

MeOPC1, + BrCHNCO --+

I

CH,Br

(3) R' = OR2 (4) R' = alkyl

I1 Cl$CHNCO

-

0

Et,N

II

CJPCNCO

CH,Br

II

CH,

( 5 ) R' = OH ( 6 ) R' = alkyl

The Arbusov reaction has also been used to prepare 1- and 2-formyl phosphonates, (7) and (8), via the corresponding acetals (Scheme l), and hence to provide a route to aminocarboxyalkylphosphonates;4N-(diphenylphosphinyl1 2

4

J. J. Yaouanc, G. Sturtz, J. L. Kraus, C. Chastel, and J. Colin, Tetrahedron Lett., 1980,21, 2689. E. A. Stukalo, E. M. Yur'eva, and L. N. Markovskii, Zh. Obshch. Khim., 1980, 50, 343 (Chem. Abstr., 1980, 93, 26 508). M. M. Campbell and N. Carruthers, J. Chem. Soc., Chem. Commun., 1980, 730. J. M. Varlet, G. Fabre, F. Sauveur, N. Collignon, and P. Savignac, Tetrahedron, 1981, 37, 1377.

77

Organophosphorus Chemistry

78

0

Br(CHJ,CH(OEt),

PbPCH,NHCHO

Scheme 1

Ph POEt

I

(EtO),P(CH,),CHO

(7)n= 1 (8) n = 2

Reagents: i, (Et0)3P; ii, H30”

0

%

0 -

Me,IkH,NHCHO

(Et O),P

*

II

(Et 0),PCH, NHCH0

methy1)formamide and the corresponding phosphonate (1 1)6 are available by analogous reactions of the quaternary ammonium salt (9). Attempts to carry out Arbusov reactions with activated halides can lead to complications, and the reaction of the trichlorobenzodioxole(12) with the amide esters (13) and (14) is no exception.’ The Arbusov product is formed in low yield, and formation of the dioxaphosphole (1 3,probably via initial alkylation at nitrogen rather than phosphorus, is the major pathway.

(1 3) R = NMe, (14) R = OEt

R +/

J OCH=NMe,

c10

C1-

“c1a > C/ H!(NMe2)R

c1 OP(0Et)R

“aa >/P O E t

+ RCH=kMe,

Cl-

(15) 5 6

7

J. Rachon and U. Schollkopf, Liebigs Ann. Chem., 1981, 99. J. Rachon, U. Schollkopf, and T. Wintel, Liebigs Ann. Chem., 1981, 709. B. Costisella and H. Gross, Phosphorus Suvur, 1980, 8, 99.

+ EtCl

Tervalent Phosphorus Acids

79

Stable Arbusov intermediates continue to be of interest. Those formed from the cyclic phosphinite (16), i.e. (17), are thought to be on the borderline between phosphonium salts and phosphoranes, on the basis of n.m.r. and dipole-moment evidence.8

(17a) R = Me, X = I (17b) R = PhCH,, X = Br

R'

\

Cl'

0

R2

+ (R*O),P

C-C' 0 ''

+

II

R'COCR2R3P(0R1),+ R'CI

'R-?

(1 8)

b-Ketophosphonic esters (18) have been prepared by the reaction of or-chloroepoxides with trialkyl pho~phites.~ The new route overcomes the problem of the Perkow reaction (leading to enol phosphates) which is associated with similar reactions of or-halogeno-ketones. Attack on Unsaturated Carbon. Arbusov reactions with vinyl halides have been used to prepare a variety of vinylphosphonates, e.g. (19) and (20).1° Variations include the use of catalysis by palladium of the addition of a secondary phosphite, which provides a stereoselective route to vinylphosphonates,ll and the photostimulated reaction of diethyl phosphite anion with vinylmercurials.12 In the latter case, the reaction appears to take place by a free-radical mechanism. 0

F 2 C = = C F X+ (ROXP

I1 + (RO)2PCF=CFX

0

0

I1 ll + (RO)2PCF=CFP(ORX

The numerous reports of the addition of tervalent phosphorus to alkenes and related compounds include reactions with p-benzoquinone dibenzenesulphonimide,13 quinone mono xi me^,^^ and fuch~0ne.l~ Treatment of the azoalkene (21) with phosphites gives mixtures of diazaphsspholes (22) and the derived acyclic compounds (23), depending on the tervalent phosphorus compound.16 I. Granoth and J. C. Martin, J. Am. Chem. Soc., 1981, 103, 2711. J. Gasteiger and C. Herzig, Tetrahedron Lett., 1980, 21,2687. l o R. Dittrich and G . Hagele, Phosphorus Sulfur,1981, 10, 127. l1 T. Hirao, T. Masunaga, Y.Ohshiro, and T. Agawa, Tetrahedron Lett., 1980, 21, 3595. 1 2 G. A. Russell and J. Hershberger, J. Am. Chem. SOC.,1980, 102, 7603. 13 M. M. Sidky, M. R. Mahrau, and M. F. Zayed, Phosphorus Sulfur,1980, 9, 337. 14 M. M. Sidky, M. F. Zayed, A. A. El-Kateb, and I. T. Hennawy, Phosphorus Sulfur, 1980, 9, 343. 15 Yu. G. Shermolovich, L. N. Markovskii, Yu. A. Kopel'tsiv, and V. T. Kolesnikov, Zh. Obshch. Khim, 1980, 50, 811 (Chem. Abstr., 1980, 93, 95 344). l6 G. Baccolini, P. Todesco, and G. Bartolli, Phosphorus Sulfur, 1980, 9, 203. 8

80

Organophosphorus Chemistry

0

Examples of the nickel(@-chloride-catalysed reaction of tervalent phosphorus with aromatic halides include the synthesis of the phosphonate (24), en route to phosphindolin-3-one (25).17 The mechanism of this general reaction has been investigated.ls In the absence of the aromatic halide, triethyl phosphite and nickel(@ chloride form tetrakis(triethy1 phosphite)nickel(o), and this compound is an effective catalyst for the conversion of iodobenzene into the phosphonate (26). On the basis of this observation and a competitive kinetic study of three para-substituted iodobenzenes, the mechanism shown in Scheme 2 has been suggested. Dialkyl pyridin-4-yl- (27), quinolin-4-yl-, and isoquinolin-1-yl4(EtOXP + NiCI, -+ [(EtOXP],Ni

5

ArNi[(EtO),P],I

I

(Slow) (- Ni")

0

II ArP(OEt), + EtI

+-

Ar$(OEt), 1-

(26) Scheme 2

$%b 0

\\P(OR),

H

+ (RO),P

.:-/. 0 17

1.9

0

\\

€'(OR), +

A H

(27) 0

T. M. Balthazor, J. Org. Chem., 1980, 45, 2520. T. M. Balthazor and R. C. Grabiak, J. Org. Chem., 1980, 45, 5425.

Tervalent Phosphorus Acids

81

phosphonates have been synthesized regiospecifically by the reaction of trialkyl phosphites with the corresponding N-(2,6-dimethyl-4-oxopyridin-l-yl)-heterocycle in the presence of sodium iodide.ls Similar reactions are successful with acridinium and xanthylium ions, but not with the 2,6-diphenylpyrylium salt (28), and the synthesis of the phosphonate (29)20 and of the thio-analogue (30)2f requires the use of sodium diethyl phosphonate. On the other hand, even nitrogroups can be replaced by secondary phosphites if the aromatic ring is sufficiently activated and the conditions are sufficiently severe.22

Cl0,-

(29) X = 0 (30) X = S

(28)X = 0 or S

The widely studied reactions of phosphines with electrophilic acetylenes have been extended to p h ~ s p h i t e sIn . ~these ~ cases the intermediates appear to be more stable, and a series of compounds can be detected by careful control of the reaction temperature. Structures have been suggested for these on the basis of 31P, 13C, and lH n.m.r. spectroscopic evidence and the isolation of the Arbusov product (31) on treatment with hydrogen bromide at - 10°C (Scheme 3).

/x \c/x

(ROhP-C

(ROXP + XC-CX

(at -50°C)

(X = C0,Me)

X L X h t - 10°C)

JX'J3

RO'

'OR

Scheme 3

The reactions of phosphites with imino-groups continue to be reported. This year, oximes appear to be popular substrates; for example, acetone oxime gives the 0-methylhydroxylamine phosphonate (32) with trimethyl phosphite2* and l9 20 21

22 23 24

A. R. Katritzky, J. G . Keay, and M. P. Sammes, J. Chem. Soc., Perkin Trans. I , 1981, 668. C. H. Chen and G . A. Reynolds, J. Org. Chem., 1980,45,2449. C. H. Chen and G . A. Reynolds, J. Org. Chem., 1980,45,2453. G . L. Matevozyan, S. N. Vodovatova, and P. M. Zavlin, Zh. Obshch. Khim, 1980,50,2803. J. C. Tebby, S. E. Willetts, and D. V. Griffiths, J. Chem. SOC.,Chem. Commun., 1981, 420. M. P. Osipova, P. M. Lukin, and V. A. Kukhtin, Zh. Obshch. Khim., 1980, 50, 1887 (Chem. Absrr., 1980, 93, 220 863).

Organophosphorus Chemistry

82

0

II

(MeOXPCMe2NHOMe

(MeO),P

Me,C=NOH

(32)

( R O ) , F O Nat

,NHP(OR),

Me2C

\

0

(R'O)2PNC0

(34)

the diphosphonate (33) with sodium dialkyl p h o s p h i t e ~ .The ~ ~ reaction of isocyanatophosphites (34) with various trichloroethylideniminesleads to cyclic products (35).26 Full details have appeared of the synthesis of stilbenes by the reaction of sodium diethyl phosphite with aromatic aldehyde^.^' The suggested mechanism involves the formation of oxiran intermediates (36), followed by further attack of phosphite anion to give the Wadsworth-Emmons intermediate (37), and hence

0

/

/"\

+ ArHC-CHAr

(EtOhPt;

0

Ar

Ar

C=C

H

'

+(EtO)2P---0 \Ar

f-

(34)

\

/

/

\

HC-CH

-0

Ar

(37) 25

26 27

M. G . Zimin, A. R. Burilov, and A. N. Pudovik, Zh. Obshch. Khim., 1980,50,751 (Chem. Absrr., 1980, 93, 71 873). I. V. Konovalova, R. D. Gareev, L. A. Burnaeva, M. V. Cherkina, A. Khayarov, and A. N. Pudovik, Zh. Obshch. Khim., 1980, 50, 1446 (Chem. Abstr., 1980, 93, 220 847). T. Minami, N. Matsuzaki, Y . Ohshiro, and T. Agawa J. Chem. SOC., Perkin Trans. I , 1980, 1731.

Tervalent Phosphorus Acids

83

stilbene. In most cases, similar reactions with aromatic ketones did not give any alkene; however, the sterically less hindered compound fluorenone gave 9,9’bifluorenylidene (38) and the spiro-ketone (39). A similar reaction of diethyl 1-[(N-sodio)anilino]cyclohexylphosphonate (40) with aromatic aldehydes provides a route to the isomeric oxirans (41). Amides of tervalent phosphorus acids generally undergo a reaction with aldehydes which involves a rearrangement; for example, the 2-anilidophospholan (42) reacts with benzaldehyde to give (43) and (44),28and the accompanying ring-opened product (45) is presumably the result of hydrolysis.

k B==8 +

0 + (EtOXP=O

\ /

\

/

I@h Na’

(><

+ArCHO

4

/p(oEt)2

ArHC-CHh

‘ 0 ’

0

(41)

(40)

NHPh O”\O

X (42)

0

x\p/CHRPh

I1

0 ’ ‘0

+ PhCHO

+ HO(CHMe),OPCHPh NHPh

X

(43)X = 0, R = PhNH (44) X = PhN, R = OH

OH (45)

Routine reports of the reactions of secondary p h o ~ p h i t e s3~0 ~and . phosphonwith substituted cyclopentadienones continue to appear. The reaction of hexamethylphosphorous triamide with derivatives of carboxylic acids has been in~estigated.~’ In all cases there is substitution of one or more dimethylamino-groups to give tervalent phosphorus compounds, e.g. (46), and (Me,N),P + n (MeCO), 0

+ (Me,N),

-

,,P(OCOMe),

+ MeCONMe,

(46) 28 29

30 31

M. M. Yusupov, A. M. Abramova, N. K. Rozhkova, and E. L. Kristallovich, Uzb. Khim. Zh., 1980, No. 3 , p. 56 (Chem. Absrr., 1981,94,4069). B. A. Arbusov, A. V. Fuzhenkova, and N. I. Galyatdinov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 904 (Chem. Absrr., 1980,93, 114 619). B. A. Arbusov, A. V. Fuzhenkova, N. I. Galyatdinov, and R. F. Shaikhullina. Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1119 (Chem. Absrr., 1980,93, 114 635). J. H. Hargis and G . A. Mattson, J. Org. Chem., 1981, 46, 1597.

4

Organophosphorus Chemistry

84 0-

MeCOX

-

I MeCX I

+ (Me, N),P

A

.P+

MeCO

I <-P+

Me,N- / Me,N

\

NMe, ,,NMe,

X-

* Me,N-P- I 1

’COMe X

NMe2

Me,N’,/ \ NMe, Me,N

/

J

0

II

(X = C1, MeCO--,

(Me,N),PX + MeCONMe,

or O,N

Scheme 4

the results support a mechanism involving initial attack of phosphorus at carbonyl carbon, as shown in Scheme 4. Attack of phosphorus on carbonyl carbon appears to be the initial step in the reaction of trimethyl phosphite with trans-but-2-enoyl However, the products that are isolated depend on the proportions of the reagents used ; for example, dimethyl trans-but-2-enoylphosphonate(47) from reaction when there is an excess of acid chloride and the diphosphonate ester (49)when equimolar quantities are used. N.m.r. evidence is presented to support the intermediacy of the oxaphospholen (48) in the formation of (49). 0

0

II

0

-

(MeOXP-CHMe

II

(MeO),PCHMeCH=C

WCOCI

\

\

O (49)

I

I

x

O

Full details have appeared of the reactions of silyl phosphites with a-halogenocarbonyl compounds and their implications for the mechanism of the Perkow Predictably, three types of products were isolated, i.e. the Perkow product (50), the Arbusov product (51), and the 1 : 1 adduct (52). The proportions of these products depended both on the substituents that were on the a-halogenocarbonyl compound and on the silyl phosphite that was used. From these product distributions, the authors have suggested that the initial step in the reaction is attack of phosphorus on carbonyl carbon. 32 33

A. Szpala, J . C. Tebby, and D. V. Griffiths, J. Chem. SOC.,Perkin Trans. I , 1981, 1363. M. Sekine, K. Okimoto, K. Yamada, and T. Hata. J. Org. Chem., 1981, 46, 2097,

Tervalen t Phosphorus A cids

85

X

I

(R40), P(OSiMe,),_ ,, + R’ R2C-COR3 (n = 2, 1, or 0)

1 iii

0

II R1R~C=CR3-OP(OSiMe,),I

, + (Me,SiO), -

OR^),,

Me,SiO

X

(0~~1,

(50)

0

I II , PCR1RZCR3+ R’ R2C-C-P(OSiMe,),-, I l l I

(51)

R3 (OR4), (52)

I

H

P(NEt2)z

(53)

Attack on Nitrogen. According to a recent report in the Russian literature, phosphorylation of indoles with tervalent phosphorus amides leads to high yields of N-phosphorylated products, e.g. (53).34 The use of triethyl phosphite, in place of phosphine, in the synthesis of phenanthren-9,lO-imine (54) from trans-10-azidodihydrophenanthren-9-01leads to a higher yield and a more convenient separation of (54) from the phosphoruscontaining b y - p r o d u ~ t .The ~ ~ reactions of cyclic phosphites and cyclic aminophosphites with diethyl azodicarboxylate lead to a variety of new spirophosphoranes (55).3s 0

II

(EtO),POH

+

+ (EtOhP

+ H,C=CH,

+ N,

cp-z C0,Et N

+

II

N C0,Et

Y , X = 0 or NMe Z = NMe, or OMe 34 35

36

(55)

A. I. Razumov, P. A. Gurevich, S. A. Muslimov, T. V. Kormina, T. V. Zykova, and R. A. Salakhutdinov, Zh. Obshch. Khim., 1980, 50, 778 (Chem. Abstr., 1980, 93, 46 783). M. Weitzberg, Z. Aizenshtat, P. Jerushalmy, and J. Blum, J. Org. Chem., 1980,45,4252. H. Goncalves, J. R. Dormoy, Y. Chapleur, B. Castro, H. Fauduet, and R. Burgada, Phosphorus Sulfur, 1980, 8, 147.

Organophosphorus Chemistry

86 (CF,CH,O),

-n

PRn + CF,CH,OSAr

R, P(OCH,CF,), - n (56)

Attack on Oxygen. The reactions of various trifluoroethyl esters of tervalent phosphorus with trifluoroethyl benzenesulphenate to give phosphoranes, e.g. (56), have been reported.37 Pyrolysis of the readily available cyclic phosphite (57) in the presence of di-tbutyl disulphide, followed by dealkylation, offers a convenient synthesis of individual diastereoisomers of thymidine 3',5'-phosphorothioate (Scheme 5).38 0 I(

ButMe&b

(57) Reagents: i, (ButS)2, hv; ii, ButNHz

Scheme 5 rR1 R' SSSR'

+ (R2,N),P

__L

R' SS-

'3 S--h(NR2,),

+

(R'S), + (R2,N),P=S

Scheme 6

The mechanism of conversion of trisulphides into disulphides with tervalent phosphorus compounds is thought to depend on the phosphorus compound. The most recent study39suggests that reactions with tris(dialky1amino)phosphines involve initial attack at terminal, rather than central, sulphur, followed by an Arbusov step (Scheme 6). The reactions of phosphites with 3,3-bis(trifluoromethyl)-3H-l,2,4-thiaselenazole(58 ;X = S)and 3,3-bis(trifluoromethyl)-3H-1,2,4diselenazole ( 5 8 ; X=Se) provide routes to the thiophosphoranes (60) and the selenophosphoranes (59), re~pectively.~~

(59) 37 38 39 40

D. B. Denney, D. Z. Denney, P. J. Hammond, and Y.-P. Wang, J. Am. Chem. SOC.,1981, 103, 1785. A. E. Sopchik and W. G. Bentrude, Tetrahedron Lett., 1981, 22, 307. D. N. Harpp, D. K. Ash, and R. A. Smith, J. Org. Chem., 1980, 45, 5155. K. Burger, R. Ottlinger, H. Goth, and J. Firl, Chem. Ber., 1980, 113, 2699.

Terualent Phosphorus Acids

87

4-t-Butyl-2,6,7-trioxa-l-phosphabicyclo[2.2.2]octane (61) undergoes simple . ~ ~absence of the alteroxidation to (62)on treatment with sulphuryl ~ h l o r i d eThe native Arbusov product (63) is presumably due to the steric bulk of the t-butyl group. Both phosphoryl and thiophosphoryl derivatives are formed on treatment of amino-phosphines with sulphur 0

(61)

But

(63)

A study of the condensation products of tris(amino)phosphines and a-dicarbony1 compounds largely resolves the apparent confusion concerning the relative importance of the structural contributions of the phosphorane (64) and the zwitterion (65).43 R' (R',NXP + O x R z + (R1,N)3P/o)P RZ or ( R 1 2 N ) 3 $ / 0 x

0

R'

R2

-0

0 '

R I

+ RCHO

(MeO)zP-N=CPh,

(66)

-

(MeO),P-N

I

I

Ph

JPCHO

0-CHR I I (MeOXP-N

0

11

(MeO)zP,

O

,C,

H

R

,N=CHR C Ph

(69) 41 42

43

C-

d$: R

R. S. Edmundson and C. I. Forth, Phosphorus Sulfur, 1980, 8, 315. R. W. Light and R. T. Paine, Phosphorus Sulfur, 1980, 8, 255. D. B. Denney, D. 2. Denney, P. J. Hammond, and K.-S. Tseng, J. Am. Chem. SOC.,1981, 103,2054.

88

Organophosphorus Chemistry

The reaction of methyleneaminophosphines, e.g. (66), with carbonyl groups is more complex than the corresponding reaction with C-C multiple The addition of 4-nitrobenzaldehyde to (66) gives the tricyclic phosphorane (68) and the phosphate (69); the authors suggest that the [3 + 21 cycloaddition product (67) is a common intermediate. Attack on Halogen. The Arbusov intermediates and their decomposition products that are obtained from the reactions of phosphites and phosphines with hypochlorites (Scheme 7) and with chlorine and alcohols (Scheme 8) have been

* R1,fiORz

R',P + R'OCl

C1-

(R' = Ph or OPh)

-

R',PO

+ RZCl

Scheme 7 R',P + Cl,

+

R',PC1,

a R',iOR2

HCJ-

+

R',PO + R'Cl+ HC1

(R' = Ph or OPh)

Scheme 8

in~estigated.~~ In general, alkoxyphosphonium salts that are derived from phosphites are less stable than those derived from phosphines, and so the former are the intermediates of choice. The reaction of phosphites with halogens has also been studied by 31P Electrophilic Reactions.-The novel tricyclic aminophosphine (71) has been prepared by thermolysis of the diazadiphosphetidine (70).47On more vigorous heating, (71) is converted into its adamantane-type isomer (72). R N

R N

/ \

R

2 ClP \N/P-NSiMe3 R

MeCN Refluv

I

RN

RN

\

P

R

R

(72)

(71)

The interest in two-co-ordinate phosphorus compounds continues to grow, and it seems amazing that these compounds were almost unknown five years ago. The synthesis and reactions of two-co-ordinate phosphinimines have been 44

45 46

47

A. Schmidpeter, W. Zeiss, D. Schomberg, and W. S . Sheldrick, Angew. Chem., Znt. Ed. Engl., 1980, 19, 825. D. B. Denney, B. H. Garth, J. W. Hanifin, Jr., and H. M. Relles, Phosphorus Sulfur,1980, 8,275. J. Michalski, M. Pakulski, and A. Skowronska, J . Org. Chem., 1980, 45, 3122. 0. J. Scherer, K. Andres, C. Kruger, Y.-H. Tsay, and G. Wolmerhauser, Angew. Chem., Int. Ed. Engl., 1980, 19, 571.

Tervalent Phosphorus Acids

89 (Me&

N-P=NSiMe, (73)

R’,N-P

/

NR3,

\

[ R2= But]

+ R3,NH

R’,N-P=NR2

[ R - SiMe,]

H R’,N-P=NSiMe, I I

‘NHBU~

NR3, (75)

(74)

reviewed,48and new reactions continue to be reported. An e.s.r. study of radical addition to [bis(trimethylsilyl)amino](trimethylsilylimino)phosphine (73) has appeared.49 The addition of amines to iminophosphines gives phosphorous triamides (74), or the tautomeric iminophosphoranes (75), depending on the nature of the substituent attached to the imidic nitrogen.50Iminophosphines react with alkyls of boron and of aluminium51in a quite different way to their reaction with the corresponding ~hlorides.~, The reactions of (76) and (77) with A1 ,Me, give the four-membered heterocycles (78) and (79), respectively. The reaction of trimethylborane with (76) gives an analogous heterocycle (80) ; however, the reaction with (77) allows the acyclic adduct (81) to be isolated, analogues of which are probably intermediates in the other cases.

RN’

‘NR

’ *‘/I

f

Me

‘Me

(78) R = But (79) R = Me,% R Me,SiN-P-NR

(76) R = But (77) R = SiMe,

Me,B

(Me,Si),N-P-N

[ R = SiMe, 1

\

[ R = But]

Me

I

/

BMe,

‘SiMe, (81)

/ Me

i\ Bu’N

/ \

NBut

‘B/

/ \

Me

Me

(80) 48 49 50

51

52

E. W. Abel and S. A . Mucklejohn, Phosphorus Sulfur, 1980, 9, 235. B. P. Roberts and K. Singh, J. Chem. SOC.,Perkin Trans. 2, 1981, 866. L. N. Markovskii, V. D. Romanenko, and A . V. Ruban, Phosphorus Sulfur,1980, 9, 221. A . H. Cowley, J. E. Kilduff, and J. C. Wilburn, J. Am. Chem. SOC.,1981, 103, 1575. E. Niecke and R. Kroher, Angew. Chem., Inr. Ed. Engl., 1976, 15, 692.

Organophosphorus Chemistry

90 BU

PI',N-P=-NBU'

+ SO,

+

N-PNPI

I

I

I

.

/-"

0

(82)

i2

1

1

ButN=S=O

(83) Pri,N

+

P-0

[Pri2N-P=O]

' 0 >PNPri, \ P-0 PI ',N (85)

(84)

Iminophosphines have also been reported to undergo the equivalent for tervalent phosphorus of the Wittig reaction.53Di-isopropylamino-t-butyliminophosphine (82) reacts with sulphur dioxide at low temperature to give t-butyliminosulphur oxide (83) and the novel heterocycle (85). The authors suggest that an initial [2 21 cycloaddition is followed by elimination of the so far unknown phosphinidene oxide (84), which trimerizes.

+

@CHR2 R',N-P %HRI

Y

R2 /CH\N

R'CHN?

R',N-P=CHR'

'CH-" R' (88)

-

ACHR'

(GNJ

II

R',W

R'ZNp\

/

CHR' (89)

Reactions of two-co-ordinate phosphorus compounds also provide insight into the relative stabilities of the acyclic and cyclic tautomers (86). For example, attempts to generate the unknown bis(methy1ene)phosphorane (87) from the 1,2,4A3-diazaphospholine(88) gave the isomeric A3-phosphiran(89).54 However, [bis(trimethylsilyl)amino]trimethylsilylmethylenephosphine (90) reacts with sulphur to give the methylene(thioxo)phosphorane (91) and its sulphur-addition product (92).5s The cyclic tautomer (93) was not observed. Further studies of

54

E. Niecke, H. Zorn, B. Krebs, and G. Henkel, Angew. Chem., Znr. Ed. Engl., 1980, 19, 709. E. Niecke, W. W. Schoeller, and D.-A. Wildbredt, Angew. Chem., Inr. Ed. Engl., 1981, 20,

55

E. Niecke and D.-A. Wildbredt, J. Chem. Soc., Chem. Commun., 1981, 72.

53

131.

Tervalent Phosphorus Acids

91

three-membered phosphorus-containing heterocyclic rings have involved the synthesis of 1,2A3,3A3-azadiphosphiridines(94).66 These compounds prefer the cyclic rather than the alternative acyclic form (99, although cycloreversion occurs above 50 "C in the case of (94; R2= Pri) (Scheme 9).

R',N-P-NHR' H

i, ii

H R',N-P-NR

I R2,NPF

(R' = SiMe,)

NR'

I

5 R1,M'

'PNRZ,

(94)R2= SiMe, or Pri [ R' = Pri]

R' ,N-P=NR1

R~,N--P=NR'

+

+

+ [ Rz,NP:]

[R',NP:]

(95)

Reagents: i, BunLi; ii, R22NPFz; iii, MeLi

Scheme 9

Although frequently suggested as reaction intermediate^,^^ phosphinidene oxides have not so far been isolated. However, the amino-substituted example (97) can be stabilized by complexation through treatment of the iminophosphine complex (96) with sulphur dio~ide.~'

N (98)

(99)

H N-

1

4 N\p,NH

NMe,

7

(100)

2M(CO), + (CO),M\I (M = Mo, W,or Cr) HN/'~_/N,N

+

Me,,NL;

LdNMe, H (101)

56 57

E. Niecke, N. Nickloweit-Luke, and R. Ruger, Angew. Chem., Int. Ed. Engl., 1981,20, 385. E. Niecke, M. Engelmann, H. Zorn, B. Krebs, and G. Henkel, Angew. Chem., Int. Ed. Engf., 1980, 19, 710.

92

Organophosphorus Chemistry

The ligand properties of 1,2,4,3-triazaphospholes have been inve~tigated.~~ While compounds (98) and (99) form 1 :1 complexes with transition-metal pentacarbonyls, 5-dimethylamino-l,2,4,3-triazaphosphole (100) forms the coordinated tetramer (101). Attempts to displace the tetramer from the metals A3-triazaphosphole (102) have led to the monomer. 2-Methyl-5-phenyl-2H-1,2,4,3 undergoes [4+ 11 cycloaddition at the a2-phosphorus with azodicarboxylic esters, followed by [2+ 21 dimerization of the initial product to give the diphosphoranes (103).59

2H-1,2,3 a2-Diazaphospholes (106) have been prepared from acetone hydrazones;6othe initially formed hydrogen chloride adducts can be ionic, e.g. (104), or covalent, e.g. (105), depending on the N-substituents. Methylation of (106) occurs at nitrogen to give (107) and phosphorylation at the carbon atom adjacent to phosphorus to give (108). c1-

RNHN=CMe,+

PC1,

Mef17Me

(105)

The phosphite coupling approach to oligonucleotide synthesis continues to be of interest. The bis-triazolyl(lO9) and bis-tetrazolyl(ll0) derivatives of tervalent phosphorus show much greater selectivity than the dichloro-compound (1 11) in phosphorylation of nucleosides,61and a new experimental procedure apparently 58 59 60

61

A. Schmidpeter, H. Tautz, J. Von Seyerl, and G. Huttner, Angew. Chem., Int. Ed. Engl., 1981,20,408. H. Tautz and A. Schmidpeter, Chem. Ber., 1981, 114, 825. J. H. Weinmaier, G. Brunnhuber, and A. Schmidpeter, Chem. Ber., 1980, 113, 2278. J. L. Fourrey and D. J. Shire, Tetrahedron Lett., 1981, 22, 729.

93

Tervalent Phosphorus Acids ROPX,

N (109) X

=

-N/ \-N

9

AN

(110) X = -N

L A (111)

x = c1

allows the use of tris(imidazo1-1-yl)phosphine, which had previously proved too unstable.62 The inconvenience caused by the instability of the generally used mononucleoside phosphite derivatives (1 14) has been overcome by replacing them with NN-dimethylaminophosphoramidites(113), which are readily available from chloro(NN-dimethy1amino)methoxyphosphine (112).s3

MeOP,

/NMe2 c1

(1 12)

+

Roc@ OH

Pri2NEt+

pB pB ROCH,

ROCH,

0

0

I

I

ROPX

MqNPOMe

(113)

N (114)

x = c1 or N4 \

‘N/ I

N=N (B = base)

(1 15)

Me

(117)

Both cis- and trans-NN-dimethylphosphoramidate(1 16)64 and phosphonate (1 17)65 analogues of thymidine 3’,5’-phosphate have been prepared by the reaction of the phosphite (1 15) with N-chlorodimethylamine and methyl iodide, respectively. Phosphite analogues (1 18) of ribonucleotides have been prepared66 and used in the synthesiss7 of a variety of analogues of diribonucleoside monophosphates, e.g. (1 19). 62

64 65 66

T. Shimidzu, K. Yamana, A. Murakami, and K. Nakamichi, Tetrahedron Lett., 1980, 21, 2717. S. L. Beaucage and M. H. Caruthers, Tetrahedron Lett., 1981, 22, 1859. A. E. Sopchik and W. G. Bentrude, Tetrahedron Lett., 1980, 21, 4679. G. S. Bajwa and W. G . Bentrude, Tetrahedron Lett., 1980, 21, 4683. B. P. Melnick, J. L. Funnun, and R. L. Letsinger, J. Org. Chem., 1980, 45, 2715; K. K. Ogilvie and M. J. Nemer, Tetrahedron Lett., 1980, 21, 4145. K. K. Ogilvie and M. J. Nerner, Tetrahedron Lett., 1980, 21, 4153.

94

Organophosphorus Chemistry

R3si0T7 0 OSIR,

I

P-x

I I

EGNP-0

I

"TiUKd

o%urd R,SiO

HO OH

(118) X = OR, N k , or OCH$Cl,

OSiR,

(1 19)

Cyclic Esters of Phosphorous Acid.-The reactions of the isomeric pairs of phosphites (120) and (121), and (122) and (123), with ozone give the corresponding phosphates with a very high degree of retention of configuration.ss The results show that the intermediate ozonides, e.g. (124), do not undergo inversion. Similar reactions of the phosphites with neopentyl and t-butyl hypochlorites give close to 1 :1 ratios of the isomeric phosphates in all cases, and so probably involve equilibration of pentaco-ordinated intermediates.

MeXMe d o 'P'I

&qp\0M 0e

OMe

MeN-P

Me

Me

-NMe

(125)

Me

Me (1 26)

The bicyclic aminophosphines (125) and (126) have been prepared and their reactions with a-diketones to give phosphoranes investigated; (126), unlike (125), is relatively stable to polymerizati~n.~~ Full details of the synthesis of a series of 68 69

D. B. Denney, D. Z. Denney, and S. G. Schutzbank, Phosphorus Sulfur, 1980, 8, 369. D. B. Denney, D. Z. Denney, D. M. Gavrilovic, P. J. Hammond, C. Huang, and K.-S. Tseng, J. Am. Chem. SOC.,1980, 102, 7072.

Tervalent Phosphorus Acids

95

diastereomerically pure 2,8-dioxa-5-aza-l-phospha(111)bicyclo[3.3.O]octanes (127) have been Two methods of synthesis are used, as shown in Scheme 10, and that from tris(dimethy1amino)phosphine also gives the phosphorane (128) through addition of dimethylamine to (127). Compounds (127) tend to oligomerize,’l and in one case a dimer was isolated and identified as (129).

HN

/cR 2CHR2

-

‘CR3 ,CH R40H

R

2

FR’ 7R35

R

4

0-P-0 (127)

Reagents: i, 3Et3N, PCh; ii, (Me2N)zP

Scheme 10

Examples of donor-acceptor adducts of aminophosphines in which both phosphorus and nitrogen are co-ordinated are rare, and the adducts are usually unstable when this does occur. However, the bicyclic aminophosphines (130) and (131) form, successively, mono- and di-adducts with diborane, all of which are remarkably Although (131) is a mixture of diastereoisomers, only adducts of the meso-form have been isolated. P-N\

Me’

‘R

(130) R = H (131) R = Me

Miscellaneous Reactions.-A kinetic study of the AIBN-initiated autoxidations of triethyl phosphite, diethyl ethylphosphonite, and ethyl diethylphosphinitehas been The results of electrochemical oxidation of the cis- and trans70

71 72

’3

C. Bonningue, D. Houalla, M. Sanchez, R. Wolf, and F. H. Osman, J . Chem. SOC.,Perkin Trans. 2, 1981, 19; see also D. B. Denney, D. Z. Denney, P. J. Hammond, C. Huang, and K . 4 . Tseng, J. Am. Chem. SOC., 1980, 102, 5073. B. J. Walker, in ‘Organophosphorus Chemistry’, ed. S. Trippett (Specialist Periodical Reports), The Chemical Society, London, 1976, Vol. 7, p. 102. D. Grec, L. G. Hubert-Pfalzgraf, J. G. Riess, and A. Grand. J. Am. Chem. SOC.,1980,102, 71 33. W.-S. Hwang and J. T. Yoke, J. Org. Chem., 1980,4S, 2088.

Organophosphorus Chemistry

96 R

R

trans-(1,32)

cis-(132)

isomers of 1,3-di-isopropy1-2,4-bis( di-isopropylamino)cyclodiphosph(~~~)azine (1 32) are quite different ;74 only the trans-isomer produces a stable radical cation. Isomeric mixtures of phosphole complexes (133) are formed in the reaction of cobaltacyclopentadienes with phosphites and with pho~phonites.~~ The free R'

Ph,P

(133)

phosphole can be obtained, in most cases, by oxidation with Ce4+ion. Phenylthiocopper is an insoluble polymer; however, it can be depolymerized in the presence of trimethyl phosphite to give the complex (134).76 This complex acts as a useful source of phenylthiocopper, converting alkyl halides into the corresponding thioethers and propargyl halides into allenyl thioethers. PhSCuP(OMe)3

(134)

3 Phosphonous and Phosphinous Acids and their Derivatives The barrier to inversion at phosphorus in phosphinous acid derivatives (136) has been suggested to be small on the basis of the results obtained from the S

II

,P X" M '\e Ph (135) X = OR or SR 74

75 '6

-

P

X

A\

/

Ph

Me

(136) X = OR or SR

A. F. Diaz, 0. J. Scherer, and K. Andres, J. Chem. SOC.,Chem. Commun., 1980, 982. K. Yasufuku, A. Hamada, K. Aoki, and H. Yamazaki, J. Am. Chem. SOC.,1980,102,4363. A. J. Bridges, Tetrahedron Lett., 1980, 21, 4401.

Tervalent Phosphorus Acids

97

NR',

+ PhCH, R3

(137)

reduction of optically active thiophosphinic acid esters (135) by a variety of However, optically active amides of phosphinousacidscan be obtained in high yield from the corresponding chiral aminophosphonium salt (137) by electrochemical reduction or by cyanolysis; both reactions occur with retention of configuration at pho~phorus.~~

'7 78

L. Horner and M. Jordan, Phosphorus Sulfur, 1980,8,221. L. Horner and M. Jordan, Phosphorus Suljiur, 1980, 8, 227.

6 Quinquevalent Phosphorus Acids BY

R. S. EDMUNDSON

The chemistry of organophosphorus compounds that possess peroxide bonds1 and that of l-oxophosphonic acids2 have been reviewed. Mechanistic aspects of organophosphorus chemistry have been discussed in two Two further articles describe our current knowledge of the chemistry and biological evaluation of anti-cancer perhydro-1,3,2-0xazaphosphorines,~~ and the chemistry of compounds possessing a single P-N bond has been summarized.’ As in the Reports for previous years, the sections headed ‘General’ cover papers which describe work on phosphonic or phosphinic acid derivatives as well as on those of phosphoric acid, or which describe compounds having more than one type of ‘phosphyl’ function within the molecule. 1 Synthetic Methods General.-Although dimeric molecules may result from condensation reactions between formaldehyde and dihydrazides derived from phosphoric or phosphonic acids, the monomeric compound (1) has been isolated8 and its structure confirmed by X-ray analysis. The reaction between dialkyl phosphoroisothiocyanatidite and dialkyl trichloroacetylphosphonates yields the compounds (2), which are not isolable in pure form since, when heated, they afford the 1,3,2,4-dioxadiphospholans (3).1° Further compounds that possess this ring system have been obtained by the reaction between the phosphinates (4) and phosphorus trich1oride.l’ The treatment of dialkyl l-oxophosphonates with sulphur ylides yields, inter alia, the compounds (7), probably via the postulated intermediate (5). The enol phosphates (8) are also formed, through either a modified intermediate or a transition state of the type (6).12 M. Konieczny and G. Sosnovsky, Chem. Rev., 1981, 49. Yu. A. Zhdanov, L. A. Uzleva, and Z. I. Glebova, Usp. Khim., 1980,49, 1730. H. M. Buck, Recl. Trav. Chim. Pays-Bas, 1981, 100, 217. F. Ramirez, Pure Appl. Chem., 1980, 52, 1021. 5 W. J. Stec, Phosphorus Chem. Directed Biol., Lect. Int. Syrnp., 1979 (publ. 1980), p. 95. T. Kawashima, Kagaku No Ryoiki, 1979, 33, 1026 (Chem. Absfr., 1980, 93, 71 582). V. P. Kukhar and V. A. Gilyarov, Pure Appl. Chem., 1980, 52, 891. J. P. Majoral, M. Revel, and J. Navech, J . Chem. Res. ( S ) , 1980, 129. 9 J. Jaud, J. Galy, R. Kraemer, J. P. Majoral, and J. Navech, Acta Crystallogr., Sect. B, 1980, 36, 869. l o I. V. Konovalova, R. D. Gareev, L. A. Burnaeva, N. K. Novikova, T. A. Faskhutdinova, and A. N. Pudovik, Zh. Obshch. Khim., 1980, 50, 1451 (Chem. Abstr., 1981, 94, 15 808). 11 M. B. Gazizov, R. A. Khairullin, and A. I. Razumov, Zh. Obshch. Khim., 1980, 50, 1882 (Chem. Absrr., 1980, 93, 239 537). 12 F. Hammerschmidt and E. Zbiral, Monatsh. Chem., 1980, 111, 1015. 1

98

Quinquevalent Phosphorus Acids

99 R' 0 \

0

II

'PC HM eOCH( OE t )Me

R'

/

(4) R20 0

0

(R'O),PNCS

(R'O),PC II (O)CCI,

CCl,

II I1

(R20),P-C

OR'

I / 0-P=O

''eat

I

NCS (2)

\\

R'O

(3)

J [ (R'O),P(O)-, R2COR3]

(R2= Me or Ar, R 3 = Me,i(X)CH,; X is a lone pair or =O) Spectroscopic properties of 5-bromo-5-nitro-l,3,2-dioxaphosphorinans have been recorded, and some compounds exemplifying this system have been dehydrobrominated by the action of trieth~1amine.l~ Several derivatives of the 3,5-di-t-butyl-l,3,2-oxazaphospholinesystem (9) have been prepared, by standard procedures, and their n.m.r. spectra recorded; in one case, i.e. (9; X = 0, R = Me), a crystal structure was also determined.14 In the reactions between dialkyl phosphoroisocyanatidites and dialkyl aroylphosphonates, many related examples of which have been recorded in

But (9) X is a lone pair, =0, or =S 13

l4

R. Valceanu and I. Neda, Rev. Chirn. (Bucharest), 1980, 31, 964 (Chem. Abstr., 1981, 94, 208 253) ; Phosphorus Sulfur, 1980, 8 , 13 1. Yu. V. Balitskii, Yu. G. Gololobov, V. M. Yurchenko, M. Yu. Antipin, Yu. T. Struchkov, and I. E. Boldeskul, Zh. Obshch. Khim., 1980, 50, 291 (Chem. Abstr., 1980, 93, 26 506).

Organophosphorus Chemistry

100

previous Reports, the formation of stereoisomeric mixtures of either 2-0x01,3,4-oxazaphospholidine derivatives or of 4-0~0-1,3,2-oxazaphospholidine derivatives (Scheme l), or indeed of O-alkylated products, depends on the nature of the substituent R2, and to a lesser extent on the nature of the alkyl groups.15 (MeO)?PNCO + (R'0)2P(0)COC,H,R2-4

1 dipolar ion I jj&$-i+

dipolar ion I1

/

[ R' = H. 'vie. or Me01

-

(MeO) P-N

0 '

\

>O

XP(O)(OR'),

Ar

Scheme 1

Synthesis of Phosphoric Acid and its Derivatives.-Aryl phosphorodifluoridates are conveniently obtained from the corresponding chlorides by the action of sodium fluoride in the presence of a crown ether.16 Aroyloxy phosphoro-dichloridates and -difluoridates are isolable from mixtures of a carboxylic acid anhydride and pyrophosphoryl ch10ride.l~ The mass spectra of the l-phosphabicyclo[2.2.2]octanes(10; R = Me, Et, or Pri; X=lone pair, 0, S, or Se)lS and (10; R=But; X=lone pair or 0)l9 have been recorded. Unlike the 4-methyl and 4-ethyl compounds, the 4-t-butyl bicyclic phosphite does not undergo ring-opening when chlorinated with sulphuryl chloride but is, instead, merely 0 ~ i d i z e d . l ~ 2-Hydroxyethyl phosphates have been described; not surprisingly, they polymerize when heated.20 Tris(tetrabuty1ammonium) hydrogen pyrophosphate has been described as a new reagent for the preparation of monosubstituted pyrophosphates from reactive (e.g. allylic) halides.21 Mixed disubstituted dihydrogen pyrophosphates have been prepared by the reaction between aryl dihydrogen phosphates and 4-methoxyphenyl hydrogen N-(2-aminophenyl)phosphoramidate in the presence of copper(r1) chloride.22 V. V. Konovalova, R. D . Gareev, L. A. Burnaeva, N. V. Mikhailova, and A. N. Pudovik, Zh. Obshch. Khim., 1980, 50, 285 (Chem. Abstr., 1980, 93, 114 399). l 6 F. Effenberger, G. Konig, and H. Klenk, Synthesis, 1981, 70. l7 F. Effenberger and G . Konig, Chem. Ber., 1981, 114, 916. l8 H. Kentamaa and J. Enqvist, Org. Mass Spectrom., 1980, 15, 520. l9 R. S. Edmundson and C. I. Forth, Phosphorus Sulfur, 1980, 8, 315. 20 K.-Y. Choi and S.-K. Choi, Taehan Hwahakhoe Chi, 1 9 8 0 , 2 4 , 4 6 3 (Chem. Abstr., 1981,94, 191 633). 21 V. M. Dixit, F. M. Laskovics, W. I. Noall, and C. D . Poulter,J. Org. Chem., 1981,46, 1967. 2 2 H. Takaku, K. Tsubuhari, and Y. Nakajima, Chem. Pharm. Bull., 1980,28, 1626. 15

Quinquevalent Phosphorus Acids

101

The synthetic value of acylphosphonates as sources of enol phosphates and related compounds has been explored. An intermediate of the form ( 6 ) is consistent with the formation of enol phosphates (8) when acylphosphonates react with sulphur-containing ylides. A factor which contributes towards the control of the product ratio of (7) to (8) is the electron-withdrawing power of the group R2.l2 Reactions of the same phosphonates with the alkynes R4C=CH in toluene give the expected (a-hydroxya1kyl)phosphonates (1 1); these, when treated with base, afford either or both of the products (12) and (13). Here the relative proportions of products, (12) and (13), depend on the nature of the base; (13) is the principal product when the base is (Me,Si),NNa in DMS0.23 0 R<JP=X

(R'O),P(0)C(OH)RT'CR4

L0' (10) ( R'O),P(O)OCR2=C

=CH R4

( R1O)?P(0)OC H RZC-

C R4

(13)

(1 2)

Fresh evidence should help to dispel lingering doubts one might have concerning the existence of monomeric metaphosphate species. Fragmentation of either threo- or erythro-( 1,2-dibromo-l-phenylpropyl)phosphonicacid (14; R1= H) by a hindered base in the presence of acetophenone (Scheme 2) yields the enol phosphate; with ethyl acetate, in the presence of aniline, N-phenylacetimino ethyl ether is rapidly formed. These and other results are consistent with the rapid formation of a metaphosphate anion, capable of reacting at a carbonyl .~~ oxygen and so activating the group towards the nucleophilic a ~ n i n e Related reactions, using the methyl ester (14; R1= Me), suggest that the methyl metaphosphate anion is formed.25 Oxetans behave like oxirans in their reactions with cyclic hydrogen phosphorothioates ; the 2-(o-hydroxyalkylthio)-esters that are initially produced undergo 0

\/

CBrPhCHBrMe (-

'0-

MeC -R2

28- [R'= H] Br-,

- PhCBr=CHMe,

-2BH)

*

[Po;-]

'OR1 (14)

MeCR'

11

NPh

B-

II

+o-PO,

opo; Me-L-R'

I

+NH,Ph

Reagents: i, MeCOR2 (R2=Ph or OEt); ii, PhNHz

Scheme 2 23 24

25

F. Hammerschmidt, E. Schneyder, and E. Zbiral, Chem. Ber., 1980, 113, 3891. A. C. Satterthwait and F. H. Westheimer, J . Am. Chem. SOC.,1981, 103, 1177 A. C. Satterthwait and F. H. Westheimer, J. Am. Chem. SOC.,1980, 102,4464; Phosphorus Chem. Directed Biol., Lect. Int. Symp., 1979 (publ. 1980), p. 117.

Organophosphorus Chemistry

102

(15)

isomerization to the 2-(co-mercaptoalkoxy)-esters.2sThe dihydropyranyl esters (15) are formed by addition of dialkyl oxyphosphoranesulphenyl chlorides to dihydropyran and subsequent dehydrochlorination with triethylamine or triethyl p h o ~ p h i t e .A ~ ~synthesis of chiral OSS-trialkyl phosphorodithioates utilizes the resolved diastereoisomeric amides (16) (see Scheme 3) and the removal of the amide function with retention of configuration, by a well-established procedure.28 R’O (R’O),P

‘a

A R2S’

‘NHtHMePh

0

R’0

/ \-

R2S

S M

Reagents: i, (+)- or (-)-PhMeCHNHz; ii, NaH, CS2; iii, R31

Scheme 3

Many of this year’s reports on the chemistry of the P-N bond concern new nitrogen-containing ring systems and their reactions. Phenyl phosphorodichloridate reacts with S-methylisothiouronium sulphate to give the expected product (17); on the other hand, ethyl phosphorodichloridate behaved unexpectedly, the product being the dihydro-l,3,2-diazaphosphorine(18).29 40x0perhydro-l,3,2-diazaphosphorineshave been prepared via the PII1 The 1,3,2-diazaphospholines (19) are obtained conventionally from NN’dib~tylbutane-2,3-di-imine.~l The 1,3,2-oxazaphospholine (20) is transformed into the 1,3,2-thiazaphosphoIine(21) by the action of phosphorus pentasulphide in the presence of aluminium chloride.32Phosphorus pentasulphide itself converts into the 1,3,2-oxazaphosphorine-4-thiones 4-hydroxy-1,3-diazole-5-carboxamides (22).33Other 1,3,2-oxazaphospholines(23) can be obtained by the cyclization of N-phosphorylated a-bromo-amidines by means of t-butoxide anion.34 The 26 27

28 29

30 31 32

33 34

0. N. Nuretdinova, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 477 (Chem. Absrr., 1980,93, 8098); 0 .N. Nuretdinova and F. F. Guseva, ibid., p. 2594 (Chem. Absrr., 1981,94,103 317). M. B. Gazizov, A. I. Razumova, and 1. Kh. Gizatullina, Zh. Obshch. Khim., 1980,50, 2386 (Chem. Absrr., 1981, 94, 139 552). A. Kotynski, K. Lesiak, and W. Stec, Pol. J. Chem., 1979,53,2403 (Chem. Abstr., 1980,93, 45 887). V.-S. Li and L. A. Cates, J . Heterocycl. Chem., 1981, 18, 503. E. E. Nifant’ev, A. I. Zavalishina, E. I. Smirnova, and M. M. Vlasova, Zh. Obshch. Khim., 1980, 50, 459 (Chem. Absrr., 1980, 93, 8151). A. M. Kibardin, T. Kh. Gazizov, and A. N. Pudovik, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1452 (Chem. Abstr., 1980, 93, 168 203). Yu. V. Balitskii and Yu. G. Gololobov, Zh. Obshch. Khim., 1980, 50, 1204 (Chem. Abstr., 1980, 93, 114 409). Sumitomo Chemical Co., Ltd, Jpn. Kokai Tokkyo Koho 80 89267 (Chem. Absfr., 1981, 94, 65 682). G. L‘abbe, A. Verbruggen, and S. Toppet, Bull. Soc. Chim. Belg., 1981, 90, 99 (Chem. Abstr., 1981, 94, 192 203).

Quinquevalent Phosphorus Acids

103

1,3,2-0xazaphospholidines (24) are the minor products from the reactions between ethyl bromopyruvate and dialkyl phosphoroisocyanatidites, the major products being the enol phosphates (25).35 The n.m.r. and mass-spectrometric properties of several (4s)- and (4R)-2alkoxy-4-alkyl-l,3,2-oxazaphospholidine 2-sulphides (26), prepared from optically active amino-alcohols by using standard procedures, have been An interesting route to good yields of 2-amino-l,3,2-oxazaphospholidine 2-oxides and 2-amino-perhydro-l,3,2-oxazaphosphorine 2-oxides is provided by the rearrangement of the phenylimino-compounds (27),37which is catalysed by boron trifluoride etherate. Bu

PhOP-(N=C
I1

0

-”\om

Bu

(20) x = 0, Y = s (21) x = Y = s

Synthesis of Phosphonicand PhosphinicAcidsand their Derivatives.-Several papers dealing with the phosphorylation of alkenes and related substances by phosphorus pentachloride have appeared during the year, but they contain little information that is essentially new. 3-Methylbutyn-3-01reacts with phosphorus pentachloride 35 36 37

I. V. Konovalova, L. A. Burnaeva, N. K. Novikova, and A. N . Pudovik, Zh. Obshch. Khim., 1980, 50, 469 (Chem. Abstr., 1980, 92, 215 358). S . Tawata, E. Kuwano, and M. Eto, Agric. Biol. Chem., 1980, 44, 1489. V. A. Gilyarov, N. A. Tikhonina, T. M. Shcherbina, and M. I. Kabachnik, Zh. Obshch. Khim., 1980,50, 1438 (Chem. Abstr., 1981, 94, 3994).

0rganophosphorus Chemistry

104

to yield a mixture of the two phosphonic dichlorides (28) and (29).38Others, e.g. (30), have been prepared by dehydrochlorination procedures; 39 (3 1) is obtainable from methyl phosphorodichloridite and 1-bromoethyl i s ~ c y a n a t e ,and ~~ a similar reaction affords the phosphonic dichloride (32).41 Re-examination of the reaction between benzaldehyde and phosphorus trichloride has resulted in the isolation of the 1,4-dioxa-2,5-diphosphorinan (33).42 A facile one-step synthesis of phosphonothioic dichlorides from alkyl chlorides involves the decomposition of the intermediate aluminium chloride-alkyl chloride-phosphorus trichloride complex with Phosphorylation of but-1-ene with a mixture of phosphorus pentasulphide and thiophosphoryl chloride gives the 1,Zthiaphospholan (34).44 CICH,CMe=CClCH,P(O)Cl*

ClCH2CCl= CMeCH,P( O)C1,

(28)

(29)

ClCH =C -P(O)Cl,

I

H,C=CR

(30)

H,C=-C -P(O)Cl,

I

NCO (31)

c1 (33)

(34)

0 R‘ (32)

Catalysis by palladium complexes features in two syntheses of phosphonic acid derivatives. Dialkyl arylphosphonates are obtained in high yields from bromo-arenes and dialkyl hydrogen phosphonates in the presence of tetrakis(triphenylpho~phine)palladium,~~ and the stereoselective formation of (Zphenyletheny1)phosphonates from 2-phenylethenyl bromides and hydrogen phosphonate^^^ occurs under comparatively mild conditions with the aid of palladium catalysts. The scope of the indicated reaction, leading to the 1 ,Zdiphosphonylated benzene derivatives ( 3 9 , is obviously capable of being widened.47 The formation of (pyrimidin-5-yl)phosphonates,e.g. (36), from dialkyl hydrogen phosphonates and 5-nitro-pyrimidines occurs with the intermediacy of 38 S9

V. G. Rozinov, V. E. Kolbina, and V. I. Glukhikh, Zh. Obshch. Khim., 1980, 50, 684 (Chem. Abstr., 1980, 93, 114 633). V. A. Efamov, A. V. Dogadina, B. 1. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1980,50,

2622 (Chem. Abstr., 1981,94, 121 650). E. A. Stukalo, E. M. Yur’eva, and L. N. Markovskii, Zh. Obshch. Khim., 1980, 50, 343 (Chem. Abstr., 1980, 93, 26 508). 41 B. N. Kozhushko, Yu. A. Paliichuk, L. Ya. Bogel’fer, and V. A. Shokol, Zh. Obshch. Khim., 1980, 50, 1273 (Chem. Abstr., 1980, 93, 204 765). 42 J. K. Michie and J. A. Miller, J . Chem. SOC., Perkin Trans. 2, 1981, 785. 43 M. P. Kalshik and R. Vaidyanathaswamy, J. Org. Chem., 1980, 45, 2270. 4 4 U.S. P. 4 231 970/1980 (Chem. Abstr., 1981, 94, 8 4 303). 45 T. Hirao, T. Masunaga, Y. Ohshiro, and T. Agawa, Synthesis, 1981, 56. 46 T. Hirao, T. Masunaga, Y. Ohshiro, and T. Agawa, Tetrahedron Lett., 1980, 3595. 47 E. P. Kyba, S . P. Rines, P. W. Owens, and S.-S. P. Chou, Tetrahedron Lett., 1981,22, 1875. 40

Quinquevalent Phosphorus Acids R’R*P( 0 ) C =CP( 0)RLR*

105

+

(a) R’ = R2 = EtO (b) R’ = EtO, R2 = Ph

P(0)R’R2

(35)

11 Meisenheimer-type complexes and subsequent elimination of the n i t r o - g r o ~ p . ~ ~ The similar replacement of a nitro-group on an aryl ring has also been observed in the benzimidazole series.49 Activation of the pyridine ring (as such, or in quinoline and isoquinoline) as the N-(2,6-dimethyl-4-oxopyridin-l -yl)ium salt allows its reaction with trialkyl phosphites and the formation of dialkyl (pyridin4-yl)pho~phonates.~~ Dimethyl (s-alky1)phosphonates have been prepared by treatment of dimethyl [l -(N’-tosylhydrazino)alkyl]phosphonates with metal b ~ r o h y d r i d e s The . ~ ~ action of benzylamines on 4,6-diphenylpyran-2-thioneto prepare 2-methylthio-4,6diphenylpyridiniiim iodides and the subsequent reaction of these with triethyl phosphite represents a useful conversion of (arylmethy1)amines into diethyl (arylmethy1)phosphonates.5 2 Treatment of O-ethyl (2-ethoxycarbonylphenyl) methylphosphinate with potassium t-butoxide yields the cyclic phosphinate (37).53 1,3,2,6-Dioxadiphosphocans(38), as cis-trans mixtures,54 and 1,3,6,2trithiaphosphocans (39) j5have been prepared by conventional types of reaction; the latter compounds, when they contain tervalent phosphorus, are in equilibrium with sixteen-membered-ring dimers, which, as their sulphides or oxides, may be is a separated into cis- and trans-forms. The macrocyclic compound further example of a type of compound already exemplified (‘Organophosphorus Chemistry’, Vol. 11, p. 112). 48

49 50 51 52

53

54 55 56

P. P. Onys’ko, Yu. G . Gololobov, G . Remennikov, and V. M. Cherkasov, Zh. Obshch. Khim., 1980, 50, 1230 (Chem. Abstr., 1981, 94, 103 472). G. L. Matevosyan, S. N. Vodovatova, and P. M. Zavlin, Zh. Obshch. Khim., 1980,50, 2803 (Chem. Abstr., 1981, 94, 157 017). A. R. Katritzky. J. G . Keay, and M. P. Sammes, J. Chem. SOC.,Perkin Trans. I , 1981, 668. H. Inokawa and H. Sahara, Nippon Kagaku Kaishi, 1980, 609 (Chem. Absrr., 1980, 93, 95 338). P. M. Fresneda and P. Molina, Synthesis, 1981, 222. T. M. Balthalor, J. Org. Chem., 1980, 45, 2519. J. P. Dutasta, K. Jurkschat, and J. B. Robert, Tetrahedron Lett., 1981, 22, 2549. J. Martin and J. B. Robert, Nouu. J. Chim., 1980, 4, 515 (Chem. Abstr., 1981, 94, 157 010). A. V. Kirsanov, T. N. Kudrya, and A. S. Shtepanek, Zh. Obshch. Khim., 1980, 50, 2452 (Chem. Abstr., 1981, 94, 121 648).

Organophosphorus Chemistry

106

/\

0

OEt

(37)

(38) A = 0,B = P(X)Me (X = 0 or S), R = Me (39) A = B = S

Koizumi et al. have extended their earlier work on the use of ethyl L-prolinate to obtain resolved tetraco-ordinated phosphorus esters. Chiral phenylphosphonic and phenylphosphonothioic diesters and other derivatives have now been obtained, following initial resolution of the chloride (41; R=Cl, X=S) and nucleophilic displacement of the chlorine: within this work, the conversion of thiones into the corresponding oxides was achieved, using 3-chloroperoxybenzoic Enantiomers of 0-ethyl 0-2,2-dichloroethenyl ethylphosphonate have been and the (-)-form of the acid (42) has been shown to have the S configuration.6 Diethyl hydrogen phosphonate that contains its sodium derivative selectively removes bromine from dialkyl (bromodifluoromethyl)phosphonates, with the formation of dialkyl (difluoromethyl)phosphonates.60(a-Fluorobenzy1)phosphonates are obtainable from (a-hydroxybenzy1)phosphonatesby treating these X

0

(43) 57 58 59

60

T. Koizumi, H. Takagi, and E. Yoshii, Chem. Lett., 1980, 1403. I. A. Nuretdinov, N. A. Buina, and F. G. Sibgatullina, Zh. Obshch. Khim., 1980, 50, 1423 (Chem. Ahstr., 1980, 93, 204 772). Z. Galdecki, M. L. Glowka, S. Musierowicz, and J. Michalski, Pol. J. Chem., 1980,54, 539. D. J. Burton and R. M. Flynn, J. Fluorine Chem.. 1980, 15, 263.

Quinquevalent Phosphorus Acids

107

with Et2NSF3; (a-hydroxyally1)phosphonates (43) react with the same reagent in an S N ~mechanism.61 ’ Desilylation of 00-di(trimethylsily1)(l-oxoalky1)phosphonates with ethanolic aniline affords the anilinium salt of the free (l-oxoalky1)phosphonic acid.62The (2-oxoalkyl)phosphonates (44) are obtainable from trialkyl phosphites and c h l o r ~ - o x i r a n and ~,~~ one such compound has also been obtained in an adaptation of the Wacker process to diethyl allylphosphonate, or, better, diethyl (prop-l-eny1)phosphonate; in the latter case, the isomeric (3-oxopropy1)phosphonate is evidently not simultaneously (o-Formylalky1)phosphonates, obtainable by the acid hydrolysis of acetals prepared from triethyl phosphite and o-bromo-acetals, have been used in the synthesis of amino-nitriles, and thence to a-amino-a-(diethoxyphosphiny1)carboxylic acids in a Strecker synthesis, and ultimately to (o-amino-w-carboxyalky1)phosphonicacids (45).65

(45) n = 0 or 1

(E t 0 ),P(0 ) C H (N,KOOE t (46)

Interest in the chemistry of (aminoalky1)phosphonicacid derivatives continues at the high level that has been established during the past two or three years. The potentially valuable intermediate (46) is obtained from triethyl phosphonoacetate and mixtures of trifluoromethylsulphonyl chloride and sodium azide.66 Amines cleave dialkylphosphinyl-oxirans to give (2-amino-l-hydroxyethy1)phosphonic acid derivati~es.~~ Several papers describe preparations of (1aminoalky1)phosphonic esters and acids, based on the reduction (hydrogenolysis) of oximes or hydrazones of (l-oxoalky1)phosphonic esters.68 A novel preparation of (l-aminoalky1)phosphonic acids utilizes the alkylation of diethyl (isocyanomethy1)phosphonate (Scheme 4).69 Two papers describe syntheses involving tervalent phosphorus compounds and benzyl N-substituted urethanes; one of them is more interesting in that it describes (aminoalky1)phosphinicacids of the type (47), few of which have so far been r e c ~ r d e d An . ~ essentially ~ ~ ~ ~ similar reaction has been used to convert

65

G. M. Blackburn and D. E. Kent, J. Chem. SOC.,Chem. Commun., 1981, 511. K. Yamaguchi, T. Kamimura, and T. Hata, J. Am. Chem. SOC.,1980, 102, 4534. J. Gasteiger and C. Herzig, Tetrahedron Lett., 1980, 21, 2687. G . Sturtz and A. P. Raphalen, J. Chem. Res. ( S ) , 1980, 175. J. M. Varlet, G. Fabre, F. Sauveur, N. Collignon, and P. Savignac, Tetrahedron, 1981, 37,

67

H. G. Hakimelahi and G. Just, Synth. Commun., 1980, 10, 429. J. Zygmunt, U. Walkowiak, and P. Mastalerz, Pol. J. Chem., 1980, 54, 233 (Chem. Abstr.,

61 62

63 64

1377. 1980,93, 239 526).

Z . H. Kudzin and A. Kotynski, Synthesis, 1980, 1028; J. Kowalik, L. Kupczyk-Subotkowska, and P. Mastalerz, ibid., 1981, 57. 6Q J. Rachon, U. Schollkopf, and Th. Wintel, Liebigs Ann. Chem., 1981, 709. 70 J. Oleksyszyn and L. Subotkowska, Synthesis, 1980, 906. 71 J. Oleksyszyn, Synthesis, 1980, 722. 68

Organophosphorus Chemistry

108 Me,hCH,NHCHO I-

(EtO),P(O)CH,NHCHO

(EtO),P(O)CH,NC iiii

(HO),P(O)CR' RZNH, 4 (Et O),P(O)CR' R2NC

a

(EtO),P(O)CHRINC

Reagents: i, (Et0)3P; ii, P o c k , Et3N; iii, ButO-, R'I; iv, ButO-, R21; v, H3O+

Scheme 4

N-substituted glycines into the phosphinic acids (48).72However, for the preparation of the [N-(hydroxyethyl)aminomethyl]phosphonates (49), a method based on the interaction of dialkyl hydrogen phosphonate and N-substituted 1,3oxazolidine is to be preferred. When heated, compound (49 ; R1= Me) undergoes internal demethylation to give (50).73 A new preparation of (2-aminoethy1)phosphonicacid esters involves the acidcatalysed ring-fission of 1 ,Zazaphosphetans ( 5 1).74 Dihydrogen (carbamoylmethy1)phosphonate (52) has been prepared from diethyl (cyanomethy1)phosphonate.75 Toluene-4-sulphonic acid catalyses the condensations between 0 R'CH-P,

I

R'NH

'

OH

(48) R = H, CH,Ph, or CH,COOH

(47)

0

I1 (R'O),PCH,N

heat

,R2

\CH,CH,OH

Me

n-

U

\

[R'= Me]

p -CH

RIO'\o

(49)

,4I

R2 CH,CH,OH

( 5 0)

0

11 RCH,CH,N-POEt U

0 H,O' __f

RCH,CH,kH,CH,CH,P 'OEt

(51) R = Ph or NC

,--I

72 73

74 75

( 5 3 ) R = Me, Ph, or PhCH,O

L. Maier and M. J. Smith, Phosphorus Sulfur, 1980, 8, 67. E. E. Nifantev, L. M. Runova, T. G. Shestakova, E. V. Bogatyreva, and V. I. Ronkov Zh. Obshch. Khim., 1980, 50, 304 (Chem. Abstr., 1980, 92, 215 494). E. S. Gubnitskaya and Z . T. Semashko, Zh. Obshch. Khim., 1980, 50, 456 (Chem. Abstr., 1980, 92, 215 497). C . J. Wharton and R. Wrigglesworth, J. Chem. SOC.,Perkin Trans. I , 1981,433.

Quinquevalent Phosphorus Acids

109

carboxamides and diethyl acetylphosphonate, affording (a-aminoetheny1)phosphonic esters (53) in low yields.76The absolute configuration of the ester (54) has been dete~mined.’~ New A3-l ,Zoxaphospholens (55) have been obtained from hypophosphorous acid or its organic derivatives on reaction with ap-unsaturated aldehyde^.^^ Base-catalysed intramolecular condensations of 0-or N-alkoxycarbonylmethyl derivatives of systems with active methylene groups yield the highly enolizable phostones (56 ; X = 0) or phostams (56 ; X = NMe).’

-

Ph

PhCH=CR*CHO

R’P(H) (0)OH

(56) X = 0 or N M e

R’, R3, R4, R:’ = alkyl or H R2 = H, Ph, or COOEt

LO‘

A [)PWHRCH,CHJI

(at 100-1500c)+

Ph\

CB>P
CH2CH,CHC1R Me A = 0 , S, M e N , or ButN B = S or MeN R = H or M e PhBu‘P(X)SH + RS0,Cl (X = 0 or S)

(57)

/p.-,R’ N “s Me

(58)

PhBu‘P(X)SSO,R

(59)

The preparation of cyclic phosphonic esters and amides (57) by the isomerization of o-chloroalkoxy-1,3,2-dioxaphosph(111)olansand related compounds has been further exemplified.s0Cleavage of 1,3,2-oxazaphospholidine2-sulphides (58) with Grignard reagents affords, inter alia, phosphinothioic acids (cf. their reactions with organolithium reagents ; see ‘Organophosphorus Chemistry’, Vol. 11, p. 125).81 Phosphinothiosulphinates (59) can be prepared from hydrogen phosphino(di)thioates and sulphinyl chlorides.s2 76 77

78

7Q

81 82

J. Zon, Synthesis, 1981, 324. Yu. P. Belov, G. B. Rakhnovich, V. A. Davankov, N. N. Godovikov, G. G. Aleksandrov, and Yu. T. Struchkov, Izv. Akad. Nauk SSSR,Ser. Khim., 1980, 1125 (Chem. Abstr., 1980, 93, 132 563). V. 1. Yudelevich, L. B. Sokolov, B. I. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1980, 50, 1419 (Chem. Abstr., 1980, 93, 204 771). H. D. Stachel and B. Hampl, Chem. Ber., 1981, 114, 405. L. Z. Nikonova and 0. N. Nuretdinova, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 918 (Chem. Abstr., 1980, 93, 114 621). C. R. Hall and T. D. Inch, Pol. J. Chem., 1980,54,489. W. Dabkowski, A. Lopusinki, J. Michalski, and C. Radziejewski, Phosphorus Sulfur, 1980, 8, 375.

Organophosphorus Chemistry

110

2,4-Di-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetandisulphide (60) reacts with dihydropyridone ketones (61) to yield bicyclic thiophosphinothioates (62) (see also refs. 174 and 175 for other reactions of this reagent).83 Arguably one of the most interesting synthetic sequences recorded during the year is the sequential addition of sulphur to (63; R = Me&), leading to the isolable and monomeric methylenethiophosphorane (64) and ultimately, by [1+ 21 cycloaddition, to the thiaphosphiran (65).84 S

N-NAr

MeOOC(N/e\ I \HO RI

R2

(66) X = O o r S R', R 2= alkyl R3= C1 or alkyl

A4-1,3,2-Oxazaphospholines(66)85 (see also ref. 14)and 3,4-dihydro-2H-1,2,4,3triazaphosphole 3-oxides (67)86 are obtainable by conventional cyclization reactions. The preparation of NN'P-tri-t-butyldiazaphosphiridine oxide (68) from t-butylphosphonic NN'-di-t-butyl-N-chlorodiamiderequires that the hydrogen R. Shabana, S. Scheibye, K. Clausen, S. 0. Olesen, and S. 0. Lawesson, Nouo. J. Chim., 1980, 4, 47 (Chem. Abstr., 1980, 93, 95 330). a4 E. Niecke and D.-A. Wildbredt, J. Chem. SOC.,Chem. Commun., 1981, 72. 85 Yu. V. Balitskii, V. V. Negrebetskii, and Yu. G. Gololobov, Zh. Obshch. Khim., 1980, 50, 2195 (Chern. Abstr., 1981, 94, 174 987). 88 G. Heubach, Liebigs Ann. Chem., 1980, 1376. 83

111

Quinquevalent Phosphorus Acids

chloride be abstracted by using a sterically hindered base such as MeBut,CO-; less sterically hindered bases result in the products of the ring-cleavage of (68). There is an activation barrier of 49 kJ mol-l for the diastereotopomerization of trans-N-t-butyl groups via pyramidal inversions of nitrogen. At 145-150 “C the compound decomposes to give 2-methylpropene, with other unknown compound~.~~ The scope of dialkyl phosphoroisocyanatidites as sources of phosphorus(1v)containing heterocyclic compounds continues to be extended.ss The products from ketenimines or imino-ethers are the cyclic phospha-ureides (69), generally obtained as mixtures of stereoisomers. The mechanisms of similar reactions have been discussed in more detail in earlier Reports.

(69)

(a) RZ= Ph or OEt, R3= Ph, R4= H (b) R2= H, R3= CCI,, R4= Ac or P(O)(OEt),

2 Reactions

General.-Descriptions of the dealkylation of phosphate and phosphonate esters by halogenotrimethylsilanes have been given in two Such reactions with chlorotrimethylsilane,in the presence of sodium iodide or potassium iodide, proceed at room temperature in methanol, but more forcing conditions are required when lithium iodide is employed. Ethenyl groups are not removed by this technique, and quaternary ammonium halides are ineffective. Reactions of hydrogen phosphorodithioates with chloroacetonitrile may proceed ‘normally’, with displacement of halogen, or ‘abnormally’, when addition across the triple-bond occurs initially, giving, inter aka, the acid chloride (70). The scope and mechanism of this addition process have been discussed in earlier Reports. (See ‘Organophosphorus Chemistry’, Vol. 11, pp. 119, 122; Vol. 12, p. 115). For the reaction with trichloroacetonitrile, the products are the thiophosphoryl chloride (70), the disulphide (71), trichlorothioacetamide, and the thioamidate (72) when 00-di-isopropyl hydrogen phosphorodithioate is used (R = PriO), or (70) and (71) when diphenyl phosphinodithioic acid (R=Ph) is the c o - r e a ~ t a n t Indeed . ~ ~ ~ ~the ~ latter acid has been suggested as a reagent for the conversion of nitriles into thiocarboxamides.s2 H. Quast and M. Heuschmann, Liebig’sAnn. Chem., 1981,967; H. Quast, M. Heuschmann, and M. 0. Abdel-Rahman, ibid., p. 943. 88 I. V. Konovalova, L. A. Burnaeva, M. V. Cherkina, and A. N. Pudovik, Zh. Obshch. Khim., 1980, 50, 1653 (Chem. Abstr., 1980, 93, 220 854); I. V. Konovalova, R. D. Gareev, L. A. Burnaeva, M. V. Cherkina, A. I. Khayarov, and A. N. Pudovik, ibid., p. 1446 (Chem. Abstr., 1980, 93. 220 847). 89 S. Andreae and A. Grimm, Z . Chem., 1980,20, 338. Qo T. Morita, Y.Okamoto, and H. Sakurai, Bull. Chem. Soc. Jpn., 1981, 54, 267. Q1 M. G. Zimin, N. G. Zabirov, V. N. Smirnov, R. A. Cherkasov, and A. N. Pudovik, Zh. Obshch. Khim., 1980,50, 24 (Chem. Abstr., 1980,92, 164 045). 92 S. A. Benner, Tetrahedron Lett., 1981, 22, 1851. 87

112

Organophosphorus Chemistry

Products of the reaction between oximes and the dithioic acids are of the general structure (73).93Addition of the same acids to the isocyanides R2NC yields the dithioates (74), which, when heated, or left to stand (if R2=Ph), yield the thioformyl-amides(75); in certain cases, the last are isolated Treatment of the sulphides (71) with diazomethane or with diazoacetic ester results in cleavage of the disulphide bond and insertion of the carbenoid moiety to give (76).95(See also refs. 122 and 123).

[R2Lsl

S

"

R,PCl

(70)

R,PSCR1R2NHOH

(7 2)

(73)

S

I1 R' R'POC, H,NO,-p (77) X = 0 or S

S

I1

II R',PNR2CHS

R' ,PSCH RZSPR',

(75)

(76)

(74)

X

II

R,PNHCCCl,

(71)

R',PSCH=NR*

S

0

II ClCH, P( OC, H,NO,-p ), (78)

0

II

(PhO),POC, H,NO,-p (79)

The reactivity of the esters (77; R1,R2= alkyl, alkoxy, aryloxy, dialkylamino, or chloromethyl), (78), and (79) to amine-catalysed alcoholysis has been studied; the effectivenessof the amine is in the order Bu3N< Bu,NH < C5H,,NH,.s6 In addition to the products that are obtainable by the action of organometallic reagents on 1,3,2-0xazaphospholidine 2-sulphides which have already been described, the 1,3,2-thiazaphospholidine2-oxide (8 1) has now been identified as the product when (80) is treated with alkylmagnesium halides or magnesium bromide etherate.s7 The intramolecular attack of a phosphoryl group on a carbo-cation centre that is generated in an (alk-3-enyl)-phosphonic or -phosphinic acid ester (and also phosphine oxide) by an electrophilic reagent (e.g. Br, or HBr) is feasible in appropriate examples such as the (2)-isomers (82); the products of this reaction 93 s4 s5 96

97

M. G . Zimin, N. G . Zabirov, R. A. Cherkasov, and A. N. Pudovik, Zh. Obshch. Khim., 1980,50, 1458 (Chem. Abstr., 1980,93, 185 679). M. G . Zimin, N. G. Zabirov, V. I. Nikitina, and A. N. Pudovik, Zh. Obshch. Khim., 1979, 49, 2651 (Chem. Abstr., 1980, 92, 129 027). B. A. Khaskin, 0. D. Sheluchenko, N. A. Torgasheva, and V. K. Promonenko, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 1606. V. E. Bel'skii, L. A. Kudryavtseva, K. A. Derstuganova, S. B. Fedorov, and B. E. Ivanov, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 1612. C. R. Hall and N. E. Williams, Tetrahedron Lett., 1980, 21, 4959.

Quinquevalent Phosphorus Acids

113

are essentially stereoisomerically pure 1,2-0xaphospholans. The corresponding (E)-00-dimethyl phosphonate undergoes a rearrangement process to afford the 1,2-oxaphosphetan(83).98 Nucleophiles react with 4,5-dioxo-l,3,2-diazaphospholidines (84; e.g. R = EtO, PhO, or Ph) at phosphorus; ring-opened products are formed initially. Where the phosphorus has a substituent that is capable of being displaced attached to it, the initial product from (84) and an amine cyclizes to give (85), unlike the products of alcoholysis of (84), which are relatively ~tab1e.O~

"

MeO'

'CH

Br-

J

(82) R = Me0 o r Ph

-

0

II

(MeO),P,

A ,Me

EB~_

(-

Me Me

MeBr)

/

MeO'

Ph (83)

CH,E 0

R'\ I1

P-NR2COCONHR2

/

Me0

>
R'

0

R3NH

R2

R'W)

R2

0

R2

Reactions of Phosphoric Acid and its Derivatives.-The use of 4-methoxyphenyl hydrogen N-(2-aminophenyl)phosphoramidate as a reagent for the preparation of diary1 phosphates and PP'-diary1 pyrophosphoric acid esters has already been referred to.22 Other new phosphorylating agents include 2-cyanoethyl 2,2,2trichloroethyl phosphorochloridate (86),lo0 bis-(2,2,Ztribromoethyl) phosphorochloridate,lo1 4,4,4-trichlorobut-2-en-l-y1phosphorodichloridate (87),lo2 and 4-chlorophenyl 5-chloro-8-quinolyl phosphorochloridate (88).103aIn the last case, the quinoline grouping is stable in acid and alkaline media and is removed specifically by zinc chloride in aqueous pyridine at room temperature; the corresponding tetrazolide (89) may be similarly ernp10yed.l~~~ Phosphorylation of carboxylic acids by diphenyl phosphorochloridate or the anilino phosphorochloridate (90) affords a synthesis of symmetrical carboxylic 98 99

100

101 102

103

G. Mass and R. Hoge, Liebigs Ann. Chem., 1980, 1028. M. Mulliez, Phosphorus Sulfur, 1980, 8 , 27. K. Grzeskowiak, Synthesis, 1980, 831. J. Engels and U. Krahmer, Synthesis, 1981, 485. P. Seidel and I. Ugi, Z. Naturforsch., Teil. B, 1980, 35, 1584. ( a ) H. Takaku, M. Yoshida, K. Kamaike, and T. Hata, Chem. Lett., 1981, 197; ( b ) H. Takaku, T. Nomoto, and K. Kamaike, Chem. Lett., 1981, 543.

114

Orgarlophosphorus Chemistry 0

NCCH,CH,O

\/O PhO

\p/o

0

II

C1,CCH=CHCwOPCl2

(87)

(88) X

=

'Cl (90)

PhNH/

CI N , -"

I

( 8 9 ) X = -N b

N

acid anhydrides; lo* other condensations that are activated by phosphorus(xv) chlorides or amides have been noted.lo5 The enol phosphates (91) can be cleaved by trialkyl(or alkenyl or alkyny1)aluminiums in the presence of tetrakis(tripheny1phosphine)palladium to yield alkenes.lo6Soft bases, such as I-, PhS-, and NC-, readily remove allyl groups from allyl diphenyl phosphates.lo7 Trimethylstannyl halides show a lower dealkylating reactivity than trimethylsilyl halides towards alkyl phosphate esters, and a combination of the two reagents has potential for the synthesis of mixed dialkyl phosphates.lo8 A fascinating way of achieving chirality in phosphate esters without chemical modification of the organic groups that are attached to phosphorus is to link those through isotopic oxygen atoms; some reference has been made to the use of this technique in previous Reports. Several further contributions on this topic have now appeared. Cyclization of the 2-hydroxypropylphosphate(92),which is of chirality ( R p ) in terms of [1s0170180], by phenyl phosphorodi-imidazolidate and subsequent methylation of the product with diazomethane, affords a mixture of six isotopically stereoisomericmethyl 1,3,2-dioxaphospholans,one of which, (93), is illustrated. These esters can be distinguished by the effect of the heavy oxygen isotopes on the 31P n.m.r. signals, enabling absolute configurations to be assigned.logA re-assignment of configuration has been made to the 2-methoxy2-oxo-4,5-diphenyl-l,3,2-dioxaphospholan that was described by Ukita ; the 'trans' form is now thought to be (94) rather than (95).llo Consequently the [160170180]pho~phate esters that were prepared by using the trans-dioxaphospholan should have the (S) configuration; a further consequence is that the lo4 R.

Mestres and C. Palomo, Synthesis, 1981, 218. M. Regitz, G. Weise, and U. Felcht, Liebigs Ann. Chem., 1980, 1232; H.-J. Liu and S. I. Sabesan, Can. J. Chem., 1980, 58, 2645. l o 6 K. Takai, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1980, 21, 2531. lo7 S. Araki, K. Minami, and Y . Butsugan, Bull. Chem. Soc. Jpn., 1981, 54, 629. Io8 J. Kowalski and J. Chojnowski, J. Organomet. Chem., 1980, 193, 191 1°9 S. L. Buchwald and J. R. Knowles, J. Am. Chem. SOC.,1980, 102, 6601. 1l0 P. M. Cullis, R. L. Jarvest, G. Lowe, and B. V. L. Potter, J. Chem. Soc., Chem. Commun., 1981, 245.

Io5

Quinquevalent Phosphorus Acids

115

( 9 5 ) R’ = MeO, R2 = =O

cyclization of monophosphate esters occurs with inversion of configuration at phosphorus. The oxygen-18 shifts in 31Pn.m.r. spectroscopy constitute a useful probe to study reaction mechanisms, in particular of the hydrolysis of phosphate triesters (Scheme 5).ll1 Only the twist-boat forms of the equatorial isomers (96; X=O, Ar = 2,4-dinitrophenyl) and (96; X = NH, Ar = 4-nitrophenyl) react with methoxide ion to give 100% inversion of configuration at phosphorus. All other esters, i.e. (96; X = O or NH), and the axial isomers (97) react with methoxide ion with 4-83 % inversion of configuration. The axial isomers (97) undergo base-catalysed hydrolysis 4-17 times slower than the epimers (96) in a reaction that is thought to be of the sN2(P) associative type.l12 A noteworthy feature of this chemistry is the influence of solvent on the site of methylation. 0

OAr

(0 = IRO) Reagents: i, CHzN2, MeOH; ii, CHzN2,HzO

Scheme 5

Caesium chloride has a powerful activation effect on exocyclic nucleophilic displacements in monocyclic and bicyclic 1,3,2-dioxaphosphorinans,reactions taking place in hours rather than weeks. Displacement of C1 or F from the monocyclic system by alcohols or phenols in the presence of CsCl leads to a ll1 112

5

D. G. Gorenstein and R. Rowell, J. Am. Chem. Soc., 1980, 102, 6165. D.G.Gorenstein, R. Rowell, and J. Findlay, J. Am. Chem. Soc., 1980, 102, 5077.

116

Organophosphorus Chemistry

kinetic product ratio of 1 : 1 (cis:trans); this changes rapidly to the thermodynamic ratio of 2: 1. On the other hand, for the trans-fused bicyclic system, the kinetic ratio is 85: 15, changing to 0: 100 (equatorial:axia1).ll3 methanolysis of cis- and of tvans-5In the toluene-4-sulphonic-acid-catalysed chloromethyl- 5 -methyl- 2-(4-nitrophenoxy) - 1,3,2-dioxaphosphorinan 2-oxides, the reaction mechanism appears to depend on the concentration of hydrogen ion; protonation at the phosphoryl group, rather than on an oxygen atom in the ring, results in configurational retention at low concentrations and in inversion at higher concentration^.^^^ The presence of an ovtho-methyl group retards the alkaline hydrolysis of dialkyl4-cyanophenyl phosphates and phosphonothioates by a factor of 1.5-2.5 ; no such steric effect occurs in the phenylimidation of the corresponding esters of tervalent Two papers discuss the reactions of diphenyl 4-nitrophenyl phosphate in the presence of functionalized micelles116 and another describes the influence of solvent (protic versus aprotic) and catalyst (tributylamine or trimethylamine) on the behaviour of the same phosphate in alcohol or water (see ‘Organophosphorus Chemistry’, Vol. 11, p. 123; Vol. 12, p. l12).l17 Dialkyl phosphorosulphenyl chlorides and bromides add to ally1 halides to give esters (98) rather than the branched-chain isomers (99), and to allene to give (100). When treated with diethylamine, (100; X = hal) gives (100; X=NEt,), which is also formed from (98) and diethylamine.l18 0 CH,X

0

I/ I

I1 (RO), PSCH,CHXCtl,X

( 1 01)

K

=

(‘I{h1ePh, (‘l12Ctl=(llMe, o r <‘HMeCH=CH,

Of two papers dealing with the thiono-thiolo rearrangement, the first llS indicates that protic-acid-catalysed oxygen-to-sulphur migrations of secondaryalkyl groups in trialkyl phosphorothionates occur in a complex fashion. In trifluoroacetic acid, almost complete inversion occurs in the chiral atom of the s-alkyl group, with concurrent formation of alkene. The second paper 120 R. J. P. Corriu, J.-P. Dutheil, and G . F. Lanneau, J . Chem. SOC.,Chem. Commun., 1981, 101. 114 S . H. Gehrke and W. S . Wadsworth, J . Org. Chem., 1980,45, 3921. 115 M. P. Ponomarchuk, L. F. Kasukhin, I. Yu. Budilova, and Yu. G . Gololobov, J . Cen. Chem. U S S R (Engl. Transl.), 1980, 50, 1937. 116 J. M. Brown, C . A. Bunton, S. Diaz, and Y . Ihara, J . Org. Chem., 1980, 45, 4169; C. A. Bunton, J. Frankston, and L. S . Romsted, J. Phys. Chem., 1980, 84, 2607. 11’ F. Ramirez and J. F. Marecek, Tetrahedron, 1980, 36, 1980. 11* S. K. Tupchienko, T. N. Dudchenko, and Yu. G. Gololobov, Zh. Obshch. Khim., 1980,50, 1686 (Chem. Abstr., 1981, 94, 30 111). 119 K. Bruzik and W. J. Stec, J. Org. Chem., 1981, 46, 1618. 1Zo K. Bruzik and W. J. Stec, J . Org. Chem., 1981, 46, 1625.

113

Quinquevalent Phosphorus Acids

117

describes the behaviour of the esters (101) in different protic acids and postulates that the rearrangement proceeds via the formation of ion-pairs. The continuing study of the reaction of hydrogen phosphoro(di)thioates with diphenyldiazomethane shows that cyclic acids are alkylated faster, and with greater exothermicity, than analogous acyclic acids.121 The reaction of diazomethane with bis(phosphin0) disulphides has already been mentioned ;95 that between the same reagent and bis(phosphinothioy1) disulphides has also been investigated, and it is similar in its outcome.122These reactions, and that which takes place with the mixed disulphides (102), are explicable in terms of the participation of i 0 n - p a i ~ s . l ~ ~ Newly reported reactions of 00-dialkyl hydrogen phosphorodithioates include that with thionyl-amines, giving bis(phosphinothioy1) disu1phides,l2* and with diketen, to yield the esters (103) as the kinetically controlled products and (104) as those of thermodynamic contr01.l~~ The acids may be S-acylated by means of N-(acy1thio)succinimides to give the trisulphides (105).126

s o

II II (KO),PXCC t1,COOhIe

S

II

( R 0)*P SC Me =C H

i

(K'O),PSSCOK'

Phosphoryl tris(triazo1ide) (106) has been prepared and used as a phosphorylating agent; when acted upon by alcohols, stepwise replacement of the triazole groups occurs,127allowing the formation of mixed phosphate esters. The participation of organophosphorus compounds in the formation of peptide bonds has received some considerable attention. The phosphoryl azidate (107) reacts with a mixture of carboxylic acid Ar'COOH and amine Ar2NH, to 121 122

123 124 125

126 127

V. V. Ovchinnikov, R. A . Cherkasov, and A. N. Pudovik, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 934 (Chem. Abstr., 1980, 93, 113 471). B. A. Khaskin, 0. D. Sheluchenko, N. A . Torgasheva, V. V. Negrebetskii, T. I. Koroleva, and V. K. Promonenkov, Zh. Obshch. Khim., 1980, 50, 2629 (Chem. Abstr., 1981, 94, 174 206). T. Miyamoto and I. Yamamoto, Agric. Bid. Chem., 1980, 44, 2581. G. A. Kutyrev, V. Yu. Mavrin, R. A. Cherkasov, and A. N. Pudovik, Zzo. Akad. Nauk SSSR, Ser. Khim., 1980, 1402 (Chem. Abstr., 1980, 93, 167 773). M. G. Zimin, M. M. Afanaset, and A . N. Pudovik, Zh. Obshch. Khim., 1980, 50, 746 (Chern. Ahsrr., 1980, 93, 113 877). S. Kato, H . Watarai, T. Katada, M. Mizuta, K. Miyagawa, and M. Ishida, Synthesis, 1981, 370. A. Kraszewski and J. Stawainski, Tetrahedron Lett., 1980, 21, 2935.

0rganophosphor us Chemistry

118

yield the ureas Ar1NHCONHAr2.128 Pentaco-ordinate phosphorus intermediates have in some cases been isolated in the reactions between carboxylic acids, e.g. 2,6-dimethoxybenzoicacid, or the monophenyl ester of phenylmalonic acid, and bis-(2-oxo-3-oxazolidinyl)phosphorylchloride (108) in pyridine; the intermediates act as activated species which, on further reaction with amines, afford carboxamides rather than phosphoryl a m i d e ~ . l ~ ~ There are also cases where the peptide bond is formed intramolecularly, being subsequently ‘retained’ or ‘expelled’. Thus the ultimate formation of (110) by interaction of the phosphoramidate (109) and tetrabutylammonium carboxylates could proceed by a series of acyl migrations involving activated pentacoordinated species (Scheme 6).130 Methanolysis of the 1,3,2-diazaphospholidin-4-0ne(1 12) leads, through a sequence (Scheme 7) of ring-opening and ring-closure reactions (cf. ref. 99), to

J

0

Scheme 6

( 1 13; K’ = MeO)

-

ii

1,

KI = Opt1 1

( 1 12; K1 = MeO)

(RZ= Ph or Me, R ’ = e . g , tolyl, R 4 = Me) Reagents: i, DBU; ii, MeOH

Scheme 7 128 129 130

A. Arrieta and C. Palomo, Tetrahedron Lett., 1981, 22, 1729. J. Cabre-Castellri and A. L. Palomo-Coll, Tetrahedron Lett., 1980, 21, 4179. M. Wakselman and F. Acher, Tetrahedron Lett., 1980, 21, 2705.

Quinquevalent Phosphorus Acids

119

the ester (113;R1= OMe). The overall reaction represents the effective intramolecular transfer of amino-groups in (111) and the formation, without expulsion, of the peptide bond in (113). I n a similar sequence, starting with the ester (111; R1= F,CH, R2= H, R3= COOCH,Ph, R4=CH,Ph), the formation of the corresponding compound (1 12) occurs with expulsion of PhCH20H, which then interacts to give (114), alkaline hydrolysis of which, followed by acidification, yields 2,4-diketopiperazine.l3’ 1 ‘,CHP(O) ( 0 H ) N HCH,CONHCH,COOCH,Ph

(1 14)

Studies on the stability of the P-N bond under acidic conditions continue. Application of the theory of participation of pentaco-ordinate intermediates in solvolytic displacement reactions of tetraco-ordinate phosphorus esters predicts that cleavage of the P-N bond in an N-protonated species should be subject to steric acceleration in five-membered rings. Modro et al.13, have shown that cleavage of the endocyclic P-N bond in 1,3,2-oxazaphospholidines by trichloroacetic acid in chloroform is faster, by a factor of lo3, than that of an exocyclic P-N bond or of a P-N bond in an analogous acyclic compound; this situation is explicable in terms of the intermediate (115). When the substrate molecule possesses both endo- and exo-cyclic P-N bonds, the rate is much reduced; this fact has been attributed to the greater basicity of the exocyclic nitrogen-containing function over the endocyclicone.

( 1 15)

The absolute configurations of the series (116) have been determined. These compounds undergo base-catalysed methanolysis with exclusive fission of the P-0 bond (Scheme 8).133

V

MeO’

x/p~Ph

F

(1 16) X = 0 or S

Reagents: i, NaOMe, MeOH; ii, EtOH, H+

Scheme 8 l3l 132

133

M. Mulliez, Tetrahedron, 1981, 37, 2027. T. A. Modro and D. A. Graham, J. Org. Chem., 1981, 46, 1923. T. Koizumi, R. Yamada, H. Takagi, H. Hirai, and E. Yoshii, Tetrahedron Lett., 1981, 22, 477.

120

Organophosphorus Chemistry

X-Ray analyses have been performed on the geometric isomers of 5-flUOrOc y c l o p h ~ s p h a m i d eand ~ ~ ~the ~ absolute configuration of (2S,4R)-( - )-4-methylcyclophosphamide has similarly been determined.134b A new oxidation product (117) of cyclophosphamide has been obtained by the ozonolysis of 0-but-3-enyl NN-bis-(2-chloroethy1)phosphorodiamidate.135A further theoretical study of the metabolites of cyclophosphamide has been carried out (see Chapter 8).ls6

Some further reactions of N-halogeno-phosphoramidates may be noted. Diary1 disulphides are cleaved by 00-diphenyl N-chlorophosphoramidate to give (118).13' Further addition reactions, between iVN-dibromophosphoramidates and alkenes, either radical-initiated or spontaneous, have been described ; the isolable products are N-(2-bromoethyl)phosphoramidates,and, by appropriate reactions of these, (2-bromoethy1)amines or a ~ i r i d i n e sN-Propargyl-phosphor.~~~ amidates (119) have been aminomethylated and the products hydrolysed to give the 1,Cdiaminobut-2-ynes (1 20).139

0

NNp(O ArS \

\

NIIP(OPh),

II 0

II

R,' PNR2CH,C-CH (1 19) R'

=

E t 0 or Me,N

RZNHCH,C=CCH,NR3R4 ( 1 20)

(118)

Mercuric oxide oxidizes the thioureides (121) to give products whose composition depends on experimental conditions. In benzene, the phosphorylated carbodi-imides (122) are formed, but in hot toluene the products are (123) and (124). In a protic medium, (125) are formed.140 Mercuric oxide reacts with bis(diphenoxyphosphiny1)imine to yield (126).14' (a) S. D.Cutbush, S. Neidle, G. N. Taylor, and J. L. Gaston, J. Chem. Soc., Perkin Trans. 2 , 1 9 8 1 , 9 8 0 ; (b) Z. Galdecki and M. L. Glowka, Acta Crystullogr., Sect. B, 1981,37, 1136. 135 J. van der Steen, J. G. Westra, G . Benckhuysen, and H. R. Schulten, J. Am. Chem. SOC., 1980, 102, 5691. 136 W. Ulmer, Znt. J. Quantum Chem., 1981, 19, 337. 137 A. V.Kharchenko, I. V. Koval, and M. M. Kremlev, Zh. Org. Khim., 1 9 8 0 , 1 6 , 7 5 4 (Chem. Abstr., 1980, 93, 167 772). 1 3 8 S. Zawadzki and A. Zwierzak, Tetrahedron. 1981, 36, 2675. 139 B. Corbel, J. P. Paugam, and G. Sturz, Can. J . Chem., 1980,58, 2183. 140 A. F. Grapov, V. N. Zentova, and N. N. Mel'nikov, Dokl. Akad. Nauk SSSR, 1980,251, 882 (Chem. Abstr., 1980, 93, 185 866). 141 H.Richter, E. Fluck, and W. Schwarz, Z . Naturforsch., Teil. B, 1980, 35, 578.

l3*

Quinquevalent Phosphorus Acids

121 S

ii

ll (E tO),PN=-C=NPh

(EtO),PNHCNHPh (121)

S

I1

(E t O),PN--C

(122)

(N € i Ph

(123)

0

\\

S

(I (F tO),PNCS (124)

S

11 (E tO),PN=C

/ \

R NHPh

(1 25) R = alkoxy, Et,N, or PhNH ’0

(126)

Reactions of Phosphonic and Phosphinic Acids and their Derivatives.-The conversion of the phosphonic ester (127) into the dichloride (129) by the action of phosphorus pentachloride proceeds stepwise via the intermediate (128).142 Further examples of the chlorination (or bromination) of 1- or 2-phosphorylated butadienes or allenes to give dihydro-A3-l, Z o x a p h o ~ p h o r i n e n s or ~~~ A3-1,2-0xaphospholens~~~ are in continuation of work presented in last year’s Report.

(127)

(128)

It has been known for some time that allenic esters of the type (130;X= halogen) rearrange easily to the butadienyl ester (131), and it has now been found that the esters (130; X = alkoxy), obtained readily from acetylenic p h o ~ p h i t e s react ,~~~ with HX to yield (13 1; X = halogen).146The stability of (130; X = C1) depends on the nature of R3.Thus, if R3 is H, compounds (130; R3=H) are unstable and give (131;R3= H) on mere distillation, whereas (130; R3= Me) are more stable, 0. P. Lobanov and B. S. Drach, Zh. Obshch. Khim., 1980,50,2142 (Chem. Abstr., 1981,94, 157 009). 143 C. M. Angelov and V. Christov, Tetrahedron Lett., 1981, 22, 359. 144 K h . Angelov, Zh. Obshch. Khim., 1980, 50, 2448 (Chem. Abstr., 1981, 94, 139 898); V. K. Brel, A. V. Dogadina, B. I. Ionin, and A. A. Petrov, ibid., p. 1652 (Chem. Abstr., 1980, 93, 220 853); V. K. Brel, A. V. Dogadina, B. I. Ionin, and A. A. Petrov, ibid., p. 1890 (Chem. Abstr., 1980, 93, 220 865). 145 V. K. Brel, A. V. Dogadina, B. I. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1980, 50, 1246 (Chem. Abstr., 1980, 93, 186 474). 146 V. K. Brel, E. D. Chunin, A. D. Dogadina, N. K. Skvortsov, B. I. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1980, 50, 770 (Chem. Abstr., 1980, 93, 94 429). 142

Organophosphorus Chemistry

122 ,x = <.,]

XCH,C=-C=-CR3,

I

~

4

0

*

H,C=C--CX=-CR3,

I

+

,O (I:tO)2PxMe

I1

0 (EtO),PXOR4

II

~

R‘OCH,

OR4

R~OCH,

\

Me 1

0

( 1 33)

but still cannot be isolated in pure form.147The esters (131 ;R1= R2= OEt, R3= H, X = OR4) are produced uia (alkeny1)phosphonates through initial addition of R40- to the central carbon atom of (130; R1=R2=OEt, R3=H, X=OR5) to give (132). The mixture of [(Z)-and [(E)-alkenyl]phosphonates eliminates R 5 0 H under the influence of dry HCI or on distillation, giving (133).145 Accounts of the addition of HCI to substituted (propa-l,2-dienyl)phosphonates also extend those mentioned in last year’s Report. Thus the ester (134) yields a mixture of the linear ester (135) (favoured by non-polar solvents) and the cyclic ester (1 36) (favoured by polar solvents). Regardless of solvent, however, the ester (134; R1= Me, R2= H) gives the corresponding compound (135) together with ~ * ~ addition of HCl to (alka-1’2(137), as a mixture of (2)-and ( E ) - f o r m ~ . The dieny1)phosphonic dichlorides, other than the parent compound, requires catalysis by tertiary amines; cyclization was found not to take place (see ‘Organophosphorus Chemistry’ Vol. 11, p. 129), and the reaction is one of mere addition, giving a variety of linear products, of which (138) can be dehydrohalogenated (by trialkylamines) to propargylphosphonic dich10ride.l~~ 0

II (R’O),PCH=C=CM~R~ (134)

0

II (RO ),PC H,CCl =CM (135)

Me

0

0

e R + pQpH

‘‘OR1

(136) 147 148

149

V. K. Brel, A. V. Dogadina, V. I. Zakharov, B. I. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1980, 50, 1256 (Chem. Abstr., 1980, 93, 186 475). T. S . Mikhailova, V. I. Zakharov, V. M. Ignat’ev, B. I. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1980, 50, 1690 (Chem. Abstr., 1980, 93, 238 167). T. S . Mikhailova, V. M. Ignat’ev, B. I. Ionin. and A. A. Petrov, Zh. Obshch. Khim., 1980, 50, 762 (Chem. Abstr., 1980, 93, 186453).

123

Quinquevalent Phosphorus Acids 0

II

(MeO),PCH=CCl

(CH, R2)

(137)

0

(I

H,C=C=CHPCL,

HC1

--+

H,C=CC1CH2PCL, (138)

+

c1

H

Me

H

(139) a; R3 = alkyl, X = S b; R3= Ph, X = Se

NP(OE I2

0

2

-“0 €1t

MeHC

or of phenylselenyl chloridelS1to The addition of alkylsulphenyl (alkadienyl)phosphonates, e.g. (1 34), yields A3-1,Zoxaphospholens, e.g. (1 39). Addition reactions using dialkyl phosphoroisocyanatidites give A3-l,2-azaphospholen-5-ones (140).152 Nucleophilic additions, e.g. of ethanol to the eneallenylphosphonate (141) to give (142), have been r e ~ 0 r d e d . l ~ ~ Addition of sulphenyl chlorides to (141) can also give A3-1,2-oxaphospholens, but, depending upon reaction conditions, 2-phosphorylated thiophens may also be forrned.l5* G. Vasilev, M. Kirilov, Kh. Angelov, Z . Domcheva, and K. Vachkov, Dokl. Bolg. Akad. Nauk., 1980, 33, 853 (Chem. Abstr., 1981, 94, 175 001). l 5 l Kh. Angelov and Kh. Khristov, Zh. Obshch. Khim., 1980, 50, 1891 (Chem. Abstr., 1980, 93,220 866). 1 5 2 N. G . Khusainova, Z . A. Bredikhina, I. V. Konovalova, and A. N. Pudovik, Zh. Obshch. Khim., 1980, 50, 1025 (Chem. Abstr., 1980, 93, 186464). 153 Yu. M. Dangyan, G . A. Panosyan, M. G . Voskanyan, and Sh. 0. Badanyan, Arm. Khim. Zh., 1980, 33, 780 (Chem. Abstr., 1981, 94, 157 015). 154 C . M. Angelov and K. V. Vachkov, Tetrahedron Lett., 1981, 22, 2517. l5O

124

Organophosphorus Chemistry

Reagents: i , ally1 halide; ii, MesSiBr; iii, heat

Scheme 9

Two papers have dealt with more unusual rearrangement reactions of appropriately unsaturated phosphonate esters. When heated, sodium allyl(etheny1)phosphinate (143) (see Scheme 9) evidently undergoes a Cope-type rearrangement to give, ultimately, the (pent-4-eny1)phosphonic acid (144). In water, at 194 "C, the half-life of (143) is about 4.5 The behaviour of the esters (145) to potential rearrangements evidently depends on the value of n.156 The ester (145; n = 2, R1= R2= H, R3= Me) undergoes a Cope reaction to give an isomeric diene. When n is zero, the nature of the product depends upon substituents. Thus (145 ; n = 0, R1= Me, R2= H, R3= H or Me) rearranges to a diene which 0

I1

(1. tO ),PC t 1 =C=C

R'(CH, )n C11=C R' R2 (145)

can be employed in Diels-Alder reactions. By contrast, when R1,R2, and R3are all methyl, a [1,5]-sigmatropic shift operates to give a phosphorylated triene. Appropriately substituted phosphonic esters can also undergo the analogous Claisen ester rearrangement. Although itself failing to undergo any rearrangement, (146) is converted into (147) (Scheme 10) when heated with an orthoester

0

II

(MeO),PCH,CH =CPhCH,COOE t (148)

0k.t

Reagents: i, R3CH2C(OEt)3, H + ; ii, Hf, heat

(147)

Scheme 10 155 156

D. I. Loewus, J . Am. Chem. SOC.,1981, 103, 2292. D. Cooper and S. Trippett, J. Chem. SOC.,Perkin Trans. I , 1981, 2127.

Quinquevalent Phosphorus Acids

125

in the presence of a trace of propionic acid. The corresponding 00-dimethyl ester analogue of (147; R2=Ph, R3= H) yields (148) when heated. Treatment of (134; R1= Et, R2= Me) with allyloxide anion (Scheme 11) yields a mixture of (149) and (150) via a mesomeric phosphonate anion. The esters (151) undergo a rapid [2,3]-sigmatropic rearrangement at, or even below, room t e m p e r a t ~ r e . ~ ~ ~ Dialkyl aroylphosphonates have been proposed as acylating agents since they react selectively with amino-groups to give N-substituted benzamides.15' Dimethyl (but-2-enyl)phosphonate, prepared as indicated in Scheme 12, has 0

II

(E tO),PCH=C=CMe,

+ H 2C==CH C H 00

I

I1 ---I--(EtO),PCH-C-CMe,

=_

I

OClI,CH=CH,

0

II

[ P = (EtO),P-]

.Me

I

'C 0 6 (OR' )?

0

II

O=P(OR'

0

),

0

II

( R' O),PC H M eC1 I,COP(OR' ),

Reagents: i, (Et0)sP; ii, HBr; iii, R2COC1

0

II

II

(R' O),PC H MeC H-C

I

P( 0R' ),

OCOR2

Scheme 12 157

M. Sekine, M. Satoh, H. Yamagata, and T. Hata, J. Org. Chem., 1980, 45, 4162.

126

Organophosphorus Chemistry

been shown to react further with trialkyl phosphite. Acidolysis of the isolable (but not purified) intermediate yields a linear 1-0x0-phosphonate, enol esters of which can be obtained by treatment of (1 52) with the appropriate acyl ch10ride.l~~ Some reactions of phenacylphosphonic acids and related compounds have been reported. Thus the acid (153) may be a-brominated and a-methylated; in pyridine, it forms a normal oxime, whereas the phosphinic acid yields (154).159 The phosphorylated keten (15 5 ) undergoes a normal Staudinger reaction, and the product takes part in further reactions at the C - N bond;160with hydrazoic acid, (155) gives the isocyanate (156).161


PliCOCH

/

(PhCOCH,),PO,lI

1

-

PhC -N

PI1

(153) 0

II

(l.tO),PCPh=C=NR

11

1I

NOH (154)

Ph,P =NK

0

0

II

(1 tO),PCPh=C=O (155)

HN

II

4 (ttO),PCHPhNCO (1 56)

In the presence of acid or a trace of alkali, benzimidazole adds to the unsaturated bond in di-(2-chloroethyl) ethenylphosphonate ; however, the sodium derivative of benzimidazole reacts with displacement of chloride anion, the product then being di-(2-benzimidazolylethyl) ethenylphosphonate.162 In the reaction between methylphosphonic difluoride and aniline, replacement of the first fluorine atom takes place very slowly. The pronounced effect that the nature of the solvent has upon the complex lH n.m.r. spectra supports the idea of equilibria within an intermediate p h ~ s p h o r a n e . ~ ~ ~ From time to time, suggestions are made regarding the validity of phosphacylium ions (157) in SN reactions of tetraco-ordinate phosphorus compounds. Some evidence against such proposals has been provided by Michalski’s group.164 The anhydride (158) undergoes alkaline cleavage to give unlabelled methanesulphonic acid; the use of optically active (158) leads to complete retention of configuration at phosphorus in the acid (159). Under neutral conditions, in aqueous acetone, the hydrolysis proceeds with complete inversion of configuration and without scrambling of l 8 0 , indicating that phosphacylium cations, in ion-pairs, are unlikely to be involved. On a more general note, the extreme sensitivity of the course of hydrolysis of (158) to the ionizing power of the 158 159 160

161

162 163

164

A. Szpala, J. C. Tebby, and D. V. Griffiths, J. Chem. SOC., Perkin Trans. 1 , 1981, 1363. L. S. Moskalevskaya and F. D. Fedorova, Zh. Obshch. Khim., 1980,50, 61 (Chem. Absrr., 1980, 92, 198 472). 0 . I. Kolodyaznyi and V. N. Yakovlev, Zh. Obshch. Khim., 1980, 50, 55 (Chem. Abstr., 1980, 92, 164 046). 0 . I. Kolodyazhnyi, V. N. Yakovlev, and V. P. Kukhar, Zh. Obshch. Khim., 1980, 50, 1418 (Chem. Abstr., 1980, 93, 204 770). G. L. Matevosyan, R. M. Matyushicheva, S. R. Rudnik, and P. M. Zavlin, Zh. Obshch. Khim., 1980, 50, 64 (Chem. Abstr., 1980, 92, 198 473). I. Granoth, Y.Segall, D. Waysbort, E. Shirin, and G. Leader, J. Am. Chem. SOC.,1980, 102,4523. J. Michalski, C. Radziejewski, Z. Skrzypczynski, and W. Dabkowski, J. Am. Chem. SOC., 1980, 102, 7974.

Quinquevalent Phosphorus Acids

127

solvent suggests that the mechanistic criteria that are employed in carbon chemistry cannot be used in phosphorus chemistry. In a recent paper,165the isomerization of optically active thiocyanates (160) into the corresponding optically active isothiocyanates is described. This reaction occurs with specific inversion of configuration at phosphorus, a process rationalized by postulating the involvement of phosphorane intermediates in which the thiocyanate and isothiocyanate groups occupy apical positions. Also described in the paper are the preparations of several optically active compounds that possess the NHC(S)NHR, NCCl,, NCO, and NHCOOBut groups bonded to phosphorus. S +

Rp-0 (157)

II

P ’j \ * Ph’ But OS02hle (158) O* = IRO

i

K

But PhPOH (159)

But’

\ A ‘P’.

O

‘SCN

(160) R = Ph or M e 0

Michalski’s group has also reported on the stereochemistry of chlorinolysis of the P-S bond in thiolate esters.166This process has now been shown to occur, unexpectedly, with retention of configuration at phosphorus, for the phosphinothioate ester (161 ; R1= Bu, R2= Ph, R3= Me) (Scheme 13). One explanation lies in the assumption of (162) as an intermediate, although this could not actually be detected by 31Pn.m.r. spectroscopy.

(163) Racemization at phosphorus in 1,l-dialkyl-l,2,3-stannathiaphospholans has been interpreted in terms of intramolecular co-ordination with the tin atom.167 Ethylation of 0-ethyl hydrogen ethylphosphonoselenonic acid by triethyl phosphite takes place with retention of configuration at phosphorus.16* 165 166 167 168

A. Lopusinski, L. Lucsak, J. Michalski, M. M. Kabachnik, and M. Moriyama, Tetrahedron, 1981, 37, 2011. B. Krawiecka, J. Michalski, and E. Tadeusiak, J. Am. Chem. SOC.,1980, 102, 6582. C. Muegge, H. Weichmann, and A. Zschunke, J. Organomet. Chem., 1980, 192, 41. I. A. Nuretdinov, E. V. Boyandina and D. N. Sadkova, Zh. Obshch. Khim., 1980, 50, 1429 (Chem. Abstr., 1980, 93, 203 996).

128

Organophosphorus Chemistry

The reactions of imidazole or benzoate ion with 4-nitrophenyl and 2,4dinitrophenyl diphenylphosphinates have been investigated. The former ester reacts much more quickly than does the latter, and in both cases the reversible formation of anhydrides of the type Ph,P(O)R ( R = I m or OCOPh) has been A study of the alkaline hydrolysis of esters of dibutylphosphinic acid has been One of the hydrolytic behaviours of the phosphinothionic acid esters (164; R1R2=Me2,Ph2, or MePh; R 3 = H , Me, Br, or NO2) seems to suggest an addition-elimination process.171 The A3-l ,2-oxaphospholen (1 65) undergoes fast methanolysis and hydrolysis at the exocyclic P-0 bond.172

Several papers describe applications of the dithiadiphosphetan (60) to the thiation of organic 173 (60) reacts with benzylamine to give (166), which can be alkylated at sulphur, and which, at 140 "C, loses H,S to give diamido-compounds. When (60) reacts with dibenzylamine, the large number of products affords evidence for the occurrence of N-to-S rearrangement^.^^^ Diphenylphosphinic amides can be alkylated, under phase-transfer conditions, either by alkyl halides175or by alkyl methane~ulphonates.'~~ 169 170 171

172 173

174 175 176

G. Wallerberg and P. Haake, J. Org. Chem., 1981, 46, 43. C.-Y. Yuan and Q . Yuan, Hua Hsueh Hsueh Pao, 1980, 38, 339 (Chem. Abstr.. 1981, 94, 47 415). B. I. Istomin, G. D. Eliseeva, and A. V. Kalabina, Org. React. (Tartu), 1979, 16, 468 (Chem. Ahstr., 1981, 94, 46 604); B. I. Istomin and G. D. Eliseeva, ibid., p. 478 (Chem. Abstr., 1981, 94, 46 605); B. I. Istomin and G . D. Eliseeva, ibid., p. 457 (Chem. Ahstr., 1981, 94, 46 603); G. D. Eliseeva, B. I. Istomin, and A. V. Kalabina, Zh. Obshch. Khim., 1980, 50, 1901 (Chem. Ahsrr., 1981, 94, 3388). D. Van Aken, A. M. C. F. Castelijno, and H. M. Buck, Recl. Trac. Chim. Pays-Bas, 1980, 99, 322. K . A. Joergensen, R. Shabana, S. Scheibye, and S. 0. Lawesson, Bull. SOC.Chim. Belg., 1980, 89, 247 (Chem. Absrr., 1980, 93, 95 349); R. Shabana, J. B. Rasmussen, and S. 0. Lawesson, ihid., 1981, 90, 75 (Chem. Abstr., 1981, 95, 24 953); R. Shabana, J. B. Rasmussen, S. 0. Olesen, and S. 0. Lawesson, Tetrahedron, 1980,36, 3047; A. A. El-Barbary, K . Clausen. and S. 0. Lawesson, ibid., p. 3309; D. R. Shridhar, C . V. R. Sastry, L. C . Vishwakarma, and G. K. A. S. S. Narayan, Org. Prep. Proced. Znt., 1980, 12, 203. K. Clausen, A. A. El-Barbary, and S. 0. Lawesson, Tetrahedron, 1981,37, 1019. E. Slusarska and A. Zwierzak, Synthesis, 1980, 717. E. Slusarska and A. Zwierzak, Svnthesis, 1981, 155.

129

Quinquevalent Phosphorus Acids

When the oxazaphospholens (167) pass into solution, they give an intermediate which is not the dipolar ion (168) and yet which, in the presence of water, gives first (169) (or a dimer) and ultimately (170). In the absence of water, the intermediate is in equilibrium with formylarene and diethyl phosphoroisocyanatidite.17' Nucleophilic displacements at phosphorus in the 1,2-azaphospholidines (171j 178 and 1,3,2-diazaphospholidines(112; R1= Me or Ph, R2= H or Me, R3=benzyl or p - t ~ l y l )and , ~ ~in~the corresponding sulphides, have been studied. The former undergoes P-N bond fission when acted upon by water or alcohols, but the system is unaffected by amines. The latter system, (112), is attacked by water or alcohols at the P-NR3 bond to give the salts (172) or the esters (113). The rate of aminolysis depends on R1,being slow if R1is phenyl and negligible if R1is methyl, in contrast to the reactions of amines with the dioxo-analogues (84). The failure, or otherwise, of ring-opening with attacking amines seems to depend on the role of the P-N bond in intermediate phosphoranes.

R',

,XH

The mechanism of hydrolysis of the phosphonic amides (173) has been discussed in detail; the results are consistent with a rate-determining fission of the P-N bond and an S K ~ ( Pmechanism.lso ) , Ph

0

3

( 1 7 3 ) R = NMe,, N

,or

/\o

NW

R. I. Tarasova, T. V. Zykova, M. V. Alparova, N. 1. Sinitsyna, and R. A. Salakhutdinov. Zh. Ohshch. Khim., 1980, 50, 757 (Chem. Ahstr., 1980, 93, 94 569). 17* M. Mulliez, Phosphorus Sulfur, 1980, 8, 37. 179 M. Mulliez and M. Wakselman, Phosphorus Sulfitr, 1980, 8, 41 l a 0 J. Rahil and P. Haake, J . Am. Chem. Soc.. 1981, 103, 1723. 177

130

Organophosphorus Chemistry

Esters of dansyldiazomethyl(methy1)phosphinic acid (174) have been prepared as reagents for photoaffinity labelling; photolysis gives high yields of the products of insertion into solvents.181

my

Me,N

0 O ,lIh ei.

h v , ROH

SO,CN,P-XMe

ArSo2CHP

I Me

I

‘Me

OR

( 1 74)

ArS0,C-PMe \+/

S Me

1*1

II

-

0

II

ArCHP-OR

I

SMe

‘Me

J. Stackhouse and F. H. Westheimer, J. Org. Chem., 1981, 46, 1891.

7 Phosphates and Phosphonates of Biochemical Interest BY D. W. HUTCHINSON

1 Introduction* Several reviews and discussions of aspects of the chemi-osmotic theory of oxidative phosphorylation have been published in the past year,l-* including a critique5 which casts doubt on the validity of the concepts behind the chemi-osmotic model of energy coupling. Apart from these reviews, no papers on chemical aspects of oxidative phosphorylation have appeared in the past year, and this topic will not be covered further in this Report. As will be discussed more fully elsewhere in this Report, the application of 31P n.m.r. to the study of enzyme mechanisms has continued at a great pace.6 The stereochemistry of enzymic phosphoryl-transfer reactions has continued to be the subject of a number of elegant investigations, and the availability of water which contains substantial amounts of 170has stimulated the use of 31P and 170n.m.r. for this p ~ r p o s e . ~ The use of immobilized enzymes for the simple, large-scale preparation of NADf and sugar phosphates is an interesting development which has been reported recently.8p The aqueous solutions of NAD+ which can be obtained by this means can be used without further purification.* The starting material for the preparation of the coenzyme is ribose 5-phosphate, which can be obtained either by the acid-catalysed hydrolysis of AMP or from glucose 6-phosphate, using an immobilized, coupled enzyme system. A detailed review of the role of phosphorus as an essential element in biology and medicine has appeared in a Specialist Periodical Report l oand recent editions of Methods in Enzymology cover nicotinamide and flavin coenzymes,llU and cobalamins.llb * Abbreviations used in Chapters 7,

8, and 9 are detailed in Biochem. J., 1970, 120, 449 and Biochem. J., 1978, 171, 1. P. Mitchell, Chem. Br., 1981, 17, 14. R. H. Fillingame, Annu. Rev. Biochem., 1980, 49, 1079. G. von Jagow and W. D. Engel, Angew. Chem., Int. Ed. Engl., 1980,19, 659. S. L. Hardt, J. Theor. Bio!., 1980, 87, 1. D. E. Green, Proc. Nutl. Acud. Sci. U S A , 1981, 78, 2240. J. R. Knowles, Annu. Rev. Biochem., 1980, 49, 877. 7 M.-D. Tsai, S. L. Huang, J. F. Kozlowski, and C. C . Chang, Biochemistry, 1980,19, 3531. 8 D. R. Walt, V. M. Rios-Mercadillo, J. Auge, and G. M. Whitesides, J. Am. Chem. SOC., 1980, 102, 7805. C.-H. Wong, S. D. McCurry, and G. M. Whitesides, J . Am. Chem. SOC.,1980,102, 7938. l o N. J. Birch and P. J. Sadler, in ‘Inorganic Biochemistry’, ed. H. A. 0. Hill (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1981, Vol. 2, p. 315. l1 (a) ‘Methods in Enzymology’, Vol. 66, ed. D. B. McCormick and L. D. Wright, Academic Press, New York, 1980; (b) ibid., Vol. 67, ed. D. B. McCormick and L. D. Wright, Academic Press, New York, 1980.

131

132

Organophosphorus Chemistry 2 Coenzymes and Cofactors

The preparation and properties of a number of analogues of NAD+ have been described in the past year. For example, those in which the adenosine moiety has been replaced by 4-acetylanilinoalkyl residues can be synthesized by the carbodi-imide-mediated coupling of the corresponding monophosphates.12 Bromination of one such analogue leads to (l), which can be used for the affinity labelling of the active sites of dehydrogenases. Pyridine-substituted NAD+ analogues which have been reported recently include the fluorescent 3-aminopyridine-adenine din~cleotide'~ and the 3-diazirino-analogue (2).l 4 The latter was prepared from 3-pyridyl-3H-diazirine and NAD+ by making use of the exchange reaction that is catalysed by nicotinamide-adenine dinucleotidase. On irradiation, (2) was an efficient photoaffinity label for lactate dehydrogenase.

bH

OH

(2)

Alkylation at N-1 of the adenine ring in NAD+ with 2,3-epoxypropyl acrylate, followed by polymerization in the presence or absence of acrylamide at pH 8, leads to N6-substituted NAD+-containing polymers (3).15 Under these conditions, the Dimroth rearrangement takes place during the polymerization reaction. These polymers are biologically active, and can be used as cofactors in enzyme reactors. This synthetic route appears to be easier than that described for similar NAD+-containing derivatives which have been obtained by copolymerizing the N6-[N-(N-acryloyl-l -methoxycarbonyl-5-aminopentyl)propionamide] of NAD+ (4)with various vinyl monomers.16 Another coenzyme derivative whose synthesis has been described recently is a carba-analogue of S-palmitoylcoenzyme A.17 H. Vutz, R. Koob, R. Jeck, and C. Woenckhaus, Liebigs Ann. Chem., 1980, 1259. S . C. Tu, Arch. Biochem. Biophys., 1981, 208, 487. D. N. Standring and J. R. Knowles, Biochemistry, 1980, 19, 2811. 1 5 F. Le Goffic, S. Sicsic, and C . Vincent, Eur. J . Biochem., 1980, 108, 143. 16 S. Furukawa, Y. Sugimoto, I. Urabe, and H. Okada, Biochimie, 1980, 62, 629. l 7 T. Ciardelli, C . J. Stewart, A. Seeliger, and T. Wieland, Liehigs. Ann. Chem., 1981, 828.

l2 13 14

Phosphates and Phosphonates of Biochemical Interest -(

0

133 CH2CH),-

o=c

OH

I

OH

pH8, 4OoC R

(3)

R

COOMe

1

HzC=CHCONH(CH2)4CHNHCO(CH

8-a-0-Tyrosyl-FAD (5) has been isolated from an enzyme which hydroxylates p-cresol to p-hydroxybenzyl alcohol and dehydrogenates the latter to p-hydroxybenzaldehyde.18Both steps are catalysed by the same protein. The FAD-aminoacid derivative is at the N-terminal end of a peptide chain.

CH,OH

YHO

OH

bH (6)

The stereochemistry of enzyme reactions which are catalysed by pyridoxal phosphatelg and the role of pyridoxal phosphate in glycogen phosphorylase20 have been reviewed. Pyridoxal(S')phospho( l)-p-D-glucose (6) has been prepared, using the Konigs-Knorr method, from pyridoxal phosphate and 2,3,4,6-tetra0-acetyl-P-D-glucopyranosyl bromide.21Since (6) shows no activity as a cofactor l*

19 20

21

W. McIntire, D. E. Edmondson, T. P. Singer and D. J. Hopper, J . Biol. Chem., 1980,255, 6553. J. C. Vederas and H. G . Floss, Acc. Chem. Res., 1980, 13, 455. E. J. M. Helmreich and H. W. Klein, Angew. Chem., Int. Ed. Engl., 1980, 19, 441. M. Takagi, S . Shimomura, and T. Fukui, J . Biol. Chem., 1981, 256, 7 2 8 .

134

Organophosphorus Chemistry

for glycogen phosphorylase, it is assumed that it is unlikely that a covalent glucosyl-enzyme is an intermediate in this enzymic reaction. P-D-Glucose cyclic 1,2-phosphate is a good competitive inhibitor of glycogen phosphorylases, and its effects are similar to those of glucose 1-phosphate. Phosphorus-31 n.m.r. studies with the glucose cyclic phosphate suggest that it is tightly bound by electrostatic forces in the inhibitor-enzyme complex.22

Vinyl- and methylene-substituted phosphonate analogues of phosphoenolpyruvate (PEP) which might mimic the preferred geometry and conformation of biologically important compounds have been prepared; 23 for example, the basecatalysed addition of methyl dimethylphosphinylacetate to dimethyl acetylenedicar boxylate, followed by hydrolysis of the intermediate (E)-and (Z)-adducts, gives the corresponding free acids (7). In a similar manner, (2)-(8) has been prepared from the anion of bis(dimethoxyphosphiny1)methane. No data on the biological properties of these analogues of PEP are presented, however. The involvement of a phosphoryl-enzyme intermediate in the PEP-dependent phosphotransferase system from Escherichia coli has been inferred from kinetic studies.24The stability constants for the binding of magnesium ions to PEP, 2- and 3-phosphoglycerates, 2,3-bisphosphoglycerate, and glucose 6-phosphate have been determined spectrophotometrically in the presence of 8-hydro~yquinoline.~~ Phosphorus-31 n.m.r. spectroscopy of the 1 : 1 complex between thiamine diphosphate and Mg2+ shows that the a-phosphorus atom is the most affected and that this complex is probably very similar to the thiamine diphosphate-Mn2+ complex.26 Details for the analysis of thiamine phosphate esters by reverse-phase h.p.1.c. have been rep~rted.~'

3 Sugar Phosphates Fructose 2,6-bisphosphate (9), which can be prepared by treating fructose 1,6-bisphosphate with DCCD and then hydrolysing the cyclic intermediate with

HO

OH

(9) 22 23 24

25 26 27

S . G. Withers, N. B . Madsen, and B. D. Sykes, Biochemistry, 1981, 20, 1748. R. M. Davidson and G. L. Kenyon, J. Org. Cliem., 1980, 45, 2698. H. Hoving, J. S . Lolkema, and G. T. Robillard, Biocliemistry, 1981, 20, 87. K. L. Manchester, Biochim. Biopliys. A c m , 1981, 630, 225. A. M. Chauvet-Monges, M. Hadida, A. Crevat, and E. J. Vincent, Arch. Biochem. Biophys., 1981, 207, 311. H. Sanemori, H. Ueki, and T. Kawasaki, Anal. Biochem., 1980, 107, 451.

Phosphates and Phosphonates of Biochemical Interest

135

alkali,28 is identical to an activator of phosphofructokinase which has been isolated from hepatocytes. Fructose 1,6-bisphosphatase is strongly inhibited by (9), and the latter may have regulatory proper tie^.^^ The structures of a series of phosphorylated oligomannosides from the yeast Hansenula wingei have been determined by a combination of chemical and 31P n.m.r. studies. The predominant compounds are a mannotriose and a mannopentose, bearing phosphoryl residues at their 6-positions. A cyclic phosphate which was isolated with these compounds is probably an artefact of the isolation p r o c e d ~ r e sSimilarly, .~~ the structures of a family of phosphorylated oligomannosides which can be isolated from /I-glucuronidase that has been newly synthesized in mouse lymphoma cells have been determined.31In this case the predominant compounds are phosphodiesters, usually with N-acetylglucosamine, and individual oligosaccharides can contain up to three phosphodiester linkages.

4 Phospholipids In a simple synthesis of choline alkyl phosphates by the phosphotriester approach, the phosphoryl oxygens are protected by methyl groups.32 Commercially available methyl phosphorodichloridate is treated with a limiting amount of the appropriate alcohol in the presence of 2,6-lutidine to give the alkyl methyl phosphorochloridate (10). Treatment of the latter with the sodio-derivative of NN-dimethyl-2-aminoethanol gives (ll), which undergoes intermolecular transmethylation on standing to give the choline alkyl phosphate. The phosphotriester route has also been used for the synthesis of phosphatidyl-a-glucosyldiacylglycerols which are derived from palmitic and oleic

M e O P ( 0 ) C 1 2 + ROH

’

-0,

RO

-

P ( o )O C H ~ C H ~ ~ ~ M ~

0 MeO,l( p-Cl

28 days, a t r . t .

,P

-OCH2CH2NMe2

RO

(11)

CDP-Diacylglycerol derivatives which contain cytosine arabinoside, e.g. (12 ) , are being investigated as possible anti-cancer agents. These pyrophosphates can be prepared from araC 5’-phosphoromorpholidate and either synthetic phosphatidic acids or those obtained from egg lecithin.34 The aruC-containing liponucleotides reduced tumour weights under conditions when araC itself had 28

29

30 31 32

33 34

S. J. Pilkis, M. R. El-Moghrabi, J. Pilkis, T. H. Claus, and D. A . Cumming, J . Biol. Chem., 1981, 256, 3171. S . J. Pilkis, M. R. El-Maghrabi, J. Pilkis, and T. Claus, J. Biol. Chem., 1981, 256, 3619. C. Hashimoto, R. E. Cohen, and C. E. Ballou, Biochemistry, 1980, 19, 5932. A. Varki and S . Kornfeld, J . Biol. Chem., 1980, 255, 10 847. C. J. Lacey and L. M. Loew, Tetrahedron Lett., 1980, 21, 2017. C. A. A. van Boeckel and J . H . van Boom, Tetrahedron Lett., 1980, 21, 3705. J. G. Turcotte, S . P. Srivastava, W. A. Meresak, B. A. Rizkalla, F. Louzon, and T. P. Wunz, Biochim. Biophys. Acta, 1980, 619, 604.

Organophosphorus Chemistry

136 CH-OR’ 0

0

II II -P-0 I

OH

no observable effect.35 This may be because the liponucleotides can deliver araCMP to sites which are inaccessible to araC or araCMP. The synthesis of the 2-phosphocholine esters (1 3) and (14) from 2-bromoethyl phosphorodichloridate has been The mercury derivative (1 3) has been used to investigate the antibody-binding site of an immunoglobulin by X-ray diffraction, and the derivative (14) can be used to attach phosphorocholine residues to insoluble supports for affinity chromatography. Analogues, e.g. (1 5), of the phosphorylated ‘core’ of lipid A have been prepared ~hemically.~’ A key step in this synthesis is the opening of an oxazoline ring (16) with dibenzylphosphoric acid to give an N2-acetyl-carbohydrate 1-phosphate. Other more usual phosphorylation methods failed to give the required 1 -phosphates.

RCOO 7

H203P0

RCOO (15) R = tetradecanoyl

OP03H2

Several studies have been carried out recently on photoaffinity labelling with photo-active phospholipids. The lipids bearing diazo- or arylazido-groups have been prepared by conventional methods and have been used to study phase 35

36 37

J. G . Turcotte, S. P. Srivastava, J. M. Steim, P. Calabresi, L. M. Tibbetts, and M. Y . Chu, Biochim. Biophys. Acta, 1980, 619, 619. T. F. Spande, J . Org. Chem., 1980, 45, 3081. M. Inage, H. Chaki, S . Kusumoto, and T . Shiba, Tetrahedron Lett., 1981, 22, 2281.

137

Phosphates and Phosphonates oj’Biochemical Interest

+ (PhCH20)2P(0)OH

QY

-

N =CMe

Q

OP(0)(CH2Ph)2

0

NHCOMe

(16)

CH200C(CH2)14Me

I

RCOOCH 0 CI H ~IIO ~ O C H ~ C H ~ ~ ~ M ~

A-

i2

R = CF3CCOO(CH2)ll- or

Q N=N

CH20(CH2)5Me

I

CH200C(CH2)12Me

I

CH2)1 2COObH CH20POCH2CH2fiMe3 I II N3QNH(

N02

I

0separations in mixtures of the lipids (17)38and to investigate the photoaffinity labelling of phospholipase A, (18)39 and of membrane proteins (19).40 The methylation of phospholipids 41 and ~phingomyelins~~ has been reviewed, The direct introduction, on a gold support, of diacyl-lecithins into the ionization chamber of a mass spectrometer can give good electron-impact spectra, showing the molecular ion and structurally significant fragment^.^^ 5 Phosphonates Resonances due to 2-aminoethylphosphonic acid and an electronegatively p-substituted phosphonic acid can be detected in the 31Pn.m.r. spectra of the unicellular protozoan Acanthamoeba c a s t e l l ~ n i iIn . ~ the ~ living cell, the resonances are sharp, suggesting that the phosphonates are in an environment which allows 38

39 40

41 42

43 44

W. Curatolo, R. Radhakrishnan, C. M. Gupta, and H. G. Khorana, Biochemistry, 1981, 20, 1374. K.-S. Huang and J. H. Law, Biochemistry, 1981, 20, 181. R. Bisson and C. Montecucco, Biochem. J . , 1981, 193, 757. F. Hirata and J. Axelrod, Science, 1980, 209, 1082. Y.Barenholz and T. E. Thompson, Biochim. Biophys. Acta, 1980, 604, 129. E. Constantin, Y.Nakatani, G. Ourisson, R. Hueber, and G. Tellev, Tetrahedron Lett., 1980,21, 4745. R. Deslauriers, R. A. Byrd, H. C. Jarrell, and 1. C. P. Smith, Eur. J. Biochem., 1980, 111, 369.

Organophosphorus Chemistry

138 P03H-

I

qOgH2

y 2

*

CH&H~

y 2

I

CHO

COOH (21)

(20)

the molecules to tumble. The catabolic pathway of 2-amino-3-phosphonopropionic acid (20) in Tetrahymenu pyrijormis appears to be the same as that in animals.45 Initial deamination is followed by decarboxylation to 2-phosphonoacetaldehyde (21). The latter can then either undergo dephosphonylation to acetaldehyde or amination to 2-aminoethylphosphonic acid. A phosphonamidate analogue (22) of carbobenzoxyglycyl-L-phenylalanine, which is a substrate of carboxypeptidase A, has been prepared from dimethyl phthalimidomethylphosphonate (23) as outlined in Scheme 1.46 Although (22) 0

* II

; 0M.e

C b z N H C H P'

/

iv - vi

0

(23) 0

CH2Ph

I1 I

Ho'2

Cb zNHCH~PNHCHCOO- L i +

(22) Reagents: i, N H i N H z ; ii, CbzCl; iii, N a O H ; iv, SOCl2; v, phenylalanine methyl ester; vi, LiOH

Scheme 1

was hydrolysed in minutes at pH 2.3, it is sufficiently stable at higher pH values for enzyme-inhibition studies to be carried out. Presumably (22) resembles the tetrahedral intermediates that are formed when peptides are hydrolysed by carboxypeptidase A, as it is a potent inhibitor of this enzyme. The herbicide N-(phosphonomethy1)glycine (24) causes the accumulation of shikimic acid in plant tissues, and, because the shikimic acid pathway operates only in plants and micro-organisms, (24) may have potential as a herbicide which is not toxic to animals. Recent studies 47 indicate that the accumulation of shikimic acid that is caused by (24) is due to the latter inhibiting 5-enolpyruvylshikimic acid 3-phosphate synthetase. H203PCH2NHCH2COOH (24) 45

46 47

A, Horigane, N. Horiguchi, and T. Matsumoto Biochim. Biophys. Acta 1980, 618,383. N. E. Jacobsen and P. A. Bartlett, J. Am. Chem. SOC.,1981, 103, 654. H. C. Steinriicken and N. Amrhein, Biochem. Biophys. Res. Commun., 1980, 94, 1207.

139

Phosphates and Phosphonates of Biochemical Interest

A convenient synthesis of a-amino-phosphonic and -phosphinic acids from 4-acetoxyazetidin-2-one (25) has been d e v e l ~ p e d Displacement .~~ of the acetoxygroup from (25) following attack by tervalent phosphorus nucleophiles, e.g. trimethyl phosphite, gives intermediates which can be hydrolysed by acid to phosphorus-containing analogues of aspartic acid (26). H

OAc

O

H

‘C’

bl,

cc!

0

H2C’ ‘ 0 -

I

cOP03H2

6 Enzyme Mechanisms When a mixture of triose phosphate isomerase and dihydroxyacetone phosphate is quenched with acid, a small amount of an intermediate is formed which is presumed to be the (Z)-enediol 3-phosphate (27).49 This compound decomposes to inorganic phosphate and methylglyoxal, and it can be trapped by the addition of fresh enzyme, yeast aldolase, or methylglyoxal ~ y n t h e t a s e .The ~ ~ occurrence of (27) is further evidence for a stepwise mechanism for aldose-ketose isomerase reactions in which a chemically defined enzyme-bound intermediate is involved. The 6-phosphate of l-chloro-2-oxo-6-hexanol(28), which has been synthesized from glutaric acid monomethyl ester, acts as an affinity label for phosphoglucose isornera~e.~~ The exact site of modification of the enzyme by this reagent has not been identified, although a similar reagent, i.e. N-(bromoacety1)ethanolamine phosphate (29), modifies a histidine residue in this enzyme.52 CH2OPO 3H

C

BrCH2CONHCH2CH20P03H2

CCH2C1

0 It

(29)

(28)

The protection of mitochondria1 F1 ATPase by inorganic phosphate, ADP, ATP, and magnesium ion against inactivation by reagents that are specific for arginine, lysine, tyrosine, and acid side-chains in proteins has been used to locate residues at the active site of the A T P ~ sIt~ is. proposed ~~ that, during the hydrolysis of ATP, the a- and P-phosphoryl groups are electrostatically bound to an arginine residue while the y-phosphoryl group is bound to lysine and tyrosine

52

M. M. Campbell and N. Carruthers, J. Chem. SOC.,Chem. Commun., 1980, 730. R. Iyengar and I. A. Rose, Biochemistry, 1981, 20, 1223. R. Iyengar and I. A. Rose, Biochemistry, 1981, 20, 1229. K. D. Schnackerz, J. M. Chirgwin, and E. A. Noltmann, Biochemistry, 1981, 20, 1756. D. R. Gibson, J. M. Talent, and R. W. Gracy, Biochem. Biophys. Res. Commun., 1977,78,

53

1241. L. P. Ting and J. H. Wang, Biochemistry, 1980, 19, 5665.

48 49

50 51

140

0rganophosphor us Chemistry

residues and a magnesium ion. The latter forms an ionic bond with an acidic group in the enzyme (30). 4-Azido-2-nitrophenyl phosphate (31) has been prepared by two methods and used as a photoaffinity label for F1 A T P ~ s ~ . ~ ~ Irradiation of 32P-labelled(31) in the presence of the ATPase gives rise to a single radioactive peptide, which has been characterized as the P-subunit.

OP03H2

I

When yeast hexokinase is incubated with [y-ls0]ATP, either alone or in the presence of lyxose, the ATP which can be recovered has not undergone any significant transfer of l 8 0 from the py-bridge to the p-non-bridging positions.55 This observation is contrary to that expected from mechanisms in which the ATP is reversibly cleaved prior to the transfer of a phosphoryl group to the product. The crystalline complex of 8-bromoadenosine 5'-phosphate with From dimensions obtained hexokinase has been determined at 3 8, res01ution.~~ from this structure and the known crystal structure of (dihydrogen tripolyphosphato)tetra-amminecobalt(~~~),~~ a model has been proposed for the attachment of ATP to the active site of the enzyme. The crystal structure of the complex that is formed between yeast hexokinase A and glucose has also been determined,5*which has allowed a detailed comparison to be made with the structure of hexokinase B.59Crystallographic studies on the binding of glucose 1 -phosphate to glycogen phosphorylase b have led to proposals being made on the catalytic mechanism of this enzyme.6o A simple method has been described for the isolation of a phosphotransferase from wheat shoots.fi1This enzyme, which will transfer phosphoryl residues from aryl phosphates to primary alcohols (particularly nucleosides), is very similar to 54 55 56 57 58

59 60 61

G. Lanquin, R. Pougeois, and P. V. Vignais, Biochemistry, 1980, 19, 4620. I. A. Rose, Biochem. Biophys. Res. Commun., 1980, 94, 573. M. Shoham and T. A. Steitz, J. Mol. Biol., 1980, 140, 1. E. A. Merritt, M. Sundaralingam, R. D. Cornelius, and W . W . Cleland, Biuchemisrry, 1978, 17, 3274. W. S. Bennett, Jr., and T.A. Steitz, J. Mol. Biol., 1980, 140, 183. W. S. Bennett, Jr., and T. A. Steitz, J. Mol. Biol., 1980, 140, 211. L. N. Johnson, J. A. Jenkins, K. S. Wilson, E. A. Stura, and G. Zanotti, J. Mol. Biol., 1980, 140, 565. J. I. Ademola and D. W. Hutchinson, Biochim. Biophys. Acta, 1980, 615, 283.

Phosphates and Phosphonates of Biochemical Interest

141

the enzyme which can be isolated from carrots.62 The phosphotransferase is relatively unstable in a soluble form, but its stability is greatly enhanced when it is attached to an insoluble Alkaline phosphatases have been the subject of a recent m o n ~ g r a p hFrom .~~ a study of the phosphorylation of alkaline phosphatase from E. coli followed by rapid denaturation of the phosphorylated enzyme and its dissociation into it has been deduced that the main rate-determining steps in the reactions that are catalysed by this enzyme are chemical dephosphorylation of the phosphorylated enzyme intermediate and dissociation of phosphate from the enzyme. The former process predominates at pH 7 but declines in importance at higher pH values. Methyl acetyl phosphate has been used as an active-sitedirected acetylating agent for ~-3-hydroxybutyrate.~~

7 Phosphorylated Proteins Phosphorylation of proteins by CAMP- and cGMP-dependent kinases has been re~iewed,~’ and a number of phosphorylated proteins, e.g. inorganic pyrophosphatase,68have been detected recently as enzyme intermediates. The sequence of the histidyl peptide which acts as the pyrophosphoryl and phosphoryl carrier of pyruvate phosphate dikinase from Bacteroides symbiosus has been determined.6Q The 2’,3’-dialdehyde of AMP has been used as an affinity label for the ATPAMP-binding site of this enzyme.7oThe ATP-AMP exchange was completely inhibited in the modified enzyme while the inorganic phosphate-pyrophosphate and pyruvate-phosphoenolpyruvate reactions were little affected. The sequences have been determined of a number of phosphorylated peptides from various sources. For example, details of the sequences of sixteen phosphoserine peptides from ovalbumins of eight animal species71and the phosphorylation site of a nuclear and those of phosphorylated his tone^^^ have all been published recently. A convenient spectrophotometric assay for the phosphorylation of peptides that is catalysed by CAMP-dependent protein kineases has been developed, using a synthetic substrate which contains an o-nitrotyrosyl group adjacent to a reactive serine residue.74Phosphorylation of this serine residue causes a change 62 63 64

65 66 67 68

6Q

70

71 72 73 74

E. F. Brunngraber, in ‘Methods in Enzymology’, ed. P. A. Hoffee and M. R. Jones, Academic Press, New York, 1978, Vol. 51, p. 387. J. I. Ademola and D. W. Hutchinson, Biotechnol. Bioeng., 1980, 22, 2419. R. B. McComb, G. N. Bowers, and S. Posen, ‘Alkaline Phosphatase’, Plenum Press, New York, 1979. M. Cocivera, J. McManaman, and I. B. Wilson, Biochemistry, 1980, 19, 2901. R. Kluger and W.-C. Tsui, J. Org. Chem., 1980, 45, 2723. D. B. Glass and E. G. Krebs, Annu. Rev. Pharmacol. Toxicol., 1980, 20, 363. N. P. Bakuleva, T. I. Nazarova, A. A. Baykov, and S . M. Avoeva, FEBSLett., 1981, 124, 245. N. H. GOSS, C. T. Evans, and H. G. Wood, Biochemistry, 1980, 19, 5805. C. T. Evans, N. H. GOSS, and H. G . Wood, Biochemistry, 1980, 19, 5809. J. Y . Henderson, A. J. G . Moir, L. A. Fothergill, and J. E. Fothergill, Eur. J. Biochem., 1981, 114, 439. C. E. Jones, H. Busch, and M. 0. J. Olson, Biochim. Biophys. Acta, 1981, 667, 209. K. Ajiro, T. W. Borun, S. D. Shulman, G. McFadden, and L. H. Cohen, Biochemistry, 1981,20, 1454. H. N. Bramson, N. Thomas, W. F. De Grado, and E. T. Kaiser, J . Am. Chem. SOC.,1980, 102, 7156.

Organophosphorus Chemistry

142

in absorption at 430nm, allowing the enzymic reaction to be monitored continuously.

8 Other Compounds of Biochemical Interest A new phosphorylated pterin (32; R=P03H2) has been isolated from Euglena gracilis, together with the corresponding 2,3-cyclic ph~sphate.'~ Phosphorylation of (32; R = H ) with phosphoryl chloride in trimethyl phosphate can give rise to (32; R=PO,H,) or the cyclic phosphate, depending on the conditions of the work-up. 0

Q OP

(33)

(34)

The stereochemistry of metabolism of allylic phosphates has been reviewed.76 During the enzymic conversion of farnesyl (33) and nerolidyl (34) pyrophosphates, an ion-pair appears to be involved as an intermediate, and the three non-bridge oxygens of the proximal phosphoryl group are able to be scrambled during the intercon~ersion.~~ It appears that a redox mechanism is not important during the enzymic cyclization of (33) to trichodiene (35). A more likely route, involving prior isomerization of (33) to (34), has been The stereo75 76

77 78

M. Bohme, W. Pfleiderer, E. F. Elstner, and W. J. Richter, Angew. Chem., Int. Ed. Engl., 1980, 19, 473. D. E. Cane, Tetrahedron, 1980, 36, 1109. D. E. Cane, R. Iyengar, and M.-S. Shiao, J. Am. Chem. Soc., 1981, 103,914. D. E. Cane, S. Swanson, and P. P. N. Murthy, J. Am. Chem. SOC.,1981,103,2136.

Phosphates and Phosphonates of Biochemical Interest

143

chemistries of the SN’cyclizations of copalyl pyrophosphate (36) to kaurene (37)79 or to ent-sandaracopimaradiene (38) 8 o have been demonstrated. The phosphocreatine shuttle has been reviewed.s1 Two intermediates (a carboxy phosphate and a carbamate) can be detected during the reaction, which is catalysed by carbamyl phosphate synthetase.82The rate-limiting step in this enzymic reaction is either the release of carbamate or a conformational change in the enzyme which permits the release of this latter compound. Angiotensin-converting enzyme is an exopeptidase which converts the naturally occurring decapeptide angiotensin I into a potent hypertensive octapeptide, angiotensin 11. N-Phosphorodipeptides are often good inhibitors of this enzyme, and values for the inhibition constants for angiotensin and the potent inhibitors N-phosphoro-L-alanyl-L-prolineand N-phosphoro-L-valyl-L-tryptophan have recently been published.83 N-Phosphorodipeptide aldehydes, e.g. (39), are inhibitors of thermolysin. These phosphorylated aldehydes have been synthesized as shown in Scheme Ls4The key step in this synthetic method is the conversion of (40) into a lactam with carbonylbisimidazole prior to reduction with diisobutylaluminium hydride. Organophosphates, e.g. (41), and their sila-analogues (42) have been prepared by the phosphorylation of the sodium salt of an appropriate phenol with a dialkyl phosphor~chloridate.~~ The cholinesterase activities of the siliconcontaining compounds are higher than those of the corresponding carbon 79

81 82 83 R4

85

R. M. Coates and P. L. Cavender, J . Am. Chem. SOC.,1980, 102, 6358. K. A. Drengler and R. M. Coates, J . Chem. SOC.,Chem. Commun., 1980, 856. S. P. Bessman and P . J . Greiger, Science, 1981, 211, 448. F. M. Raushel and J. J . Villafranca, Biochemistry, 1980, 19, 3170. R. E. Galardy, Biochem. Biophys. Res. Commun., 1980, 97, 94. H. N. Khatri, C . H. Stammer, M. M. Bradford, and R. A. McRorie, Biochem. Biophys. Res. Commun., 1980, 96, 163. R. Tacke, M. Strecker, and R. Niedner, Liebigs Ann. Chem., 1981, 387.

Organophosphorus Chemistry

144 Me

I

BOC-NHCHCONHCHCOOMe

i-iii

\

(PhCH20)

Me

I

)NHCHCONHCHCOOH

I

( C H )~3

NHN02 ~ ~ ~ N H

~

(40)

Me

I

v-/

Reagents: i, CFKOOH; ii, (PhCH20)2P(O)Cl; iii, NaOH; iv, carbonylbisimidazole; v, BuiZAlH; vi, Hz, Pd/C Scheme 2

0 6 Sibleg

analogues. Norborn-5-ene-2,3-dicarboximido diphenyl phosphate is a convenient activating reagent for peptide synthesis, as the coupling reactions can be performed at room temperature in aqueous The biochemistry of the inorganic polyphosphates has been described in a recent book.87 A method for the thermal dehydration of 32P-labelled orthophosphate to pyrophosphate has been developed for the preparation of material with high specific radioactivity.88 Inorganic phosphate can be determined accurately in nanogram amounts as the tris(trimethylsily1) phosphate by g.1.c.mass spectrometry .

86 87

** 89

Y. Kiso, T. Miyazaki, M. Satomi, H. Hiraiwa, and T. Akita, J . Chem. SOC.,Chem. Commun., 1980, 1029. I. S . Kulaev, ‘The Biochemistry of Polyphosphates’, Wiley, New York, 1979. K. S . Lam and C. B. Kasper, Anal. Biochem., 1980, 108, 279. G . Graff, T. P. Krick, T. F. Walseth, and N. D. Goldberg, Anal. Biochem., 1980, 107, 324.

’

Cyclophosphamide and its Congeners BY W. J. STEC

1 Introduction

Of all alkylating agents, cyclophosphamide (1) (2-[bis-(2-~hloroethyl)amino]tetrahydro-2H-l,3,2-oxazaphosphorine 2-oxideZ has probably the broadest impact in terms of clinical toxicity because of its frequency of usage and the wide variety of its side effects.l More than 10000 publications concerning the chemistry, biochemistry, and pharmacology of (1) are mentioned in the preface to ‘A Review of Cyclophosphamide’, edited in 1975. The cyclophosphamide Collection of Abstracts has recorded between 200 and 280 original publications annually in recent years. During the 12th International Cancer Congress, (held at Buenos Aires, in October 1978), cyclophosphamide was the subject of more than 100 lectures. The general aspects of cyclophosphamide and related ghosphoramide mustards are discussed in a recent excellent re vie^.^

C1CH2CH2

ClClI,CH,

I

I

Although the understanding of the mode of action of anti-tumour alkylating drugs attracts the attention of medicinal chemists, the recent developments in the chemistry of cyclophosphamide (also called Endoxan and Cytoxan) and its congeners (2), (3), and (4) seem to merit an entire chapter of this volume.

4

0. M. Friedman a n d S. K. Carter, Semin. Oncol., 1978, 5, 193. D. L. Hill, ‘A Review of Cyclophosphamide’, Thomas, Springfield, Illinois, 1975. H. Burket (Asta-Werke) personal communication. 0. M. Friedman, A. Myles, and M. Colvin, in ‘Advances in Cancer Chemotherapy’, ed. A. Rosowsky, Marcel Dekker, New York, 1979, p. 143.

145

146

Organophosphorus Chemistry 2 The Rationale for the Synthesis of Cyclophosphamide

The use of nitrogen mustards against certain types of lymphoma was prompted by the observation that the mustard gases that were used in warfare suppressed the production of lymphocytes. Unfortunately, the anti-tumour effect of nitrogen mustards proved to be transient, and there was extensive recurrence of disease, with the added complication of resistance to the mustards. One of the earliest attempts to devise modifications of the nitrogen mustard structure that would have inherently greater specificity for tumours, based on a biochemical rationale, was the work by Friedman and Seligman.6 Taking into account the results reported by Gomori that the activity of phosphoramidase was localized in certain t ~ m o u r s ,Friedman ~ and Seligman have synthesized a number of Nphosphorylated derivatives of nitrogen mustards. These were thought to be likely to be latently active, potential drugs with selective toxicity towards cancer tissues, because nitrogen mustards, owing to extensive cleavage of P-N bonds, should be released to higher extents in cancer tissue than in the normal tissue. On the basis of the phosphoramidase rationale, Arnold and Bourseaux synthesized cyclophosphamide as a ‘transport form’ of bis-(2-~hloroethyl)amine(nitrogen mustard, or nor-HN2).* From extensive studies on the metabolism of (l), it is now known that the original premise on which the synthesis of phosphorylated derivatives of nitrogen mustards as effective anti-cancer drugs was based is largely discounted. Indeed, (1) does require metabolic transformation in vivo to become active; however, there is no evidence that such activation is brought about by a phosphoramidase-mediated release of nor-HN2 in tumour cells. 3 The Current Status of Knowledge of the Metabolism of Cyclophosphamide Definitely superior to nor-HN2 and other nitrogen mustards, cyclophosphamide, which is itself non-toxic to tumour cells in c ~ l t u r eis , ~hydroxylated (primarily in the liver l o ) to 4-hydroxycyclophosphamide (5a), which spontaneously decomposes to the phosphoramide mustard (8); l 2 ,l 3 in all probability, this is the active form of the drug. From the evidence accumulated in the past few years, it seems likely that metabolism of (1) proceeds as shown in Scheme 1. As mentioned above, initial activation of the parent compound occurs at the carbon atom that is adjacent to the nitrogen atom in the ring to produce (5a), which tautomerizes to the open-chain aldophosphamide (5b). The tautomers (5) may be further oxidized to 4-ketocyclophosphamide (6) and carboxyphosphamide (7), respectively. These do not exhibit significant anti-tumour activity, and they 5 6

7

8 9

10

11 12 13

L. S . Goodman, M. M. Wintrobe, W. Dameshe, M. J. Goodman, A. Gilman, and M. McLennan, J. Am. Med. Assoc., 1946, 132, 126. 0. M. Friedman and A. M. Seligman, J . Am. Chem. SOC.,1954,76,655. G . Gomori, Proc. SOC.Exp. Biol. M e d , 1948, 69, 407. H. Arnold and F. Bourseaux, Angew. Chem., 1958, 70, 539. N. Brock, Arzneim.-Forsch., 1958, 8, 1. N. Brock and H.-J. Hohorst, Arzneim.-Forsch., 1963, 13, 1021. R. F. Struck, M. C. Kirk, L. B. Mellett, S . El Dareer, and D. L. Hill, Mol. Pharmacol., 1971, 7, 519. M. Colvin, C . A. Padgett, and C. Fenselau, Cancer Res., 1973, 33, 915. C . Fenselau, M.-N. Kan, S . Billets, and M. Colvin, Cancer Res., 1975, 35, 1453.

147

Cyclophosphamide and its Congeners

Scheme 1

most probably represent inactivated excretion products.11* 149 l6 Spontaneous /3elimination of acrolein from (5b) leads to the formation of the phosphoramide mustard (8), which is the biologically active alkylating agent that is derived from cycloph~sphamide.~~ Compound (8) was first described, as a product of the microsomal metabolism of (l), by Colvin and co-workers.12Shortly thereafter, Connors and associates confirmed this finding in an activation system that is in rat microsomes.ls The mustard (8) does not require microsomal activation, l ~ fact that the treatment of microsomally since it is very cytotoxic in ~ i f r 0 . The activated (1) with ethanol produces diastereoisomers of 4-ethoxycyclophosphamide was explained by direct displacement of the Chydroxy-group of (5a) by ethanol. l6 Hohorst and his associates have produced 4-mercapto-derivatives (11) 18* l9 by the treatment of (5a), or of the metabolites of (1) in human body A. Takamizawa, Y.Tochino, Y.Hamashima, and T. Iwata, Chem. Pharm. Bull., 1972, 20, 1612. 15 J. E. Bakke, V. J. Feil, and R. G . Zaylskie, J. Agric. Food Chem., 1971, 19, 788. 1 6 T. A. Connors, P. J. Cox, P. B. Farmer, A. B. Foster, and M. Jarman, Biochem. Pharmacol., 1974, 23, 115. 1 7 C. L. Maddock, A. H. Handler, 0. M. Friedman, G . E. Foley, and S. Farber, Cancer Chemorher. Rep., 1966, 50, 629. 18 G . Peter, T.Wagner, and H.-J. Hohorst, Cancer Treat. Rep., 1976, 60, 429. 19 T.Wagner, G.Peter, G. Voelcker, and H.-J. Hohorst, Cancer Res., 1977, 37, 2592. 6 14

Orgariophosphorus Chemistry

148

fluids, with mercaptans ; they have explained that 4-mercapto-cyclophosphamides are produced via 4-mercaptohemithioacetal derivatives of (5b). An alternative explanation includes speculations on the participation of the iminophosphamide (9) in the metabolic pathways. The addition of either an alcohol or a mercaptan across the nitrogen-carbon double-bond of (9) may be expected to occur r e a d i l ~ . ~ However, studies on model systems have shown the rather low hydrolytic activity of the N-phosphinylated Schiff-bases (12),20 and the postulation of (9) as a metabolite of (1) seems to be rather speculative. Since the chemistry of hemiaminals such as (5a) is rather obscure, more evidence for the chemical behaviour of this class of compounds must be obtained before the mode of transformation of (5a) into 4-alkoxy- and 4-mercapto-cyclophosphamides can be elucidated.

I

OH

H

(16)

It is worth mentioning, however, that certain types of antibiotics [e.g. sibiromycin (13), antramycin (14), and tomaymycin (15), possessing hemiaminal moieties] demonstrate strong anti-tumour properties. 21 Acrolein (lo), produced from the decomposition of (5b), has been considered as the cytotoxic agent. First discovered in metabolic studies on (1) by Alarcon and Meienhofer,22 acrolein has been shown, however, to possess cytotoxic activity at levels that are much higher (forty-fold) than those found to occur from the metabolism of cyclophosphamide. 23 Earlier studies had shown that (16), although it undergoes microsomal activation at C-4 and also produces acrolein, is relatively noncytotoxic and does not show anti-tumour effects in whole animals.24In recent 20 21

22

23 24

B. Krzyzanowska and W. J. Stec, Synthesis, 1978, 521. L. H. Hurtley, J. Antibiot., 1977, 30, 349. R . A. Alarcon and J. Meienhofer, Nature (London), New B i d . , 1971, 233, 250. N. E. Sladek, Cancer Res., 1973, 33, 1 1 50. H. Arnold, F. Bourseaux, and N. Brock, Arzneim-Forsch., 1961, 11, 143.

Cyclophosphamide and its Congeners

149

studies it has been demonstrated that the acrolein that is produced as a metabolite of (1) is the causative factor of the urotoxic side-effects of (l), (2), (3), and (4); in particular, of chemorrhagic c y s t i t i ~ . ~ ~This - ~ ' observation has prompted investigators to attempt the trapping of (10) by means of biological scavengers such as cysteine and glutathione. 29 The most effective regional detoxification of (1) and of its congeners in the kidney and urinary tract was achieved by sodium 2-mercaptoethanesulphonate(17), which is now used in combined chemotherapy with (l), (2), and (3).27e30 The most important step in detoxification is the addition of (17) to the double-bond of (lo), resulting in an addition product (18), which was detected chromatographically in the urine and whose structure was verified by independent ~ynthesis.~'It has also been demonstrated that (17) reduces the rate of disintegration of (5) in the urine by causing the formation of (19), which was also verified by chromatographic analysis of urine.27 28q

Besides the metabolic pathways shown in Scheme 1, cyclophosphamide also undergoes dechloroethylation (catalysed by a mixed-function oxidase) 31 and possibly hydroxylation at the 6-p0sition,~~ but these reactions do not seem to play a significant role in the chemotherapeutic activity. The selective toxicity of (1) has been a subject of much debate;33 of several hypotheses proposed, two have received much attention. Some investigators 34-36 believe that (5a) is the transport form of the drug and enters the cells much more ~ ~ et ~ 7 1have . ~ ~postulated easily than does (8); however, Struck et ~ 1and. Friedman that (8) is both the circulating and the alkylating form of (1). Sladek 39 and Cox 3 4 P. J. Cox, Biochem. PharmacoI., 1978, 28, 2045. W. Scheef, H. 0. Klein, N. Brock, H. Burkert, U. Ciinther, H. Hoefer-Janker, D. Mitrenga, J. Schnitker, and R. Voigtmenn, Cancer Treat. Rep., 1979, 63, 501. 27 N. Brock, J. Stekar, J. Pohl, U. Niemeyer, and G. Schemer, Arzneim.-Forsch., 1979, 29, 659. 28 M. J. Berrigan, H. L. Gurtoo, S. D. Sharma, R. F. Struck, and A. J. Marinello, Biochem. Biophys. Res. Commun., 1980, 93, 799. 29 H. L. Gurtoo, J. H. Hipkens, and S. D. Sharma, Cancer Res., 1981, 41, 3584. 30 N. Brock, J. Pohl, and J. Stekar, Eur. J. Cancer, 1981, 17, 595. 3 l K. Norpoth, Cancer Treat. Rep., 1976, 60, 437. 32 T. A. Connors, P. J. Cox, P. B. Farmer, A. B. Foster, M. Jarman, and J. H. Macleod Biomed. Mass Spectrom., 1974, 1, 130. 33 N. Brock and H.-J. Hohorst, 2. Krebsforsch., 1977, 88, 185. 34 P. J. Cox, B. J. Phillips, and P. Thomas, Cancer Res., 1975, 35, 3755. 35 B. E. Domeyer and N. E. Sladek, Cancer Res., 1980, 40, 174. 36 T. A. Connors, Biochimie, 1978, 60, 979. 37 R. F. Struck, M. C. Kirk, M. H. Witt, and W. R. Laster, Biomed. Mass Spectrom., 1975, 2, 46. 38 0. M. Friedman, I. Wodinsky, and A. Myles, Cancer Treat. Rep., 1976, 60, 337. 39 N. E. Sladek, Cancer Res., 1973, 33, 651. 25

26

150

Organophosphorus Chemistry

have attributed the selective toxicity of (1) to differences in the levels of aldehyde dehydrogenase in tumours and in normal tissues. According to these investigators, high levels of aldehyde dehydrogenase in normal tissues and in tumours that are not sensitive to (1) afford protection in these tissuesby detoxifying the metabolites of (1) via their conversion into (6) and (7). The fact that aldehyde dehydrogenase activity is very low in bone marrow and in tumour cells, where (1) appears to exert its greatest effect, strongly supports this hypothesis. However, in recent studies it has been shown that, although dehydrogenaseoxidases are involved in the detoxification of (l), aldehyde dehydrogenase, measured with acetaldehyde as the substrate, does not appear to play a significant role in the metabolism of (1) or in the biological effects that are dependent upon its metabolism.40 An important recent observation that (5a) and 4-mercaptocyclophosphamide (1 1) both undergo fast decomposition in the presence of nucleases (e.g. 3’,5’-CAMPphosphodiesterase) may be the basis for the missing link in the concept of transformation of the transport form of activated (1) into the cytotoxic compound (8).41Since lymphogenic cells from several mouse myelomas that are very sensitive to (1) show a high activity of DNA-polymerase-linked 3’,5’exon~clease,~~ the above observation forms a new working hypothesis for the mode of action of cyclophosphamide, explaining its selective cytotoxicity towards rapidly proliferating cells. The metabolism of (5) in vitro has been studied. Rabbit muscle glyceraldehyde 3-phosphate dehydrogenase and bovine liver catalase did not metabolize (5) ; neither did a rat hepatic lOOOg soluble fraction, when conditions were made optimal for phosphoramidase-catalysedmetabolism. Purified horse liver alcohol dehydrogenase converted (5) into a metabolite that was tentatively identified as the hydroxyphosphamide (20). An NAD-linked aldehyde dehydrogenase activity

HOCH,CH,CH,O

/ \

N(CH,CH,Cl),

(20)

was found in all of the normal and neoplastic tissues that were examined when butyraldehyde or benzaldehyde was used as the substrate. Aldehyde oxidase activity was found in some of the normal tissues but not in the neoplasms. The NAD-linked aldehyde dehydrogenase activity greatly exceeded that of aldehyde oxidase in all tissues. These findings suggest that the formation of (7) from ( 5 ) is predominantly catalysed by NAD-linked aldehyde dehydrogena~es.~~ Very recently, the same authors have demonstrated that cyanamide, which is an inhibitor of the NAD-linked aldehyde dehydrogenase, markedly depresses the conversion of ( 5 ) into (7) in v i m in cyanamide-treated, functionally anephric mice.4 4 40

41 42 43 44

J. H. Hipkens, R. F. Struck, and H. L. Gurtoo, Cancer Res., 1981, 41, 3571. H.-J. Hohorst, L. Bielicki, and G . Voelcker, Excerpta Med. in the press. Y . - C .Chen, E. W. Bohn, S. R. Planck, and S. H. Wilson, J . Biol. Chem., 1979,254,ll 678. B. E. Domeyer and N. E. Sladek, Biochem. Pharmacol., 1980,29, 2903. B. E. Domeyer and N. E. Sladek, Biochem. Pharmacol., 1981, 30, 2065.

Cyclophosphamide and its Congeners

151

Although cyclophosphamide, when administered in uiuo, has been reported to bind covalently to DNA, RNA, and proteins, neither the mechanism and site(s) of binding nor the significance to chemotherapy of its binding to various macromolecules has been determined. The elucidation of these mechanisms may be essential in understanding the factors that are responsible for the desirable effect of (1) as a cancer chemotherapeutic agent and those responsible for the undesirable side effects (mutagenicity and the promotion of sister-chromatid exchanges). Cyclophosphamide that was labelled with tritium in the chloroethyl side-chain and that which was labelled with 14Cat the 4-position were used to investigate the binding of cyclophosphamide to native calf thymus DNA and microsomal proteins in an incubation system in ~ i v o The . ~ ~3H label became bound to D N A and to some extent to proteins, whereas the 14C label from [14C]-(1) became bound essentially to proteins only. This finding strongly suggests that the metabolite (8) interacts with D N A whereas acrolein is responsible for interaction with proteins via addition to free sulphydryl groups or the formation of Schiff bases. In recent studies on the metabolism of 3H- or laclabelled (1) in uiuo, the following hypothesis 4 0 was involved : amongst the various known metabolites of (1) that are formed in the liver, some of the (5a) and most of the acrolein bind to liver proteins, and the remaining ( 5 ) and (8) that have failed to bind are released to the circulation. These metabolites enter extrahepatic tissue cells, where intact (5a) predominantly binds to proteins and where (8) [either from the circulation or from the intracellular decomposition of (5a)l predominantly binds to nucleic acids. This hypothesis assumes that most of (1) is metabolized in the liver and that relatively little of its metabolism takes place in extra-hepatic tissues. It also predicts that both (5a) and (8) should be detectable in the blood, and also strongly supports an earlier suggestion3' that (8) is a circulating and alkylating form of (1). The hypothetical structures (21) and (22) of the adducts that are formed in uivo between metabolites of (1) and components of nucleic acids were

OR

O-CHCH,CH,O

I

Deoxyribose

0 -~---N(cH,cH,c~),

?'

Deoxyribose (22)

In model studies, Ludlum et al. have shown that (8), when it reacted separately with guanosine and with deoxyguanosine in aqueous solution, at pH 7.4, formed adducts; in each case, these have been isolated by reverse-phase h . p . l . ~ .The ~~ structure of the main adduct, as determined by a combination of ultraviolet 45 46

H. L. Gurtoo, R. Dahms, J. Hipkens, and J. B. Vaught, Life Sci., 1978, 22,45. J. R. Mehta, M. Przybylski, and D. B. Ludlum, Cancer Res., 1980, 40, 4183.

152

Organophosphorus Chemistry

spectroscopy and field-desorption mass spectrometry, is that of the phosphoramide mustard (8), one arm of which has reacted with guanosine or deoxyguanosine in position 7. These adducts are much less stable than 7-methylguanosine and they decompose with a half-life of 2.3 h at 37°C and pH 7.4. This instability may be relevant to the anti-tumour effect of (1). The cytotoxic action of a nitrogen mustard is generally thought to depend on the number of cross-links that are produced in cellular DNA and on their resistance to repair. However, the presence of a highly unstable nucleoside might lead to excessive scission of strands, which could also be lethal. The presence of an unstable adduct could also contribute to a mutagenic or carcinogenic outcome. The residual damage might by itself, or after repair by an error-prone process, lead to the transfer of misinformation in a replicative or transcriptive process. Although the same biological effects are considered, the different sites of alkylation of DNA by means of metabolites of (l), (2), and (3) are postulated. As the result of the experiments in virro to investigate the interaction of 3H-labelled (l), (2), and (3) with DNA and with constituents of DNA, Lindemann and Harbers have postulated that (8) reacts with orthophosphate groups, leading to phosphotriesters in DNA." None of the other phosphoramide mustard derivatives has been as extensively evaluated as cyclophosphamide. The only derivative which has a higher therapeutic index than (1) against Yoshida ascites sarcoma is (2). Both (2) and (3) are somewhat more effective than (1) against the L1210 tumour in mice.48 Compound (2) is significantly more effective than (1) against the DS carcinosarcoma and TA nephroblastoma in the rat 4 9 and has recently been given the status of a clinically used drug against some tumours that are resistant to (1). A number of papers on the metabolism of (2) have been published; they indicate that it follows essentially the metabolic pathways of (l).409 51 As shown in Scheme 2,4-hydroxyisophosphamide (23a), aldoisophosphamide (23b), carboxyisophosphamide (24), 4-ketoisophosphamide (25), and NN'-bis-(2-chloroethyl)phosphorodiamidic acid (26) have been found as the metabolites of (2) either in vitro or in vivo. However, the formation of the dechlorethylation products (27) and (28) represents a quantitatively more significant pathway for (2) than for (1). It has been shown that about 50% of (2) is converted into (27j.52The rate of conversion of (2) into alkylating moieties was about one-half that of (l).53Information on the metabolism of other analogues of (1) and (2) is sparse. According to available results, the analogues are metabolized by the same pathways as (1) and (2). Microsomal oxidation of 4-methylcyclophosphamide (29) and of 6-methylcyclophosphamide (30) produces methyl vinyl ketone and crotonalde hyde, respectively. * 509

47 48 49 50

51 52

53 54

H. Lindemann and E. Harbers, Armeim.-Forsch., 1980, 30, 2075. S. K. Carter, Cancer Chemother. Rep. ( P t . 3), 1972, 3, 33. J. Stekar, Armeim.-Forsch., 1976, 26, 1793. D. L. Hill, W. R. Laster, M. C. Kirk, S. El Dareer, and R. F. Struck, Cancer Res., 1973, 33, 1016. A. Takamizawa, S. Matsumoto, T. Iwata, Y. Tochino, K. Katagiri, K. Yamaguchi, and 0. Shiratori, J. Med. Chem., 1974, 17, 1237. K. Norpoth, G. Miller, and H. Raidt, Arzneim.-Forsch., 1976, 26, 1376. L. M. Allen and P. J. Creaven, Cancer Chemother. Rep. (Pt. I ) , 1972, 56, 603. P. J . Cox, P. B. Farmer, and M. Jarman, Biochem. Pharmacol., 1975, 24, 599.

Cyclophosphamide and its Congeners

153

vH,CH,Cl

11 0

I1

/cHzCH2C1

4 The Synthesis of Analogues of Cyclophosphamide and their Metabolites

Subsequent to cyclophosphamide, a German group studied a series of more than 800 homologous substituted compounds 33 and detected three other oxazaphosphorine compounds which exert a more selective carcinotoxic effect, both pharmacologically and clinically. These are isophosphamide (2) [2-(2-chloroethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine2-oxideYalso called Holoxan@], trophosphamide (3) (2-[bis-(2-chloroethyl)amino]-3-(2chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxideY also called Ixoten*!), and sulphosphamide (4) [2-(2-mesyloxyethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine2-oxide]. The last compound is characterized by a pronounced antileukaemic action and by its induction of immunotolerance.

154

Organophosphorus Chemistry

Perhaps the strongest criticism from an organic chemist of this tremendous work is of the neglect of stereoisomerism of the great number of compounds under investigation. Besides the fact that all 2-amino-2H-l,3,2-oxazaphosphorine 2-oxides, by virtue of their asymmetric phosphorus atom, are chiral, and optical isomers thereof must exist, many ring-substituted oxazaphosphorinesalso consist of the isomeric mixtures. Since the importance of stereochemistry as a determinant of pharmacological activity is widely recognized, and neglect of the importance of chirality of a drug (as in the case of thalidomide) may lead to severe consequences,5 5 many investigators undertook active research on the separation of isomeric species and the resolution (or stereospecific synthesis) of chiral oxazaphosphorinans. The first to emphasize the problem of the knowledge of the isomeric composition of oxazaphosphorinesthat bear exocyclicalkylating functions as essential for obtaining consistent results in biological studies were Feil and Lamoureux.56 Following the original synthesis of 4-methylcyclophosphamide (29),24they pointed out that the compound that is obtained from the condensation of 3-aminobutan-1-01 with NN-bis-(2-chloroethyl)phosphoramidodichloridate (32) consists of a mixture of two isomers, in the ratio 3:2.

rr~ns-(30) X = 0,Y = NH,R = Me trQnP(33) X = NH,Y = 0,R = Ph

cis-(30)X = 0 ,Y = NH,R = Me ~i~-(33) X = NH,Y = 0,R = Ph

Parallel studies on the microsomal metabolism of (29) and of 6-methylcyclophosphamide (30) were performed on compounds with unrecognized isomeric omp position.^^ Struck et al. undertook the studies on the separation of racemic isomers of (29) and reported the first biological evaluation of 4-substituted isomers of (1) in 2riu0.~~ The synthesis and absolute configurations of the four optically active forms of (29) were reported in 1977.58Their preparation required the synthesis of enantiomers of 3-aminobutan-1-01 (31) of known absolute configuration. Condensation of each enantiomer of (31) with (32) in the presence of triethylamine gave, in each case, a mixture of two separable isomers of (29). Their synthesis is depicted in Scheme 3. 55 56 57

58

G. Blaschke, H. P. Kraft, K. Fickentscher, and F. Kohler, Arzneim.-Forsch., 1979, 29, 1640, and references cited therein. V. J. Feil and C. J. H. Lamoureux, Cancer Res., 1974, 34, 2596. R. F. Struck, M. C. Thorpe, W. C. Coburn, and M. C. Kirk, Cancer Res., 1975,35,3160. R. W. Kinas, K. Pankiewicz, W. J. Stec, P. B. Farmer, A. B. Foster, and M. Jarman, J. Org. Chem., 1977,42, 1650.

Cyclophosphamide and its Congeners

155

0

N(CH,CH,Cl),

ez$\

Me

H

N(CH,CH,CI),

I K;7pNo Me

(z,4R)-(29)

H (2R,4R)-(29)"

(R14311 (a) For simplicity, only one conformation is shown Scheme 3

Because the four enantiomeric compounds (29) had predetermined configurations at (2-4, assignment of the spatial orientation of exocyclic substituents at C-4 and at P atoms with respect to the oxazaphosphorinanyl ring system is equivalent to the assignment of the absolute configuration. This was achieved on the basis of criteria of chemical shifts in 31Pn.m.r. spectra and v ( P 0 ) vibrations in i.r. spectra. Apart from the reassessment of cis/truns geometry that had previously been erronously a~signed,~' a spectral analysis, using 'H and 18C n.m.r., of each of the four diastereoisomers revealed the conformational stability of (2R,4S)- and of (2S,4R)-(29) in solution. The correctness of assignment of cis-trans geometry and of the absolute configurations of all four optically active forms of (29) was recently proved by an X-ray examination of (-)(2S,4R)4methylcyclophosphamide.6B 5g

2.Gaidecki and M. L. Gidwka,

Acra Crystallogr., Sect.

B. 1981, 37, 1136.

Organophosphorus Chemistry

156

Shih et al. have published a description of the synthesis of a series of 4-arylcyclophosphamides.60 With respect to studies of the anti-tumour activity of analogues of (I), perhaps the most interesting is 4-phenylcyclophosphamide (33), which has been thoroughly studied by Zon et a1.61The synthesis of both isomers of (33) and their separation into individual diastereoisomeric species was performed in the usual way. Thus, treatment of ethyl benzoylacetate with 0-methylhydroxylamine hydrochloride and pyridine gave a 75 % yield of the intermediate oxime, which subsequently reacted with LiAlH4 to give 3-amino-3phenylpropan-1-01 in 79 % yield. Its cyclization with (32) in the presence of two equivalents of NEt, afforded crude (33), which was chromatographed on silica gel, using ethyl acetate as the eluent, to give analytically pure crystals of the ‘faster’ [cis-(33)] and ‘slower’ [trans-(33)] eluting diastereoisomers in nearly quantitative yields. The structural findings are in accord with a number of reported spectroscopic correlations, which allowed the authors to assign the cisltrans geometry to both isomers, but additional confirmation was provided by X-ray crystallography. In the solid state, as expected, cis-(33) was shown to exist in a chair-like structure, with the phenyl substituent equatorially disposed. The bis-(2-chloroethyl)amino-substituentoccupies the axial position. Studies on the synthesis and biological evaluation of (33) followed earlier work by Zon et al. on the synthesis of the 4,5-benzo-annulated cyclophosphamides (34) and (35).62As would be predicted on the basis of knowledge of the metabolic pathways of cyclophosphamide, (34) and (35) do not show any significant activity against L1210 lymphoid leukaemia in mice.

(34)

(35)

Although 6-methylcyclophosphamide (30) has not been obtained in optically active forms, the separation into cis-/trans-isomers has been performed; the assignment of spatial arrangements of exocyclic groups that are attached to the oxazaphosphorine ring was based on criteria similar to those used for the assignment of cisltrans geometry of the isomeric compound (29).63 The introduction of a single substituent into the 5-position of cyclophosphamide causes the appearance of a second centre of chirality in the molecule, and again four isomers should be considered. However, so far, no optically active 5-substituted cyclophosphamides have been reported, and only cisltrans isomerism has been appreciated. Zon has reported that condensation of 3-amino6o

62 63

Y . E. Shih, J. S. Wang, and C. T. Chen, Heterocycles, 1978, 9, 1277. V. L. Boyd, G. Zon, V. L. Himes, J. K. Stalick, A. D. Mighell, and H. V. Secor, J. Med. Chem., 1980, 23, 373. S. M. Ludeman and G . Zon,J. Med. Chem., 1975, 18, 1251. P. B. Farmer, M. Jarman, T. Facchinetti, K. Pankiewicz, and W. J. Stec, Chem.-Biof. Interact., 1977, 18, 45.

Cyclophosphamide and its Congeners

157 H

H

exo- ( 3 7 )

endo-(37)

2-bromopropan-1-01 (liberated in situ from its hydrobromide) with (32) gave a diastereoisomeric mixture of 5-bromocyclophosphamide (36) in 34 % yield.64 Careful chromatography on silica gel afforded components that were labelled ‘fast’ and ‘slow’, according to their rates of elution. Proton n.m.r. spectra (at 220 MHz) of the diastereoisomeric samples of (36) exhibited a high degree of complexity, and characteristic features concerning cis uersus trans relationships were not apparent. Treatment of each isomer of (36) with sodium hydride converted each of them into exo- and endo-3,5-dehydrocyclophosphamides (37). The geometry of both isomers of (37) was not elucidated, and they were further investigated as ‘slow’ and ‘fast’ isomers, assigned according to their chromatographic mobilities. The highly regioselective mode of ring-closure is consistent with reported rules for cyclization reactions, viz. that ‘3-exo-tet’ processes [(36)-+(37)] are favoured over ‘5-exo-tet’ transformation^.^^ Hydrolytic studies have shown that stereoisomers of (36) are more prone to hydrolysis than those of (37), but the products of hydrolysis of (36) were different from those obtained from (37). The structural features of (36) and (37) were not elucidated, and the structures of the products of hydrolysis of these compounds were not assigned. More conclusive are the studies of Foster et al. on the 5-flUO1-0-and 5-chlorocyclophosphamides.66Following the preliminary studies on the influenceof factors that cause the retardation of the B-elimination reaction (5)-+(8)+ an improved synthesis of [5,5-2H2]~y~Iopho~phamide (38) 6 8 was developed. It was

cis-(39) 64 65

66 15’

68

trans-(39)

S. M. Ludeman, G . Zon, and W. Egan, J. Med. Chem., 1979,22, 151. J. E. Baldwin, R. C. Thomas, L. I. Kruge, and L. Silberman, J. Org. Chem., 1977,42, 3846. A. B. Foster, M. Jarman, R. W. Kinas, J. M. S. van Maanen, G. N. Taylor, J. L. Gaston, A. Parkin, and A. C. Richardson, J. Med. Chem., 1981, 24, 1399. P. J. Cox, P. B. Farmer, A. B. Foster, E. D. Gilby, and M. Jarman, Cancer Treat. Rep., 1976, 60, 483. M. Jarman and G. N, Taylor, J. Labelled Compd. Radiopharm., 1981,18,463.

158

Organophosphorus Chemistry

shown that 5,5-dideuteriation of cyclophosphamide did not significantly alter the physicochemical properties and the rate of 4-hydroxylation7but, owing to the operation of a primary isotope effect ( k ~ /=k5.3), ~ retardation of the B-elimination (5)+(8) + [2H]-(10) markedly and adversely affected the anti-tumour activity of derivatives of cyclophosphamide. Therefore, it became of interest to explore the consequences of accelerating this process. It was assumed that this might be achieved by the introduction of metabolically stable electronegative substituents, e.g. C1 and F, at position 5 of cyclophosphamide. The synthesis of 5-fluorocyclophosphamide (39) was achieved by condensing 3-amino-2-fluoropropan-1-01 (prepared in the multi-step procedure) with (32). The separation of isomers was performed as usual, by column chromatography on silica gel. The ‘fast’ compound was believed to be the cis-isomer; because spectroscopic data and 13Cn.m.r.) were not conclusive, X-ray crystallography was applied. (lH, l@F, In the crystal phase, cis-(39) exists in a slightly distorted boat conformation, with apical nitrogen and carbon atoms. The isomer of lower chromatographic mobility was shown to be trans-(39). In the solid phase, this exists in a distorted chair conformation, with the fluorine and phosphoryl oxygen atoms essentially equatorial. The crystal structure of the trans-isomer contrasts with that reported for cycloph~sphamide,~~~ 7 0 in which the ring adopts a chair conformation, with the phosphoryl oxygen axial. It is interesting to notice that the one-bond spin-spin coupling constant, lJ(13C-F), for pseudo-axial fluorine in cis-(39) in solution is slightly smaller than that for equatorial fluorine in trans-(39), which follows the more general trend that is observed for six-membered ring s y ~ t e m s . ~ lThe - ~ ~route to 5-chlorocyclophosphamide (40) via the key intermediate 3-amino-2-chloropropan-1-01 closely resembled that used in the synthesis

of (36). The structbres of the cis- and trans-isomers of (40) were assigned on the basis of 13C n.m.r. data. It is proposed that the phosphoryl oxygen occupies the axial position in both isomers; the ‘fast’ isomer (i.e. of higher chromatographic mobility) possesses the chlorine in an equatorial position [cis-(40)] while the ‘slow’ isomer has the chlorine axial, and hence has the trans configuration [trans-(40)].The proposed configuration of this last compound has also been confirmed by X-ray crystallography. Studies on stereodifferentiated metabolism of stereoisomeric species (uide supra) will be discussed in the following section. Amongst the studies on the relationship between structure and biological activity of anti-tumour alkylating agents, perhaps the most classical were 139 70

71 72 73

J. C. Clardy, J. A. Mosbo, and J. G. Verkade, J. Chem. SOC.,Chem. Commun., 1972, 1163. S. Garcia-Blanco and A. Perales, Acta Crystallogr., Sect. B, 1972, 28,2647. W. J. Stec, 2. Naturforsch., Teil. B, 1974, 29, 109. G. Adiwidjaja, B. Mayer, H. Paulsen, and J. Thiem, Tetrahedron, 1979, 35, 373. D. G. Gorenstein, J. Am. Chem. SOC.,1977, 99, 2254.

Cyclophosphamide and its Congeners

159

attempts to synthesize the enantiomers of (l),(2), (3), and (4) and their metabolites stereospecifically. Initiated independently in two laboratorie~,~~g 76 they involved the synthesis of optically pure N-( 3-hydroxypropyl)-a-methylbenzylamines and their condensation with (32). The corresponding diastereoisomers of 3-(a-methylbenzyl)cyclophosphamide (41), after separation, were successfully converted into enantiomers of cyclophosphamide by means of hydrogenolytic splitting of the benzylic N-C bond (Scheme 4).75 Using the same approach, Ph

\EH/Me

Ph \&/Me

I

I

+ (32) &

CN\EHo ’ 0

3

enantiomers of ( 1 )

‘N(CH,CH,CI),

(41)

Reagents: i, NEta; ii, separation of diastereoisomers; iii, Hz,Pd Scheme 4

enantiomers of (l), labelled with deuterium at carbon in the positions that are a to the exocyclic nitrogen atom, were It is interesting to notice that racemic (1) crystallizes only in the form of the m ~ n o h y d r a t ein , ~contrast ~ to the enantiomers of (1). The enantiomeric homogeneity of isomers of cyclophosphamide, originally assigned on the basis of the rational argument that transformations of optically pure enantiomers of a-methylbenzylamine, as depicted in Scheme 4,should lead to optically pure enantiomers of (l), has been re-confirmed directly by lH and 31Pn.m.r. spectroscopy, using the optically active shift reagent tris-[3-(trifluoromethylhydroxymethylene)-(+ )-camphorato]europium(111). 7 7

In contrast to the statement that the optical rotatory dispersion spectra of enantiomers of cyclophosphamide exhibit a plain curve,77the c.d. spectrum of (+)-(1) exhibits a positive Cotton effect at 193 nm, while (-)-(1) shows a negative Cotton effect at the same ~ a v e l e n g t h . ~ ~ The absolute configuration of (-)-(1) was established by X-ray analysis as (- )-(S)-(l).79Independently, Zon et al. have assigned the absolute configuration R for ( +)-(1).80 The only difference between the conformation of racemic (1) and its enantiomers in the solid state exists in the relative orientation of the 2-chloroethyl groups of the bis-(2-chloroethyl)amino moiety with respect to the oxazaphosphorinane ring system. 74 75

G. Zon, Tetrahedron Lett., 1975, 3139. R. Kinas, K. Pankiewicz, and W. J. Stec, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1975, 23, 981.

76

77 78 79 80

P. J. Cox, P. B. Farmer, A. B. Foster, L. J. Griggs, M. Jarman, R. Kinas, K. Pankiewicz, and W. J. Stec, Biomed. Mass Spectrom., 1977, 4, 371. G. Zon, J. A. Brandt, and W. Egan, J. Nutl. Cancer Inst., 1977, 58, 1117. G. Snatzke, unpublished results. D. A. Adamiak, W. Saenger, R. W. Kinas, and W. J. Stec, Angew. Chem., 1977, 89, 337; 2. Naturforsch., Teil. C, 1977,32, 672. I. L. Karle, J. M. Karle, W. Egan, G . Zon, and J. A. Brandt, J . Am. Chem. SOC.,1977,99, 4803.

OrganophosphorusChemistry

160

The synthesis of enantiomers of cyclophosphamide, based on the less common and more elaborate resolving agent (- )-(S)-a-naphthyl(pheny1)methylsilyl chloride (42), has been reported by Verkade et a1.,81who were able to perform the silylation of the N-lithio-derivative of racemic (1) by means of (42). This a-naphthyl

I

,Si

Me,' 4 Ph

information contrasts with other reports, where the very fast intramolecular alkylation of N-metallated cyclophosphamide, leading to the bicyclic product (43), is described; this last process is considered to be responsible for the unsuccessful attempts at N-alkylation of N-metallated cyclophosphamide by means of external alkylating agenka2983 The diastereoisomers of N-silylated cyclophosphamide, after separation, were converted into enantiomeric forms of (1) via N-Si bond cleavage, using cyclohexylammoniumfluoride. The key feature of the synthetic route that was employed for the first stereospecific preparation of enantiomers of cyclophosphamide has been applied to / C H zCH,C1

Ph

Ph

\*

Me/CH-N

\ P( O)C1,

+

c

o

+

CNCH,CH,CH,OH

P'' N/

\eH/Me d-cH2cH,ci

No

Q+ enantioniers of (2)

CH,CH,CI

(44) Reagents : i, separation of diastereoisomers; ii, Hz, Pd

Scheme 5 81 82

83

T. Kawashima, R. D. Kroshefsky, R. A. Kok, and J. G . Verkade, J. Org. Chem., 1978, 43, 1111. G . Zon, S. M. Ludeman, and W. Egan, J. Am. Chem. SOC.,1977, 9 9 , 5 7 8 5 . K. Pankiewicz, R. W. Kinas, W. J. Stec, A. B. Foster, M. Jarman, and J. M. S. van Maanen, J. Am. Chem. SOC.,1979,101,7713.

Cyclophosphamide and its Congeners

161

the preparation of the optical isomers of isophosphamide (2). Their synthesis is presented in Scheme 5. The resolving functionality is introduced here on the exocyclic nitrogen atom and the exo-N-or-methylbenzyl derivative (44) of (2) is separated into diastereoisomers, which are further deben~ylated.~~ Although the total yield was very low, the desired optically pure enantiomers of (2) were fully characterized. This has not been achieved in a similar approach reported by Zon et al.85The absolute configuration of enantiomeric (2) was established by means of stereochemical correlation. The isomer (- )-(S)-(1) was converted into (+)-(S)-(43), and the same enantiomer of (43) (as proved by 31Pn.m.r. spectra that were run in the presence of a europium shift reagent) was obtained by means of two consecutive conversions of (+)-(R)-(2)into (+)-(R)-(45); the latter further rearranged to (+)-(S)-(43) when heated.83

Independently of this stereochemical correlation, the absolute configuration of the laevorotatory isomer of (2) was assigned as (-)-(S)-(2) by means of X-ray crystallography.86The six-membered ring has a chair conformation and the exocyclic oxygen occupies an equatorial position, while it is axial in the ra~emate.*~* 88 The general method for the preparation of enantiomeric species of (l), (2), .~~ of any enantiomer of a-methyl(3), and (4) has been e l a b ~ r a t e dCondensation benzylamine with 3-chloropropan-1-01 gives N-(3-hydroxypropyl)-cc-methylbenzylamine. Condensation of the latter with phosphoryl chloride gives the mixture of diastereoisomeric chloranhydrides (46), in the ratio 80: 20. This mixture, upon reaction with ethyleneimine, gives the diastereoisomers of 2ethyleneimino-3-(a-methylbenzyl)tetrahydro-2H-1,3,2-oxazaphosphorine2-oxide (47), in the ratio 2:s. Although the predominant isomer may be separated by crystallization from carbon tetrachloride, the unseparated mixture of (47), on treatment with anhydrous hydrogen chloride, can be converted into a diastereoisomeric mixture of 2-(2-chloroethylamino)-3-(~-methylbenzyl)tetrahydro-2~1,3,2-oxazaphosphorine2-oxide (48), as shown in Scheme 6, and these diastereoisomers can then be separated by column chromatography. The diastereoisomeric compounds (48) are the key intermediates in the synthesis of enantiomers of (11, (21, (31, and (4). Thus, treatment of (R,Rp)-(48) with chloroacetyl chloride leads to N-chloroacetylation (Scheme 7). Reduction of N-chloroacetylated (48) 84 85

86 88

R. W. Kinas, K. Pankiewicz, W. J. Stec, P. B. Farmer, A. B. Foster, and M. Jarman, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1978, 26, 39. S. M. Ludeman, D. L. Bartlett, and G. Zon, J . Org. Chem., 1979, 44, 1163. D. A. Adamiak, M. Gdaniec, K. Pankiewicz, and W. J. Stec, Angew. Chem., 1980,92,578. H. A. Brassfield, R. A. Jacobson, and J. G. Verkade, J. Am. Chem. SOC.,1975, 97, 4143. A. Perales and S. Garcia-Blanco, Acta Crystallogr., Sect. B, 1977, 33, 1935.

I I Ph

O NH

I

c1

Ph (S, Sp)-(46)

I

Me-C-H

V k p / O I

+

(S, Rp)-(46)

7 I I

Me-6-H

Me-6-H

scheme 6

Conformational properties of all cyclic compounds were not elucidated. The assignment of absolute configuration at the P atom in both isomers of (46) is based on the assumption that their reactions with ethyleneimine proceed with inversion of configuration.

I

+

I

Me-C-H

Reagents: i, NEt3; ii, B H , NEt3; iii, HCI; iv, separation of diastereoisomers

Pocl,

+

Me-C-H

G

Me-C-H

I I Ph

&Ao

r'

G

zz*

n R

Cyclophosphamide and its Congeners

163

0

II

I

Ph

0

I1 k z y p \ N (

C H, CHzC1),

I

i

0

0

I1

O=CCH,Cl

CH,CH,Cl (+)-(S1- (3)

[(+)-Rl Reagents: i, ClCHzCOCl; ii, B2H6; iii,

H2,Pd

Scheme 7

with diborane gives (R,Rp)-(51), which, upon hydrogenolysis, is converted into (-)-(S)-(1). In the same way, (R,Sp)-(48) may be converted into (+)-(R)-(1). 3-Chloroacetylation of ( - )-(S)-(1) with chloroacetyl chloride gives 3-chloroacetylated (+)-(R)-(1); reduction of the carbonyl function with diborane gives (+)-(S)-(3). (+ )-(S)-Cyclophosphamide is a substrate for the preparation of (- )-(R)-(3). Hydrogenolysis of one of the key intermediates, i.e. (S,Rp)-(48), leads to (+)-(S)-(49), which is one of the optically active forms of the major metabolite of (2); upon reaction with chloroacetyl chloride, this gives (+ )-(R)-(50),whereas its reduction with diborane gives (+)-(R)-(2), as shown in Scheme 8. This enantiomer of isophosphamide, on treatment with sodium hydride, gives (+)-(R)-(51). Methanesulphonic acid opens the aziridinyl ring to produce an enantiomeric form of sulphosphamide (4). Although racemic (3) and (4) are crystalline substances, all attempts at crystallization of their enantiomeric forms have failed; they exist as colourless, syrupy ~ i l s . 9~2 ~ ~

Organophosphorus Chemistry

164 0

0

Reagents: i, H2, Pd; ii, ClCHKOCl; iii, B2H6; ivy NaH; v, MeS03H

Scheme 8

The hydrolytic behaviour of (43) has also been established The essential role of 31Pn.m.r. spectroscopy for purity control, and for assaying diastereoisomeric and enantiomeric homogeneity, was demonstrated. The applicability of other chiral amines, e.g. (S)-or-naphthylethylamine, for the preparation of enantiomers of (1) was p r e ~ e n t e d . ~ ~ Although descriptions of other attempts to resolve chiral oxazaphosphorines have been published,89the original (and elegant) method of synthesis of enantiomers of (3) has been reported.g0 Commercially available ( + )-(S)-mandelic acid was converted into the methyl ester, which was then condensed with an equimolar amount of 2-chloro-l,3,2-dioxaphosphorineto give the phosphite (52). 2-[Bis-(2-chloroethyl)amino]-3 -(2-chloroethyl)tetrahydro-2H- 1,3,2-oxazaphosphorine (54) has been obtained from the condensation of N-(2-chloroethyl)-3-aminopropan-1-01and [bis-(2-chloroethyl)amino]phosphoramidodichloridite.gl Both (52) and (54) were separately converted into the platinum(I1) complexes (53) and (59, respectively, as shown in Scheme 9. Equilibration (by means of heating) of equimolar amounts of the two platinum iodide complexes in benzene for 7 hours gave the diastereoisomeric mixture of (56), which was separated into individual diastereoisomeric compounds. Each of them, when treated with NaCN in MeOH at - 50 "C, liberated enantiomeric 2-[bis(2-chloroethyl)amino] - 3 - (2-chloroethyl) tetrahydro-2H- 1,3,2-oxazaphosphorine, which, without separation, was oxidized to the corresponding enantiomer of (3). 89 9O

91

N. Bodor, K. Knutson, and T. Sato, J. Am. Chem. SOC.,1980, 102, 3969. A. E. Wrdblewski and J. G . Verkade, J. Am. Chem. SOC.,1979, 101, 7719. A. Okruszek and J. G . Verkade, Phosphorus Sulfur, 1978, 7 , 2 3 5 .

Cyclophosphamide and its Congeners P-O-C---H

/

165

Ph

+ Cis-[Cl,Pt(CNPh),]

\

cis- [C4Pt(5 2),]

\t*

C0,Me

( 5 2)

CiS-[I2Pt(52),]

CH,CH,Cl

(53)

I

P-N(CH,CH,Cl),

+ cis-[CJPt(CNPh),] -+ cis-[Cl,Pt(54),]

\L

(54)

cis- [ I,Pt(54),] (55) (53) + ( 5 5 )

*

cis-[1,~t(52)(54)1 ii-iv, enantiomers of (3) (56)

Reagents: i, NaI; ii, separation of diastereoisomers; iii, NaCN; iv, Nz04 Scheme 9

Basically the same approach has been applied to the synthesis of both enantiomers of (2).92An effort has been made to synthesize enantiomers of the metabolites. For example, a description of the synthesis of optically active ( 6 ) has been published.93 The synthesis of W-labelled (2), which is important for metabolic studies, has been described.9 4 Earlier work on the synthesis of deuterium-labelled cyclophosphamide should be mentioned. 96 The syntheses of 4-hydroperoxycyclophosphamide, 4-hydroperoxyisophosphamide, and 4-hydroperoxytrophosphamidewere accomplished by ozonation of (l), (2), and (3), respectively, in an acetone-water medium that contained H202.9 7 4-Hydroperoxy-derivatives, when treated with triphenylphosphine in CHzClz at 0 "C, were converted into 4-hydroxyoxazaphosphorine 2-oxides. Compound (5a) that was obtained in that way was treated (without purification) with alkyl mercaptans in the presence of catalytic amounts of trichloroacetic or trifluoroacetic acid to give the 4-(alkylmercapto)cyclophosphamides (1 1;R = Et), (1 1 ; R = HOCH,CH,), (11; R = But), or (1 1 ; R = PhCH,). 9 8 The procedure leading to the compounds (11) was shown to be slightly stereoselective. Only diastereoisomers with axial RS groups and axial phosphoryl oxygen are stable, crystalline compounds, while other diastereoisomers decompose when exposed 399

92

9s 94

95 96

97 g~

959

A. E. Wrbblewski, S. M. Socol, A. Okruszek, and J. G. Verkade, Znorg. Chem., 1980, 19, 3713. K. Misiura, K. Pankiewicz, W. J. Stec, and M. Jarman, Experientia, 1981, 37, 216. J. M. S. van Maanen, L. J. Griggs, and M. Jarman, J. Labelled Compd. Radiopharm., 1979, 18, 385. M. Jarman, E. D. Gilby, A. B. Foster, and P. K. Bondy, Clin. Chim. Acta, 1975, 58, 61. M. Jarman, P. J. Cox, P. B. Farmer, A. B. Foster, R. A. V. Milsted, R. W. Kinas, and W. J. Stec, in 'Stable Isotopes' (Proceedings of the Third International Conference), ed. E. R. Klein and P. D. Klein, Academic Press, New York, 1979, p. 363. H.-J. Hohorst, G. Peter, and R. F. Struck, Cancer Res., 1976, 36, 2278. G. Peter and H.-J. Hohorst, Cancer Chemother. Pharmacol., 1979, 3, 181.

Organophosphorus Chemistry

166

to temperatures higher than 0°C. The lack of optical activity of these compounds is quite obvious. By the analogous route, several similar derivatives [ l l ; R=HO,C(CH,)n], (11; R=HO,CC,H,CH,), [ l l ; R=HO(CH,)n], [11; R = EtO,C(CH,)n], and (1 1 ; R = HOCH,CH,OCH,CH,) were ~btained.~@ The conformational properties of compounds (1 1) have not been elucidated. Following the previously elaborated method of synthesis of Qhydroperoxycyclophosphamide,loOvan der Steen et al. performed the ozonolysis of 0-3butenyl NN-bis-(2-chloroethyl)phosphorodiamidate(57), and they isolated the new compound (58) in ca 20% yield from the reaction mixture.lol Compound (58) can be converted into 4-hydroperoxycyclophosphamide(in 70 % yield) by dissolving it in acetone-CH,C1, and refluxing the solution for 30 minutes. Refluxing for a longer period primarily resulted in the formation of peroxycyclophosphamide (59). The conversion of (58) into the stable compound (6) was also noticed under these conditions. It is suggested that the oxaziridine group of (58) is cis to the phosphoryl oxygen.

-

(57)

(59)

(60)

Although several attempts have been made to synthesize (5a),lo2 the only successful way consists of the oxidation of (20) by using pyridinium chlorochromate at - 20 "C.lo3 An earlier report on the absence of a measurable isotope effect for the hydroxylation of the C-4 position of cyclophosphamide by liver microsomes prompted the suggestion32that cleavage of the isotopically substituted bond is not ratelimiting, as might be expected for an oxene-insertion reaction.lo4An alternative mechanistic rationale, involving initial hydroxylation of the N-3 to give 3hydroxycyclophosphamide (60)followed by an unspecified rearrangement of (60) to (5a), has been verified by Zon et al.lo5 Condensation of W(3-hydroxy99

T. Hirano, W. Klesse, J. H. Heusinger, G . Lambert, and H. Ringsdorf, Tetrahedron Lett., 1979, 883.

100

101

A. Takamizawa, S. Matsumoto, T. Iwata, K. Katagiri, Y. Tochino, and K. Yamagushi, J . Am. Chem. SOC.,1973,95,985. J. van der Steen, J. G . Westra, C. Benckhuysen, and H. R. Schulten, J. Am. Chem. SOC., 1980, 102, 5691.

R. F. Struck, Cancer Treat. Rep., 1976, 60, 317. 103 A. Myles, C. Fenselau, and 0. M. Friedman, Tetrahedron Lett., 1977, 2475. 104 D. M. Jerina, J. W. Daly, B. Witkop, P. Zaltzman-Nirenberg, and S. Udenfriend, Biochemistry, 1970,9,447. 105 J. A. Brandt, S. M. Ludeman, G. Zon, W. Egan, J. A. Todhunter, and R. Dickerson, J. Med. Cheni., 1981, 24, 1404.

Cyclophosphamide and its Congeners

167

propy1)-0-benzylhydroxylamine with (32) gave 3-benzyloxycyclophosphamide, hydrogenolysis of which gave (60) as a fine powder, in ca 20% yield. Small amounts of cyclophosphamide were also found amongst the products. Besides field-desorption m.s. evidence, (60) was identified as its 0-acetyl derivative. Since incubation of (60) with phenobaibital-induced rat liver microsomes led to ca 15% conversion into cyclophosphamide after 15 minutes at 37"C, it is rather unlikely that (60) can play an important role in the metabolism of cyclophosphamide. 3-Chlorocyclophosphamide has been obtained in the reaction of (1) with t-butyl hypochlorite.lo6 Me

CH,-C-

Me

'

- CH,-,C

I

CO, R

I I

m

(61) a; R = CH,CH,SOMe b; R = CH,CH,hMe, Cl-CH,CH,N

s

.

CO,H

(62)

An interesting approach to the application of polymers as carriers of drugs has been applied to cyclophosphamide.107Two types of polymers, (61) and (62), have been prepared. The compounds (61) contain cyclophosphamide units that are each bound to a polymer chain by means of an oligomethylene bridge attached to its endocyclic nitrogen, while in compound (62) the cyclophosphamide moieties are connected with polymer via a methylenemercapto-function,attached at C-4 of cyclophosphamide. Although the preliminary anti-tumour tests were not promising,lo8the concept of delivery of activated forms of (l), (2), and (3), or their final cytotoxic metabolites, into the tumour cells is an interesting and creative approach to the development of chemotherapy. 106 1°7

108

K. Pankiewicz, unpublished results. L. Gros, H. Ringsdorf, and H. Schup, Angew. Chem., Znt. Ed. Engl., 1981, 20, 3 0 5 ; and references cited therein. T. Hirano, H. Ringsdorf, and D. S. Zaharko, Cancer Res., 1980, 40, 2263.

Organophosphorus Chemistry

168

Y CHzCH2

(63) X = C1, OSO,Me, or Br Y = OSO,Me, C1, Br, or I R = H, Me, Et, o r CH,CH,Cl Reagents: i,

03,

aq. THF; ii, HzOz

Scheme 10

As a continuation of earlier studies on active metabolites of anti-cancer oxazaphosph~rines,~~~ the synthesis (Scheme 10) and the anti-tumour activity of pre-activated analogues (64) of isophosphamide and sulphosphamide have been described.110 In contrast to the ozonolytic cyclization reaction that produces only one diastereoisomeric form of 4-hydroperoxycyclophosphamide,l l 1 both stereoisomers of compounds (64), having cis and trans configurations of the OOH that is attached to C-4 and P=O groups, have been obtained. Unfortunately, 31Pn.m.r. spectroscopy, which would clearly support this claim, has not yet been applied to this problem. Treating chromatographically homogeneous, crystalline (64a; X = C1, Y =OSO,Me, R = Me), of m.pt 119-120 “C,with 5 % aqueous NaOH gave the bicyclic compound (65a) quantitatively, whereas treatment of the crude ozonolysis product with alkali gave (65a) and isomeric

TsOH

L T

CICH,CH(

\

\CH,CH,OSO,Me

‘Me

(64a)

CH,CH,OSO,Me

(64b)

I

(653) 10Q

(65b)

A. Takamizawa, S. Matsumoto, T. Iwata, Y.Tochino, K. Katagiri, and K. Yamaguchi, J. Med. Chem., 1975, 18, 376.

A. Takamizawa, S. Matsumoto, T. Iwata, I. Makino, K. Yamaguchi, N. Uchida, K. Kasai, 0. Shiratori, and S. Takase, J. Med. Chem., 1978, 21, 208. 111 A. Takamizawa, S. Matsumoto, T. Iwata, and I. Makino, Chem. Pharm. Bull., 1977, 25, 110

1877.

Cyclophosphamide and its Congeners

169

(65b), which were separated in the ratio of approximately 5 : 1 after column chromatography on silica gel, with acetone-chloroform (1 :1) as the eluting system. It has been postulated that (64a) and (64b) differ in the spatial orientation of exocyclic substituents at the phosphorus atom. Epimerization of (64a) at P is claimed to be catalysed by toluene-p-sulphonic acid. The same catalyst causes the equilibration of (65a) with (65b). The mechanism of this equilibration is unknown, but acid-catalysed epimerization has been reported by Verkade as the process that accompanies the hydrolysis of 2-dimethylamino-4,6-dimethyltetrahydro-2H-l,3,2-dioxaphosphorine2-0xides.l~~ Further detailed studies on the epimerization of (64) and (65) and on the role of acid and water molecules are desired. The chemistry of hydroperoxy-derivatives of (1) and (2) has been summarized in the recent review on organophosphorus compounds that contain the peroxide bond. l3 Besides compounds with structures closely resembling these of (l), (2), (3), and (4), a number of phosphorylated derivatives of nitrogen mustards have been reported. Some of them should be mentioned. In a multi-step procedure, diastereoisomers of 2’,3’-bis-(2-chloroethyl)aminophosphoryl-3’-amino-3’-deoxyadenosine (66) were obtained.114 4,6-Dimethylcyclophosphamides (67) have been prepared and detailed conformational studies were performed.l16

HoYAde

0

trans-(67)

%/;I

iClCH,CH,),N

cis-(67)

The results of conformational analysis resemble those reported for enantiomers of 4-methylcyclophosphamide.5 8 From these studies, the conclusion was drawn that the chair conformation of (1) with the bis-(2-~hloroethyl)amidofunction equatorial is biologically more active than that with the axial disposition of this function. 2-Dimethylamino-5-t-butyltetrahydro-2H-1,3,2-oxazaphosphorine 2oxides were studied by means of X-ray crystallography and n.m.r. spectroscopy. The importance of the effect of 3-substitution on the conformational properties of this class of compounds was demonstrated.ll6 J. A. Mosbo and J. G. Verkade, J. Am. Chem. SOC.,1972,94, 8224. M. Konieczny and G. Sosnovsky, Chem. Rev., 1981. 81,49. 114 A. Okruszek and J. G. Verkade, J . Med. Chem., 1979,22, 881. 115 D. W. White, D. E. Gibbs, and J. G. Verkade, J. Am. Chem. SOC.,1979,101, 1937. 116 S. Chandrasekaran and W. G. Bentrude, Tetrahedron Lett., 1980, 21, 4671. 112

113

170

Organophosphorus Chemistry

5 Biological Properties of Newly Synthesized Analogues of Cyclophosphamide A number of reports describing the biological effects of cyclophosphamide have appeared recently. Blurring of vision,l17lung damage,l18teratogenic effect,11s,l B o cranofacial malformations in Rhesus monkeys,121 embryotoxicity,122cyclophosphamide-induced spermatogenic effects,123the effects of cyclophosphamide on the biochemistry of collagen in granulation tissue, skin, and and the induction in vitro of reversibleimmunosuppressionand the inhibition of regeneration of receptors of B cells by metabolites of cyclophosphamide126have been reported. The preponderance of (2) as an anti-cancer drug in chemotherapy has been documented.126 Anti-cancer screening tests against L1210 lymphoid leukaemia in mice have revealed that, while both diastereoisomers of (33) afford toxic metabolites, trans-(33) had therapeutic activity and cis-(33) did not. The relevance of these findings to results reported for diastereoisomers of (29)63and for enantiomers of (1) is briefly discussed.s1The results of metabolic studies and the anti-tumour activity of diastereoisomeric optically active forms of (29) and of enantiomers of (1) and (2) are summarized in a recent review.127Also, the synthesis of enantiomers of (1) that are labelled with deuterium at carbon in a position that is tc to the exocyclic nitrogen atom has been appreciated in studies on the stereodifferentiatedmetabolism of (1) in mice, rats, and rabbits.127 New data, indicating 40-80 % higher thgrapeutic indices for (S)-(1) and for (S)-(2) in animal screening tests against 16/C mammary adenocarcinoma, Lewis lung carcinoma, P-388 leukaemia, and B16 melanotic melanoma lines in mice than those for racemic drugs, have been obtained.128Screening tests (in vivo) against L1210 lymphoid leukaemia in mice with samples of (37) were uniformly negative [test/control (T/C) percentage < 1251, but the diastereoisomer ‘fast’ (36) gave a value for T/C of 146. This lower level of anti-cancer activity relative to cyclophosphamide was also reflected in the lower therapeutic index (TI=LD50/ED90)of 25 that was obtained for (36), as compared to 95 for cyclophosphamide, against the ADJ/PC6 mouse plasma cell tumour. Of the aforementioned samples that were screened, only the diastereoisomer ‘fast’ (37) showed activity in uitro (KB cell culture; 2.2 ,ug ml-l), and the marked toxicity of ‘fast’ (37) without microsomal activation was evident from growth-inhibition tests with Walker 256 cells, which gave a value for the ID5,, of 1.5 ,ug ml-l. This 117 118 119 120 121 122 123 124 125 126 127 128

G.Kende, S. R. Sirkin, P. R. M. Thomas, and A. I. Freeman, Cancer, 1979,44, 69. C. H.Collis, Cancer Chemother. Pharmacol., 1980, 4, 17. G. Reznik and J. Hecht, Arzneim.-Forsch., 1979, 29, 479.

K.T.Kitchin, B. P. Schmid, and M. K. Sanyal, Biochem. Pharmacol., 1981, 30, 59. H. M. McClure, A. L. Wilk, E. A. Horigan, and R. M. Pratt, The Cleft Palate J., 1979, 16, 248. U.Clausen, H. G. Krengel, and H. J. Schrors, Arzneim.-Forsch., 1980, 30, 1585. P. M. Adams, J. D. Fabricant, and M. S . Legator, Science, 1981, 211, 80. T.M. Hansen, Dan. Med. Bull., 1979, 26, 45. F. L. Shand and J. G. Howard, Eur. J. Immunol., 1979, 9, 17. N. Brock, in ‘Advances in Medical Oncology, Research and Education’, Vol. 5, ed. B. W. Fox, Pergamon Press, Oxford, 1979, p. 39. W. J. Stec, in ‘Phosphorus Chemistry Directed Towards Biology’, ed. W. J. Stec, Pergamon Press, Oxford, 1980, p. 95. C. Radzikowski and Z. Kleinrok, personal communication.

Cyclophosphamide and its Congeners

171

toxicity level for 'fast' (37) is comparable to that observed with microsomally activated cyclophosphamide (ID,,= 0.5-1.0 ,ug ml-l), and has thus been ascribed to the facile hydrolytic conversion of 'fast' (37) into an active phosphoramide mustard alkylating agent.6 4 In the case of other S-halogeno-cyclophosphamides (39) and (40), the metabolism by rat liver microsomes was stereoselective; the cis-isomers were poorly metabolized, whereas the trans-isomers were metabolized with an efficiency comparable to that of cyclophospharnide itself. However, there was no evidence that the yield of phosphoramide mustard (8) that was produced by the trans-analogues was significantly greater than that from (l), following microsomal4-hydroxylation. Hence, the halogen substituents did not accelerate the p-elimination of acrolein from the acyclic aldehydotautomers. As expected, the poorly metabolized cis-5-fluoride (39) had little activity against the ADJ/PC6 tumour in mice. However, the cis-5-chloride (40) was as active as the trans-isomer, and each had approximatelyhalf the therapeutic index of cyclophosphamide. The trans-5-fluoride (39) was much less active, having an ED,, value some 16-fold larger than that of (1).66 Comparative data uersus L1210 leukaemia in uiuo for 4-hydroperoxy- and peroxy-derivatives of (l), (2), and (3), along with data for (l), (2), and (8), indicate a superior effect for 4-hydroperoxyisophosphamide.97 A preliminary evaluation of the curative effect after a single injection of (11; R = Et) or (11 ; R = HOCH,CHJ in rats bearing Yoshida ascites sarcoma, or of (11;R = HOCH,CH,) in nu/nu mice that bear human breast carcinoma xenografts, suggested that these derivatives of cyclophosphamide possess the same efficacy as activated cyclophosphamide itself.gE The derivative [l 1; R = HO,C(CH,),] has been proved to be highly carcinotoxic against Yoshida ascites tumour in the rat.gg The monomeric compounds [11; R = HO(CH,),O(CH,),], [11; R = HO(CHd317 111; R = HO(CH2)619 111; R = HO(CH2)111, [11; R = HO,C(CH&I, and [ l l ; R=HO,C(CH,),] and their derivatives, covalently bound to a polymeric carrier (68), were studied in uitro and in uiuo. The rate of release of 4hydroxycyclophosphamide from monomeric and polymeric derivatives was

r

CO,H -FH'

'YH-CHCH,

(68)

1

t

OH C1CH,CH2,

C ,

HCH,CL

(69)

examined under physiological conditions (pH 7.0, at 37.0 "C) in uitro. Greater hydrophobicity and greater length of the alkyl chain of substituents at the 4position of the 1,3,2-0xazaphosphorine ring decreased the rate of hydrolysis. The polymeric derivatives were more slowly hydrolysed than were their corresponding monomers. Toxicity in mice indicated that the rate of hydrolysis in vitro is related to toxicity in viuo. The optimal anti-tumour activity (a maximum of 270% increase in the life-span in L1210-bearing mice) and the effective

172

Organophosphorus Chemistry

dose range of each derivative of low molecular weight were similar to those of cyclophosphamide. The polymeric derivatives exhibited much less anti-tumour activity (a maximum of 50 % increase in the life-span)than did cyclophosphamide. The monomeric derivatives that included a short alkyl chain, such as propanol and propionic acid, caused acute lethal toxicity, which limited the upper dose that was usable for anti-tumour activity. Polymeric derivatives, when compared on a molar basis with their corresponding monomers, were relatively more toxic to the mice; this limited their maximum dose.lo8Compound (58) exhibited cytostatic activity in vitro. On BHK cells, it had the same cytostatic action as 4hydroperoxycyclophosphamide.On 3T3f cells, the cytotoxic capacity was even stronger.lol Compound (60), when tested against L1210 leukaemia in mice, exhibited anti-cancer activity comparable to that of cyclophosphamide.lo5 Interesting anti-tumour activity was found in the compounds (64). Highest efficacy was found for (64; R = Me, X = C1, Y = OSO,Me), whose life-span activity in L1210-implanted BDFl mice was greater than that of 4-hydroperoxyisophosphamide, (l), or (2). The superiority of this compound by oral administration was especially apparent.l1° Preliminary tests with diastereoisomers of (66) have shown that they are inactive against L1210 in mice.l14 The compounds (67) were tested in KB tumour cells in culture; this preliminary test showed that trans-(67) possessed some activity whereas cis-(67) did This result, together with that reported by Zon61 and also results on the selective dechloroethylation of only one of four diastereoisomers of (29), namely (2R,4S)-(29), leading to (69), indicates the relevance of molecular architecture of xenobiotics to their fate during metabolism.12g 6 Concluding Remarks Although the results reported recently (and not covered by the excellent review by Myles, Friedman, and Colvin 4, on the synthesis and the biological evaluation of cyclophosphamide and its congeners did not lead to the discovery of anticancer drugs better than (1) and (2), they have had a great impact on the understanding of the metabolism and the mode of action of alkylating agents. The enormous progress in accuracy and in the quantitation of metabolism was possible because of the development of (and easy access to) new techniques ~~$ such as g.c.,130 g.c.-chemical-ionization rn.s.,l3l field-desorption n ~ . s . ,132 and 31Pn.m.r.133,134 The difficulty in estimating the therapeutic improvements that are offered by new derivatives of cyclophosphamide results from the different test systems that have been used in different laboratories.

130

G . Abel, P. J. Cox, P. B. Farmer, N. J. Haskins, M. Jarman, K. Merai, and W. J. Stec, Cancer Res., 1978, 38, 2592. B. M. Bryant, M. Jarman, M. H. Baker, I. E. Smith, and J. F. Smyth, Cancer Res.,

l3l

I. Jardine, C.Fenselau, M. Appler, M.-N. Kan, R. B. Brundrett, and M. Colvin, Cancer

129

1980,40,4734.

132 133 13*

Res., 1978, 38, 408. M. Przybylski, H. Ringsdorf, U. Lessen, G. Peter, G. Voelcker, T. Wagner, and H.-J. Hohorst, Biomed. Mass Spectrom., 1977, 4, 209. G. Zon, Prog. Med. Chem., 1981, 19, in the press. M. Jarman, R. A. V. Milsted, J. F. Smyth, R. W. Kinas, K. Pankiewicz, and W. J. Stec, Cancer Res., 1979, 39, 2762.

Cyclophosphamide and its Congeners

173

From the point of view of organic chemists, development of the art of stereospecific synthesis and syntheses of enantiomers of the compounds (l), (2), (3), and (4) represent an interesting new approach to the preparation of optically active monoalkyl phosphorodiamidates, known so far only in racemic forms. The method elaborated by Verkade et aLg099 2 represents a novel approach to the synthesis of optically active organophosphorus compounds that are chiral at phosphorus. Owing to the preparation of enantiomers of cyclophosphamide that are stereospecifically labelled with deuterium, i.e. (S)-and (R)-[2H,]-(l), the first studies on the stereodifferentiated metabolism of (1) in mice, rats, and rabbits have been performed. The pseudoracemate approach, which allows the differences in the rates of metabolism of enantiomers to be measured by means of m.s., has been f o r m ~ l a t e d .135 ~ ~ The , complexity of mixed-function oxidase, which Nature created and which evolved for the rejection of any xenobiotics from the mammalian body, is reflected in its low diastereoselectivity with respect to chiral cyclophosphamides [active forms of (l), (2), (3), and (4), and the corresponding 4-hydroxy-derivatives, may exist as diastereoisomeric mixtures by virtue of asymmetry of both phosphorus and C-41; therefore the biological results with enantiomers of (1) are as yet insufficient to support a prediction that either enantiomer would be superior to its antipode or to the racemate in cancer chemotherapy. However, other factors could elicit differences in therapeutic response between the enantiomers. For example, stereoselective uptake among stereoisomers of (5a) could result in different intracellular concentrations of the product of their decomposition, i.e. (8), despite the absence of stereoselectivity in the enzymatic activation of (1). Therefore, further biological studies with the enantiomers of (l), (2), (3), and (4) should be continued. It should be emphasized that, from hundreds of analogues of (l), the only compounds which have shown a promising improvement in therepeutic efficacy, as compared with the parent compounds (1) and (2), are their laevorotatory enantiomers. Besides these, several new examples which enrich the understanding of the structure-biological activity relationship have been prepared. Taking into account the tremendous increase in our understanding of the mechanism of action of enzymes that are responsible for the transfer of phosphoryl groups that has been achieved by the application of P-chiral phosphates and phosphor~thioates,~~~ it can be anticipated that enantiomers of cyclophosphamide and its congeners, as well as their metabolites, will be valuable chemical tools for studies on the mode of action of purified forms of mixed-function oxidase. The discovery by H u t ~ h i n s o n lthat ~ ~ partial alkylation of the naturally occurring RNAs by such difunctional electrophiles as nitrogen mustard and its derivatives can increase their interferonogenic activity opens up a new avenue in the search for greater understanding of the mode of biological action of cyclophosphamide and its congeners. The generally accepted opinion that 135

13’

P. J. Cox, P. B. Farmer, M. Jarman, R. W. Kinas, and W. J. Stec, Drug. Metab. Dispos., 1978, 6, 617. J. R. Knowles, Annu. Rev. Biochem., 1980, 49, 877. D. W. Hutchinson, in ‘Phosphorus Chemistry Directed Towards Biology’, ed. W. J. Stec, Pergamon Press, Oxford, 1980, p. 113.

174

Organophosphorus Chemistry

alkylating agents interfere with the process of orderly pairing of the genetic material, or of DNA, and that they prevent successful division of cells, may be carefully questioned. The idea that metabolites of cyclophosphamide and other alkylating drugs can cross-link nucleic acids, which can then act as inducers of interferon, seems very optimistic for all who agree that the long-term future of organic chemistry lies in its application to biochemical problems. However, further experimental data are required. Acknowledgement The author owes a debt of gratitude to many colleagues who supplied him with their recently published works, with papers in print, and with some relevant information that was not yet ready for publication.

9 Nucleotides and Nucleic Acids BY J. B. HOBBS

1 Introduction The past year has seen a continuing high level of activity in most areas of nucleotide research, with the demands for defined-sequence oligonucleotides posed by genetic engineering techniques providing particular stimulus to the synthesis of oligonucleotides. A book on the synthesis and applications of nucleotide analogues’ and two volumes of symposium reports 2, demand particular recommendation. 2 Mononucleotides Chemical Synthesis.-Phosphorylation of nucleosides, using phosphoryl chloride in trialkyl phosphate solution, remains the method most commonly used to prepare 5’-mononucleotides. Thus am-tubercidin (1); a series of 5-alkyluridine~,~ and 1-b-D-ribofuranosylbarbituricacid (2) have been converted into their 5’-monophosphates in good yield. The 5-alkyl-uridine monophosphates were converted into the corresponding triphosphates via the phosphoromorpholidate method to afford possible substrates for RNA polymerase.6 The 5’-monophosphate of (2) is a remarkably strong inhibitor of orotidine 5’phosphate decarboxylase, because, it is thought, the anionic form of the analogue possesses an electron distribution closely similar to that of the putative transition state for decarboxylation of orotidylate.‘j While the dithiolan derivative (3) of 5-formyl-2’-deoxyuridineis converted into its 5’-monophosphate, in low yield, on treatment with phosphoryl chloride in wet acetonitrile and pyridine (the Sowa-Ouchi procedure), the application of the same method to the oxime (4) resulted in the formation of 5-cyano-2’-deoxyuridine 5’-monophosphate.’ The 5’-monophosphate of (4) was prepared by treatment with 2,2,2-tribromoethyl phosphoromorpholinochloridate, followed by deprotection using a Zn/Cu 1

K. H. Scheit, ‘Nucleotide Analogues: Synthesis and Biological Function’, Wiley, New York,

2

Phosphorus Chemistry Directed to Biology (Lectures of an International Symposium, 1979), ed. W. J. Stec, Pergamon, Oxford. Nucleic Acids Symp. Ser., 1980, Vol. 7. F. Seela, Q.-H. Tran-Thi, and H.-D. Winkeler, Chem. Ber., 1981, 114, 1217. A. Szemzo, A. Szabolcs, J. Sagi, and L. Otvos, J. Carbohydr., Nucleosides, Nucleotides,

1980. 3 4 5

6 7

1980, 7, 365. H. L. Devine, R. S. Brody, and F. H. Westheimer, Biochemisrry, 1980, 19, 4993. J. S. Park, C. T.-C. Chang, C. L. Schmidt, Y . Golander, E. De Clercq, J. Descamps, and M. P. Mertes, J. Med. Chem., 1980, 23, 661.

175

176

Organophosphorus Chemistry

couple in 90% acetic acid. The 5’-monophosphates of (3) and (4) were effective inhibitors of thymidylate synthetase,’ but, unlike 5-nitr0-2’-deoxyuridylate,* they do not inhibit the enzyme in the absence of its cofactor. On treatment with dibenzyl phosphate, the 5’-diazo-nucleoside (5) (formed by treating the corresponding N-nitroso-amide with butyl-lithium) affords the corresponding phosphotriester (6) as the sole product in a clean r e a ~ t i o n In .~ a similar alkylation reaction, UMP was treated with the ff uorescent compound

~ H ~ (Oo)YOR

( 5 ) R = CHN2

(6) R = (PhCH20)2P(0)OCH2

OH (7)

R

(8) R

= Urd-5’ =

H

Y. Wataya, A. Matsuda, and D. V. Santi, J . Biol. Chem., 1980, 255, 5538. T. M. Chapman, J. M. Simpson, D. C. Kapp, and P. Butch, J. Carbohydr., Nucleosides, Nucleotides, 1980, 7,241.

177

Nucleotides and Nucleic Acids

5-dimethylamino-2-oxidoisoquinolin-l-yldiazomethaneto afford the phosphodiester (7), which could also be prepared by condensing the phosphate (8) with uridine, using TPS-C1.l0 These reactions permit the fluorescent tagging of nucleotides. When 0,s-dimethyl thiophosphorochloridate is treated with 5’-monomethoxytrityl-2’-deoxythymidineYand pyridine is then added, the corresponding S-methyl 3’-phosphorothioate (9) is formed in high yield, and the same result is obtained when base and nucleoside are added in the reverse order.” On performing the same reaction in acetonitrile, with l-methylimidazole as base, a high yield of the phosphotriester (10) is obtained. N.m.r. studies have revealed that the starting material is O-demethylated rapidly in pyridine, and it has been suggested that the true phosphorylating species is (1 1). The corresponding 1-methylimidazolium species is comparatively unreactive. Infrared spectroscopic data indicate that the species that is formed on treatment of 3’-O-acetyl-2’-deoxythymidine5’-phosphate with TPS-Cl in pyridine, once tentatively suggested as being the metaphosphate, is in fact the N-phosphorylpyridinium inner salt (12).12 Thy 0

0

MMTrO

II

-0-P-R

0- P -SMe

I

II I Y

OR

(9) R = H (10) R = Me

(11) Y

=

C5H5N+ or C1-, R

=

MeS

(12) Y = C5H5N+, R = 0-([3’-OAc]dThd-5‘)

HOOCCH20- ( Ino-5‘ )

H2NCH2CH2NHCOCH20-(Ino-5’)

(13)

(14)

The 2’(3’)-phosphorothioates of inosine and other nucleosides have been prepared by treating the 2’,3’-O-di-n-butylstannylenenucleosides with thiophosphoryl chloride and tri-n-butylamine in methanol, to afford the methyl phosphorothioates ; these were then hydrolysed to the ribonucleoside 2’(3’)phosphorothioates in alkali.13 The inosine and guanosine compounds were cyclized to the corresponding 2’,3’-cyclic phosphorothioates, using ethyl chloroformate and tri-n-butylamine, the products being completely resistant to hydrolysis by a ribonuclease from Streptomyces aureofaciens. Compounds (13) and (14) were treated with triethyl phosphite and 6M-HCl in DMF to give the corresponding 2’(3’)-phosphites; on treatment with trimethylsilyl chloride, sulphur, and pyridine, these gave the required 2’(3‘)-phosphorothioates. An S. Nishimura and M. Saneyoshi, Chem. Pharm. Bull., 1980,28, 1695. U. Asseline and Nguyen Thanh Thuong, Tetrahedron Lett., 1981, 22, 847. l2 V. F. Zarytova, E. M. Ivanova, D. G . Knorre, I. K. Korobeinicheva, and T. V. Maltseva, Dokl. Akad. Nauk SSSR, 1980,255, 355 (Chem. Abstr., 1981, 94, 157 179). l3 A. Holy and P. Kois, Collect. Czech. Chem. Commun., 1980, 45, 2817. lo

l1

178

Organophosphorus Chemistry

alternative synthetic route, using (14) and thiophosphoryl tri-imidazolide, proved unsatisfactory. The 5’-phosphorodiamidate, 5’-phosphorodi-imidazolidate,and 5’-phosphorodimorpholidate of 5-fluoro-2’-deoxyuridine have been synthesized by treating 3’-O-acetyl-2’-deoxy-5-fluorouridinewith phosphoryl chloride in triethyl phosphate, and then treating the resultant phosphorodichloridate with the appropriate amine, followed by deacylation with amrnonia.l* The phosphorodiamidates are reportedly reasonably stable to alkali at elevated temperatures. Their efficiencies in inhibiting the growth of L5178Y (murine leukaemia) cells corresponded to their rates of hydrolysis to the 5’-phosphate, suggesting that they possess little intrinsic anti-cancer activity. Several novel phosphoramide mustard analogues of pyrimidine deoxyribonucleosides [(15)-( 1S)] have been prepared by treating the corresponding nucleoside with bis-(2-chloroethyl)phosphoramidic dichloride and triethylamine in DMF.15 The stereoisomers were not separated. All compounds with the oxygen function at the 3’-position showed strong activity in inhibiting the replication of L1210 leukaemia cells in uitro. An enzyme has been isolated from Chlorella pyrenoidosa which specifically catalyses the formation of adenosine 5’-phosphoramidate from adenosine 5’-phosphosulphate and ammonia.16 The reason for its formation, and its metabolic fate, are not known. Successive treatments of phosphoryl chloride in THF with one equivalent of 2,2,2-trichloroethanol and ethylamine, and then 2-cyanoethanol, afford 2cyanoethyl 2,2,2-trichloroethyl phosphorochloridate, which may be used in anhydrous acetonitrile, with l-methylimidazole, to phosphorylate suitably protected nucleosides at free hydroxyl groups to give the corresponding phosphotriesters in high yie1d.l’ Since the trichloroethyl and cyanoethyl groups may be removed separately, such phosphotriesters are useful synthetic intermediates. Alternatively, if phosphoryl chloride is treated with three equivalents of 1,2,4triazole in dioxan in the presence of excess triethylamine, and the mixture is added to 5’-O-dimethoxytrityl-2’-deoxythymidine, with subsequent successive additions of two different alcohols, phosphotriesters of the type (19) are obtainedls in good yields after chromatography. No bisnucleoside alkyl phosphotriesters were obtained, although some symmetrical nucleoside bisalkyl phosphotriesters were obtained as minor products. The phosphorylating agent was suggested (though not proven) to be phosphoryl tris(triazo1e). Bromoacetaldehyde reacts with AMP, at pH 5-7, more rapidly than chloroacetaldehyde to give 1,N6-ethenoadenosine5’-phosphate, and with GMP to give a complex mixture of products, one of which appears to be 1,N2-ethenoguanosine 5’-phosphate. With polynucleotides, bromoacetaldehyde reacts with adenine and cytosine bases in single-stranded (but not double-stranded) regions, and it may thus be of use as a probe.ls A large series of alkyl and aryl esters of ara-CMP l4 15

16

17 18 19

M. E. Phelps, P. W. Woodman, and P. V. Danenberg, J. Med. Chem., 1980, 23, 1229. T.-S. Lin, P. H. Fischer, and W. H. Prusoff, J. Med. Chem., 1980,23, 1235. H. Fankhauser, J. A. Schiff, and L. J. Garber, Biochem. J., 1981,195,545. K. Grzeskowiak, Synthesis, 1980, 831. A. Kraszewski and J. Stawinski, Tetrahedron Lett., 1980, 21, 2935. K. Kayasuga-Mikado, T. Hashimoto, T. Negishi, K. Negishi, and H. Hayatsu, Chem. Pharm. Bull., 1980, 20, 932.

179

Nucleotides and Nucleic Acids

’y”r” F\y 0

DMTrO

$*-f.,

t

o

N( CH2CH2C1 )

(15) X = NH, Y = 0, R = T h y

(19) R1= CH2CH2CN or CH20COCH2Ph

(16) X = NMe, Y = 0, R = Thy

(17) X

=

Y

=

NH, R

=

Thy

(18) X = NH, Y = 0, R = 5-iodouracilyl

R2= Et, CH2CC13, CH2CH2CN, CH2CHBrCH2Br, or CH20COCH2Ph

has been prepared by esterification of N4-acety1-2’,3’-di-O-acylatedara-CMP with TPS-Cl and the appropriate alcohol and subsequent deblocking with ammonia.2o The C1-C8 alkyl esters showed high antiviral activity against herpes simplex virus (HSV-1) and carcinostatic activity against L1210 cells. Heating 5-(acetoxymercuri)-2’-dUMP with iodobenzene and lithium tetrachloropalladate in methanol, under reflux, affords 5-phenyl-2’-dUMP in low yield.21 This direct arylation is thought to proceed via a zerovalent palladium complex. Alternatively, if 5-iodo-2’-dUMP is first silylated with 4-(t-butyldirnethylsilyloxy)pent-3-en-Zoneand then irradiated at 254 nm in acetonitrile, in the presence of 1,4-dimethoxybenzene7 5-(2,5-dimethoxyphenyl)-2’-dUMPis obtained, in modest yield, following desilylation. In aqueous solution, 2’-deoxythymidine 5’-(4-nitrophenyl)phosphate forms thymidylate oligomers in addition to pdT and 4-nitrophen01.~~ The symmetrical pyrophosphate dT5‘ppS‘dT is an early product of the reaction, but is converted into other products such as pdTpdT and cyclic pdTpdT as reaction proceeds. The addition of monomeric and polymeric imidazole derivatives and metal dications does not affect the rate of degradative oligomerization but alters the product distribution; this observation has been ascribed to the formation of phosphorimidazolidateintermediates and to steric and metal-chelating influences. Dinucleoside monophosphates containing 2’-fluoro-2’-deoxyadenosine,i.e. dAflpdAfl, dAflpA, and ApdAfl, have been prepared by standard phosphodiester methods and characterized by spectroscopic methods.23The dimers are stacked with higher base-base overlap and preferential 3’-endo conformation in the furanose ring, compared with ApA. Dinucleoside monophosphates that contain 8,2’-anhydro-8-thio-9-~-~-arabinofuranosyladenine [As, (20)] and the corresponding inosine analogue [Is, (2111, i.e. ASpIS,ISpAS, and PpP, have also been prepared, by similar All of the dimers are rather resistant to hydrolysis

23

M. Saneyoshi, M. Morozumi, K. Kodama, H. Machida, A. Kuninaka, and H. Yoshino, Chem. Pharm. Bull., 1980,28,2915. C. F. Bigge and M. P. Mertes, J . Org. Chem., 1981,46, 1994. T. Shimidzu and A. Murakami, Tetrahedron, 1981, 37, 51. S. Uesugi, Y. Takatsuka, M. Ikehara, D. M. Cheng, L. S. Kan, and P. 0. P. Ts’o, Bio-

24

chemistry, 1981, 20, 3056. S. Uesugi, T. Shida, and M. Ikehara, Chem. Pharm. Bull., 1980,28,3621.

20

21 22

7

180

Organophosphorus Chemistry R

R1$1ER2

( 2 2 ) R 1= O H , R2= H

6H (20

R = NH2

( 2 1 ) R = OH

( 2 3 ) R1=

H, R

2

=

OH

Row 01

OR

E t 2N-y=X

“

O

0w

OH r

I

a

I I

O=P-OH HO

0

O OR w OR r a ( 2 5 ) R = TBDMS, X i s absent

Ur aOHa

( 2 6 ) R = TBDMS, X = 0

(27) R

=

TBDMS, X = NPr

( 2 8 ) R = TBDMS, X = Se (29) R

=

TBDMS, X = S

by snake venom phosphodiesterase, and spectroscopic data suggest that they adopt a left-handed stacked conformation. Dinucleoside monophosphates with U, C, A, and G as the 5’-terminus and either l-(6-deoxy-~-~-allofuranosyl)uracil (22) or 1-(6-deoxy-a-~-talofuranosyl)uracil(23) at the 3’-terminus have also been prepared, by standard methods, with a view to investigating the specificity of ribonu~leases.~~ Where differenceswere observed, compounds with (23) at the 3’-position were less easily degraded by the appropriate sequence-specific ribonuclease than those that contained (22). (Aminoacy1)dinucleosidephosphate analogues of the acylated CpA end of tRNA have been prepared.262’-Amino2’-deoxyadenosine and 3’-amino-3’-deoxyadenosinewere amino-acylated at the amino-group of the sugar by the 4-nitrophenyl ester of a suitably protected amino-acid, and then coupled to N4,2’,5’-triacetylcytidine 3’-phosphate, using DCC. Subsequent deblocking afforded the desired analogues of ‘charged‘ CpA. J. Smrt, Collect. Czech. Chem. Commun., 1980, 45, 2550. S. Chladek and G. Butke, J. Carbohydr., Nucleosides, Nucleotides, 1980, 7 , 297.

z5 N. Sh. Padyukova and 26

Nucleotides and Nucleic Acids

181

Some material was resistant to digestion by pancreatic ribonuclease, suggesting that some isomerization of the 3’-5’ phosphodiester had occurred, and some material was resistant to snake venom phosphodiesterase, suggesting that 3’-3’ (or 3’-2’) bonds had been formed. The analogues were used to investigate the substrate specificity of the acceptor site of 70s ribosomes of E. c o k Z 7Diuridine 3’-phosphate (24) has been prepared by standard phosphotriester methods.28 It is rather unstable in an alkaline medium (pH ca 11) compared to UpU, and thus any 3’-3’ linkages that are formed during the synthesis of oligoribonucleotides may be rapidly eliminated by brief treatment with base without affecting 3’-5’ linkages. Compound (24) is a poorer substrate for pancreatic ribonuclease than UpU and a very poor substrate for spleen phosphodiesterase. Several phosphoramidate analogues of UpU have been prepared.29 If 2’,5’-di0-(t-butyldimethylsily1)uridine in T H F is treated first with diethylamino phosphorodichloridite and then with 2’,3-di-O-(t-butyldimethylsilyl)uridine, the protected phosphoramidite analogue (25) of UpU is obtained in good yield. Under nitrogen, (25) is stable, but it is oxidized slowly by air to the phosphoramidate (26). If (25) is treated with aqueous iodine, or with iodine-n-propylamine, or with selenium in DMF, or with sulphur in pyridine, then the phosphoramidate (26), or its imino- (27), seleno- (28), or thio-analogue (29), respectively, is formed. The silylated derivatives (26)-(29) were all obtained as diastereoisomeric mixtures, some of which were separable by t.1.c. Desilylation with fluoride afforded dinucleoside phosphate analogues which were stable to pancreatic ribonuclease and to spleen and snake-venom phosphodiesterases. When a compound that was believed to be adenosine 5’-[(R)-160,170,180]phosphate was cyclized by treatment with diphenyl phosphorochloridate and tri-n-butylamine in dioxan and subsequently with potassium t-butoxide in DMF, then methylated (using methyl iodide), and the resulting methyl ester of chiral cAMP was examined by 31P n.m.r., the surprising result was obtained that cyclization had occurred with retention of c o n f i g ~ r a t i o n .Moreover, ~~ if the non-methylated cAMP that was obtained was hydrolysed in water of known isotopic composition (using beef heart cAMP phosphodiesterase), re-cyclized as described above, methylated, and the chirality was then analysed, the enzymic reaction also appeared to have proceeded with retention of c~nfiguration.~~ This contradicted a previous result, using the chiral thiophosphate cAMP[S], and a new using the same chiral phosphate. Careful re-examination showed that the absolute stereochemistry of the 2-methoxy-2-oxo-4,5-diphenyl-l,3,2dioxaphospholan (‘Ukita’s Triester’), which is vital to the assignment of chirality in the chiral AMP, was and not cis, as previously thought, and also that the absolute chirality of the 5’-[160,170,180]AMPthat had previously 34 been designated (R) was in fact (S). Cyclization to cAMP and the enzymic hydrolysis 27 28

29

30

31 32

33 34

A. Bhuta, K. Quiggle, T. Ott, D. Ringer, and S. Chladek, Biochemistry, 1981, 20, 8. B. Rayner, C. B. Reese, and A. Ubasawa, J. Chem. SOC.,Chem. Commun., 1980, 972. M. J. Nemer and K. K. Ogilvie, Tetrahedron Lett., 1980, 21, 4153. Ri L. Jarvest, G. Lowe, and B. V. L. Potter, J. Chem. SOC.,Chem. Commun., 1980, 1142. R. L. Jarvest and G. Lowe, J. Chem. SOC.,Chem. Commun., 1980, 1145. J. A. Coderre, S. Mehdi, and J. A. Gerlt, J. Am. Chem. SOC.,1981, 103, 1872.

P. M. Cullis, R. L. Jarvest, G. Lowe, and B. V. L. Potter, J . Chem. SOC.,Chem. Commun., 1981,245. P. M. Cullis and G . Lowe, J. Chem. SOC.,Chem. Commun,, 1978, 512.

182

Organophosphorus Chemistry

of cAMP therefore must occur with inversion of configuration at phosphorus, in line with other results. The stereochemical course of the transfer of phosphoryl groups, catalysed by adenosine kinase, has been investigated by using the beef liver enzyme to convert a mixture of (Rp)-adenosine 5’-[y-thi0-y-~~O]triphosphate and adenosine into ADP and [a-l8O]adenosine 5’-pho~phorothioate.~~ The latter product was phosphorylated, using adenylate kinase and ATP (which phosphorylates the pro-R oxygen), and converted into the chiral ATP[a-l8O,a-S], which was then degraded and methylated. By mass spectrometry, all the was found in the trimethyl phosphorothioate, and hence la0was in the non-bridging position in the ATP[a-l*O,a-S], and thus the pro-S oxygen in [a-laO]AMPIS], and phosphoryl transfer occurred with inversion, probably by direct displacement. The stereochemistry of the hydrolysis of 5’-AMP[S] when catalysed by venom 5’-nucleotidase has been investigated by allowing the enzyme to hydrolyse [OI-~~O]AMP[S] of defined chirality: both (Rp)- and (Sp)-isomers were used, and the thiophosphate that was released in each case was analysed by the method of Webb and Trentham, detailed last year.36Hydrolysis was found to proceed with inversion, again probably by direct di~placement.~’ If 2’,3’,5’-tri-0-acetyl-N2-tritylguanosineis treated with a dialkyl or diary1 phosphorochloridate, triethylamine, and a catalytic quantity of 4-dimethylaminopyridine, fair yields of 06-phosphorylated derivatives of the type (30) are formed readily.38If dibutylphosphinothioyl bromide or diphenylphosphinothioyl chloride is used instead, the corresponding products (31) are formed. While species of the type (30) rapidIy decomposed in aqueous pyridine to afford the parent nucleoside, those of type (31) were stable enough to be deacylated in a mixture of t-butylamine and methanol. However, they decomposed rapidly in acid. Such compounds could potentially be formed during the synthesis of oligonucleotides. The hydrolysis of a number of nucleotidyl-(5’+N)amino-acid esters (32) has been studied as a function of pH, to define the factors affecting the stability of the P-N bond.39 Hydrolysis occurs only in an acidic medium, probably via protonation of the nitrogen atom, with the inductive and steric effects of the side-chain influencing the rate of hydrolysis. Cyclic Nuc1eotides.-Some new 2-substituted analogues of 1,N6-ethenoadenosine 3’,5’-monophosphate have been reported.40 These were prepared either by treating 2-alkyl-, 2-alkylthio-, or 2-aryl-derivatives of cAMP with chloroacetaldehyde, or else via alkaline hydrolysis of 1,N6-etheno-CAMPto give (33), which was ring-closed with nitrous acid (to give 2-aza-1,W-etheno-CAMP) or with an aldehyde to give a 2-substituted product. All of the new analogues were active 35

J. P. Richard, M. C. Carr, D . H. Ives, and P. A. Frey, Biochem. Biophys. Res. Comnrun.,

36

J. B. Hobbs, in ‘Organophosphorus Chemistry’ (Specialist Periodical Reports), ed. D. W. Hutchinson and J. A. Miller, The Royal Society of Chemistry, 1981, Vol. 12, p. 177. M.-D. Tsai, Biochemistry, 1980, 19, 5310. H. P. Daskalov, M. Sekine, and T. Hata, Tetrahedron Lett., 1980, 21, 3899. B. Juodka and S. Sasnauskiene, J . Carbohydr., Nucleosides, Nucleotides, 1981, 8, 19. J. P. Miller, T. S. Yagura, R. B. Meyer, jun., R. K. Robins, and H. Uno, J. Carbohydr., Nucleosides, Nucleotides, 1980, 7, 167.

1980,94, 1052.

37 38 3g

40

Nucleotides and Nucleic Acids

183

in stimulating protein kinase I or I1 isozymes to some degree. A large number of analogues of CAMP^^-^^ and c G M P have ~ ~ been used to probe structural requirements at the CAMP-binding site on the regulatory subunit of protein kinases types I and 11419 42 and to probe the binding site of a cGMP-activated cyclic nucleotide phosph~diesterase.~~ The charge on the cyclophosphate ring is an essential requirement for activation of the protein kinases, and differences may be discerned between types I and I1 in their response to modification in this region.42 If the 2’-deoxythymidine 3’,5’-phosphoramidite (34) is treated with methanol, the corresponding methyl phosphite (35) is Treatment of (35) with dimethylchloroamine affords (36) in high yield, as stereoisomers that are separable by chromatography on silica gel. N.m.r. spectroscopy suggests that the transisomer of (36) has a chair conformation but that the cis-isomer may prefer a

x\ 0O

/R A

R

R1 0 R~OOCCHN-P-

I

II o

I I

H

y O

0-

bH

AcoY-Y

( 3 0 ) X = 0, R = 0 - a l k y l

~

6H

( 3 2 ) B = U r a , C y t , Ade, or Gua R L = P h C H 2 or o t h e r ( B = Ura) R“= H or E t

or 0 - a r y l

( 3 1 ) X = S , R = Bun o r Ph

( 3 4 ) R = M e 2 N , X is a b s e n t

( 3 5 ) R = M e O , X is a b s e n t

(33) 41 42

43

44

( 3 6 ) R = Me2N,

X = 0

( 3 7 ) R = Me, X

= 0

(38) R = MeO, X = S

T. S. Yagura, Z. Kazimierczuk, D. Shugar, and J. P. Miller, Biochem. Biophys. Res. Commun., 1980, 97, 737. T. S . Yagura and J. P. Miller, Biochemistry, 1981, 20, 879. C. Erneux, D. Couchie, J. E. Dumont, J. Baraniak, W. J. Stec, E. G. Abbad, G . Petridis, and B. Jastorff, Eur. J. Biuchem., 1981, 115, 503. A. E. Sopchik and W. G. Bentrude, Tetrahedron Lett., 1980,21,4679.

B

184

Organophosphorus Chemistry X

I

*‘\’

H

0

Y

(39) (40)

2

N

~

/ \ -

-

~OH -

o

y

o

~

H

”

Ade

x x

= =

OH

170 , Y =180 18

011

(42)

0 , Y =l70

(41) X = PhNH, Y = 160

tiiist conformation. Either the dimethylamino-group is highly destabilizing in the axial position of the chair form of cis-(36), or else the chair+twist conversion might also be significant in the binding of a cyclic nucleotide to its receptor. Treating (36) with methyl iodide affords the methylphosphonate (37) as a pair of diastereoisomers, separable on silica gel, whose absolute stereochemistry could be assigned by comparison of their 13Cspectra with those of model methylphosphonates of known config~ration.~~ It was noted that the axial methyl group on phosphorusin the (Rp)-isomer of (37) shifts the C-3’and C-5’ resonances downfield, a result also found in thymidine cyclic methyl phosphates; this establishes a new n.m.r. criterion for assigning absolute configuration in these compounds. Irradiating (36) with di-t-butyl disulphide in benzene-acetone solution affords the cyclic phosphorothioate methyl ester (38) in good yield, as separable diastereoisomers which are quantitatively and stereospecifically demethylated on refluxing in t-butylamine to afford the crystalline cyclic phosp h o r ~ t h i o a t e s .Configurational ~~ assignments were made, using 31Pn.m.r. data. The free-radical sulphurization was found to be cleaner and superior to that using elemental sulphur. Oxygen-17 n.m.r. spectroscopy has been used to demonstrate the configurational differences in the diastereoisomers of cyclic 2’-deoxyadenosine 3’,5’-[170,180]monophosphate.47 The 170-enriched P-anilidate of cdAMP was prepared, using the method detailed last year36 but employing [170]POC1 to prepare the 2-chlorophenyl N-phenyl[170]phosphoramidic chloride that was used. The separated P-anilidates were then treated with sodium hydride and P O , to afford (39) and (40). The lJ(170-P) coupling is larger for (39) than for (40),and in the oxygen-decoupled 31Pn.m.r. spectra the phosphorus signal for (39) is more shielded than that for (40). Compound (39) was hydrolysed by beef heart CAMP phosphodiesterase, and the resulting 5’-[160,170,180]dAMPwas converted into the triphosphate enzymically.The dATP that was obtained was cyclized, using adenylate cyclase (a reaction known to proceed with inversion), and the resultant cdAMP was methylated with diazomethane and examined using 31P n.m.r. Since line-broadening by 1 7 0 results in the resonance of phosphorus atoms linked to 1 7 0 becoming undetectable, the only signals that are visible in the spectrum are those resulting from the elimination of [170]pyrophosphate by the cyclase. Consequently, if l80is found in the 45

G. S. Bajwa and W. G . Bentrude, Tetrahedron Lett., 1980, 21, 4683. E. Sopchik and W. G . Bentrude, Tetrahedron Lett., 1981, 22, 307. J. A. Coderre, S. Mehdi, P. C. Demou. R. Weber, D. D. Traficante, and 3. A. Gerlt, J . Am. Chem. SOC.,1981, 103, 1870.

413 A. 47

Nucleotides and Nucleic Acids

185

axial position of the product, the initial enzymic hydrolysis had proceeded with inversion - as was found to be the case.32This result has already been mentioned, above. The crystallographic analysis of 2’-deoxyadenosine 3’,5’-(R~)-phosphoranilidate (41) confirms the configurational assignment previously made, using 31P n.m.r. data, and supports the empirical rule that, in chair-shaped 1,3,2dioxaphosphorinans, the I lJ(P-X) I for an axial substituent X of nuclear spin 3 is greater than I lJ(P-X) I for the equatorial isomer.48 Hydrolysis of cGMP by phosphodiesterase in [180]waterresulted in the GMP that was recovered containing a single atom of l80, showing that the catalysed hydrolysis proceeds via nucleophilic attack of water at phosphorus, with P-0 bond cleavage, and that enzyme-catalysed phosphate-water exchange does not occur.4g The [180]GMP that was obtained was converted into GTP, using guanylate kinase and pyruvate kinase, and then either re-converted into GMP, using phosphohydrolase, or converted into cGMP, with guanylate cycla~e.~O No loss of isotope occurred in the phosphohydrolase reaction, but 33% of the lSO was lost during the cyclization, showing that the three terminal oxygens of GMP are torsionally equivalent, and that the bridging Pa-O-Pa oxygen is lost on cyclization. Arrhenius and van’t Hoff plots of the hydrolysis of cytidine 2’,3’-phosphate by pancreatic ribonuclease A show a dramatic change in gradient and in the values forAH* and AS* at 4 0C.51A transition in the structure of water at this temperature, resulting in an alteration in the transition state for the reaction or possibly in the conformation of the protein, has been suggested as the reason. Affinity Chromatography.-A number of different methods have been devised for immobilizing inosine nucleotides. IMP and IMPCS], the latter prepared by treating 2’,3’-O-ethoxymethylideneinosinewith thiophosphoryl chloride and subsequent deblocking, were converted into the 2’,3’-cyclic ketals of laevulinic acid by condensation with ethyl laevulinate in the presence of ethyl orthoformate and acid and subsequent d e b l ~ c k i n g .Dichlorothiophosphoric ~~ acid 4-nitrophenyl ester was treated with imidazole and then 2’,3’-O-isopropylideneinosine,to afford, after deblocking and catalytic reduction, inosine 5’-phosphorothioate 4-aminophenyl ester (42). The laevulinate derivatives and the 2’(3’)-phosphate and -phosphorothioate derived from (13)13 were coupled to 6-aminohexylSepharose 4B by using ethyl chloroformate to generate a mixed anhydride,53 while (42) and the 2’(3’)-phosphorothioate derived from (14) l3 were coupled to CNBr-Sepharose 4B.53The resulting affinity columns bound guanyloribonuclease from Streptomyces aureofaciens, those derived from the 2’(3’)-phosphorothioates showing the highest biospecific affinity, allowing a good purification factor. 8-(6-Aminohexyl)inosine 5’-monophosphate was prepared by treating 8-bromo5’-IMP with 1,6-diaminohexane, and was coupled to CNBr-Sepharose 4B.54So, 4*

Z. J. Lesnikowski, W. J. Stec, W. S. Zielinski, D. Adamiak, and W. Saenger, J. Am. Chem.

49

N. D. Goldberg, T. F. Walseth, J. H. Stephenson, T. P. Krick, and G. Graff, J . Biol. Chem.,

50

T. F. Walseth, G . Graff, T. P. Krick, gnd N. D. Goldberg, J . B i d . Chem., 1981, 256, 2176. J. A. Biosca and C. M. Cuchillo, Biochem. J., 1980, 189, 655. P. Kois and A. Holy, Collect. Czech. Chem. Commun., 1980, 45, 2830. P. Kois, I. Rosenberg, and A. Holy, Collect. Czech. Chem. Commun., 1980, 45, 2839. Y.D. Clonis and C. R. Lowe, Eur. J. Biochem., 1980,110,279.

SOC,.1981, 103, 2862. 1980,255, 10 344. 51 52 53 54

186

Organophosphorus Chemistry

too, was the IMP laevulinate ketal described above, via the interposition of a 1,6-diaminohexane spacer. Both columns specifically bound IMP dehydrogenase from Escherichia coli, though the IMP analogues were inactive as substrates for the enzyme. Elution with IMP, XMP, or GMP allowed useful purification of the enzyme. An affinity chromatography system of columns of agarose and of phosphocellulose bearing 5-(2-[N-(2-aminoethyl)carbamyl]ethyl}-6-azauridine 5’-mOnOphosphate as an affinity ligand, linked in tandem by a flow dialysis system, has been used to purify UMP synthase to h ~ m o g e n e i t y 8-(6-Aminohexyl)amino.~~ 2’-AMP, prepared from 8-bromo-2’-AMP and 1,6-diaminohexane, has been immobilized on CNBr-Sepharose 4B and used to purify bovine brain 2’,3’-cyclic nucleotide 3’-pho~phodiesterase.~~ ATP has been oxidized with periodate and the resultant dialdehyde then condensed with adipic dihydrazide, coupled to CNBrSepharose, and used to investigate the binding characteristics of rat liver glucocorticoid-receptor complexes.57GDP, when oxidized with periodate and coupled to Sepharose via adipic dihydrazide, affords an effective affinity column for rat liver succinyl-CoA synthetase,; the GDP dialdehyde, in the presence of magnesium ions, was an affinity label for the enzyme.58Adenosine 2’,5’-diphosphateSepharose binds interferon-induced 2’-5’-oligoadenylate synthetase, allowing a useful assay system for this enzyme to be devised.59 The use of tosyl chloride as an activating agent for agarose has been described.60 Sepharose CL6B in dry dioxan is treated with tosyl chloride and pyridine at room temperature and the gel is then washed and transferred to aqueous medium, being stored at 4 “C. Ligands such as N6-(6-aminohexyl)-5’-AMPmay then be coupled via their terminal primary amino-groups, in bicarbonate buffer at pH 10.7, at 40 “C. Such columns exhibit good biospecificity. The covalent links that are formed are very stable, and the immobilization process does not introduce extra charged groups on the support, in contrast to the cyanogen bromide technique. If Whatman 540 paper, washed in 3M-NaOH and air-dried, is stirred with cyanuric chloride in dioxan-xylene, it becomes activated and may be used to immobilize single-stranded DNA on paper, if shaken with the nucleic acid at pH 5-6.61 The quantity of DNA that is bound and the stability of binding are critically pH-dependent, but the cyanuric-chloride-activated paper, stored dry in uacuo, retains its binding capacity for an extended period, and the method is claimed to be superior to that using diazobenzyloxymethylated paper. Doublestranded DNA may be immobilized for affinity chromatography and drugbinding studies by treatment with the nitrogen mustard 4-bis-(2-chloroethyl)amino-L-phenylalanine in DMSO ; this cross-links the strands, leaving a primary amino-group available for reaction, which couples to the acid azide 55

R. W. McClard, M. J. Black, L. R. Livingstone, and M. E. Jones, Biochemistry, 1980, 19, 4699.

56

57 58

59 60

61

Y.Nishizawa, T. Kurihara, and Y . Takahashi, Biochem. J., 1980, 191, 71. V. K. Moudgil and J. K. John, Biochem. J., 1980, 190, 809. D. J. Ball and J. S. Nishimura, J. Biol. Chem., 1980, 255, 10 805. M. I. Johnston, R. M. Friedman, and P. F. Torrence, Biochemistry., 1980, 19, 5580. K. Nilsson and K. Mosbach, Eur. J. Biochem., 1980, 112, 397. H.-D. Hunger, H. Grutzmann, and C. Coutelle, Biochim. Biophys. Acta, 1981, 653, 344.

Nucleotides and Nucleic Acids

187

groups resulting from treatment of Enzacryl with nitrous acid.62Washing with Tris buffer inactivates any remaining acid azide groups, leaving DNA irreversibly coupled by both strands via a small number of linkages. Some 64% of the immobilized DNA was available for intercalation by ethidium bromide. rRNA-cellulose, prepared by irradiation of a slurry of cellulose and ribosomal RNA in ethanol, has been used to isolate the eukaryotic initiation factor eIF-2 from rat liver m i c r o ~ o m e sand , ~ ~ poly(U), when bound to CNBr-Sepharose, has been used to characterize polyadenylated RNA population^.^^ If mono- and poly-nucleotides are exposed to the water-soluble compound l-ethyl-3-[3-(dimethylamino)propyl]carbodi-imideand a high concentration of sorbitol, any monosubstituted phosphate groups that are present become esterified, and the resulting nucleotidic material is strongly retained at pH 8.7 on chromatographic supports that contain dihydroxyboryl groups (which were prepared by coupling 3-aminophenyl boronic acid to aminoethylcellulose or to aminoethylpolyacrylamide via a succinate spacer).65 Thus polynucleotide fragments may be isolated by grafting a cis-diol group on to species which lack them. The method may be used for 5'-terminal phosphates on DNA and on RNA and for 3'-terminal phosphate on DNA; a 3'-terminal phosphate on RNA would become cyclized by the carbodi-imide. The bound material is released by buffers at pH 5.5. A comparative study of the fractionation of RNA and oligoribonucleotides on boronate-agarose, boronate-cellulose, and boronate-polyacrylamide columns has been made.66 3 Nucleoside Polyphosphates Chemical Synthesis.-A review has appeared that deals with the non-enzymic hydrolysis of ATP, with enzyme-mediated nucleophilic attack at phosphorus, and with the effect of metal ions, particularly magnesium, on these p r o c e s s e ~ . ~ ~ The rates of hydrolysis of magnesium and calcium salts in water and in aqueous acetonitrile at 70 "Chave been studied over the pH range 0-10, as also have the products formed from tris- and tetrakis-(tetra-n-butylammonium) ATP in mixtures of t-butyl alcohol and acetonitrile.6s In the latter series of experiments, the formation of t-butyl phosphate was taken as indicative of the formation of a metaphosphate intermediate. The results suggest that displacement of Pr in ATP4- and ATP3- occurs via metaphosphate, and in ATP- and ATP acid via quinquecovalent oxyphosphorane intermediates, while ATP2- may involve either mode of breakdown. In water, in the absence of Mg2+, ATP3- generates metaphosphate much faster than ATP4-, but Mg2+and Ca2+dramatically increase its rate of formation from ATP*-, while the rate of formation from ATP3- is barely affected. ATP4- is thought to become complexed by Mg2+at Pa and at Pa to elicit this result (Scheme 1). e2 63 64

65 66

67 68

A. J. MacDougall, J. R. Brown, and T. W. Plumbridge, Biochem. J., 1980, 191, 855. 0. Nygird, P. Westermann, and T. Hultin, Biochim. Biophys. Acta, 1980, 608, 196. J. W. Bynum and E. Volkin, Anal. Biochem., 1980, 107, 406. N. W. Y . Ho, R. E. Duncan, and P. T. Gilham, Biochemistry, 1981, 20, 64. B. Pace and N. R. Pace, Anal. Biochem., 1980, 107, 128. F. Ramirez and J. F. Marecek, Pure Appl. Chem., 1980, 52, 2213. F. Ramirez, J. F. Marecek, and J. Szamosi, J. Org. Chem., 1980, 45, 4748.

188

Orgariophosphorus Chemistry 0

0

II

0

0

II

II

0

II

0

II

I1

t

P-0-

Scheme 1

A number of studies have appeared which have used exchange of oxygen isotopes in nucleotide phosphate groups to throw light on enzymic mechanisms. During the hydrolysis of MgATP by myosin or its subfragments, exchange of oxygen occurs between water and the terminal phosphate of the enzyme-bound nucleotide, and this may be monitored by incubating unlabelled ATP in [180]H20,69or [y-180]ATPin H2160,6g9 7 0 in the presence of the enzyme and analysing the isotopic composition of the phosphate that is released by its methylation to trimethyl phosphate with diazomethane and then mass-spectrometric a n a l y s i ~ . ~ ~ * ~ ~ Results obtained using actin-heavy meromyosin (HMM) suggest that the enzyme contains two different types of active site on myosin; each exhibits a different exchange rate, which varies with the concentration of actin. An ingenious method for determining positional exchange of isotopes in nucleoside triphosphates has been devised, in order to evaluate transient cleavage of ATP + ADP that occurs at active sites of [By-180, yJ803]ATP (43) 0

0

0

0

li II (A~o-~')-O-P-O-P-O-P-OI I II

b-

0-

II

A-

I

0-

0 0 -P-

0

I

I

S 0

0

0

(46)

S

I

I

b"

(Ad0-5')-0-P.

I \;o-~--o-P-o

0

I I 0

(48) 0 = 18o , a D = 17o

71

0

0

(47)

70

0-

I 0/7\@

S

69

I-

0

S

I

(45)

(Ado-5')-O-P.

II I

(44)

0

') -0-P-I

0

I1

(A~o-~')-O-P-O-P-O-P-OO-

(43)

( Ado-5

0

, o =160

K. K. Shukla, H. M. Levy, F. Ramirez, J. F. Marecek, S. Meyerson, and E. S. Kuhn, J. B i d . Chem., 1980, 255, 1I 344. C. F. Midelfort, Proc. Nutl. Acud. Sci. USA, 1981, 78, 2067. M. R. Webb, Biochemistry, 1980, 19, 4744.

Nucleotides and Nucleic Acids

189

is prepared by activating ADP with carbonylbisimidazole, followed by treatment with [180,]orthophosphate and [aB-180, B-lsOz]ATP (44) by activating AMP with the same reagent, its condensation with [legJor t hophosphate, re-activation of the resulting [aB-l80, P-1803]ADP,and condensation with [160,]orthophosphate. These compounds (43)and (44) are incubated with enzyme and the ATP fraction is then recovered, treated with DCC to form adenosine 5'-trimetaphosphate, and ring-opened with water to afford ATP in which the original B- and a-phosphate groups have been randomized. The new y-phosphate is hydrolysed to orthophosphate, using glycerokinase and D-glyceraldehyde, and the orthophosphate is then methylated and analysed as above. Half of the orthophosphate that is released is derived from the y-phosphate of the original ATP molecule and the other half from the B-phosphate. This latter contains the B-non-bridging oxygens of the original molecule, but not the By-bridging oxygen. Thus, isotopic scrambling between the &bridging oxygen and the B-non-bridging oxygens in (43)and (44) is readily determined. Applying the technique to (43)and (44) without exposure to the enzyme established the necessary premise that random hydrolysis at B- and y-phosphates, and thus non-discriminatory interchange, should occur. Then, using (44) allows bridge-non-bridge scrambling on an enzyme that is performing transient ATP -+ ADP cleavage to be assessed; using (45)allows exchange of oxygen isotope between y-phosphate and water to be monitored, in addition to bridge-non-bridge scrambling. The method has been used to investigate the mechanism of cleavage of ATP by myosin, where exchange of oxygen isotopes between the y-phosphate and water was found to proceed much faster than bridge-non-bridge ~crambling.'~ Phosphorus-31 n.m.r. may also be used to monitor positional exchange reactions of isotopes, as in the study of the exchange of By-bridging and B-nonbridging oxygen atoms in [y-ls0]ATP that is catalysed by carbamoyl phosphate synthetase from Escherichia C O Z ~ . In ~ ~ the presence of ADP, the same enzyme catalyses the exchange of bridging and non-bridging oxygen atoms in [180]carbamoyl phosphate in the partial back-reaction, the exchange rate being four times faster than the net synthesis of ATP. Exchange of &-bridging and B-nonbridging oxygen atoms in [B-1802]ATPis catalysed by carbamoyl phosphate synthetase from rat liver in the presence of bicarbonate and acetylglutamate, but the addition of ammonia halts the exchange.74Using HC1803-as a substrate, in the absence of ammonia, the orthophosphate that is released from ATP by the ATPase activity of the enzyme was found to contain one l80atom, but l a 0 was not incorporated into ATP, and neither were added [14C]ADPnor [32P]~rthophosphate. The y-phosphate group of one enzyme-bound ATP molecule is thought to be transferred to bicarbonate, affording ADP (in which the Bphosphate can rotate) and carboxyphosphate. In the absence of ammonia, the reaction may reverse, regenerating ATP, or carboxyphosphate may be cleaved to bicarbonate and orthophosphate. Addition of ammonia renders the reaction irreversible. 72

M. A. Geeves, M. R. Webb, C. F. Midelfort, and D. R. Trentham, Biochemistry, 1980, 19, 4748.

73

74

F. M. Raushel and J. J. Villafranca, Biochemistry, 1980, 19, 3170. V. Rubio, H. G. Britton, S. Grisolia, B. S. Sproat, and G. Lowe, Biochemistry, 1981, 20, 1969.

190

Organophosphorus Chemistry

The stereochemical course of transfer of phosphoryl groups during the ~ ~sample of reaction catalysed by myosin ATPase has been e l u ~ i d a t e d .A [By-l8O, y-1801]ATP[yS](45) of known chirality (3P-R) was hydrolysed by myosin subfragment 1 (SF 1) in [170]H20and the chiral thiophosphate that was released was isolated and its stereochemistry elucidated as described previo~sly.~~9 37 The thiophosphate that was formed possessed (RP) chirality (46), showing that hydrolysis had proceeded with inversion. The same substrate and method have also been used to determine the stereochemical course of phosphoryl transfer when catalysed by beef heart mitochondria1 A T p a ~ e Again, . ~ ~ (46) was formed, indicating hydrolysis with inversion of configuration, most probably by direct in-line transfer of thiophosphate from (45) to water. In a similar investigation, (Rp)-adenosine 5’-[a-1eO]phosphorothioate(47) and its (Sp)-diastereoisomer were prepared, using chemical methods to generate a racemic mixture of [a-’80]ADP[aS] isomers, which were then separated and configurationally assigned by making use of the fact that only the (SP)-[~-~~O]ADP[~S] is a substrate for pyruvate k i n a ~ e Treatment .~~ of the separated products afforded (47) and its diastereoisomer, which were hydrolysed in [170]H20,using 5’-nucleotidase; the chiralities of the resulting thiophosphate were determined as before.37 Again, inversion at phosphorus had occurred. The influences of 170atoms in broadening 31Pn.m.r. signals of bonded phosphorus atoms, and the inverse influence of 31Pnuclei on the 1 7 0 n.m.r. spectrum, have been investigated for a number of nucleotides, including [a-1702]AMP[S], [a-170,a/?-170]ATP[aS],[y-1703]ATP,[aB, /?y-1702,B-1702]ATP,Mg[y-1703]ATP, and Mg[a/?,/?y-1702, B-1702]ATP.The line-broadening effect of 170on the 31P signals of all directly bonded 31Pnuclei was found in all these compounds. On complexing to Mg2+, however, the signals of 31Pnuclei that are bonded to 170 are observed to sharpen, providing a possible method for studying interactions between diamagnetic metal ions and n u c l e ~ t i d e s . ~ ~ The stereochemistry of nucleotidyl-transfer reactions, catalysed by DNA polymerase I from Escherichia coli, has been determined unambiguously as follows:79[a-l8O2]dAMP[S]was prepared and used as a substrate for adenylate kinase and ATP (which phosphorylates specifically the p r o 4 oxygen atom) and pyruvate kinase and PEP to afford (S~)-[cc-l~0,]dATP[aS](48), which was used as a substrate with dTTP and poly[d(A-T)] primer for DNA polymerase I. The resultant polymer could be cleaved by the nuclease activity of the same enzyme, affording pdTp(S)dA, and on successive treatments with hydrazine and alkali the thymine ring was degraded and the 5’-sugar phosphate residue eliminated, leaving a single isomer of [a-laO]dAMPIS]. If this was converted into [a-lsO]dATP[aS] enzymically, as above, and used as substrate for DNA polymerase I as above, all the l80isotope was lost in the pyrophosphate that was eliminated on polymerization. Hence the [a-180]dAMP[S] was the (Rp)-isomer (47), and polymerization of (48) had proceeded with inversion. The exchange 75 76

M. R. Webb and D. R. Trentham, J. Biol. Chem., 1980,255, 8629. M. R. Webb, C. Grubmeyer, H. S. Penefsky, and D. R. Trentham, J. Biol. Chem., 1980, 255, 11 637.

77

78 79

M.-D. Tsai and T.-T. Chang, J. Am. Chem. Soc., 1980, 102, 5416. M.-D. Tsai, S. L. Huang, J. F. Kozlowski, and C. C. Chang, Biochemistry, 1980,19, 3531. R. S. Brody and P. A. Frey, Biochemistry, 1981, 20, 1245.

191

Nucleotides and Nucleic Acids

reaction that is catalysed by primer-independent polynucleotide phosphorylase from Micrococcus luteus has been investigated by incubating (SP)-ADP[aS] with [32P]orthophosphate and the enzyme.8oWhen the label was found to have been exchanged into ADP[aS], the ADP[aS] fraction was isolated; on incubation with pyruvate kinase and phosphoenolpyruvate, it was all converted into ATP[orS]. Since this enzyme is specific for (SppADP[aS], the radioactive material that was formed also had (Sp) configuration, and exchange had occurred with retention of configuration, possibly via a dual-inversion process involving an oligonucleotidic intermediate. If IMP[S] was treated with diphenyl phosphorochloridate and 5’-AMP, the unsymmetrical (Sp)-thiopyrophosphate (49) and its (Rp)-diastereoisomer were obtained, and they were separable on DEAE-cellulose.sl Treatment of (49) with one equivalent of periodate, followed by alkali, resulted in degradation, with IDP[aS] and ADP[BS] being formed; the IDP[aS] was a substrate for pyruvate kinase and PEP, establishing its absolute configuration as (SP) and thus also that of (49). When (49) and its diastereoisomer were incubated separately with ApApA and T4 RNA ligase at pH 8.3, only (49) afforded ApApAp(S)I as the product. This was cleaved at the thiophosphate link by snake venom phosphodiesterase at a similar rate to (Rp)-Ap(S)A, establishing that the stereochemistry at the thiophosphate link in ApApAp(S)I was (RP) and thus that the reaction that is catalysed by T4 RNA ligase had proceeded with inversion. If 2’,3’-CAMP was treated with thiophosphoryl chloride and subsequently hydrolysed in acid, S

(49)

X

(50) X = (51) X =

16

0, Y =

180

180 , Y = 160

a mixture of the 2’- and 3’-phosphates of 5’-AMP[S] was obtained. If the mixture was incubated with ATP and T4 RNA ligase, a single isomer of AS’pp(S)Ap was formed, which was easily shown to possess the same chirality as (49), demonstrating that the absolute stereochemistry at the reactive phosphoryl centre was the same in both the pyrophosphate-formation and the ligation steps that are catalysed by the enzyme. The stereoisomers of [a-lsO]dADP have been prepared from the (RP)- and the (Sp)-isomers, (50) and (5 l), of cyclic [180]dAMP by pyrophosphorolysis, using the ‘reverse’ adenylate cyclase reaction of Brevibacterium Ziquefaciens to generate (SP)- and (Rp)-[a-ls0]dATP, respectively, and using these as substrates for glycerol kinase to give the corresponding [CC-’~O]~ADP isomers.82The [180]cAMP isomers could be used similarly. Independent configurational assignment at the so 82

J. F. Marlier, F. R. Bryant, and S. J. Benkovic, Biochemisrry, 1981, 20, 2212. F. R. Bryant and S. J. Benkovic, J. Am. Chem. Soc., 1981, 103, 696. J. A. Coderre and J. A. Gerlt, J. Am. Chern. SOC.,1980, 102, 6594.

192

0rganophosphor us Chemistry

a-phosphorus atom was obtained by the reaction of each isomer of [a-ls0]dADP with [Co(NH3)J3+to form the a,@-bidentatecomplexes, which were separated on cross-linked cyclohepta-amylose columns to give the A- and A-isomers (Scheme 2). Isomer (52) gives (54) and (56); isomer (53) gives (55) and (57). If Y

0

1

I

p,

o./p\o/

I

0

4

O

l

I

0-(Ado-5’)

X

(NH3I4

A X

7

Y---P

/

I ‘O-(Ado-5/)

0-P-0

-

x (55) x

(54)

=l60,Y =l80 =

180, Y

=

160

=

180

+ 0,

I

0

18 (52) X =l60, Y = 0 18 16 (53) x = 0, Y = 0

I

X

(NH3I4

n ( 5 6 ) X =l6O, (57)

x

=

Y

180 , Y = 160

Scheme 2

the oxygen atom of a P-0 bond is complexed to cobalt, the P-0 bond order is reduced, and thus the shift in the phosphorus signal in the 31Pn.m.r. spectrum diminished. The values of the shifts in the ( 5 5 ) A/(57) A pair thus reveal that le0 is complexed to cobalt in ( 5 9 , and this suffices to define the stereochemistry in (53). Since (50) gave rise to (53) and (51) to (52), this independently establishes inversion of the stereochemistry at phosphorus by adenylate cyclase, in line with previous results using phosphorothioates. Diastereoisomers of ATP[aS] and ATP[PS] have been tested as substrates for creatine kinase in the presence of different bivalent metal ions.83In the presence of Mg2+, the (Rp)-diastereoisomers are preferred, and in the presence of Cd2+ the (Sp)-diastereoisomers. For the reverse reaction, the (Rp)-isomer of ADP[aS] is preferred with Mg2+,and only the (&)-isomer of ATP[BS] is formed from prochiral ADP[pS], while the results with Cd2+show that the (Sp)-isomers are favoured in each case. These results are consistent with the previous observation that Mg2+ co-ordinates preferentially to oxygen and Cd2+ to sulphur. The substrate is thought to bind to the enzyme as the A&-bidentate chelate and to form the A,a,@-bidentate metal-ADP complex as evectual product, though whether the shift in co-ordination occurs before or after the transfer of a phosphoryl group is not clear. Similar studies have been performed with yeast 83

P. M. J. Burgers and F. Eckstein, J. Biol. Chem., 1980, 255, 8229.

Nucleotides and Nucleic Acids

193

Phe-tRNAPhe synthetase from baker’s yeast,**and again the h-isomer of the &y-bidentate metal-ATP complex was thought to be the substrate. The enzyme catalyses the phenylalanine-dependent interchange of ATP[BS] and ATP[yS], and, on performing the interchange reaction in equimolar [l*C]ATPand ATP[BS], [14C]ATP[yS]was formed at 85% of the rate of synthesis of total ATP[yS], suggesting that much of the interchange occurs via the dissociation of thiopyrophosphate from the enzyme and then its re-binding in the correct orientation for the synthesis of ATP[yS]. This ‘direct interchange’ reaction and the ATPpyrophosphate exchange reaction that is catalysed by valyl- or methionyl-tRNA synthetase in the presence of the cognate and non-cognate amino-acids have been investigated, and total interchange in the presence of the cognate aminoacids was found to be predominantly exchange-mediated, while that in the presence of the non-cognate amino-acids arises mainly from ‘direct inter~hange’.~~ It has been suggested that the direct interchange reaction may be a contributory mechanism for preventing the mis-acylation of tRNA by non-cognate aminoacids by diverting the enzyme to a non-productive pathway. Nucleoside 5’-[y-thio]triphosphates have been used as substrates for eukaryotic RNA polymerases.ss Since very little transfer of thiophosphate to pre-initiated RNA occurs, the RNA segments that are formed with [y-thioltriphosphateat the 5’-end, being specifically retained on mercury-agarose columns, allow quantitative estimation of the initiation rate, and a comparison of the results obtained with ATP[yS] and GTP[yS] allows the 5’-terminal nucleotide for specific transcripts to be determined. ADP[BS] and ATP[yS] are potent inhibitors of the alkaline phosphatase activity of rat intestinal brush-border membrane vesicles.87 Adenosine 5’-[,9,y-imido]triphosphate, Ado(S’)PP[NH]P, is a weaker competitive inhibitor of this enzyme, but, upon oxidation by periodate, the analogue is thought to act as an affinity label. Adenosine 5’-[a,p-methylene]diphosphate is photophosphorylated to the corresponding triphosphate analogue by spinach chloroplasts, apparently by binding and being directly phosphorylated at the ADPbinding site.s8 Adenosine 5’-[B,y-methylene]triphosphateis able to replace ATP as an acceptable substrate for the synthesis of encephalomyocarditis-virusspecific double-stranded DNA, but not for the synthesis of single-stranded DNA. It is thought that synthesis of the single-stranded material requires extra energy, which may be provided via a separate ATPase function in the replication complex, and Ado(S’)PP[CH,]P is non-hydr~lysable.~~ Careful analysis of commercial preparations of Ado(S’)PP[NH]P by t.l.c., using a luciferin-luciferase assay to detect any ATP that is formed, showed that 5’-adenylyl phosphoramidate, Ado(S’)P[NH]PP, and ATP were all present, with the level of contamination by ATP ranging from 0.02% to 0.3% in fresh samples and rising to 10% on incubating Ado(S)PP[NH]P in aqueous solution for three weeks.90Hydrolysis of Ado(S’)PP[NH]P at the phosphoramidate link 84 85 86

87 89

B. A. Connolly, F. Von der Haar, and F. Eckstein, J . Biol. Chem., 1980, 255, 1 1 301. L. T. Smith and M. Cohn, Biochemistry, 1981, 20, 385. D. Bunick and R. Weinmann, Biochim. Biophys. Acra, 1980, 610, 331. S. P. Shirazi, R. B. Beechey, and P. J. Butterworth, Biochem. J., 1981,194, 797, 802. J. C. Jain and A. Horak, Biochem. Biophys. Res. Commun., 1980,97, 166. T. M. Dmitrieva, T. P. Eremeeva, G. I. Alatortseva, and V. I. Agol, FEBS Lett., 1980,115, 19. S. M. Penningroth, K. Olehnik, and A. Cheung, J . Biol. Chem., 1980, 255, 9545.

Organophosphorus Chemistry

194

to afford 5’-adenylyl phosphoramidate and orthophosphate, and subsequent attack by orthophosphate, giving ATP and ammonia, are thought to give rise to the ATP that is formed; Ado(S’)PP[NH]P samples should thus be monitored carefully before use, and phosphate buffers avoided if contamination by ATP is to be minimized. Similar results may be anticipated for Guo(S’)PP[NH]P, but were not observed for Ado(S’)PP[CH,]P. In the presence of glucose, hexokinase from yeast is specifically and strongly inhibited by ATP complexes of tervalent metals with ionic radius less than 0.89 A, which are not hydrolysed at neutral These include AIATP. While citrate has previously been considered an activator of hexokinase, investigations of its kinetics of ‘activation’ suggest that it reacts with the AlATP that is normally present as a contaminant in commercial ATP samples, forming aluminium citrate (which is very stable) and releasing ATP, and that the non-linear temporal course of the hexokinase reaction is due to the AlATP contaminant. Chromium(111) complexes of nucleoside 5’-triphosphates inactivate the (Na+ K+)-ATPase from beef brain and pig kidney.92 CrATP appears to act analogously to an affinity label, binding to the ATP-binding site of the enzyme, where it is cleaved, slowly forming a non-reactive phosphoprotein. The cobalt(rI1) and chromium(II1) complexes of Ado(S’)PP[CH,]P, which are substitution-inert complexes that are inactive in phosphoryl transfer, have been used for binding and structural studies of CAMP-dependent protein k i n a ~ e A . ~ manganese ~ ion binds to an inhibitory site on this enzyme, and measurements of nuclear and of electron spin relaxation rates have allowed the determination of certain interatomic distances, i.e. between the metal atoms, the nucleotide, and the hydroxyl group of serine which becomes phosphorylated. The distance between the y-phosphorus of ATP and the oxygen atom of the OH in serine is about 5.3 A, which is too great for molecular contact; it is thought that a dissociative mechanism, gener94 ating a metaphosphate intermediate, may A novel reagent has been devised for preparing the ‘cap’ structures that are frequently encountered in viral mRNA. 95 Treatment of methyl phosphorodichloridate with thiophenol and 7-methyl-GMP in pyridine leads to the formation of the unsymmetrical pyrophosphate (58) in good yield, in a single step. Presumably thiophenol demethylates the unsymmetrical pyrophosphate triester intermediate that is formed. If (58) is then treated with AMP (or GMP) and iodine or silver salts in pyridine, m7G5’pppAand m7G5’pppG are formed, in fair yield. Nucleoside [P-32P]triphosphates of extremely high specific activity may be obtained via the phosphorolysis reaction of poly- or oligo-ribonucleotides that is

+

0 HO -f‘ 1

-0 l ,

OH

OH

( 5 8 ) R = 7-methylguanosinyl-5‘ y1

92

93 94 95

0

\sua

OH (59)

R. E. Viola, J . F. Morrison, and W. W. Cleland, Biochemistry, 1980, 19, 3131. H. Pauls, B. Bredenbrocker, and W. Schoner, Eur. J . Biochem., 1980, 109, 523. J. Granot, A. S. Mildvan, H. N. Bramson, and E. T. Kaiser, Biochemistry, 1980,19,3537. J. Granot, A. S. Mildvan, and E. T. Kaiser, Arch. Biochem. Biophys., 1980, 205, 1. 1. Nakagawa, S. Konya, S. Ohtani, and T. Hata, Synrhesis, 1980, 556.

Nucleotides and Nucleic Acids

195

catalysed by polynucleotide phosphorylase from E. ~ o l i Excess . ~ ~ poly(A), poly(U), poly(C), or an oligoribonucleotide with a 3’-terminal guanosine residue is incubated with [32P]orthophosphate, polynucleotide phosphorylase, pyruvate kinase and phosphoenolpyruvate. The nucleoside 5’4 P-32P]diphosphatesthat are released on phosphorolysis are immediately converted into the corresponding triphosphates and separated chromatographically. When ava-CMP was converted into its 5’-phosphoromorpholidate and treated with prednisolone 21-monophosphate or cortisol 21-monophosphate, the corresponding ara-cytidine 5’-diphosphate-prednisolone and -cortisol compounds were formed; they exhibited useful activity against L1210 lymphoid {9-[2-(Phosphono-oxy)ethoxy]leukaemia in vitro and in viuo and low methy1)guanine [‘acycloguanosine monophosphate’ (59)] was phosphorylated slowly to the corresponding diphosphate by GMP kinase in erythrocytes and in Vero cells, the rate in the latter being independent of the presence of infecting herpes simplex virus (HSV), suggesting that no viral enzyme was involved.ga Wheat embryonic axes that had been fed with 6-azauridine have been found to phosphorylate the analogue to the triphosphate level and to incorporate 6-azaUMP into RNA.99 6-Aza-UMP is known to inhibit the biosynthesis of pyrimidines, but since 6-aza-UTP is also known to inhibit RNA polymerase in uitro, its formation in viuo suggests that inhibition of RNA synthesis in uivo may represent an alternative cytotoxic mechanism. Formycin (i.e. 8-aza-9-deaza-adenosine) 5’-triphosphate is a substrate for membrane-bound adenylate cyclase activity from rat osteosarcoma cells.1ooSince formycin is fluorescent, the cyclic nucleotide product may be separated by reversed-phase h.p.1.c. and quantitated by fluorimetry, affording a new, non-radioactive, direct method for assaying for adenylate cyclase. Incubation of 2’-fluoro-2’-deoxy-ADP or -CDP, or 2’-chloro-2’-deoxyUDP, with ribonucleoside diphosphate reductase from E. coli results in the release of halide, pyrophosphate, and base and the inactivation of the enzyme, with concomitant loss of titrable sulphydryl groups.1o1$lo2These results could conceivably follow if the 3’-OH function of the nucleotide is oxidized to a ketogroup, and experiments with 3’-tritiated UDP (prepared by reduction of 2’,5’di-O-trityl-3’-ketouridine with borotriti-ide and subsequent phosphorylation) afford evidence that the 3’-C-H bond is indeed broken in the reaction, with a small quantity of 3 H 2 0being formed.lo2A mechanism to explain these findings, involving a radical cation intermediate, has been tentatively suggested. (E)-5(2-Bromovinyl)-2’-deoxyuridine5’-triphosphate (60), prepared from the parent nucleoside by standard methods, is found to be much more inhibitory to the utilization of dTTP by HSV-1 DNA polymerase than by other viral and cellular DNA polymerases, by competing strongly with the natural substrate.lo3 Com96 97 OR 99

100

G. Kaufmann, M. Choder, and Y. Groner, Anal. Biochem., 1980, 109, 198. C. I. Hong, A. Nechaev, and C. R. West, Biochem. Biophys. Res. Commun.,1980,94,1169. W. H. Miller and R. L. Miller, J. Bioi. Chem., 1980, 255, 7204. S. Rodaway and A. Marcus, J. Biol. Chem., 1980, 255, 8402. E. F. Rossomando, J. H. Jahngen, and J. F. Eccleston, Proc. Nut/. Acnd. Sci. USA, 1981, 78, 2278.

101 102

103

J. Stubbe and J. W. Kozarich, J. Biol. Chem., 1980, 255, 5511. J. Stubbe and D. Ackles, J. B i d . Chem., 1980, 255, 8027. H. S . Allaudeen, J. W. Kozarich, J. R. Bertino, and E. De Clercq, Proc. Nutl. Acad. Sci.

USA, 1981,78,2698.

196

Organophosphorus Chemistry 0

H40gP30

v -

r

S-

H40gP

3 0 1 d OH

OH

L

H03S

(63)

pound (60) is inhibitory even after the initiation of synthesis of DNA, and its strong selective inhibition of DNA polymerase of HSV-1 may account for its inhibition of replication of HSV-1 in infected cells. The disulphide of 6-thioinosine 5’-triphosphate (61) and its non-hydrolysable By-methylenediphosphonateand By-imidodiphosphate analogues, all prepared by oxidation of the corresponding conventionally prepared monomers with iodine, act as affinity labels at the ATP-binding sites of Ca2+-ATPaseof sarcoplasmic reticulum, apparently forming The kinetics of inactivamixed disulphides with thiol groups at the active tion (which was reversible by incubation with dithiothreitol) showed that two nucleotide-binding sites, with different rates of inactivation, were present. The fluorescent compound 2’,3’-0-(2,4,6-trinitrocyclohexadienylidene)-ATP (62) competes with ATP to bind specifically to the ATP-binding site of eel electroplax (Na+,K+)ATPase with characteristics (in the absence of other ligands) that lo4

R. Patzelt-Wenczler, H. Kreickmann, and W. Schoner, Eur. J. Biochem., 1980, 109, 167.

Nucleotides and Nucleic Acids

197

indicate a single homogeneous high-affinity binding site.lo5 Compound (62) is prepared by treating ATP, at pH 9.5, with excess 2,4,6-trinitrobenzenesulphonic acid; it and similar analogues are potent inhibitors of (Na+,K+)ATPase. The conformational and stacking properties of fluorescent nucleotide analogues that contain 1 -aminonaphthalene-5-sulphonatebound to the polyphosphate chain by a y-phosphoamidate bond have been investigatedlo6and the ability of the corresponding GTP analogue (63) to bind to the exchangeable nucleotidebinding site of tubulin, and of (63) and other analogues of GTP to promote the assembly of tubulin, have been studied.lo7Generally, analogues with a substituent attached to the y-phosphate group failed to promote assembly. Studies involving the binding of large numbers of nucleotide analogues to enzymes, with a view to establishing structural and conformational requirements for binding of a substrate to the active site, inter alia, have been described for yeast hexokinase,los RNA polymerase from E. c ~ l i , ~CF1 O ~ ATPase from chloroplasts,110 and the nucleotide-transport system of mitochondria.lll Diadenosine 5’,5””-P1,P4-tetraphosphatehas been found to inhibit terminal deoxynucleotidyl transferase from calf thymus strongly and specifically, by competing with dNTP substrates, although it is without noteworthy effect on DNA polymerases a,p, and y from mouse.l12It also inhibits the ADP-ribosylation of histone by bovine thymus poly(ADP-ribose) p01ymerase.l~~ When certain strains of bacteria are starved of amino-acids they exhibit a ‘stringent response’ and the accumulation of guanosine 3’,5’-bis(pyrophosphate), ppGpp, which was thought to be an effector molecule with a causal role in eliciting the stringent response and suppressing the synthesis of RNA. Evidence (using mutants) has now been presented for the occurrence of the stringent response without the accumulation of ppGpp,ll48115 and although one report suggests that ppGpp slows transcriptional elongation by binding to RNA polymerase and causing it to slow when transcribing certain DNA sequences,116 the need for a re-examination of its significance is indicated. Affinity Labelling.-The technique of photoaffinity labelling has again been widely used. Myosins from several sources were labelled specifically by U.V. irradiation at 0 “C in the presence of ADP, ATP, or UTP.l17 While non-specific labelling might be expected by this method, good evidence was obtained for specific labelling at the catalytic site, and, indeed, at a single peptide of the lo5 E.

G. Moczydlowski and P. A. G. Fortes, J. Biol. Chem., 1981, 256, 2346, 2357. L. R. Yarbrough, and J. L. Bock, J . Biol. Chem., 1980,255, 9907. lo7 M. Kirsch and L. R. Yarbrough, J. Biol. Chem., 1981,256, 106; L. R. Yarbrough and M. Kirsch, ibid., p. 112. lo* L. J. Dorgan and S. M. Schuster, Arch. Biochem. Biophys., 1981, 207, 165. logW. J. Smagowicz and K. H. Scheit, Nucleic Acids Res., 1981, 9, 2397. U. Franek and H. Strotmann, FEBS Lett., 1981, 126, 5. ll1 E. Schlimme, K . 4 . Boos, and E. J. de Groot, Biochemistry, 1980, 19, 5569. 112 K. Ono, Y. Iwata, H. Nakamura, and A. Matsukage, Biochem. Biophys Res. Commun., lo6

1980,95, 34.

Y.Tanaka, N . Matsunami, and K. Yoshihara, Biochem. Biophys. Res. Commun.,

1981, 99, 837. 114 A. Spadaro, A. Spena, V. Santonastaso, and P. Donini, Nature (London), 1981, 291, 256. C. C. Pao and B. T. Dyess, J. Biol. Chem., 1981, 256, 2252. 116 R. E. Kingston, W. C. Nierman, and M. J. Chamberlin, J . Biol. Chem., 1981, 256, 2787. 117 H. Maruta and E. D. Korn, J. Biol. Chem., 1981,256, 499. 113

198

Organophosphorus Chemistry

myosin heavy chain. 8-Azido-CAMP has been used to label cell-surface CAMP receptors in DictyosteZiurn discoideurn,l18CAMP-receptor proteins in rat ovarian follicles,11g and a CAMP-binding site on the regulatory subunit of CAMPdependent protein kinase I1 from pig heart (where a tyrosine residue was shown to have become labelled.)lZO Some novel photo-activable nucleotides have been prepared. Treatment of AMP or ADP, activated by mesitoylation of the terminal phosphate, with 4-azidobenzylamine or lithium azide afforded the corresponding phosphoro(4-azidobenzy1)amidates (64) and the phosphorazidates (65), respectively.121The previously described compound 3’-0-{3-[N-(4-azido-2-nitrophenyl)amino]propiony1)-ATP (66) has been converted into its CrIII salt by heating with hydrated chromium chloride, at 75 “C and at pH 3; the salt proved to be a non-hydrolysed, competitive inhibitor of (Na+,K+)ATPaseunder normal assay conditions and an effective affinity label on irradiation.lZ2The 8-azido-derivative of (66) has been prepared as a cross-linking photoaffinity label by coupling N-(4-azido-2-nitropheny1)-galanine to 8-azido-ATP, using carbonylbisimidazole; when it was used for the photoaffinity labelling of F2 ATPase from Micrococcus Zuteus, analysis of the labelled proteins suggested that cross-linking of the o(- and /?-subunits of the enzyme had indeed The butyryl analogue (67) of (66), and the analogous 5’-diphosphate, have been used for the photoaffinity labelling of coupling factor 1 (CF-1) from E. coli and its isolated subunits, as also have 3’-0-[4-azidobenzoyl]-ADP and -ATP.lZ4(E)-5-(3-azidostyryl)-2’-dUMP (68) is a photoaffinity labelling reagent for thymidylate synthetase from Lactobacillus casei and a light-dependent inhibitor of L1210 murine leukaemia and human tumour cell growth in uitro and of replication of vaccinia virus.125 An elegant method for preparing nucleotide photoaffinity probes of DNAdependent RNA polymerase has been described.lZ6If RNA polymerase was incubated with AMP, UTP, and poly[d(A-T)] template, pApU was formed via the ‘abortive initiation reaction’ in good yield. This was isolated and treated with 4-azidophenyl phosphorimidazolidate to give p-(4-azidophenyl)adenyly1(3’-5’)uridine 5’-diphosphate (69), which was a far more efficient initiator of the synthesis of RNA than the ADP analogue (70) that was prepared similarly. Moreover, incubating (70) with the polymerase, poly[d(A-T)], and [E-~~P]UTP allowed the synthesis of labelled (69); incubating (69) with enzyme, template, and [ R - ~ ~ P I A T allowed P the synthesis of labelled (71), and so on, allowing oligonucleotides that bear a 5’-photoaffinity label to be prepared to the length desired. The alteration in the labelling pattern of the subunits of RNA polymerase M. H. Juliani and C. Klein, J. Biol. Chem., 1981, 256, 613. J. S. Richards and A. I. Rolfes, J . Biol. Chem., 1980, 255, 5481. 120 A. R. Kerlavage and S. S. Taylor, J . Biol. Chem., 1980, 255, 8483. 121 L. V. Vinogradova, S. S. Tretyakova, N. I. Sokolova, and Z. A. Shabarova, Vestn. Mosk. Univ., Khim., 1980, 21, 179 (Chem. Abstr., 1980, 93, 132 731). 122 K. B. Munson, J. Biol. Chem., 1981, 256, 3223. 123 H.-J. Schaefer, P. Scheurich, G. Rathgeber, K. Dose, A. Mayer, and M. Klingenberg, Biochem. Biophys Res. Commun., 1980, 95, 562. 124 J. Lunardi, M. Satre, and P. V. Vignais, Biochemistry, 1981, 20, 473. 125 E. De Clercq, J. Balzarini, C. T.-C. Chang, C. F. Bigge, P. Kalaritis, and M. P. Mertes, Biochem. Biophys. Res. Commun., 1980, 97, 1068. 126 L. H. De Riemer and C. F. Meares, Biochemistry, 1981, 20, 1606, 1612.

11* 119

199

Nucleotides and Nucleic Acids

OH (64) R = 4-N3C6H4CH2NH , n = 1 or 2 (65) R = N3

, n

I c =o

= 1 or 2

(66) n = 2 (67) n = 3

( 6 9 ) R = ApU

(70) R = A (71) R = A p U p A

on photoaffinity labelling with the di-,tri-, and tetra-nucleotide probes suggested that a change of conformation, possibly with loss of the G subunit, may occur as the oligonucleotide grows longer. Periodate-oxidized nucleotides and polynucleotides have again found much use as affinity labels. Thus, oxidized AMP has been used to label the ATP-AMP exchange site of pyruvate phosphate dikinase from Bacteroides syrnbios~s,l~~ oxidized ADP and ATP have been used to characterize nucleotide-binding sites of Ca2+,Mg2+-activated ATPase in E. coliand an unc A mutant strain t h e r e ~ f , ~ ~ * ~ and oxidized ATP has also been used for the affinity labelling of adenylate cyclase from bovine brain130 and a nucleotide-binding peptide that is located on the B-fragment of diphtheria toxin.131 In this last study, ADP-ribose (in which the l-aldo-group of the ribose is potentially available for the formation of a Schiff base) was also used as an affinity label. Periodate-treated tRNATrp has been used to label avian-myeloblastosis-virus-codedreverse trans~i-iptasel~~ and C. T. Evans, N. H. Goss, and H. G. Wood, Biochemistry, 1980, 19, 5809. P. D. Bragg, H. Stan-Lotter, and C. Hon, Arch. Biochem Biophys., 1981, 207, 290. lZ9P. D. Bragg and C. Hon, Biuchern. Biophys. Res. Commun., 1980, 95, 952. 130 K. R. Westcott, B. B. Olwin, and D. R. Storm, J. B i d . Chem., 1980,255, 8767. 131 R. L. Proia, S. K. Wray, D. A. Hart, and L. Eidels, J. Biol. Chem., 1980, 255, 12 025. 132 A. Araya, E. Hevia, and S. Litvak, Nucleic Acids Res., 1980, 8, 4009. lZ7 128

200

Organophosphorus Chemistry

periodate-treated tRNAfMet to label methionyl-tRNA transformylase from E. ~ 0 l i .In l ~most ~ of these studies, the aldehydic groups of the label bind covalently but reversibly to a primary amino-group (thought to be E-NH, of lysine) on the enzyme, and binding is rendered irreversible by reduction with cyanohydridoborate, which reduces the resultant Schiff base, but not the aldehyde, preventing hydrolytic reversal of the condensation. Tryp tophanyl-t RNA synthetase has been affinity-labelled, using mesitoylAMP (72).134If (72) that was labelled with 14C in the adenylate moiety was employed, tryptic mapping of the labelled enzyme showed that one neutral peptide had labelled predominantly, and thus that the adenylate moiety actually ‘tags’ the enzyme. Most other affinity-labelling studies have used alkylating reagents. Treatment of adenosine 5’-phosphoromorpholidate with 2-bromoethanol in pyridine and with dioxan-HC1 affords adenosine 5’-(2-bromoethyl)phosphate, which displays characteristic affinity-labelling behaviour for an ADP-binding activator site on the allosteric enzyme isocitrate dehydr0gena~e.l~~ 6-Chloro-9-~-~-ribofuranosylpurine 5’-phosphate irreversibly inactivated the enzyme IMP dehydrogenase from E. coli K12, apparently reacting with a thiol In at the IMP-binding site to give a 6-(alky1mercapto)purine nuc1e0tide.l~~ mutant strains, this inactivation could be reversed by the addition of thiol reagents. Methods for the attachment of protein affinity-labelling reagents to tRNA have been devised.13’ If tRNAf‘et from E. coli is treated with bisulphite and a bifunctional amine (carbohydrazide, 1,3-diaminopropane, or 1,8-diaminooctane), the N4-amino-groups of cytidine residues in non-base-paired regions are replaced by the diamine, thus allowing the introduction of side-chains of variable length that terminate with primary amino-groups. The resultant modified tRNA is then treated with the N-hydroxysuccinimide ester of an acid, carrying an alkylating or photoreactive function, to introduce the affinity-labellinggroup. Another method of rendering tRNA reactive is to introduce a reactive group at the amino function of amino-acylated tRNA, and lysyl-tRNALYS from yeast or E. coli, bromoacetylated at the &-NH2group of lysine, has been used for the affinity labelling of eukaryotic elongation Octauridylate, (pu),, has been rendered reactive by condensing the cis-diol function of the 3’-terminus with the nitrogen mustard (73) to form a keta1.139 The resulting oligonucleotide bound to the mRNA-binding site of rat liver ribosomes, and protein S3/S3a was found to become labelled predominantly, implying that it is situated at the mRNA-binding site. The fully protected tetrathymidylate (74), in which the 5’-phosphate group is protected as the bisanilidate and inter-nucleotidic links are protected as ethyl esters, was synthesized, and the cis-diol function of the 3’-terminal uridine condensed with (73) to 133

134 135 136

13’ 138 139

C. Hountondji, G.Fayat, and S. Blanquet, Eur. J. Biochem., 1980, 107, 403. I. A. Madoyan, 0. 0. Favoroka, G. K. Kovaleva, N. I. Sokolova, 2.A. Shabarova, and L. L. Kisselev, FEBSLett., 1981, 123, 156. S. Roy and R. F. Colman, J. B i d . Chem., 1980, 255, 7517. H.J. Gilbert and W. T. Drabble, Biuchem. J., 1980, 191, 533. L. H.Schulman, H. Pelka, and S. A. Reines, Nucleic Acids Res., 1981, 9, 1203. A. E. Johnson and L. I. Slobin, Nucfeic Acids Res., 1980, 8, 4185. J. Stahl and N. D. Kobets, FEBS Lett., 1981, 123, 269.

Nucleotides and Nucleic Acids

20 1

CHO

afford a relatively hydrophobic, alkylating analogue of oligo(dT), which was applied to ascites tumour cells and could be shown to enter the cells and preferentially to alkylate poly(A) tracts of intracellular RNA.l*O Myosin SF-1 has previously been reported as being specifically inactivated at an ATPase active site by the 1,lo-phenanthroline-containingcomplex [CoIII(phen)(ATP)], but recent suggest that a decomposition product of this species, i.e. [CoII(phen)], and maybe also [CoIII(phen),], are responsible for the actual inactivation, rather than [CoIII(phen)(ATP)]. Since sites to which the CoIII species is bound cannot simultaneously be inactivated by the CoII species, the CoIII species is presumably not bound, or not exclusively bound, to the active site, and thus ‘affinity labelling’ studies involving [CoIII(phen)(ATP)] should be regarded circumspectly, and re-investigated. 4 Oligo- and Poly-nucleotides Chemical Synthesis.-One of the most promising strategies in the ‘phosphotriester’ approach to oligonucleotide synthesis is the phosphite coupling method, in which the inter-nucleotidic link is first introduced as a phosphite triester and then oxidized to phosphate. A drawback to this approach is the instability of an intermediate nucleoside phosphomonochloridite to hydrolysis and aerial oxidation, but this may be circumvented by using deoxynucleoside phosphoramidites as intermediate^.^^^ Treatment of methyl phosphorodichloridite with dimethylamine in ether at - 15 “C affords chloro(NN-dimethy1amino)methoxyphosphine, which reacts with a base-protected 5’-O-dimethoxytrityl-2’-deoxynucleoside at room temperature to give the phosphoramidite (75). The quantity of 3’-3’-linked material formed as by-product is small. If (75) is treated with 1 H-tetrazole and a 3’-O-acylated 2’-deoxynucleoside, the corresponding 3’-5’linked methyl dinucleoside phosphite is formed in virtually quantitative yield. B

DMT rO d O - r - I V MOMe e2

(75)

T

T

T r O ~ O - OMe / - O ~ O A c

(76)

140

G. G. Karpova, D. G . Knorre, A. S. Ryte, and L. E. Stephanovitch, FEBSLcrr., 1980,

I4l

J . A. Wells, M. M. Werber, and R. G . Yount, J. Biol. Chem., 1980,255,1552. S . L. Beaucage and M. H. Caruthers, Tetrahedron Lett., 1981, 22, 1859.

122, 21. 142

202

Organophosphorus Chemistry

The coupling procedure is equally applicable to solid-phase phosphotriester synthesis, in which the 3’-blocked nucleoside is coupled to silica gel via this position. Following oxidation with aqueous iodine and deprotection, the corresponding dinucleoside phosphates are obtained in high yield. In a different study, methyl phosphorodichloridite was treated with excess triazole or 1H-tetrazole in THF-pyridine at - 20 “C, then cooled to - 70 “C and treated sequentially with and 3’-O-acetyl-2’-deoxyone equivalent each of 5’-O-trityl-2’-deoxythymidine thymidine, to afford (76) in good yield after oxidation with aqueous iodine.143 The quantity of 3’-3’-linked by-product that was formed was less than that found using methyl phosphorodichloridite, and it was almost eliminated when triazole was used, reflecting the lower reactivity and higher specificity of the intermediate phosphoramidites which are presumably formed. If phosphorus trichloride is treated with excess imidazole in THF, at O’C, the supernatant after precipitation of imidazolium hydrochloride contains an unstable, highly reactive species which contains no chlorine and which is thought to be tri-imidaz~lylphosphine.~~~ If unprotected uridine in pyridine-THF at -78 “C was treated with this material, and the products were oxidized with aqueous iodine and separated on DEAE-cellulose, two series of products were obtained, of the types (Up), (n= 2-6) and (Up),U ( m =1-5). All the products were degraded fully by sequential treatment with snake venom phosphodiesterase and KOH, showing that no 5‘-5’ links were formed. 2’-5’ Links and 3’-5’ links were present in the UpU fraction in the ratio 2: 1, as shown by enzymic degradation. No 3’-3’ links were detected, but these would have been labile under the work-up conditions. It was suggested that polymerization occurred via the 2’,3’-cyclic phosphorimidazolidite (77), formed via selective attack at 2’- and 3’-OH groups. Protected oligodeoxyribonucleotideshave been phosphorylated at a free 3’-OH group by treatment with phosphorylbisimidazolide at room temperature.145 The 3’-phosphorylbisimidazolide product may be hydrolysed with 80% acetic acid to afford the phosphate or treated with a diamine to insert a spacer arm at the 3’-phosphate terminus. Caesium fluoride reportedly catalyses the reaction of 4-chlorophenyl 5-chloro-8-quinolyl 5’-O-dimethoxytrityl-2’-0tetrahydropyranyl-N-acylnucleoside3’-phosphates with 5’-hydroxynucleosides to give good yields of the corresponding ribodinucleoside monophosphates rapidly under mild conditions, presumably via phosphorofluoridate intermediate~.~~~ Phosphite analogues of nucleotides have been synthesized as follows :14’ 5’-O-monomethoxytrityl-2’-O-(t-butyldimethylsilyl)uridine was treated with trichloroethyl phosphorodichloridite in THF-collidine at - 78 “C, and subsequently with 3’-O-laevulinyl-2’-O-(TBDMS)uridine (TBDMS = t-butyldimethylsilyl), to afford (78). After removal of the protecting groups by standard procedures, diuridine 3’,5’-phosphite (79), which was stable to ribonuclease A and 143 144

J. L. Fourrey, and D. J . Shire, Tetrahedron Lett., 1981, 22, 729. T. Shimidzu, K. Yamano, A. Murakami, and K. Nakamichi, Tetrahedron Lett., 1980, 21, 27 17.

145

E. Yu. Krynetskii, N. F. Sergeeva, V. D. Smirnov, and Z. A. Shabarova, Yestn. Mosk.,

14*

Unio., Khim., 1980, 21, 491 (Chem. Abstr., 1981, 94, 84 419). H. Takaku, T. Nomoto, M. Murata, and T. Hata, Chern. Lett., 1980, 1419. K. K. Ogilvie and M. J. Nemer, Tetrahedron Lett., 1980, 21, 4145.

14’

94

Nucleotides and Nucleic Acids HOyO?Ura

OTBDMS

OTBDMS

~

R1O 0

203

OR^

O-P-

R2

0

’ P ‘ Im

R1 ( 7 8 ) MMTr

R2

R3

OCH2CC13

laevulinyl

X absent

( 8 0 ) TBDMS

OCH2CC13

TBDMS

absent

( 8 1 ) MMTr

OCH2CC13

TBDMS

absent

( 8 2 ) MMTr

OMe

TBDMS

absent

( 8 7 ) MMTr

Me

TBDMS

0

( 9 1 ) MMTe

OCH2CC13

laevulinyl

0

(92) H

OCH2CC13

laevulinyl

0

( 9 3 ) MMTr

OCH2CC13

H

0

(77) I m = l - i m i d a z o l y l

HO

OH

R R ( 7 9 ) OH

X absent

( 8 3 ) OH

NH, N E t , o r NPr

( 8 4 ) OH

Se

( 8 5 ) OH

S

( 8 6 ) NH2 0 0

TrO

II O-P-OCH2CH2CN I OC6H4 C 1- 4 (88)

0

R1O

II

0-P-R2

I

OC6H4C1-2 R1 ( 8 9 ) DMTr

R2 l-triazolyl

( 9 0 ) MMTr

PhNH

spleen phosphodiesterase but was cleaved to uridine and uridine 3’-phosphite by snake venom phosphodiesterase, was formed. Oxidation of (79) with aqueous iodine afforded UpU. Selective removal of R1or of R3from (78) allowed extension to higher oligomers. Compounds (80)-(82) have also been prepared by methods analogous to (78) and used for the construction of novel inter-nucleotidic linkages.148Treatment of (80) with iodine and a primary amine, or selenium in DMF, or sulphur in pyridine, using the conditions described above for the phosphoramidite (25),29 and subsequent deprotection afforded the phosphoramidates (83), the phosphoroselenoate (84), and the phosphorothioate (85), respectively. Treatment of (81) with a zinc-copper couple, and then acetic acid, followed by ammonia, and subsequent desilylation with fluoride gave the phosphoramidate (86), and methylation of (82) with methyl iodide afforded the 148

M. J. Nemer and K. K. Ogilvie, Tetrahedron Lett., 1980, 21, 4149.

204

Organophosphorus Chemistry

corresponding methylphosphonate (87) in an Arbusov reaction. The stereoisomers of (83)-(86) could be separated prior to the deblocking stage. Compounds (83)-(86) were not degraded by spleen phosphodiesterase, but (86) was completely degraded by snake venom phosphodiesterase and ribonuclease A. In contrast, the venom enzyme degraded one isomer of (83)-(85) completely, but not the other. Since the (Rp)-isomer of (85) is known to be degraded selectively, the stereochemistry of the other isomers may be tentatively assigned by analogy. Rapid routes to phosphotriester intermediates that are useful for the phosphotriester method have been described. Coupling 5’-O-trityl-2’-deoxythymidine and 4-chlorophenyl2-cyanoethylphosphate with TPS-CI, or, better, with mesitylenesulphonyltetrazole (MS-tet) afforded (88) in high yield, and this method was used with similar success for other base-protected n u c l e o ~ i d e s .Alternatively, ~~~ phosphorylation of the 3’-OH group of a protected nucleoside with 4-chlorophenyl phosphorobistriazolide and subsequent treatment with excess 2-cyanoethanol affords the same type of intermediate.150 4-Chlorophenyl phosphorobistriazolide has also been used to phosphorylate, at the 3’-position, a diribonucleoside monophosphate that is blocked at the 2’-position by 2-nitrobenzyl groups during the synthesis of a he~aribonuc1eotide.l~~ 2-Chlorophenyl phosphorobistriazolide has been used to phosphorylate 5’-O-dimethoxytrityl-2’deoxynucleosides at the 3’-position to afford intermediates such as (89), which, on treatment with excess 2-cyanoethanol, affords triesters analogous to (88).152 No 3’-3’ coupling was observed when using the bistriazolide. Selective deblocking of the triesters at the 5’-position or at the phosphate group and condensation using TPS-tet allowed the rapid elaboration of fully protected di- and tri-deoxyribonucleotide blocks that were suitable for block coupling. Treatment of 5’-O-monomethoxytrityl-2’-deoxythymidine with 2-chlorophenyl phosphoranilidochloridate affords the corresponding thymidine 3’-(2-chloropheny1)phosphoranilidate (90). The anilido-group is readily removed with sodium hydride and carbon dioxide to afford the corresponding phosphodiester, which is then linked to the 5’-OH group of a similar residue, using TPS-tet, and an oligonucleotide chain is thus constructed. Moreover, treatment of (90) with sodium hydride and carbon disulphide converts the phosphoranilidate into a thiophosphate group, which is a useful reaction for modifying terminal phosphate groups following oligonucleotide 4-Chlorophenyl phosphoranilidochloridate has been used to phosphorylate the 3’-OH of N,5’-O-protected deoxyribonucleosides. The products served as 3’-terminal units during the synthesis of protected oligonucleotides, and subsequent removal of the anilidogroup with isoamyl nitrite rendered them functional for block ~0ndensation.l~~ Block condensation is exemplified by the following: (78) was oxidized with aqueous iodine to afford (91). Treatment of (91) with acetic acid afforded (92), 149 150

N. T. Thuong, M. Chassignol, and C. Barbier, Tetrahedron Lett., 1981, 22, 851. S. A. Narang, R. Brousseau, H. M. Hsiung, and J. J. Michniewicz, Methods Enzymol.,

151 152

E. Ohtsuka, T. Wakabayashi, and M. Ikehara, Chem. Pharm. Bull., 1981,29, 759. C. Broka, T. Hozumi, R. Arentzen, and K. Itakura, Nucleic Acids Res., 1980, 8, 5461. Z. J. Lesnikowski, W. J. Stec, and W. S. Zielinski, Synthesis, 1980, 397. E. Ohtsuka, S. Shibahara, T. Ono, T. Fukui, and M. Ikehara, Heterocycles, 1981,15, 395.

1980, 65, 610.

153 154

Nucleotides and Nucleic Acids

205

and, with hydrazine-acetic acid-pyridine, (91) lost the laevulinyl group to form (93). When (93) was treated with trichloroethyl phosphorodichloridite in THF, followed by (92), and the product was oxidized with aqueous iodine, the fully protected tetramer that is analogous to (91) was formed in good yield.155Repetition of the cycle twice more, followed by complete deblocking, afforded (up),, in good yield. While the example that is given employed uridine, other nucleosides with appropriate N-acyl protection may be used with equal facility : N-deacylation during deblocking with hydrazine was reportedly not observed. A series of phosphorodichloridites incorporating the phosphate-protecting groups that are most commonly used in oligonucleotide synthesis was prepared by treatment of the appropriate alcohol or phenol with phosphorus trichloride in ether at -78 “C,and the individual compounds were evaluated for use in condensation and deprotection in the phosphite coupling method described above.156The trichloroethyl and tribromoethyl compounds gave good results, the protecting group being removable by a zinc-copper couple, and so did the cyanoethyl group, which was removed with ammonia. The coupling yields with benzyl and methyl phosphorodichloridites were poorer, though deblocking with t-butylamine was conveniently easy. The treatment with oximate that is required to remove a 4-chlorophenyl group from phosphate when using this approach also effected desilylation, with consequent transphosphorylation and degradation. Two novel phosphate-protecting groups, for use in oligonucleotide synthesis, which are removed by /3-elimination have been described. The 2-sulphonylethyl group may be introduced into phosphotriester intermediates of the type (94) in the usual way ( c f . 2-cyanoethanol, previously described) and is removed, prior to coupling, by triethylamine in dry pyridine.15’ Its applicability in oligonucleotide synthesis was shown by a preparation of (dTp), IdT. The diphenylmethylsilylethyl group was introduced by the following method : S,S-di-(4-methoxyphenyl) phosphorodithioate and 2-(diphenylmethylsily1)ethanol were condensed, using TPS-Cl in pyridine; on treatment with sodium hydroxide in dioxan, the product lost one 4-methoxythiophenol residue, affording (95), which was condensed with 5’-O-monomethoxytrityl-2’-deoxythymidine to yield (96).158Further treatment of (96) with alkali in dioxan removed the methoxythiophenol group, thus freeing the phosphate group for coupling. At the conclusion of oligonucleotide synthesis, the 2-(diphenylmethylsily1)ethyl groups were removed with fluoride, which attacked the silicon atom, liberating ethylene and phosphate. The trityl ethers that are frequently employed to protect nucleosides and nucleotides at the 5’-position (and others) are quickly and quantitatively removed by using powdered zinc bromide in an aprotic solvent nitromethane is reportedly ideal.160 Glycosidic bonds are unaffected during this procedure, and the bogey of depurination during detritylation with protic acids is thus eliminated. N-Acyl groups and the more common phosphate-blocking groups are also :1599160

155 156

157 158

159 160

K. K. Ogilvie and M. J. Nemer, Can. J. Chem., 1980, 58, 1389. K. K. Ogilvie, N. Y. Theriault, J.-M. Seifert, R. T. Pon, and M. J. Nemer, Can. J. Chem., 1980,58, 2686. N. Balgobin, S. Josephson, and J. B. Chattopadhyaya, Tetrahedron Lett., 1981, 22, 1915. S. Honda and T. Hata, Tetrahedron Lett., 1981, 22, 2093. V. Kohli, H. Blocker, and H. Koster, Tetrahedron Lett., 1980, 21, 2683. M. D. Matteucci and M. H. Caruthers, Tetrahedron Lett., 1980, 21, 3243.

0rganophosphorus Chemistry

206

unaffected. Mono- and di-methoxytrityl groups at the 5’-position seem to be removed at the same rate, while the rate of removal from the 3’-position is slower, and it has therefore been suggested that specific bidentate chelation [see (97)] enhances the detritylation. The detritylation of tritylated aristeromycin would afford an interesting comparison. The 2-(methy1thiomethoxy)ethoxycarbonyl group has been introduced as a protecting group for the 3‘-position of nucleosides during oligonucleotide synthesis.161It is introduced by the reaction of the chloride (98) with the hydroxyl group which it is desired to protect, and is removed by treatment first with mercuric perchlorate and 2,4,6-collidine in aqueous acetone and subsequently with ammonia in aqueous dioxan. T 0

0

RO

II I OH

4-MeOC6HqS-P-OCH2CH2SiMePh2

II

O-P-0CH2CH2SO2Ph

I

OC6H4C1 - 2 (95)

OH

T

CH3SCH20CH2CH20COC1 (98)

DMTrO JO!-

- O S 0 2 0

CHMe2

OR CHMe2 (99)

Quinoline-8-sulphonyltetrazole,prepared by treating quinoline-8-sulphonyl chloride with tetrazole, has been described as a convenient reagent for performing coupling reactions during the synthesis of ribo-oligonucleotides by the phosphotriester method, affording high yields of coupled products.162 The reagent decomposes on storage, and must be freshly prepared. The yuinoline-8-sulphonic acid by-product of coupling precipitates as a neutral inner salt and is removed by filtration. 161 162

S. S. Jones, C. B. Reese, and S. Sibanda, Tetrahedron Lett., 1981, 22, 1933. H. Takaku and M. Yoshida, J. Org. Chem., 1981, 46, 589.

Nucleotides and Nucleic Acids

207

Two studies have been published in which the rates of formation of phosphotriester and sulphonate by arylsulphonyl coupling agents in the synthesis of oligodeoxyribonucleotides by the phosphotriester method are compared. In one, TPS-tet was compared with TPS-3-nitro-l,2,4-triazole(TPS-nt) and also (MS-nt) in effecting the coupling with mesitylenesulphonyl-3-nitro-l,2,4-triazole of 5’-O-dimethoxytrityl-2’-deoxythymidine 3’-(4-~hlorophenyl)phosphateand 3’O-acetyl-2’-deoxythymidine.All three agents gave nearly quantitative coupling yields and about 1 % of 5’-sulphonated by-product when one molar excess of coupling agent was used, with marginal preference for MS-nt.la3 In the second study, TPS-Cl, mesitylenesulphonyl chloride (MS-Cl), TPS-tet, MS-tet, and 1:3 mixtures of MS-Cl and MS-tet and of TPS-Cl and TPS-tet were compared for TPS-tet and MS-tet effected much their ability to perform a similar c0up1ing.l~~ faster coupling than TPS-Cl and MS-CI, but MS-tet gave rapid sulphonation of the 5’-OH function, and TPS-tet a lower, but still significant, amount of sulphonate. However, the mixtures of sulphonyl chloride and tetrazole gave the most rapid rates of coupling and the least quantities of sulphonate by-products, suggesting that TPS-Cl is not converted into TPS-tet by the tetrazole prior to coupling, but preserves its integrity. Indeed, when TPS-Cl was treated with tetrazole in dry pyridine at room temperature, no TPS-tet product was detected. Thus, TPS-Cl and TPS-tet may give rise to different activated intermediates. It is thought that reaction with either reagent first affords an intermediate (99), which, in the presence of excess tetrazole, rapidly forms the corresponding phosphorotetrazolidate; this is a more efficient coupling agent. Intermediate (99) could also be attacked by more of the 3’-phosphate to afford a symmetrical pyrophosphate. In the absence of tetrazole (TPS-C1 alone), this represents an abortive reaction, but, in the presence of the tetrazole, the pyrophosphate reacts, giving the phosphorotetrazolidate and 3’-phosphate back for further activation. While circumstantial, the rationale is attractive; TPS-Cl plus TPS-tet was selected as the reagent of choice. Much effort has been expended on solid-phase synthetic methods. The most popular choice of support is the cross-linked polyacrylmorpholide resin Enzacryl K2.lS5-l7OTypically, a 5’-blocked deoxynucleoside (which is also protected at the 3’-position in the case of ribonucleosides) is succinylated at its unprotected hydroxyl function and the succinate is converted into its pentachlorophenyl ester, using DCC. This then reacts with a primary amino-group that is at the end of a spacer arm which has been attached to the functionalized resin. The terminal nucleoside is thus anchored by an ester linkage. The 5’-blocking group is removed and the chain is elongated in the 5’-direction. All researchers used phosphotriester methods, but, since the choice of blocking group, condensing la3 M.

J. Gait and S. G . Popov, Tetrahedron Lett., 1980, 21, 2841. Acids Res., 1980, 8, 5445. M. Ikehara, Tetrahedron Lett., 1981, 22, 765. A . F. Markham, M. D. Edge, T. C. Atkinson, A. R. Greene, G. R. Heathcliffe, C. R. Newton, and D. Scanlon, Nucleic Acids Res., 1980, 8, 5193. M. L. Duckworth, M. J. Gait, P. Goelet, G . F. Hong, M. Singh, and R. C. Titmas, Nucleic Acids Res., 1981, 9, 1691. K. Miyoshi, T. Miyake, T. Hozumi, and K. Itakura, Nucleic Acids Res., 1980, 8, 5473. K. Miyoshi, T. Huang, and K. Itakura, Nucleic Acids Res., 1980, 8, 5491. P. Dembek, K. Miyoshi, and K. Itakura, J. Am. Chem. SOC.,1981,103,706.

la4 A. K . Seth and E. Jay, Nucleic 165 E. Ohtsuka, H. Takashima, and

168 189 li0

208

Organophosphorus Chemistry

agent, technique (e.g. single-unit or block coupling, or elimination of failure sequences), deblocking procedure, and method of isolation of products varies from group to group, the reader is recommended to consult individual references. Generally, however, the oligonucleotide product was cleaved from the polymer by using ammonia, and ion-exchange h.p.1.c. was used to analyse the products. In other reports, cross-linked polystyrene resin 172 or silica gel 173 were employed as the supporting polymers. A commercially available chloromethylpolystyrene was converted into the aminomethylpolystyrene via potassium phthalimide, and the aminomethyl group was extended by coupling to j3-alanine, the terminal amino-group being finally coupled to the nucleoside-succinylate ester described above.171 The initial coupling of a trinucleotide block to the derivatized polystyrene afforded a lower yield than when polyacrylmorpholide resin was used, but subsequent coupling yields were better. Polystyrene resin was found to be easier to dry, by using pyridine, than polyacrylmorpholide resin. Vydak TP silica gel was activated under reflux in HCl and derivatized by treatment successively with (3-aminopropyl)triethoxysilane,succinic anhydride, and chlorotrimethylsilane; it was then treated with a base-protected 5’-O-monomethoxytrityl-3’-O-TBDMS-nucleosideand DCC in pyridine, in the presence of 4-dimethylaminopyridine to anchor the terminal nucleoside residue to the gel.173In this case, the phosphite coupling procedure was employed, and the oligonucleotide was finally cleaved from the gel with ammonia and pyridine. Several methods have been reported for insertion of a phosphate group at the 5’-end of a protected oligonucleotide that has been prepared via the phosphotriester route and which bears a 5’-OH group. In one, 2-cyanoethyl phosphate was coupled to the oligonucleotide by using MS-tet, and deblocking with ammonia afforded the 5’-pho~phate.l~~ In another, 5-chloro-8-quinolyl phosphate was condensed at the 5’-terminus, using 2,2’-dipyridyl diselenide and triphenylphosphine as the condensing agents.175An ingenious method uses morpholinophosphorobis-(3-nitro-l,2,4-triazolidate)in dioxan, which phosphorylates the 5’-OH; the resulting species is then hydrolysed in aqueous buffer to leave a phosphoromorpholidate group at the 5’-position of the oligon~cleotide.~~~ This may be hydrolysed to the 5’-phosphate at pH 2, or treated with orthophosphate or pyrophosphate, or with AMP in DMF, to produce the 5’-diphosphate, triphosphate, adenylylphosphate, etc. Enzymic methods for the synthesis of 5’-phosphorylated oligoribonucleotides have also been ~ e p 0 r t e d . lOligonucleo~~ tides that bear a 5’-phosphate group are potential substrates for ligases, and thus a step to building longer oligonucleotides. Upon treatment of ATP with NNN’-tris-(2-chloroethyl)-N’-(4-formylphenyl)propane-1,3-diamine in aqueous DMF, at pH 8.2, a compound was isolated 1 7 1 9

171 172

173 174

175 176

177

K. Miyoshi, K. Arentzen, T. Huang, and K. Itakura, Nucleic Acids Res., 1980, 8, 5507. V. N. Dobrynin, B. K. Chernov, and M. N. Kolosov, Bio-org. Khim., 1980,6,138 (Chern. Abstr., 1980, 93, 8416). K . K. Ogilvie and M. J. Nemer, Tetrahedron Lett., 1980, 21, 4159. H. M. Hsiung, W. L. Sung, R. Brousseau, R. Wu, and S. A. Narang, Nucleic Acids Res., 1980, 8, 5753. H. Takaku, M. Kato, M. Yoshida, and R . Yamaguchi, J. Org. Chem., 1980,45, 3347. G . van der Marel, G . Veeneman, and J. H. van Boom, Tetrahedron Lett., 1981, 22, 1463. S. M. Zhenodarova, E. A. Sedelnikova, 0. A. Smolyaninova, M. I . Khabarova, and E. G . Antonovich, Bio-org. Khim., 1980, 6 , 1516 (Chem. Ahstr., 1981, 94, 79 747).

Nucleotides and Nucleic Acids

c1

209 OH

which appeared to be This product was a substrate for RNA polymerase, and thus RNA tracts with an alkylating group at the 5'-triphosphate terminus can be formed. The N-(2-chloroethyl) group in (100) has poor alkylating activity, owing to withdrawal of electrons from nitrogen by the 4-formyl group, but it can be potentiated by reduction of the formyl group with borohydride. When d(TpA) was treated with diphenyl phosphorochloridate in DMF and with ethylenediamine or hexane-l,6-diamine, the inter-nucleotidic phosphate group was converted into the corresponding N-( o-amino-alky1)phosphoramidate in fair yield.179The primary amino-group that was thus introduced allowed the nucleotide to be immobilized on activated Sepharose 4B, or acylated by the N-hydroxysuccinimide ester of 4-azidobenzoic acid to introduce a photoreactive group. Alkyl triesters of oligonucleotides, such as (MeO),TrdTp(Et) ndT(Ac), where n = 2, 5 , or 8, may be obtained by transesterification of the corresponding products of triester synthesis, in which the inter-nucleotidic phosphates are blocked by chlorophenyl groups, using caesium fluoride and the relevant alcohol.lso The reaction takes place readily at room temperature, and little variation in reactivity was observed when using methanol, ethanol, isopropyl alcohol, and 1,2-isopropylideneglycerol. Phosphotriester synthesis methods have been used to prepare two decathymidylate analogues, i.e. d[Tp(Me)Tp],dTp( Me)dT, containing alternating methylphosphonate and phosphodiester links.lsl A key intermediate (101) T

178 179

180

181

T

M. A. Grachev, A. A. Mustaev, and S. I. Oshevski, Nucleic Acids Res., 1980, 8, 3413. N. I. Sokolova, I. V. Ponomarenko, Z. A. Shabarova, and M. A. Prokofiev, Dokl. Akad. Nauk S S S R , 1980, 253, 1395 (Chem. Abstr., 1981, 94, 16020). V. A. Petrenko, P. I. Pozdnyakov, G. F. Sivolobova, and T. N. Shubina, Bio-org. Khim., 1980, 6, 431 (Chem. Abstr., 1980, 93, 132 726). P. S. Miller, N. Dreon, S. M. Pulford, and K . B. McParland, J . Biol. Chem., 1980, 255, 9659.

21 0

Organophosphorus Chemistry

allowed the separation of the methylphosphonate stereoisomers on silica gel, and thus the two decathymidylate analogues that were elaborated from the separated isomers of (101) contained stereo-regular backbones. The two oligomeric analogues showed different c.d. spectra and different tendencies to form complexes with complementary polynucleotides, and largely different susceptibilities to enzymic cleavage, suggesting that the configuration of the methylphosphonate link may control these interactions. Oligodeoxyribonucleotide analogues that contain exclusively methylphosphonate inter-nucleotidic links, with sequences that are complementary to the anticodon loop of tRNALys and the -ACCA acceptor stem of tRNA,lS2and to the Shine-Dalgarno sequence at the 3’-end of 1 6 s rRNA in E. C O I ~have , ~ been ~ ~ prepared by phosphotriester synthesis methods; evidence was presented that the analogues are able to influence specific events in the synthesis of proteins by complementary binding to target sequences. Species-specific differences were noted, and the influences observed with cell-free systems were not necessarily reproduced in intact organisms. Mammalian cells in culture appeared to be able to take up methylphosphonate oligonucleotides up to nine units long, but E. coli B was not permeable to oligomers longer than four units.la3 Oligothymidylate analogues of (dTp),dT and (dTp),,dT that contained P-S-C(5’) thioester links were substrates for T4 polynucleotide kinase, T4 DNA polymerase, E. coli DNA polymerase I, S1 nuclease, and snake venom phosphodiesterase, and were able to prime the replication of poly(dA) by T4 DNA polymerase, although in most of the cases the analogue reacted at a lower rate than the corresponding thymid~1ate.l~~ The metal-ion-catalysed condensation of guanosine 5’-phosphorimidazolidate on poly(C) has been studied at 0 ° C in 2,6-lutidine buffer, at pH 7.lS5Polymerization proceeds efficiently, and oligomers that are 3 0 - 4 0 residues long can be obtained which are predominantly 2’-5’-linked if Pb2+is used for catalysis and 3’-5’-linked if Zn2+is used, as evidenced by the suceptibility of the products to ribonuclease T,. In the absence of the template, polymerization was far less efficient. It is noteworthy that the 3’-5’ link is formed in the presence of Zn2+, since the 2’-OH is markedly more reactive in the absence of template. The selfcondensation, in the absence of catalysing metal ions, of the 5’-phosphorimidazolidates of pApC and pCpA on poly(U-G) and of pGpU and pUpG on poly(C-A) have also been reported.lS6 ImpUpG and TmpGpU condensed efficiently on poly(C-A), but, while the condensation of ImpCpA on poly(U-G) was moderately efficient, that of ImpApC was poor. In many cases the products were predominantly 3’-5’-linked. Evidently, template-directed reactions occur in doublehelical structures. An investigation of the oligomerization of d(pGpGpT), d(pTpGpG), and d(TpGpGp) by a water-soluble carbodi-imide in the presence of the complementary dodecanucleotide template d(pApCpC), has found that P. S . Miller, K . B. McParland, K. Jayaraman. and P. 0. P. Ts’o, Biochemisfrj; 1980, 20, 1874. lS3 K. Jayaraman, K. McParland. P. Miller, and P. 0. P. Ts’o, Proc. Nufl. Acud. Sci. USA, 198 1,78, 1537. 184 V. N. Rybakov, M. I. Rivkin, and V. P. Kumarev, Nucleic Acids Res., 1981, 9, 189. 185 R. Lohrmann, P. K. Bridson, and L. E. Orgel, Science, 1980, 208, 1464. 186 R. Lohrmann and L. E. Orgel, J. Mol. Ecol., 1979, 14, 243 (Chern. Abstr., 1980, 93, 90 349). 182

Nucleotides and Nucleic Acids

21 1

template-induced condensation is only observed in the case where a 3’-terminal phosphate is present, i.e. d(TpGpGp), when hexa- and nona-nucleotide products are formed.ls7 Much effort has again been applied to the synthesis of the 2’-5’-linked inhibitor of protein synthesis pppA2’pS’A2’p5’A (‘2-5A’) and its ‘core trimer’ (A2’p5’A2’p5’A), as well as analogues of these compounds. The majority of synthetic routes have used phosphotriester methods. Two preparations of core trimer have been detailed,188.189 one of them notably employing the tetraisopropyldisiloxane-l,3-diyl group for the simultaneous protection of the 3’- and 5’-hydroxyl functions of adenosine residues,lsg and analogues of core trimer with 2’-deoxyadenosine, ara-adenosine, 3’-deoxyadenosine, or 2’,3’-dideoxyadenosine in place of the 3’-terminal adenosine residuelgOand with 3’-deoxyadenosine replacing all three adenosine residues lgl have also been described. Two phosphotriester syntheses of 2-5A itself have been d e ~ c r i b e d , ’lg3 ~ ~and, ~ in addition, analogues that contain the 5’-[,!ly-methylene]diphosphonate, or a single residue of 3’-0methyladenosine at the 3’-terminus, or all three adenosine residues replaced by 3’-0-methyladenosine were also prepared.lg2 The analogue with a single 3’-0methyladenosine residue at the 3’-terminus activated 2-5A-dependent endonuclease in cell extracts and inhibited the synthesis of protein in intact cells more powerfully than 2-5A, possibly because it was comparatively resistant to nucleases; the other analogues were inactive.lg4Other methods for the preparation of 2-5A have included oligomerization of N6-benzoyl-3’-0-(2-nitrobenzyl)adenosine 5’-phosphate with DCClg3and the Pb2+-catalysedoligomerization of adenosine 5’-phosphorimidazolidate.195T4 RNA ligase has been used to graft pCp to the 3’-terminus of 2-5A and core trimer,lg6and if [32P]pCpwas employed, the resulting materials were effective probes for radio-binding and radioimmunoassay of 2-5A and core trimer. Compounds in which pCp was added to the 3’-terminus were more stable to nucleolytic degradation in rabbit reticulocyte lysate extracts and Ehrlich ascites tumour cells than those without, suggesting that a specific degradation pathway from the 3’-terminus exists for the unmodified compounds. Moreover, ppp(A2’p),ApCp activated 2-5A-dependent endonuclease and inhibited the synthesis of protein in reticulocyte extracts. 3’-dATP is a substrate for 2-5A synthetase from rabbit reticulocyte lysates, permitting the preparation of ppp(3’dA)2’~5’(3’dA>2’~5’( 3’dA), which was a slightly stronger inhibitor of the synthesis of protein in reticulocyte lysates than 2-5A.lg7 N. G. Dolinnaya and Z . A. Shabarova, Bio-org. Khim., 1980, 6, 209 (Chem. Abstr., 1980, 93, 72 174). J. B. Chattopadhyaya, Tetrahedron Lett., 1980, 21, 41 13. C.Gioeli, M.Kwiatkowski, B. Oberg, and J. B. Chattopadhyaya, Tetrahedron Lett., 1981,

187

189

22, 1741. 190 191

J. Engels, Tetrahedron Lett., 1980, 21, 4339. R. Charubala and W. Pfleiderer, Tetrahedron Lett., 1980, 21, 4077.

192

J. A. J. den Hartog, R . A. Wijnands, J. H. van Boom, and R. Crea, J. Org. Chem., 1981, 46, 2242. M, Ikehara, K. Oshie, A. Hasegawa, and E. Ohtsuka, Nucleic Acids Res., 1981,9, 2003.

193

195 196

C. Baglioni, S. B. D’Alessandro, T. W. Nilsen, J. A. J. den Hartog, R . Crea, and J. H. van Boom, J. B i d . Chem., 1981, 256, 3253. H. Sawai, T.Shibata, and M. Ohno, Tetrahedron, 1981, 37, 481. R.H.Silverman, D. H. Wreschner, C. S. Gilbert, and I. M. Kerr, Eur. J. Biochem., 1981,

le7

P.Doetsch, J. M. Wu, Y.Sawada, and R. J. Suhadolnik, Nature (London), 1981, 291, 395.

194

115, 79,

8

212

Organophosphorus Chemistry

Enzymatic Synthesis.-A systematic study of the use of polynucleotide phosphorylase from Micrococcus luteus or Escherichia coli to synthesizetriribonucleoside diphosphates by addition of a single nucleoside 5’-diphosphate residue to a dinucleoside monophosphate receptor has been performed.lS8The yield of singleaddition product depends critically on time, temperature, structure of the acceptor, and enzyme, with the E. coli enzyme catalysing the addition of a pyrimidine nucleotide residue more effectively. Copolymers that contain tubercidin (7-deaza-adenylic acid) and adenosine have been prepared by treating mixtures of the nucleoside 5’-diphosphates with polynucleotide phosphorylase from M. l u t e ~ s Tubercidin .~~~ 5’-diphosphate was incorporated into polymer by the enzyme more readily than ADP, and the tubercidin-containing copolymers promoted the synthesis of polylysine more readily than poly(A) in a proteinsynthesizing system, possibly because tubercidin residues show less tendency to stack. While 5-mercaptouridine 5’-diphosphate was not a substrate for polynucleotide phosphorylase on its own, copolymers containing 5-mercaptouridine and uridine could be formed when UDP was added.2005-Mercapto-UDP was a poorer substrate for the enzyme than UDP, however. The copolymers were strong inhibitors of RNA polymerase, the degree of inhibition increasing with the thiol content. Copolymers that contain 4-thiouridine and uridine may be prepared by incubating mixtures of the corresponding 5’-diphosphates with polynucleotide phosphorylase, and strongly inhi bit reverse transcriptase from avian myeloblastosis virus, the degree of inhibition again increasing with the thiol content.201 Moreover, the 4-thiouridine residues may be tagged with a spin-label by treatment of the copolymer with 4-(a-iodoacetamido)-2,2,6,6tetrame t hylpiperidin-1-oxy 1, or, a1terna tively, 4-t hiouridine 5’-diphosphate may be alkylated with this reagent and then copolymerized with UDP as before. The spin-labelled copolymers also inhi bit the reverse transcriptase coded by avian myeloblastosis virus, but whereas inhibition by the 4-thiouridine-containing copolymer is reversible with dithiothreitol, that by the spin-labelled copolymers is not, hinting at a different mode of inhibition. N4-Ureido-2’-deoxycytidine 5’-triphosphate, prepared by treating dCTP with bisulphite and semicarbazide, is a substrate for terminal deoxynucleotidyl transferase from calf thymus, and a polymeric tail of ureidocytosine could thus be attached to (pdT), or to (pdA)Gprimers.2o2Upon oxidation with NBS, the ureidocytosine bases were converted into 4-aminocarbonylazo-2-pyrimidinone residues, which were labile in acid solution. At the monomer level, this decomposition promoted the polymerization of 1-glyceryl methacrylate, and it is thus envisaged that DNA may be tagged at the 3’-terminus with a poly(1-glyceryl methacrylate) tail, allowing heavy-atom labelling. Copolymers containing 2’-deoxyadenosine or 2’-deoxycytidine and 2-aminopurine-2’-deoxyriboside have been prepared by incubating mixtures of the corresponding 5’-triphosphates 198 199

2oo

201 202

S. M. Zhenodarova, V. P. Klyagina, and 0. A . Smolyaninova, Bio-org. Khim., 1980, 6, 1505 (Chem. Abstr., 1981, 94, 79 746). F. Seela, Q.-H. Tran-Thi, H. Mentzel, and V. A. Erdmann, Biochemistry, 1981, 20, 2559. Y.-K. Ho, J. Aradi, and T. J. Bardos, Nucleic Acids Res., 1980, 8, 3175. P. E. Warwick, A. Hakam, E. V. Bobst, and A. M. Bobst, Proc. Natl. Acad. Sci. U S A , 1980,77,4574. G. L. Brown, R. F. Hartman, and S. D. Rose, Biochim. Biophys. Acta, 1980, 608, 266.

Nucleotides and Nucleic Acids

213

with terminal deoxynucleotidyl transferase and (dA), primer and used as templates for DNA polymerase c( in order to investigate the molecular basis of transition Replacement of adenine by 2-aminopurine in poly(dA) caused the ratio of mis-insertion of dCMP for dTMP in the complementary strand to rise by a factor of at least 230, suggesting that the formation of 2aminopurine-cytosine base-pairs is involved in the 2-aminopurine-stimulated induction of A-T -+ G-C transition mutations. Polynucleotides containing cytidine, guanosine, or adenosine modified at their exocyclic groups, mostly prepared as copolymers with the unmodified nucleoside by using polynucleotide phosphorylase, have been transcribed, using RNA polymerase, Mn2+,and the four common ribonucleoside triphosphates in order to assess the ability of the modification to cause transcriptional errors.2o4The results indicated that transcriptional ambiguity arose when hydrogen-bonds of the length and number appropriate to normal base-pairing were prevented from forming. 2’-Deoxy-4thiothymidine 5’-triphosphate is a substrate for DNA polymerase, and, using a circular single strand of the DNA of bacteriophage fd I as template, the complementary strand could be synthesized in which 2’-deoxy-4-thiothymidine occupied 90% of the sites that are normally occupied by 2’-deoxythymidine, albeit at a lower rate than Subsequent ligation to the circular doublestranded form was more rapid than normal, apparently because DNA ligase showed higher affinity for the analogue-containing substrate. T4 RNA ligase has again found application in the joining of an oligonucleotide that bears a 5’-terminal phosphate to an acceptor oligonucleotide with a free 3’-OH group, notably in joining fragments of tRNA sequence.206v207 In a study in which a tetradecanucleotide was joined from three fragments (4+ 6 + 4), considerable variation in yield was noted when the 4+(6+4) sequence was compared with (4 + 6) + 4,indicating a sequence preference in reactions involving RNA ligase that is thought to depend on the structure of the 3’-end of the acceptor The power of enzymatic techniques in the breaking and making of polynucleotides is nicely exemplified by the construction of a composite tRNA gene that contains a transplanted sequence for the anticodon loop.2o8 Sequencing.-Two further reactions that are useful for effecting pyrimidinespecific cleavage of DNA for use in the Maxam-Gilbert sequencing technique have been described.209Potassium permanganate preferentially oxidizes thymine residues at neutrality, so treatment of DNA with this reagent, quenching with ally1 alcohol, and subsequent treatment with piperidine effects thymine-specific cleavage. Treatment of DNA with hydroxylamine hydrochloride at pH 6 and subsequently with piperidine allows cytosine-specific cleavage. These procedures 203 204 205

206 207

208 209

S. M. Watanabe and M. F. Goodman, Proc. Narl. Acad. Sci. USA, 1981,78, 2864. B. Singer and S. Spengler, Biochemistry, 1981, 20, 1127. B. Hofer and H. Koster, Nucleic Acids Res., 1981, 9, 753. E. Ohtsuka, T. Doi, H. Uemura, Y. Taniyama, and M. Ikehara, Nucleic Acids Res., 1980, 8, 3909. G.-H. Wang, L.-Q. Zhu, J.-G. Yuan, F. Liu, and L.-F. Zhang, Biochim. Biophys. Acta, 1981, 652, 82. M. Yarus, C. McMillan, 111, S. Cline, D. Bradley, and M. Snyder, Proc. Natl. Acad. Sci. USA, 1980,77, 5092. C . M. Rubin and C. W. Schmid, Nucleic Acids Res., 1980, 8 , 4 6 1 3 .

214

Orgarlophosphorus Chemistry

offer some advantages over the hydrazine-sodium chloride methods of the original technique, and should be regarded as coniplementing them. An endoribonuclease activity (Phy M), isolated from the slime-mould Physarum polycephalum, cleaves single-stranded RNA at 50 “C in 7M-urea specifically and uniformly on the 3’-side of uridylate and adenylate residues; this is a useful property in RNA sequence analysis, since, in conjunction with results from cleavage by a pyrimidine-specific endonuclease, the pyrimidines are distinguished (as well as the adenine residues).21o The gel sequencing of nucleic acids may be complicated by the presence of stable secondary structure, resulting in the oligonucleotides that are generated in the sequencing technique showing abnormal mobility (‘compression’) in gel electrophoresis. This may be avoided by treatment of the nucleic acid (usually DNA) with methoxylamine and bisulphite, since the N4-methoxycytosine residues that are generated fail to form base-pairs efficiently with guanine, and effects of secondary structure are eliminated.211 Current gel sequencing techniques require that the nucleic acid to be sequenced be radioactively labelled at the 3’- or 5’-terminus. RNA may be labelled at the 3’-OH terminus by treatment with [Y-~~P]ATP and nucleotide pyrophosphate transferase from Streptomyces grisms, which transfers pyrophosphate to the 3’-OH group, the label ending in the ,8-position.212However, if the terminal residue is a pyrimidine nucleoside, transfer of pyrophosphate is inefficient. In this case, ~ G p [ ~ ~ may P l p be prepared from GMP and [Y-~~PIATP by using the same enzyme, and ligated to the 3’-terminus with T4 RNA ligase. A novel strategem for the 3’-terminal labelling of DNA uses [ W ~ ~ P ] A Tand P reverse transcriptase to insert the label at the cleavage site that is generated by treatment . ~ ~method ~ is necessarily dependent with the restriction endonuclease H i n ~ d I I 1The on the cleavage sequence of the restriction endonuclease. A major problem in RNA sequencing is that of cleaving RNA at specific sequences, in analogy to the cleavage of DNA by restriction endonucleases. However, the enzyme ribonuclease H from E. coli specifically cleaves RNADNA hybrids, When a nonadeoxyribonucleotide of known sequence was allowed to hybridize to a 59-nucleotide fragment of MS2 RNA that contained the complementary sequence, and the complex was treated with RNase H, the RNA was split specifically at the position corresponding to the 3’-end (on the RNA sequence) of the heteroduplex, thus providing an example of ‘addressed fragmentati~n’.~~~

Other Studies.-When nucleic acids are involved in secondary or tertiary interactions, their bases tend to be masked from attack by reagents which normally modify them. If the normal reaction that modifies the base leads to weakening of the glycosyl bond, permitting the elimination of the base and strand cleavage, limited modification of the end-labelled nucleic acid by such a reagent can be used to generate a series of oligonucleotides that are separable on sequencing 210

211 212

213 214

H. Donis-Keller, Nucleic Acids Res., 1980, 8, 3133. N. S. Ambartsumyan and A . M. Mazo, FEBS Lett., 1980, 114, 265. A. Simoncsits, Nucleic Acids Res., 1980, 8, 41 11. M. Fuke, Seikuguku, 1980, 52, 1079 (Chem. Abstr., 1981, 94, 99 195). V. G. Metelev, N. P. Radionova, N. V. Chichkova, I. G . Atabekov, A. A. Bogdanov, Z . A. Shabarova, V. Bergin, I. Jansone, and E. J . Gren, FEBS Lert., 1980,120, 17.

Nucleotides and Nucleic Acids

215

gels and which show bands only at positions where the bases are not involved in secondary interactions, and hence are available for modification. Treatment with dimethyl sulphate in cacodylate buffer, followed by strand scission (using borohydride and aniline) probes guanosine sites : treatment with dimethyl sulphate followed by hydrazine hydrate probes cytidine sites : and treatment with diethyl pyrocarbonate in cacodylate buffer, followed by aniline for scission, probes adenosine sites. These reactions are effective from 0 to 90 "C at pH 4.58.5. A comparison of the ladder gels that are afforded by using these reagents under native conditions with those obtained using denaturing conditions allows regions of higher-order structure to be located. The technique has been proven by mapping the progressive denaturation of yeast tRNAPhe with increasing A similar approach to the examination of secondary structure employs ethylnitrosourea (ENU), which alkylates exposed phosphodiester bonds but not those masked by secondary interactions. Alkylation of endlabelled yeast tRNAPhe with ENU in cacodylate buffer, at 20 "C for the native structure or at 80 "C for the denatured form, followed by heating for 5 minutes at 50 "C in Tris buffer at pH 9 (to effect random cleavage of the phosphotriesters that are formed), furnishes series of fragments which, when compared on sequencing gels, show which phosphodiester groups are masked.216The same method has been used to show which phosphodiester bonds in yeast tRNAVa1 become protected against alkylation by ENU on binding of the cognate aminoacyl-t RNA syn t hetase.217 A systematic study of the reactivity and products of methylation of the common ribonucleoside 5'-phosphates with methyl methanesulphonate at pH 7.4 has been reported, the products being isolated and then characterized by lH and 13C n.m.r.218The order of reactivity determined was N-7 of GMP > N-3 of CMP, N-1 of AMP and 5'-phosphate > N-1 of GMP and N-3 of UMP. The methylation of DNA219 and of RNAZz0by 13C-enriched methyl methanesulphonate can conveniently be monitored by examination of the methylated nucleic acids by 13C and 31P n.m.r. The signals of methyl carbon could be assigned by comparison with model compounds, allowing identification of the products without degradation and separation, and the alternative use of [14C]methyl methanesulphonate permitted the degree of methylation to be calculated. The number of apurinic and apyrimidinic sites that were formed on treatment of SV40 DNA with various electrophilic carcinogens and mutagens has been measured by treatment of the damaged DNA with exonuclease 111 from E. coli (an enzyme which specifically cleaves phosphodiester bonds adjacent to apyrimidinic sites) and gel-electrophoretic analysis of the products.221No direct correlation between the number of apyrimidinic sites produced by a given mutagen and its mis-sense mutagenic activity, as indicated by the Ames test, was observed. In the cases of alkylation by methyl- and ethyl-nitrosourea, the number of 215

$16 217 a18 219 220

231

D. A. Peattie and W. Gilbert, Proc. Natl. Acad. Sci. USA, 1980, 77, 4679. V. V. Vlassov, R. Giegt, and J. P. Ebel, FEBS Lett., 1980, 120, 12. V. V. Vlassov, D. Kern, R. Giegk, and J. P. Ebel, FEBSLett., 1981, 123, 277. C. Chang and C.-G. Lee, J. Carbohydr., Nucleosides, Nucleotides., 1980, 7 , 93. C. Chang, J. D. Gomes, and S. R. Byrn, J . Am. Chem. SOC.,1981, 103, 2892. C. Chang and C.-G. Lee, Biochemistry, 1981, 20, 2657. N. R. Drinkwater, E. C. Miller, and J. A. Miller, Biochemistry, 1980, 19, 5087.

216

Organophosphorus Chemistry

alkali-labile lesions in the treated DNA was markedly higher than the number of apyrimidinic sites produced, probably because these agents alkylate phosphodiesters to form alkali-labile phosphotriesters, while the other agents investigated did not. A review on mechanisms of reaction between nucleic acids and the chemical carcinogens which react with them directly has been published.222When DNA is incubated with ( i-)-7P,8a-dihydroxy-9a710x-epoxy-7,8,9,10-tetrahydrobenzo[alpyrene (BP diol epoxide) and subsequently treated with 0-1M-NaOH, it is cleaved at the alkylated sites. End-labelled DNA fragments of defined sequence were therefore treated with BP diol epoxide and alkali, and separated on denaturing polyacrylamide sequencing gels, where the positions of the bands revealed the preferred sites of strand scission.223Guanine residues were found to be preferred by a factor of 3 to 4 over other bases as the points of cleavage. In a separate the kinetics of the nicking that followed treatment of DNA with BP diol epoxide were consistent with the numbers of AP sites produced, and, as in the study described above,221no direct evidence for formation of phosphotriesters as a step in the nicking mechanism could be obtained. It was thought that BP diol epoxide may react at N-7 of g ~ a n i n e . ~224~ ~ g The roles of s u p e r ~ x i d eoxygen , ~ ~ ~ radicals generated by xanthine oxidase,226 the anti-tumour glycoside antibiotic c h a r t r e u ~ i nand ~ ~ ~cuprous complexes of 1,10-phenanthroline228> 2 2 9 in DNA strand scission have been investigated. To summarize, the role of the antibiotic and of the phenanthroline complexes seems to be to produce hydrogen peroxide and superoxide radicals from oxygen in the presence of reducing agents. Xanthine oxidase also forms these species. Peroxide and superoxide do not seem to effect strand scission directly, but to act as a source of hydroxyl radicals (particularly, by a Fenton reaction225in the presence of adventitious metal ions), which cause strand breakage, though the precise mechanism remains a matter for conjecture. Hydroxyl radical may thus be the simplest mutagen, and, since superoxide is formed in all living systems, the principal cause of intrinsic mutagenesis. The copper(1)-phenanthroline system showed a preference for cleaving double-stranded DNA, possibly due to i n t e r ~ a l a t i o n . ~ ~ ~ A number of novel bifunctional alkylating reagents have been synthesized and tested for their ability to effect inter-strand DNA cross-linking, and for their cytotoxic and anti-tumour effects.230 l-(2-[(2-Chloroethyl)thio]ethyl)-3-cyclohexyl-l-nitrosourea (102) was found to be a particularly effective reagent, causing rapid inter-strand cross-linking in DNA in physiological conditions and 222 e23 225

226 227

228 229

230

D. E. Hathway and G. F. Kolar, Chem. SOC.Rev., 1980, 9, 241. W. A. Haseltine, K. M. Lo, and A. D. D’Andrea, Science, 1980, 209, 929. H. B. Gamper, J. C. Bartholomew, and M. Calvin, Biochemistry, 1980, 19, 3948. S. A. Lesko, R. J. Lorentzen, and P. 0. P. Ts’o, Biochemistry, 1980, 19, 3023. K. Brawn and I. Fridovich, Arch. Biochem. Biophys., 1981, 206, 414. M. Yagi, T. Nishimura, H. Suzuki, and N. Tanaka, Biochem. Biophys. Res. Commun., 1981, 98, 642. D. R. Graham, L. E. Marshall, K. A. Reich, and D. S. Sigman, J . Am. Chem. Soc., 1980, 102, 5419. L. E. Marshall, D. R . Graham, K. A. Reich, and D . S. Sigman, Biochemistry, 1981, 20, 244. J. W. Lown, A. V. Joshua, and L. W. McLaughlin, J . Med. Chem., 1980, 23, 798.

Nucleotides and Nucleic Acids

217

showing activity against L1210 leukaemia in rodents. The interaction of a highly reiterated sequence of human DNA with the nitrogen mustard methylbis(2-chloroethy1)amine (HN2) has been investigated,231using sequencing gels to pinpoint the sites of reaction in the way previously described for BP diol e p o ~ i d e HN2 . ~ ~ ~was found to produce alkali-labile lesions predominantly at guanine positions. Following exposure of calf thymus DNA to NN’-bis-(2chloroethy1)-N-nitrosoureain cacodylate buffer, at pH 7, and subsequent acidic depurination, 6-(2-hydroxyethyl)guanine was identified as a Since Walkylated guanine residues in nucleic acids are thought to represent promutagenic lesions, this observation could explain the observed carcinogenic action of the reagent.

NHCON-

S

I

0.

Adenine and cytosine react with a-halogenoketones below pH 6, and aromatic nitrenes attack aromatic bases faster than they attack amino-acid side-chains of proteins. Using these two principles, several reagents that are designed to effect cross-linking between nucleic acids and proteins have been In studies which have investigated the nature of the covalent bonding in naturally occurring n u c l e o p r ~ t e i n s ,the ~~~ covalent link that is formed between DNA and DNA topoisomerase I from E. coli or M . Zuteus has been found to be a phosphodiester link to ~ e r i n e and , ~ ~ the ~ protein that is linked to nascent DNA chains in adenovirus that is replicating in vitro is also attached by a phosphodiester link to ~ e r i n e . ~ ~ ~ Cytosine bases in bulk RNA or tRNA from yeast or calf thymus DNA have been converted into 4-thiouracil by prolonged treatment of the nucleic acid with liquid H2S in pyridine at 40°C.237Some discrepancy was noted between the number of cytosine bases lost and the amount of 4-thiouracil formed, possibly due to the formation of disulphides. Not all cytosine residues can be modified: in tRNA, after reaction for 12 hours, about 2.7 cytosine residues of the 21 that are available had been converted into 4-thiouracil. Poly(U), poly(C), and 231

332

S. M. Grunberg and W. A. Haseltine, Proc. Natl. Acad. Sci. USA, 1980, 77, 6546. W. P. Tong, M. C. Kirk, and D. B. Ludlum, Biochem. Biophys. Res. Commun., 1981,100, 351.

233 234

235

236

G. Fink, H. Fasold, W. Rommel, and R. Brimacombe, Anal. Biochem., 1980,108, 394. Y . - C . Tse, K. Kirkegaard, and J. C. Wang, J. Biol. Chem., 1980, 255, 5560. J. M. Hermoso and M. Salas, Proc. Narl. Acad. Sci. USA, 1980, 77, 6425. M. D. Challberg, S. V. Desiderio, and T. J. Kelly, jun., Proc. Natl. Acad. Sci. USA, 1980, 77, 5105.

237

K. Miura and T. Ueda, Chem. Pharm. Bull., 1980,28, 3415.

218

Organophosphorus Chemistry

poly(A) have been spin-labelled by treatment with N-(2,2,5,5-tetramethyl-3carbonylpyrrolin-1 -oxyl)imidazole (1 03) in cacodylate buffer at pH 7.5, the carbonylpyrroline moiety being transferred to the 2’-OH group of the ribose rings.238The extent of spin-labelling was independent of the nature of the base but varied with the degree of rigidity of the secondary structure of the polynucleotide, with poly(U) becoming more highly labelled than poly(C) or poly(A). When poly(U) and poly(A) were irradiated with U.V. light in 2-propanol, 6-(2hydroxyprop-2-yl)-5,6-dihydro-UMP residues were formed in poly(U) and 8-(2-hydroxyprop-2-y1)-AMP residues in p ~ l y ( A ) While . ~ ~ ~ the abilities of the modified polynucleotides to act as messengers in a cell-free protein-synthesizing system were reduced, no change in the functional specificity, as evidenced by inhibition of the formation of polyphenylalanine or of polylysine, or the misincorporation of other amino-acids, was observed. When single-stranded DNA was heated in neutral aqueous buffers for prolonged periods, slow conversion of adenine residues into hypoxanthine residues was This form of hydrolytic damage could represent a spontaneous promutagenic lesion in DNA in uivo. A DNA glycosylase activity has been identified which specifically releases hypoxanthine from DNA that is damaged in this way, and is therefore presumed to operate in the repair of DNA. Fluorescent labelling of tRNAPhe from yeast and from E. coIi has been performed by oxidation of the 3’-terminal residue with periodate and subsequent condensation with dansylhydrazine or fluorescein thiosemicarba~ide.~~~ The modified tRNAs were used to measure binding parameters on 70s ribosomes of E. coli. A comprehensive review on the structures of binary complexes of mono- and poly-nucleotides with metal ions of the first transition group has appeared.242 A general kinetic method has been detailed which allows the determination of the dissociation constants of any metal-ATP complexes which are inhibitory substrate analogues for any enzyme that requires MgATP2- as a For instance, at low Mg2+ concentrations, lanthanide-ATP complexes act as linear competitive inhibitors of hexokinase with respect to MgATP2-. At higher Mg2+concentrations the double-reciprocal plots give a concave curve, since free Mg2+increases the concentration of MgATP2- at the expense of that of lanthanide-ATP complex. Using the data obtained, and the known dissociation constant of MgATP2-, the dissociation constant of the lanthanide-ATP complex can be calculated. The method applies equally well to metal-ADP complexes that are inhibitory for enzymes that utilize MgADP- as substrate. The concentration dependence of chemical shifts of protons in the n.m.r. spectra of nucleoside 5’-triphosphates in the presence and absence of metal ions has been used to obtain information on the self-association of the nucleotides and on the way in which it is influenced by metal ions.244Self-association is promoted by Mg2+, 2s8

Zs9 240

241 242

24s 244

A. I. Petrov and B. I. Sukhorukov, Nucleic Acids Res., 1980, 8, 4221. 2. Livneh, E. Livneh, and J. Sperling, Photochem. Photobiol., 1980, 32, 131. P. Karran and T. Lindahl, Biochemistry, 1980, 19, 6005. B. D. Wells and C. R. Cantor, Nucleic Acids Res., 1980, 8, 3229. H. Pezzano and F . Podo, Chem. Rev., 1980,80, 365. J. F. Morrison and W. W. Cleland, Biochemistry, 1980, 19, 3127. K. H. Scheller, F. Hofstetter, P. R. Mitchell, B. Prijs, and H. Sigel, J. Am. Chem. SOC., 1981, 103, 247.

Nucleotides and Nucleic Acids

219

which binds to the polyphosphate chain, neutralizing part of the negative charge, and more so by Zn2+and Cd2+,which appear to form intermolecular metal-ion bridges. Transition-metal cations in the + 2 state seem to promote the formation of macro-chelates with purine nucleoside 5’-triphosphates, and in favourable cases the lH n.m.r. data could be used to indicate the sites of binding of metal ions. Raman difference spectrophotometry has been used to observe competitive binding to nucleoside 5’-monophosphates by metal ions in mixtures that contain different heavy-meta1 ions.245

5 Analytical Techniques and Physical Methods Phosphorus-31 n.m.r. spectroscopy has again been used to yield much valuable information in nucleotides at monomer and polymer level. The pH dependence of the chemical shifts and of the coupling constants observed for the guanosine thiophosphate analogues GTP[&S],GTPCBS], GTPCyS], GDP[mS], and GDP[BS] [(SP)stereoisomers, where relevant] has been used to determine pK, values for these Large solvent shifts in the 31P n.m.r. spectra of nucleotides have been observed, particularly for dipolar aprotic Hydrogen-bonding to phosphate, or the lack of it, seems to be the chief determinant of the magnitude of the solvent effect, and possibly changes in solvation must be considered carefully before attempting to correlate changes in chemical shift with changes in torsional angle in the phosphate group. The structure of the base-stacked Mn2+-AMP complex has been studied, using measurements of 15N,13C,and 31Pelectron-nuclear relaxation times.248Phosphorus-3 1 n.m.r. has been used to determine the concentrations of Mg2+, MgATP2-, and MgADPin intact Ehrlich ascites tumour cells.249 In a reaction of the type: MgATP

+ X +MgADP + XP

31P n.m.r. may be used to measure simultaneously the concentrations of the various phosphate-containing species, and thus to evaluate the equilibrium constant. If ATP is replaced by ATP[PS], AG for the above reaction becomes more exergonic by some 2.5 kcal mol-l, and the equilibrium is thus displaced towards the right-hand side by a factor of about 60. Thus, measuring the equilibrium constant for such a reaction by utilizing the thionucleotide permits the equilibrium constant for the same reaction involving the oxynucleotide to be calculated immediately. This is a convenient procedure when the equilibrium for the oxynucleotide reaction lies far to the left-hand side of the equation, and has been used to determine values of the equilibrium constant for the reactions catalysed by pyruvate kinase and 3-phosphoglycerate k i n a ~ e . ~ The ~ O reaction that is catalysed by creatine kinase from rabbit muscle has also been investigated by 31Pn.m.r., and the equilibrium constant and the shifts in 31P resonances on 245 246

247 248 248

250

M. R. Moller, M. A. Bruck, T. O’Connor, F. J. Armatis, jun., E. A. Knolinski, N. Kottmair, and R. S. Tobias, J. Am. Chem. SOC.,1980, 102, 4589. P. Rosch, H. R. Kalbitzer, and R. S. Goody, FEBS Lett., 1980, 121, 211. D. B. Lerner and D. R. Kearns, J. Am. Chem. Soc., 1980, 102, 7611. G. C. Levy and J. J. Dechter, J. Am. Chem. SOC.,1980,102,6191. R . K. Gupta and W. D. Yushok, Proc. Natl. Acad. Sci. USA, 1980,77, 2487. C. L. Lerman and M. Cohn, J. Biol. Chem., 1980,255, 8756.

220

Organophosphorus Chemistry

binding of the metabolites to the enzyme have been determined.251 Other protein-nucleotide interactions which have been investigated by 31P n.m.r. include myosin-nucleotide complexes,252the ATP-Ca2+-G actin complex,253 and complexes between elongation factor Tu and guanine n u ~ l e o t i d e s . ~ ~ ~ Phosphorus-3 1 n.m.r. studies on polydeoxyribonucleotides have included studies on self-complementary alternating c o p ~ l y r n e r 256 s ~and ~ ~ ~on DNA.256-259 The signals obtained for poly[d(A-T)] indicate an alternating phosphodiester backbone for this copolymer (and others) in the B form,255but a single uniform backbone conformation in fibres in the A form.256There seems to be some disagreement as to whether the phosphodiester orientations in DNA vary or 257 although the phosphodiester backbone is thought to experience fast internal m o t i o n ~ . ~ ~ 2 5 9~ * Changes in values of chemical shifts are seen when intercalating ligands are added, probably due to changes in the geometry of the sugar-phosphate chain on unwinding.260 Studies involving polyribonucleotides, using 31P n.m.r., have included the partial assignment of phosphorus resonances and the observation of temperatureand metal-ion-induced conformational changes in tRNAPhe of yeastze1,262 and the investigation of the structures, in solution, of 5s RNA from Bacillus licheniand p ~ l y ( I ) . ~ ~ ~ f o ~ m i sthe , ~ acid ~ ~ poly(A) double In organisms of higher organization, 31Pn.m.r. has been used to investigate the structural disposition of DNA in fd virusze6 and in the lipid-containing bacteriophage PMLZe7 A study of the c.d. and of the U.V. spectra of the 2’-deoxy-5-methylcytidylatecontaining self-complementary copolymer poly[d(G-m5C)] indicates that it undergoes a transition from the B form to the Z form at a lower concentration of salt than does poly[d(G-C)] and is stable in the Z-form under typical physiological conditions.268It may, therefore, occur in this form in uiuo. Picosecond time-dependent fluorescence-depolarization techniques have been used to monitor the re-orientation of ethidium bromide that is intercalated in DNA and RNA, and hence to obtain information on the torsional dynamics of the 251 252

253 254

255 256

257 258

259 260

261

262 263 264 265 266

267 268

B. D. N. Rao and M. Cohn, J. B i d . Chem., 1981, 256, 1716. J. W. Shriver and B. D. Sykes, Biochemistry, 1981, 20, 2004. M. Brauer and B. D. Sykes, Biochemistry, 1981, 20, 2060. A. Nakano, T. Miyazawa, S. Nakamura, and Y. Kaziro, FEBS Lett., 1980, 116, 7 2 . J. S. Cohen, J. B. Wooten, and C. L. Chatterjee, Biochemistry, 1981, 20, 3049. H. Shindo, J. B. Wooten, and S . B. Zimmerman, Biochemistry, 1981, 20, 745. B. T. Nall, W. P. Rothwell, J. S. Waugh, and A. Rupprecht, Biochemistry, 1981,20, 1881. S. J. Opella, W. B. Wise, and J. A. DiVerdi, Biochemistry, 1981, 20, 280. M. E. Hogan and 0. Jardetzky, Biochemistry, 1980, 19, 3460. R. L. Jones and W. D. Wilson, J. Am. Chem. Soc., 1980, 102, 7776. D. G. Gorenstein, E. M. Goldfield, R. Chen, K. Kovar, and B. A. Luxon, Biochemistry, 1981, 20, 2141. P. J. M. Salemink, E. J. Reijerse, L. C. P. J. Mollevanger, and C. W. Hilbers, Eur. J. Biochem., 1981, 115, 635. P. J. M. Salemink, H. A. RauC, A. Heerschap, R. J. Planta, and C. W. Hilbers, Biochemistry, 198 1, 20, 265. D. B. Lerner and D. R. Kearns, Biopolymers, 1981, 20, 803. J. M. Neumann and S. Tran-Dinh, Biopolymers, 1981, 20, 89. J. A. DiVerdi and S. J. Opella, Biochemistry, 1981, 20, 280. H. Akutsu, H. Satake, and R. M.Franklin, Biochemisrry, 1980, 19, 5264. M. Behe and G. Felsenfeld, Proc. Natl. Acad. Sci. USA, 1981, 78, 1619.

Nucleotides and Nucleic Acids

221

nucleic acid m01ecules.~~~ The dependence of the e.s.r. parameters of spinlabelled adenine ribonucleotides on associative interactions with the unmodified nucleotides has been used to derive thermodynamic parameters of association of nucleotides and to determine the factors that govern association at different pH values.27o Drugs which bind to DNA are frequently positively charged, and thus show poor solubility in organic solvents. However, on addition of a solute, such as sodium tetraphenylboronate, which acts as a phase-transfer reagent, the solubility of such drugs is generally much increased. If DNA in an aqueous medium is then allowed to achieve equilibrium with the drug-solute-organic solvent system, partition analysis permits the determination of drug-DNA binding constants which were experimentally unattainable by using this method in the absence of the phase-transfer reagent.271 The secondary-ion mass spectrometry of nucleotides that have been deposited on silver foil and are bombarded with argon cations has been and high-resolution analysis of the major ions observed in the mass spectrum of salmon sperm DNA fragments has been performed.273A method for the quantitative analysis of CAMP in cultured tobacco tissue, employing g.1.c.-m.s. with multiple ion detection, has been reported.274

270 271

D. P. Millar, R. J. Robbins, and A. H. Zewail, Proc. Natl. Acad. Sci. USA, 1980,77, 5593. A. I. Petrov and B. I. Sukhorukov, Mol. Biol. (Moscow), 1980, 14, 439 (Chem. Abstr., 1980, 93, 132 727). T. R. Krugh, S. A. Winkle, and D. E. Graves, Biochem. Biophys. Res. Commun., 1981, 98, 317.

272 273

A. Eicke, W. Sichtermann, and A. Benninghoven, Org. Mass. Spectrom., 1980, 15, 289. D. Gaudin and K. Jankowski, Org. Mass Spectrom., 1980, 15, 78. L. P. Johnson, J. K. MacLeod, C. W. Parker, and D. S. Letham, FEBS Lett., 1981,124, 119.

I0 Ylides and Related Compounds BY B. J. WALKER

1 Methylenephosphoranes Preparation and Structure.-Information useful to those of us interested in ylides and their reactions is included in a recent comprehensive review of synthetic methods using a-heterosubstituted organometallics.' The conformations and energetics of the simplest methylenephosphonium ylide (1) have been predicted from ab inifiu orbital theory at the Hartree-FockSCF The results suggest an sp2-hybridized carbanion and a very low barrier to rotation about P-C. Phosphine-phosphonium ylide tautomerism (2) has been further investigated and, predictably, strongly electron-withdrawing a-substituents favour the ylide form.3 The equilibrium is dependent on solvent and on temperature, although the exact effects are not entirely clear from the published data.

Ph,P=CH,

+ C4C-X

-

Ph,k--CH,C-CI

(X = S or NAr)

c1-

1

I1

ZPh,P=ct

t

2Ph3P-Me

C1-

1,

+

+ Ph,P=C=C=X

C1-

(3) x = s (4) X = NAr

The cumulated ylides (3) and (4) have been synthesized by the reaction of methylenetriphenylphosphorane with thiophosgene and with isocyanide dichlorides, respectively.* 1 2

3

4

A. Krief, Tetrahedron, 1980, 36, 253 1 . R. A. Edes, P. G. Gassmann, and D. A. Dixon, J . Am. Chem. SOC.,1981, 103, 1066. T. A. Mastryukova, I. M. Aladzheva, I. V. Leont'eva, P. V. Petrovskii, E. I. Fedin, and M. I. Kabachnik, Tetrahedron Lett., 1980,21, 2931. H. J. Bestmann and G. Schmid, Chem. Ber., 1980,113, 3369.

222

Ylides and Related Compounds

223 Me0

Me0

0

Reagents: i, PhaP, MeNO2; ii, HsO+; iii, Na2C03; iv, MeBr

Scheme 1

(2-Oxocycloalkylidene)trip henylphosphoranes ( 5 ) have been obtained from bromo-enol ethers and triphenylphosphine, followed by dealkylation and treatment with mild base (Scheme l).5 The allylic phosphonium salt (6) undergoes coupling on treatment with one mole equivalent of aqueous sodium hydroxide to give the dimeric ylide-salt (8) and the ylide (7);6 compound (8) undergoes a Wittig reaction with benzaldehyde to give the diene salt (9). Convincing evidence has been presented that the 1-alkoxyalkylidenephosphoniumylides (1 1) are involved in the reactions of the labile 1-iodo-1-alkoxyalkylphosphonium salts (101.7 +

Br-

Ph,P-CH,-CH=-CHCO,Et

(6 )

,CO,Et

Ph

NaOIl

Ph,P=CH-CH=CHCO,Et (7 1

-

Br-

Ph,P=CH r \ P P h ,

I

+

Et,P-

1

C -R’

I

0RZ (10)

-

+

Et,P-c

R’

-/ ‘OR2

A variety of cyclic ylides have been synthesized. The reaction of the cyclic phosphine (12) with 1,4-dibromobutane followed by treatment with base gives a mixture of ylides (13), (14), and (15), as shown in Scheme 2.8 The cyclic monoylides (17) and double ylides (18) have been prepared by treatment of the double IS

*

E. Ohler and E. Zbiral, Chem. Ber., 1980, 113, 2326. M. W. Bredenkamp, J. S. Lesch, J. S. Malherbe, E. M. Molner, and D. F. Schneider, Tetrahedron Lett., 1980, 21,4199. P.-E. Hansen, J. Chem. SOC.,Perkin Trans. 1, 1980, 1627. H. Schmidbaur and A. Moertl, Z. Naturforsch, Teil. B., 1980, 35, 990.

Organophosphorus Chemistry

2 24

9

pPMe

+ @ + -P b

(12)

\I

(15)

Scheme 2 R, P

R,

R2P-+

I

CH2

I1

(14)

(13)

Reagents: i, Br(CH2)4Br; ii, base

CH,

\

8

2Br-

(16)

(17)

(18)

A

P R,

8 M'

(19)

salt (16) with one and two moles of base, re~pectively.~ The double ylide (18) appears to exist as a mixture of fluxional forms, but no contribution from a carbodiphosphorane could be detected. However, treatment of (18) with dimethylzinc gives the co-ordinated carbodiphosphorane (19). Diphosphonium ylide anions (20) were obtained by further reaction of the double ylides (18) with base. The first examples of unco-ordinated cyclic carbophosphoranes (21) have been prepared (Scheme 3).1° The stability of these compounds decreases with decreasing ring-size, owing to increasing angular strain at the P=C=P structural unit.

(21) n = 2, 3, or 4

Reagents: i, Br(CH&Br; ii, 2Me3P=CHz

Scheme 3 9

10

H. Schmidbaur, T. Costa, and B. Milewski-Mahrla, Chem. Ber., 1981, 114, 1428. H. Schmidbaur, T. Costa, B. Milewski-Mahrla, and U. Schubert, Angew. Chem., Int. Ed. Engl., 1980, 19, 555.

Ylides and Related Compounds

225

Continuing investigations of poly-ylide ligands have led to the synthesis of the bidentate ligand (22)11 and the phosphonium ylides (23) and (24), where germanium replaces the carbanionic carbon atom.12 In the case of the mono-ylide (24), both lH and 31Pn.m.r. data suggest that fluxional behaviour occurs through rapid intramolecular transfer of germanium dichloride from phosphorus to phosphorus. +

Me,P-BH,

Br-

Me,P-0

+/-\

2!

Me,P

Bu'Li+

PMe,

I1

Me,P

PMe,

I

I

C1,

Triphenylphosphine is known to react with carbon tetrabromide to give 1,l-dibromomethylenetriphenylphosphorane and hence 1,l-dibrorno-alkenes.l3 Bestmann and his co-worker l4 have now applied this reaction to the synthesis of enynes, as shown in Scheme 4. In contrast, alkyldi(t-buty1)phosphines react with 2Ph,P + CBr, + R'CHO

-

R' CZEZ C B r

R'CH==CBr, ii

(X

2)

*

+ Ph,PBr, + Ph,PO -

R'CGC-CCH-PPh,

+

bi

R'C-CCH-CHR' Reagents: i, R14N+ OH-; ii, Ph3P=CH2; iii, R2CH0

Scheme 4

carbon tetrachloride or tetrabromide to give the ylides (25), which react with carbon dioxide and phenyl isocyanate to give phosphonyl ketens 26) and phosphonyl ketenimines (27), re~pective1y.l~ l1 l2 13

l4 l5

H. Schmidbaur and E. Weiss, Angew. Chem. Int. Ed. Engl., 1981, 20, 283. W.-W. du Mont, G. Rudolph, and N. Brunks, Angew. Chem., Znt. Ed. Engl., 198 , 20,475. e.g. H. Teichmann, Z . Chem., 1974, 14, 216. H. J . Bestmann and H. Frey, Liebigs Ann. Chem., 1980, 2061. 0. I. Kolodiazhnyi, Tetrahedron Lett., 1980, 21, 3983.

226

Organophosphorus Chemistry 0

II

But,PCR=C=O

But,PCH,R

+ CX,

I

-+

(X = Br or C1)

But,P=CHR

+ CHX,

(25 1

But,PCR=C=NPh

(27)

Reactions.-Aldehydes. The synthesis of cycloalkenes by phosphorus-based intramolecular olefination has been reviewed.16 Ab initio M.O. calculations have been applied to the Wittig reaction. SCF calculations on the simplest Wittig reaction [reaction (l)] indicate a concerted pathway of very low activation energy

to a phosphetan intermediate (28), with no apparent involvement of the betaine form (29).17 Although this is interesting, and supports current thinking about the Wittig mechanism, one is tempted to ask how this relates to the more realistic situation with three phenyl substituents at phosphorus and bulky substituents at carbon. The energy difference between the apical-oxygen (30) and equatorialoxygen (31) pseudorotational isomers of the oxaphosphetan (28) has been calculated18as 19.3 kJ mol-l, and this small value is supported by the observation of two pseudorotational forms of Wittig intermediates in other systems by 31Pn.m.r. spectroscopy.

In an excellent and comprehensive investigation of the Wittig reaction,Ig

31Pand lH n.m.r. studies of the reaction of reactive salt-free ylides with aldehydes and non-hindered ketones at - 78 "C provide convincing evidence for the existence of oxaphosphetan intermediates, but no evidence for betaine intermediates. In some cases the oxaphosphetan was actually crystallized. Crude rate studies indicate that adducts of methylene ylides decompose faster than those derived from ethylene ylides, and the effect of lithium halides on all these intermediates l6

l7 l8

l9

K. R. Becker, Tetrahedron, 1980, 36, 1717. R. Holler and H. Lischka, J. Am. Chem. SOC.,1980, 102, 4632. H. J. Bestmann, J. Chandrasekhar, W. G. Downey, and P. von R. Schleyer, J. Chem. SOC., Chem. Commun., 1980, 978. E. Vedejs, G . P. Meier, and K. A. J. Snoble, J . Am. Chem. SOC.,1981, 103, 2823.

Ylides and Related Compounds

227

has been studied in detail. Methylenetriphenylphosphonium ylide, prepared from lithium alkyl, appears to be best described as (32), while higher alkylidene ylides are largely ‘free’ ylide. However, at the intermediate stage, insoluble lithium halide-betaine adducts (33) are rapidly formed in both cases, although oxaphosphetan structures can still be observed by 31Pn.m.r. spectroscopy. Experiments Ph,kH$HR

CH,Li B i

Ph3i--

I

Br-

0Li (33)

(3 2)

involving ‘crossover’ confirm that oxaphosphetans that are derived from alkylidene ylides and aromatic aldehydes are capable of reversible dissociation (‘betaine-reversibility’), while similar oxaphosphetans that are derived from aliphatic carbonyl compounds are not. One important conclusion that must be drawn from the high cis selectivity that is observed even in some reversible Wittig condensations, is that high trans selectivity should no longer be accepted as sufficient evidence for reversibility in condensations that involve stabilized ylides. Finally, lithium salts appear to affect stereochemistry by altering the condensation step, and not by inducing cis-trans equilibration of the oxaphosphetan; however, attempts to describe a transition state for condensation which explains the observed stereochemistry still leave a lot to be desired. The Wittig reaction 2o and PO-stabilized olefination 21 in two-phase systems have been further investigated. While the Wittig reaction is virtually uneffected by added phase-transfer catalyst, similar reactions of PO-stabilized carbanions give greatly increased yields in the presence of such catalysts. The results have been rationalized on the basis of neutral phosphonium ylides and salt-like PO-stabilized carbanions, the former not requiring the help of phase-transfer catalysis to diffuse into the organic layer. In view of this, it is not too surprising that the high yields of olefins that are obtained from Wittig reactions with aliphatic aldehydes in the presence of crown ethers can also be obtained by replacing the crown ether with small amounts of water! 22

MSeR3 +

Ph,P=CR1R2

CHO

+

GR’

Ph,P =CHOMe

RZ

H

(35)

(34)

cis-Alkenes are now so readily obtained by Wittig reactions that they have been used as intermediates in the synthesis of trans-alkenes!231-Alkyl(or ary1)seleno-lvinylcyclopropanes (34) have been prepared with very high (2)stereospecificity by using standard Wittig methods, and without resort to salt-free ~ o n d i t i o n s . ~ ~ 2o

21 22 23 24

E. V. Dehmlow and S. Barahona-Naranjo, J. Chem. Res. ( S ) , 1981, 142. E. V. Dehmlow and S. Barahona-Naranjo, J. Chem. Res. ( S ) , 1981, 143. M. Delmas, Y.Le Bigot, and A. Gaset, Tetrahedron Lett., 1980, 21, 4831. G. Just and D. R. Payette, Tetrahedron Lett., 1980, 21, 3219. S. Halazy and A. Krief, Tetrahedron Lerr., 1981, 22, 1833.

0rganophosphorus Chemistry

228

Methoxymethylenetriphenylphosphorane(35) continues to be used to convert aldehydes into their one-carbon homologues;25however, it appears that t-butyllithium is preferred to n-butyl-lithium as the base for generating these ylides, since the use of the latter led to significant amounts of alkene, derived from butylidenetriphenylphosphorane.26 Ph,P=CH(CH=CH),CO,R

+ ArCHO

--+

Ar(CH=CH),+,CO,R

(Ar = 1-anthryl or 2-anthryl)

(36)

Examples of syntheses of dienes and of trienes by the Wittig reaction include the a-anthrylalkenoic acids (36),27the trienyne (37),28 and triene cyclopropyl bromides (38) for conversion into lipid hydro peroxide^.^^ The same reaction has also been used to convert all-cis-triene aldehydes (39) into tetraenes without isomerization .3 O

Me0

(37)

CHO

(39)

The use of potassium t-butoxide as a base appears to offer advantages in the generation of bromomethylene ylides (40),31which react with aldehydes to give predominantly (Z)-l-bromo-alkenes. The phenoxide ylide (41) undergoes normal Wittig reactions with aromatic aldehydes.3zThe 13C-labelledester (43) has been prepared by Wittig reaction of the appropriately labelled salt (42), using oxiran as a base.33 e.g. D. Heissler and J.-J. Riehl, Tetrahedron Lett., 1980, 21,4707; ibid., p. 471. B. M. Trost and T. R. Verhoeven, J. Am. Chem. SOC.,1980,102,4743; see also A. Maercker, Org. React., 1965, 14, 280. 27 P. Arjunan, N. Shymasundar, K. D. Berlin, D. Najjar, and M. G. Rockley, J. Org. Chem., 1981, 46, 626. 28 J. A. M. Peters, T. A. P. Posthumus, N. P. Van Vliet, F. J. Zeelan, and W. S. Johnson, J. Org. Chem., 1980,45, 2208. 29 N. A. Porter, D. H. Roberts, and C. B. Ziegler, Jr., J. Am. Chem. SOC.,1980, 102, 5912. 3 0 W. Boland and L. Jaenicke, Liebigs Ann. Chem., 1981, 92. 31 M. Matsumoto and K. Kuroda, Tetrahedron Lett., 1980, 21, 4021; see also ref. 14. 32 L. Crombie, W. M. L. Crombie, and S . V. Jamieson, Tetrahedron Lett., 1980, 21, 3607. 33 W.-D. Woggan, F. Ruther, and H. Egli, J. Chem. SOC.,Chern. Comrnun., 1980, 706. 25

26

Ylides and Related Compounds

229 Me0

+ RCHO

Ph,P=CHBr

+

P-CH a -

RCH=CHBr

(40)

-0

(41)

0,

+

(CH, ),CH 0

(CH,),

A

Ph,;-CHC02Me I3CH3 I-

\c/H

I1

PhH

C

(4 2)

‘C02Me

I’CHf

(43)

Lactols, e.g. are known to act as equivalents of aldehydes in the Wittig reaction; however, in the case of (49, different products, (48)and (49)respectively, are obtained on reaction with the ylide (46) and with the phosphonate carbanion (47),35 presumably due to base-catalysed cyclization of (48) in the latter case. Perhaps surprisingly, the stable B-keto-ylide reacts with the aldehyde (50) to give the (Z)-alkene (51) stereo~pecifically.~~

9 tiOH poH (45)

(44)

Ph,P

0

H (45)

0 (45)

+

+ ( E t O J q 0

1(46)

-

0

H

0

H

0 (49)

(47)

(48)

H

H

35

36

OCH,Ph

OMe R. D. Little and G. W. Muller, J. Am. Chern. SOC.,1981, 103, 2744. T. R. Hoye and A. J. Caruso, J. Org. Chem., 1981, 46, 1198. K. Tatsuta, Y . Anemiya, S. Maniwa, and M. Kinoshita, Tetrahedron Lett., 1980, 21, 2837.

Organophosphorus Chemistry

230

0 Ph,fi(CH,),CO,H

I\

X-

Ph$ (CH,), CO,H

(52) n = 2, 3, 5 , 10, or 11

(53)

The reported failure of o-carboxyalkyltriphenylphosphonium salts (52) to undergo the Wittig reaction 37 is surprising, especially in view of the extensive use of (52; n=5) in prostaglandin synthesis.38 The products (53) that were isolated from this reaction would, of course, be formed if small amounts of water were present at any period during the long reaction times. P-Chlorinated phosphonium ylides have been reported39 to react with aldehydes to give single diastereoisomers of (2-ch1oroalkyl)phosphine oxides (55) in each case, rather than undergoing olefination. A mechanism involving an oxetan intermediate has been suggested; however, an intermediate vinylphosphonium salt (54), as in the case of related rearrangements of triarylphosphonium ylide~,~O seems more likely. This latter mechanism would also explain the stereochemistry of the reaction. R'

I Buf-P=CHR2 I CI

+ RTHO

-

R'

0-

I I Bu'-P+-CHR~--CHR~

I

C1

Reactions of Ketones. The Wittig reaction of (2,2-diethoxyvinylidene)triphenylphosphorane with hexafluoroacetone provides a further example of a stable oxaphosphetan (56).41 In fact (56) requires heating at temperatures above 100 "C before decomposition occurs, to give l,l-diethoxy-4,4,4-trifluoro-3-trifluoromethylbuta- 1,2-diene. The (2)-isomers of trisubstituted alkenes (57) are formed in high yield and with high stereoselectivity by the salt-free Wittig reaction of acyclic a-alkoxy37 38

39 40

41

K. S. Narayanan and K. D. Berlin, J . Org. Chem., 1980, 45, 2240. e.g. B. J. Walker, in 'Organophosphorus Chemistry', ed. D. W. Hutchinson and J. A. Miller, (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1980, Vol. 1 1 , p. 216. 0. I. Kolodiazhnyi, Tetrahedron Lett., 1981, 22, 1231. S. Trippett, in 'Organophosphorus Chemistry', ed. S. Trippett (Specialist Periodical Reports), The Chemical Society, London, 1970, Vol. 1, p. 34. R. W. Saalfrank, W. Paul, and H. Liebenow, Angew. Chem., Znt. Ed. Engl., 1980, 19,713.

Ylides and Related Compounds

23 1

- )I<; F3C=

Ph,P=C-C(OEt),

+ (CF,),CO

(at

FC

/

Et0-c

> 100°C)

I

C F,

(56)

Ph

OEt

’\

C=C=C’

F,C /

Ph,P=CHR’

’OEt

+0

( a t - 78’C)

(57)

ketones and reactive y l i d e ~ ,and ~ ~ the procedure offers an alternative to the Schlosser method.43Wittig olefination and silicon-based olefination of 2-(t-butyldimethylsily1oxy)cycloalkanones (58) are complementary in that the former reaction, using carbethoxymethylenetriphenylphosphorane,gives almost exclusively the (E)-alkene (59), while the reaction with the corresponding silyl carbanion gives predominately the (Z)-alkene (60).44

The alkylation of o-hydroxybenzyltriphenylphosphonium salts (61) with a-halogeno-ketones in the presence of base gives chrom-3-enes via an intramolecular Wittig reaction.45 Intramolecular Wittig reactions are also involved in the synthesis of 4-azabicyclo[3.3 .O]nonanes, e.g. (62), from carbethoxycyclopropyltriphenylphosphoniumsalts and i m i d e ~ . ~ ~ 42

43 44

45

46

C. Sreekumar, K. P. Darst, and W. C. Still, J. Org. Chem., 1980, 45, 4260. S. Trippett, in ‘Organophosphorus Chemistry’, ed. S. Trippett (Specialist Periodical Reports), The Chemical Society, London, 1974, Vol. 5, p. 177. G . L. Larson, J. A. Prieto, and A. Hernandez, Tetrahedron Lett., 1981, 22, 1575. B. Begasse and M. Le Corre, Tetrahedron, 1980, 36, 2409. J. M. Muchowski and P. H. Nelson, Tetrahedron Lett., 1980, 21, 4585.

232

a

Organophosphorus Chemistry

CH,hPh, Jjr-

R'CHXCOR'

R'

OH

0

0

The fluorinated analogue (63) of the a-methylene-y-lactone structure, which is frequently encountered in natural systems, has been prepared47aby olefination with the triphenylphosphine-dibromofluoromethane-zinc reagent.47b Difficulties have been e n c o ~ n t e r e din~ ~ the synthesis of (k)-modhephene (66) owing to the low reactivity of the tricyclic ketone precursor (64) towards nucleophiles, including Wittig reagents. However, the high-temperature Wittig conditions that are known49 to be effective with other hindered, easily enolizable

ketones gave a high yield of epimeric olefins (65),which could readily beisomerized to (66). An improved method for the conversion of hindered ketones into their homologous aldehydes has been developed by C~rey.~O The reaction of the ketone, e.g. (67), with the phosphine-stabilized carbanion (69), followed by methylation, gives the coresponding enol-ether, e.g. (68), which can be hydrolysed 47

48 49 50

( a ) M. Suda, Tetrahedron Lett., 1981, 22, 1421; (b) S. Hayashi, T. Nakai, N. Ishikawa, D. J. Burton, N. G. Naal, and H. S. Kesling, Chem. Lett., 1979, 983. A. B. Smith, 111, and P. J. Jerris, J. Am. Chern. SOC.,1981,103, 194; see also M. C. Pirrung, ibid., p. 82. J. M. Conia and J.-C. Limassett, Bull. SOC.Chim. Fr., 1967, 1936. E. J. Corey and M. A. Tius, Tetrahedron Lett., 1980, 21, 3535.

233

Ylides and Related Compounds

Reagents: i, PhaPCH(Li)OMe (69); ii, MeI; iii, H30+

Scheme 5

to the aldehyde (Scheme 5). In all cases studied, the yields were much higher than those obtained from similar reactions with ylides and with PO-stabilized carbanions. Not surprisingly, attempts to synthesize 1,4-di-t-butylcyclo-octatetraene through dimeric coupling of the hindered ylide (70) were U ~ S U C C ~ S S ~ U

(70)

Miscellaneous Reactions. Ylides that were generated in situ from tertiary phosphines and activated alkenes have been used as catalysts for transe~terification.~~ The authors have proposed that the six-membered intermediate (73) is involved; however, all their results can be accommodated by abstraction of a proton from the alcohol by the ylide (71) to give (72),53followed by base-catalysed esterexchange. R',P + H2C=CHX

(71)

~

3

~

+~ 0 ~ ~ ~0 2-

(72)

R' :P-Cy-

CH, X

(73)

Thermolysis of rn- and p(acy1oxy)benzoyl ylides (74) gives, predictably, the corresponding methyl arylpropiolate (76).54However, similar reactions of the o-(acy1oxy)benzoyl ylides are more complex, and involve the formation of an acetylene or cyclization to the chromone ( 7 9 , depending on the nature of the acyl group. Chromones (78) are also the products of intramolecular Wittig reaction of the carbonate carbonyl group in the ylide (77),55and the reaction has been used to synthesize desmethoxycapillarisin (78 ;R1= H, R2= R3= R4= OH).56 51 52

53 54 55 56

M. J. Miller, M. H. Lyttle, and A. Streitwieser, Jr., J . Org. Chem., 1981, 46, 1977. S. Hashimoto, I. Furukawa, and T. Juroda, Tetrahedron Lett., 1980, 21, 2857. M. G. Burnett, T. Oswald, and B. J. Walker, J . Chem. SOC.,Chem. Commun., 1977, 155. B. Babin, J. Dunogues, and M. Petraud, Tetrahedron, 1981, 37, 1131. H. Takeno and M. Hashimoto, J. Chem. SOC.,Chem. Commun., 1981, 282. H. Takeno, M. Hashimoto, Y. Koma, H. Horiai, and H. Kikuchi, J . Chem. SOC.,Chem. Commun., 1981,474.

234

Organophosphorus Chemistry

C=CC 0,Me

X'

(76)

+ 0

(77)

(78)

Bestmann and his co-workers have continued their investigations of phosphacumulene ylides. The reaction of N-phenyl(triphenylphosphorany1idene)ketenimine (79) with a-,/3-, and y-oxacarboxylic acids provides routes to cyclic ketones, imides, and i ~ o i m i d e sThe . ~ ~ reactions that are involved are outlined in Scheme 6; the particular pathway that is followed depends on the acid used. NPh

Ph,P=C=C=NPh

(79)

__f

+

Ph,P=CH-C

(- P11,PO)

'0

/

RCOXC0,H

RCOXCO

I /ExR

3 ( - PI1 PO) Ph3P=7H

0

57

R

tA0 0

Ph,P=CCONHPh +-

COXCOR

I

COXCOR

Scheme 6 H. J. Bestmann, G. Schade, and G. Schmid, Angew. Chem., Znt. Ed. Engl., 1980,19, 822.

Ylides and Related Compounds

235

Ph,P=C=C=X

H

Ph,P=C

(8 0)

+

--+

0-CR'

C

C

II

fiCOR2

P11,PO)

1

\

R' COCCO R2

R'

\ dX( / \N,Np"

NNHPh

R2C0

(X = 0, NPh, or 9-fluorenyl) Ph,P=CH

\C//x

S

s

II

(80) + PhCOCNHR

_.)

(X = NPh or 9-fluorenyl)

/

o
II

NR

Scheme 7

Heterocycles are also the products from the reactions of the cumulene ylides (80) with phenylhydrazones and benzoyl thioamides, as shown in Scheme 7.58 On heating alone, the N-aryl(triphenylphosphorany1idene)ketenimines (8 1) dimerize to give (82),59 while their reaction with 1,3-dipoles gives cycloaddition products, e.g. (83).60 The reaction of (triphenylphosphorany1idene)keten with certain carboxylic esters has been used to synthesize a variety of heterocycles, e.g. (84)61 and (85).62

Ph,$ Ph,P=C=C=NPh

+P h C d - 0

-+

Phv \ N

P

h

(83) 58 59

H. J. Bestmann, G . Schmid, and D. Sandmeier, Tetrahedron Lett., 1980, 21, 2939. H. J. Bestmann, G . Schmid, R. Bohme, E. Wilhelm, and H. Burzlaff, Chem. Ber., 1980, 113, 3937.

6o 62

H. J . Bestmann and G. Schmid, Tetrahedron Lett., 1981, 22, 1679. K. Nickisch, W. Klose, E. Nordhoff, and F. Bohlmann, Chem. Ber., 1980, 113, 3086. W. Klose, K. Nickisch, and F. Bohlmann, Chem. Ber., 1980, 113,2694.

Organophosphorus Chemistry

236

(84)

(85 1

The use of [bis(alkylthio)vinylidene]triphenylphosphoranes (86) as synthetic reagents has been in~estigated.~~ These compounds, which are conveniently prepared from the corresponding phosphonium salt, provide routes to 1,l-bis(alky1thio)-allenes (87) and -butatrienes (88), 1,2-bis(alkylthio)acetylenes (89), and tris(alky1thio)ethylenes(90). Triazole-1-carbonitrile (93,a precursor of the a-cyanimino-carbene (93), has been prepared by the reaction of the keto-ylide (91) with c y a n a ~ i d e . ~ ~ Phosphonium ylides react with pyrylium and thiopyrylium salts to give 1-(4H-pyran-4-y1)- (94) and l-(4H-thiopyran-4-yl)-triphenylphosphoniumsalts (95);65these compounds give the corresponding ylide on treatment with base, and the reaction has been used in a general synthesis of unsymmetrical A494’-bi4H-pyrans (96) and -thiopyrans (97).66 The 1,3-diazafulven-6-yltriphenylphos-

Ph,P=C=C

/

S R‘

R’S hlel

.,/I

\ C=C=CH, /

*

‘SR’

RZS

(87)

\t\=c=o

R’S

\

/

R2S

63 64 65 66

R’S C =CH SR3

(90)

R’SC

CS R’

(89)

\

C-C-C-CAr,

/

RZS

(88)

H. J. Bestmann and K. Roth, Tetrahedron Lett., 1981, 22, 1681. D . Danion, B. Arnold, and M. Regitz, Angew. Chem., Int. Ed. Engl., 1981, 20, 113. V. I. Boer and A. V. Dombrovskii, Zh. Obshch. Khim., 1980, 50, 1473. G. A. Reynolds and C. H. Chen, J. Org. Chem., 1980, 45, 2458.

Ylides and Related Compounds Ph I I Ph,P=C-COMe (91)

237 Ph

'"'

t

\

/

fl

+ Ph,PO

N\N/NCN

-

Ph,P=CHCOAr

hl e

N,,

+ Y-

Y(X = 0 or S)

(94) x = o (95)

x= s

(96) X = 0 (97) x = s

phonium salt (99) is the product of the reaction of the 1,3-diazacyclopentadienylium salt (98) with methylenetriphenylph~sphorane.~~ The ylide anion (101) has been generated by treatment of the parent ylide (100) with a base.6s The anion (101) acts as an equivalent of a vinyl anion; it is readily alkylated to give (102), which, on refluxing in toluene that contains a catalytic amount of benzoic acid, gives the isomeric alkenes (103) (Scheme 8). 67

68

R. Gompper and K.-P. Bichlmayer, Tetrahedron Lett., 1980, 21, 2879. M. P. Cooke, Jr., Tetrahedron Lett., 1981, 22, 381.

238

-

Organophosphorus Chemistry Ph, P\c

C , I

0,E t

Ph,P'C/COzEt I

Ph",.

-%

/CO,Et I

CHC0,Et

II

Reagents: i, LiNPriz, THF, at -78 "C; ii, RX; iii, PhCOzH, heat

Scheme 8

An example of a rearrangement of an ylide to a phosphine is provided by the methylene ylide (104), which, over several days, forms the cyclic phosphine (105).69Thermal isomerization of the salt (106) gave (2-hydroxy-5,8,8-triphenyIbenzo[c]hept afulvenyl)t riphenylphosphonium bromide (107) in high y ield.7O The ylide (108),derived from (106), reacted readily with benzaldehyde to give the corresponding alkene, and with diphenylketen and phenyl isocyanate to give the fused-ring systems (109) and (1 lo), respectively (Scheme 9). The triboluminescence (i.e. the emission of light caused by the application of mechanical force) of hexaphenylcarbodiphosphorane has been in~estigated.~~ Numerous transition-metal complexes of ylides have been prepared, both with the metal directly attached to the ylidic carbon, e.g. (111),72 (112),73(113),74

71

D. Hellwinkel, W. Krapp, and W. S. Sheldrick, Chem. Ber., 1981, 114, 1786. F. Toda and K. Tanaka, Tetrahedron Lett., 1980,21,4869. G . E. Hardy, W. C. Kaska, B. P. Chandra, and J. I. Zink, J. Am. Chem. SOC.,1981, 103,

72

J. Stein, J. P. Fackler, Jr., C. Paparizos, and H.-W. Chen, J. Am. Chem. SOC.,1981, 103,

69

70

1074. 2192. 73 74

H. Schmidbaur, J. R. Mandl, J.-M. Bassett, G. Blaschke, and B. Zimmer-Gasser, Chem. Ber., 1981, 114, 433. H. Schmidbaur, G. Muller, K. C. Dash, and B. Milewski-Mahrla, Chem. Ber., 1981, 114, 441.

Ylides and Related Compounds

Ph,C

239

e+ H PPh,

Ph,C

4%

PPh,

(106)

Ph,C

B~-

(1 10)

(107) Reagents: i, at 220 " C ;ii, Ph2C=C=O;

iii, PhN=C=O

Scheme 9 Me,AuPPh,

+ Ph,P=CH2

+

Me,AuCH,PPh, (111) ;2

Ph,P-PPh,

I -Au

I AuI

hle,P'

'PMe,

;2

Me,P'

'PMe,

LJ

Au

I

Au

I

Au

M e2

RZ

QMe I

+ 2Me,P=-CH,

+

(1 15)

and (1 14),74and with co-ordination via some other atom, e.g. (1 15)75and (116).76 Benzylbenzylidenephosphonium ylides (117) react with lithium alkyls and 75 76

H. Blau and W. Malisch, Angew. Chem., Int. Ed. Engl., 1980,19,1019; W. Malisch, H. Blau, and U. Schuber, ibid.,p. 1020. R. A. Pickering, R. A. Jacobson, and R. J. Angelici, J. Am. Chem. Soc., 1981,103, 817.

0rganophosphorus Chemistry

240

(1 17)

( 1 18) M = Li ( 1 19) 7vI = N a

sodamide to give metallated products (1 IS) and (1 19), re~pectively.~~ Spectroscopic and X-ray structural investigations indicate that co-ordination of the metal atom is equally to the benzylidene carbons and to the aryl rings. 2 Reactions of Phosphonate Anions The phosphonate cuprates (120) and (121), formed in the reaction of lithium dibutylcuprate with diethyl vinylphosphonate, react rapidly with electrophilic reagent^.'^ A range of a-alkoxyphosphine oxides (122) are now available for use in olefin synthesis.79 Bu,C u Li

0

R'O

\

11

Ctl -PPh,

R2' (122)

The synthesis of olefins by using phosphine oxides has been used to prepare isomerically pure ( E ) - and (Z)-alkenes.60 The standard reaction of the carbanion of the oxide (123) with aldehydes gives predominantly the erythvo-alcohol 77

7* 79 80

H. Schmidbaur, U. Deschler, B. Milewski-Mahrla, and B. Zimmer-Glasser, Chem. Ber., 1981, 114, 608. R. Bodalski, T. J. Michalski, and J. Monkiewicz, Phosphorus Sulfur, 1980, 9 , 121. M. Maleki, A. Miller, and 0. W. Lever, Jr., Tetrahedron Lett., 1981, 22, 365. A. D. Bass and S. Warren, J. Chem. SOC.,Chem. Commun., 1981, 100.

24 1

Ylides and Related Compounds

(124), which on purification and treatment with base gives (2)-alkene stereospecifically. (E)-Alkene is obtained by acylation of (123) to give the P-ketophosphine oxide (125), reduction by borohydride to give predominantly the threo-alcohol(126), followed by purification and treatment with base (Scheme 10). 0

II

IR'

i, ii _+

C,- R2 / '

'H

HO

I

(124) i , iii

$-

0

ll Ph,P-CHR'

PhP-C

II

0

I

---H

I C,-

-% /

CORZ

lR1

40

+ Ph,P;;II

H

0

\

HO

'R2

(126)

(125)

Reagents: i, BuLi, THF; ii, R2CHO; iii, R2COzEt; iv, NaBH4; v, NaH, D M F

Scheme 10

The influence of solvent and counter-ion on the reaction of phosphonate carbanions with benzylideneaniline has been investigated.81 These reactions differ from those with carbonyl compounds in the higher basicity of nitrogen compared with oxygen anions; in the presence of less than one equivalent of base, the initially formed adducts (127) abstract a proton from the starting phosphonate to form a diastereoisomeric mixture of the conjugate acids (128). 0

0 II

II

(E tO)zP-

?HA1

0

II

0

(EtO),P-CHAr

I

Ph N H

CHAr /

II

+ (EtO),P-CHAr

(128) M. Kirilov and J. Petrova, Phosphorus Sulfur, 1980, 9, 87.

Organophosphorus Chemistry

242

The advantageous use of crown ethers in the phosphonate synthesis of olefins has been 82 The phosphonate (129) failed to undergo intramolecular olefination under a variety of conditions; however, the addition of two mole equivalents of crown ether and potassium carbonate (as the base) gave the desired cyclic olefin (130) in good yield.82 This method is recommended for general use in the synthesis of other systems that contain the cyclopentenone unit.

8,

0

h,

OTHP

II

-

,Ct I,COCH,P(OMe),

kC.0,

18-crown-6 PhMe, heat

OTHP

OTHP

OTHP

0

II

Me Ph,P--CH,NPh (131)

The problems that are associated with converting enolizable ketones into their enamines by the Wittig-Horner reaction have been largely overcome through the use of N-methylanilinomethyldiphenylphosphine oxide (1 31 y 3 Apparently, the lower basicity of the carbanion that is produced from this reagent allows the formation of alkenes [predominantly ( E ) ] in excellent yields, even with readily enolizable ketones. Olefination using N-substituted aminomethanebisphosphonates gives isomeric mixtures of the phosphonenamines (1 32), which can be hydrolysed to keto-enol mixtures of the corresponding acylphosphonates (Scheme 1 l).s4 Intramolecular reactions of phosphonate carbanions continue to be used extensively in the synthesis of cyclic alkenes; for example, the ring system of 0

It

RCH,COP(OEt),

,NMe, CHNMe, 3 RCII=C

+

Ill +

0

II , l2 WOE t

(132)

RCH--C

O ‘H Reagents: i, Mg, EtOH, CCh; ii, RCHO; iii, H30+

Scheme 11 82

P. A. Aristoff, J. Org. Chem., 1981, 46, 1954.

85

N.L.J. M.Broekhof, F. L. Jonkers, and A. Van der Gen, Tetrahedron Lett., 1980,21,2677.

84

B. Costisella, I. Keitel, and H. Gross, Tetrahedron, 1981, 37, 1227.

24 3

Ylides and Related Compounds A

brefeldin A (1 33),85 bicyclo[3.3.O]oct-2-en-3-ones(1 34),86 and various heterocycles (135).s7The key intermediate (137) in a partial synthesis of carbomycin B and of leucomycin A,88 has been prepared via intramolecular olefination of the phosphonate (136).89 0

/-

0

II

(EtO),P

‘

C -NEt 7-

R’

/

(E t O), P; ,

Na’

R2

+

+ x- co

0

dN

W

R2

0

1.5 Na (at 40°C

Phhle and higli dilution)

What appears to be a general method of synthesis of electron-donor molecules of the type (138) and of unsymmetrical 4’-thiopyran-4-yl-4H-pyrans(139) 91 from 4H-pyran-4-yl-phosphonateshas been developed (Scheme 12). However, 92 is complicated similar use of the analogous 4H-thiopyran-4-yl-phosphonates by the equilibrium between the lithiated 4H- and more stable 2H-species (140); this leads to low yields of alkenes in some cases. A49

85 86

87 88 89 90

91 92

P. Raddatz and E. Winterfeldt, Angew. Chem., Znt. Ed. Engl., 1981, 20, 286. M. J. Begley, K. Copper, and G. Pattenden, Tetrahedron Lett., 1981, 22, 257. J. Motoyoshiya, A. Teranishi, R. Mikoshiba, I. Yamamoto, H. Gotoh, J. Endo, Y. Ohshiro, and T. Agawa, J. Org. Chem., 1980, 45, 5385. K. C. Nicolaou, M. R. Pavia, and S. P. Seitz, J. Am. Chem. SOC.,1981, 103, 1222. K. C. Nicolaou, M. R. Pavia, and S. P. Seitz, J. Am. Chem. Sac., 1981, 103, 1224. G. A. Reynolds and C. H. Chen, J. Org. Chem., 1981,46, 184. C. H. Chen and G. A. Reynolds, J. Org. Chem., 1980,45,2449. C. H. Chen and G. A. Reynolds, J. Org. Chem., 1980,45, 2453.

9

244

Organophosphorus Chemistry 0

II

-

i, ii

i. iii

c-

R4 R3

;3

R2

(139) R'

Reagents: i, BuLi, THF at -78° C; ii, RbCH=CHCHO;

=

R2 = Ph

iii,

Scheme 12

R4

0

NC

II I

Ph,P -CCO, But

Ph

Ph

(141)

New PO-stabilized carbanions include the 1-isocyano-substituted phosphine oxide (141) 93 and phosphonate (142).94The former reagent undergoes normal olefination reactions with aryl aldehydes to give vinyl isocyanides, while the latter reagents can be alkylated step-wise to mono- and di-substituted derivatives, which give (1-aminoalky1)phosphonates(143) on acid hydrolysis (Scheme 13). 0

II (EtO),P-CH

0

R'

II I (EtO),P-C--R2

NC

0

NC

(142)

R'

II I 5 (EtO),P-C-R2

NC (143)

Reagents: i, RIX; ii, base; iii, R2X; iv, H30+

Scheme 13

In the synthesis of the aliphatic segment (144) of rifamycin S, the doubly substituted ( E ) olefinic group is readily introduced; however, attempts to use an ethoxycarbonylethylphosphonateto introduce the triply substituted olefin function gave almost exclusively the unwanted The problem was solved by the use of dimethyl 1-cyanoethylphosphonate,which gave > 90% of 93 94 95

J. Rachon and U. Schollkopf, Liebigs Ann. Chem., 1981,99. J. Rachon, U. Schollkopf, and T. Wintel, Liebigs Ann. Chem., 1981, 709. H. Nagaoka, W. Rutsch, G. Schmid, H. Iio, M. R. Johnson, and Y . Kishi, J . Am. Chern. Soc., 1980, 102, 7962.

Ylides and Related Compounds

245

b

H0

R=

the (2)-isomer. It is interesting to note that the diethyl ester gave much more of the (,?)-isomer. The lactol (145) is surprisingly unreactive in the Wittig reaction, and, in a partial synthesis of the ionophore antibiotic X-l4547A, the (E,E)dienoate (146) was most readily obtained by silylation of (145), followed by reaction with the carbanion of ethyl 4-(diethy1phosphono)crotonate(Scheme 14).96 ButMe,SiO

E tO,C

0

II

Reagents : i, ButMezSiCl, imidazole; ii, (Et0)2PCH2CH=CHCOzEt, LiNPriz Scheme 14

A series of allyl vinyl ethers have been prepared by the Horner-Wittig reaction of dimethyl diazomethylphosphonate (147) with aliphatic ketones in the presence of allyl alcohols.97Competition from the alternative cyclopropanation 98 reaction of the alcohol is minimal. 0

II

(MeO),PCHN,

+ R',CO + R2R3C=CR4CH,0H

Bu'Otl

R',C=CHOCH,CR4=CRzR3

(147)

Several reports of unexpected products from attempted olefination reactions have appeared ; for example, phosphonyl-stabilized carbanions (148) that carry an organo-heavy-metal substituent gave good yields of vinylphosphine oxides rather than vinylmetallic corn pound^.^^ The anion that is generated from 2-indenylethyl(diphenyl)phosphine oxide undergoes reaction with benzaldehyde at the indene ring to give (149), rather than normal olefination (see Scheme 15),loo 913 97 913 99

100

M. P. Edwards, S. V. Ley, and S. G. Lister, Tetrahedron Lett., 1981, 22, 361. J. C. Gilbert, U. Weerasooriya, B. Wiechman, and L. Ho, Tetrahedron Lett., 1980,21,5003. U . Weerasooriya, J. C.Gilbert, and D. Giamalva, Tetrahedron Lett., 1979, 4619.

H.-J. Tilhard, H. Ahlers, and T. Kauffman, Tetrahedron Lett., 1980, 21, 2803. K. Berghus, A. Hansen, A. Rensing, A. Woltermann, and T. Kauffmann, Angew. Cifem., Int. Ed. Engl., 1981, 20, 117.

Organophosphorus Chemistry

246

Ph2P-CHM

(148) (M

+ R’R‘CO =

-

0

II

Ph2PCH=CR1Rz

PbPh,, SnPh,, SbPh,, or TePh)

CHPh

Reagents: i, LiNPr’z; ii, PhCHO

Scheme 15

and the initial adduct (150) from the carbanion of diethyl 1-(trimethylsi1oxy)-1phenylmethanephosphonate and carbonyl compounds undergoes rearrangement and loss of diethyl phosphite anion, rather than elimination to give an alkene.lol This latter reaction has been used in a new synthesis of benzoins and hence of 2-phenylbenzo[b]furans(151).

-

\

OSiMe,

In spite of the possible alternative reactions, the phosphonate (152) can be converted into the 1,Cdianion (1 53) by lithium-tin exchange in the intermediate monoanion.102The dianion (1 53), which reacts with electrophiles exclusively at the 8-carbon, is probably stabilized by intramolecular chelation of lithium (Scheme 16). lol 102

R. E. Koenigkramer and H. Zimmer, J. Org. Chem., 1980, 45, 3994. R. Goswami, J. Am. Chem. SOC.,1980,102, 5974.

Ylides and Related Compounds

247

Reagents: i, NaH, THF; ii, BuLi, at -78 "C

Scheme 16

A series of phosphonate analogues, e.g. (154), of phosphoenolpyruvic acid have been prepared through the addition of phosphonate carbanions to dimethyl acetylenedicarboxylate (Scheme 17).lo3 0

II

(MeO),PCH,CO,Me + MeO,CC=CCO,Me

0

0

jro2Me1)

(MeO)2/C 'H

C0,Me

I

CHC0,H (HO)2PACo2H (154)

C0,Me Reagents: i, Na, PhH; ii, aqueous buffer; iii, HCl (as.)

Scheme 17

3 Selected Applications in Synthesis Pheromones.-Compounds that have been prepared by conventional Wittig reactions include the optically active pheromone analogues (155), (1 56), and (157), from the optically active ylide (158),lo4 the female sex pheromones (159) of the German and the cyclononane analogue (160) of Cecropia juvenile hormone I.lo6 Me, Et

*m R

/CH

Ph,P=CH-CH

* /

\

Me Et

(155) R = (CH,),C&OCOMe

(156) R = AuCH,),OH (157) R = /++ACH,),CHO 103 104

1°5

lo6

R. M. Davidson and G. L. Kenyon, J. Org. Chem., 1980,45, 2698. H. J. Bestmann, H. L. Hirsch, H. Platz, M. Rheinwald, and 0. Vostrowsky, Angew. Chem., Znt. Ed. Engl., 1980, 19, 475. K. Mori, S. Masuda, and T. Suguro, Tetrahedron, 1981, 37, 1329. H. A. Pate1 and S. Dev, Tetrahedron, 1981, 37, 1577.

9*

248

Organophosphorus Chemistry

MeCoCHMe(CY),CHMe(CH,),

R

(159) R = H or OH (160)

C0,Me

Cyclic ylides have been relatively little studied compared with their acyclic counterparts; however, a novel synthesis of gossyplure (163; R=Ac), the sex pheromone of the female pink bollworm moth, using the cyclic ylide (161), has been reported (Scheme 18).lo7The phosphine oxide (162) was obtained exclusively as the (2)-isomer, while further reaction of (162) gave (163) as a mixture of isomers, the composition of the mixture depending on the solvent used.

Br-

Me(CH,),CH =CH(CH,),

(163) Reagents: i, ButOK, THF, at r.t.; ii, THPO(CH2)&HO; iii, BuLi; iv, Me(CH2hCHO; v, HMPT, at 60°C

/

Scheme 18

I. 11. 1, 111

Ph,P=CH(CH,),OH

R-,C(Me)CH,CH,OH

( E ) - and (2)-(164)

1, I V . 1. I l l

Ph;P--CHMe

R

(E 1- (164) 111, 1. I V

Ph,P=CHMe

+A HO

(Z 1 - ( 164 1 Reagents: i, BuLi; ii, MeI; iii, RCHO, at -78OC; iv,

Scheme 19 107

J. M. Muchowski and M. C. Venuti, J. Org. Chem.. 1981, 46, 459.

throughout)

Ylides and Related Compounds

249

In a rather confusing paper,lo8the use of the Wittig reaction in different ways (Scheme 19) for the synthesis of all four isomers [(32)- and (3E-);(6R)- and (6s)-] of the sex pheromone (164) of the white peach scale insect is described. Prostaglandins.-The 2-oxoheptylidene ylide (165),lo9 the 2-oxoheptylphosphonate (166),110 and the ylide carboxylate (167)111 continue to be extensively used for the introduction of a side-chain in syntheses of prostaglandins and related compounds. 0 Ph,P=CHCO(CH,),CH, (165)

II

(RO)2PCH,CO(CH2)4CH,

Ph,P=CH

(CH,),CO;

(167)

(166)

Carbohydrates.-The Wittig reaction of 3-methoxycarbonylprop-2-enylidenetriphenylphosphorane with (168) has been used in a new synthesis of (+)-biotin (169) from D-arabinose.l12 The strange reagent that includes six-valent phosphorus that is shown in the paper is presumably a misprint.

p o \ C O P h

9/ A

+ Ph,P=CH-CH=CHCO,Me 0

(168)

Carotenoids and Related Compounds.-The use of both the Wittig reaction and PO-activated olefination in the synthesis of terpenes has been reviewed.l13 108

109 110

111

112

113

R. R. Heath, R. E. DoolittIe, P. E. Sonnet, and J. H. Tumlinson, J. Org. Chem., 1980, 45,2910. S. Kosuge, N. Hamanaka, and M. Hayashi, Tetrahedron Lett., 1981, 22, 1345; S. Ohuchida, N. Hamanaka, and M. Hayashi, ibid., p, 1349. M. F. Ansell, M. P. L. Caton, and J. S . Mason, Tetrahedron Lett., 1981, 22, 1141; E. Temesvari-Major, L. Gruber, I. Tomoskozi, and G. Y . Cseh, ibid., 1980,21,4035; T. R. Williams and L. M. Sirvio, J . Org. Chem., 1980, 45, 5082; S. P. Briggs, D. I. Davies, R. F. Newton, and D. P. Reynolds, J. Chem. SOC.,Perkin Trans. I , 1981, 150. S. Y. Briggs, D. I. Davies, R. F. Newton, and D. P. Reynolds, J. Chem. SOC.,Perkin Trans. I , 1981, 150; E. Temesvari-Major, L. Gruber, I. Tomoskozi, and G. Y . Cseh, Tetrahedron Lett., 1980, 21, 4035; W. Skuballa, ibid., p. 3261; F. Cassidy, R. W. Moore, G. Wooton, K. H. Baggaley, G. R. Green, L. J. A, Jennings, and A. W. R. Tyrrell, ibid., 1981, 22, 253; L. Castellanos, A. Gateau-Olesker, F. Panne-Jacolot, J. Cleophax, and S . D. Gero, Tetrahedron, 1981, 37, 1691; J.-P. Depres, A. E. Greene, and P. Crabbe, ibid., p. 621; S . Kosuge, N. Hamanaka, and M. Hayashi, Tetrahedron Lett., 1981, 22, 1345; S. Ohuchida, N. Hamanaka, and M. Hayashi, ibid., p. 1349. F. G. M. Vogel, J. Paust, and A, Niirrenbach, Liebigs Ann. Chem., 1980, 1972. G. Cainelli and G. Cardillo, Acc. Chem. Res., 1981, 14, 89.

Organophosphorus Chemistry

250

iii. iv + -

O

4 (170) [ ( E ) :( 2 )= 3 : 21

[(4E, 8E):(42,8 E ) = 3 : 21

Me0,C

Me0,C (171)

(172)

; iii, HCI, H20, THF;

Reagents : i, Ph3P=CHCOMe; ii,

0

II

-

iv, PhaP=CMeCOaMe; v, (Et0)2P-CHC02Me

Scheme 20

Full details have appeared114 of the synthesis of the (all-E)-[12.1.0] bicyclic diterpene structure (172), which is thought to be the structure of (1S73R)-(-)casbene. As shown in Scheme 20, the method uses Wittig and phosphonate olefinations extensively. Attempted separation of ( E ) - and (2)-isomers of (170) resulted in large losses of material, and the (all-E)-isomer (171) was best purified at the triene stage. Isopropylidenetriphenylphosphoranehas been used to prepare a variety of gem-dimethylated terpenes.'15 114

115

L. Crombie, G. Kneen, G. Pattenden, and D. Whybrow, J. Chem. SOC.,Perkin Trans. I , 1980, 1711. P. A. Christenson and B. J. Willis, J. Org. Chem., 1980, 45, 3068; R. L. Snowden, Tetrahedron Lett., 1981, 22, 101.

Ylides and Related Compounds

25 1

(174) X = 2-pyridyl, 3-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, or 3-thienyl

A variety of aromatic carotenoid analogues, e.g. (173), have been synthesized from the appropriate aldehyde and substituted benzylphosphonium salts in the presence of 1,2-epoxybutane.l16 Heteroaromatic analogues (174) have also been prepared by standard methods.l17 9-Bromo- (177) and 13-bromo-retinals (178) have been prepared from the phosphonium salts (175) and (176), respectively,l18 and the 11,lZallenic retinoid (180) is available from the ylide (179).l19 8-Lactam Antibiotics.-Intramolecular Wittig and Horner-Wittig reactions have been used extensively to construct the five-membered ring in a variety of P-lactam antibiotics. These include trans-6-ethyl-2-penems (1 81),120acarbapenems (182)120b 116

A. Shimada, Y. Esaki, J. Inanaga, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett.,

117

H. R. Brahmana, K. Katsuyama, J. Inanaga, T. Katsuki, and M. Yamaguchi, Terra-

1981,22, 773.

hedron Lett., 1981,22, 1695. M. G . Motto, M. Sheves, K. Tsujimoto, V. Balogh-Nair, and K. Nakanishi, J . Am. Chem. SOC.,1980, 102, 7947. 119 J. Sueiras and W. H. Okamura, J. Am. Chem. SOC.,1980, 102, 6255. l20 (a) A. Longo, P. Lombardi, C. Gandolfi, and G. Franceschi, Tetrahedron Lett., 1981,22, 355; (b) R. Sharma and R. J. Stoodley, ibid., p. 2025. 118

252

Organophosphorus Chemistry

RZ

R'

(177) R' = Me, RZ= Br (178) R' = Br, RZ= Me

(1 80)

and (183),121 the thienamycin skeleton (184),122and a number of derivatives (185)123and (186)lz4of olivanic acid. Non-benzenoid Aromatic Compounds.-The synthesis of syn-l,6-ethano-8,3methano[l4]annulene (188) has been achieved,125using a double olefinationlZ6 with the appropriate diphosphonate (187). Wittig reactions of a variety of bis-phosphonium ylides with bis-aldehydes have been investigated as possible routes to ann~1enes.l~' In general, acyclic products were obtained; however, the bis-salt (189) and the aldehyde (190) gave the new [28]annulene (191), albeit in very low yield. T. Kametani, S.-P. Huang, T. Nagahara, S. Yokohama, and M. Ihara, J. Chem. SOC., Perkin Trans. I , 1981, 964. lZ2 B. Venugopalan, A. B. Hamlet, and T. Durst, Tetrahedron Lett., 1981, 22, 191. 123 J. H. Bateson, R. I. Hickling, P. M.Roberts, T. C. Smale, and R. Southgate, J. Chem. SOC., Chem. Commun., 1980, 1084; R. J. Ponsford and R. Southgate, ibid., p. 1085. lZ4 A. J. G. Baxter, P. Davis, R. J. Ponsford, and R. Southgate, Tetrahedron Lett., 1980, 21, 5071. lZ5 E. Vogel, H. M.Deger, P. Hebel, and J. Lex, Angew. Chem., Int. Ed. Engl., 1980, 19, 919. lZ6 B. J. Walker, in 'Organophosphorus Chemistry', ed. D. W. Hutchinson and J. A. Miller (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1981, Vol. 12, p. 236. lZ7W.Kemp and C. D. Tulloch, J. Chem. Res. (Sj, 1981, 28. 121

Ylides and Related Compounds

253

co, (186)

0

CHO

(EtO),P 0

/

Several steps

(187) A

0rganophosphorus Chemistry

254

(193) R' = C q O H , R2 = H (194) R' = H, RZ= C H 2 0 H

Miscellaneous Applications.-The synthesis of leucotrienes, which are the slowreacting substances of anaphylaxis (SRSA), continues to attract intense effort. The (5S,6S)- (193) and (5S,6R)-epoxides(194), which are useful intermediates in these syntheses, have been prepared, using the reaction of D-arabinoascorbic acid with the phosphonium ylide (192) as a key step.128 w

,

P

-P

h

,

(195)

+

OHC-

0

C02Me (196)

i

(at - 78°C)

/\/\/?/cH=cH-cH=?H-14

11

/

C0,Me

(197) a; 7E, 9 Z , 11E, 142 b;7E,9E, 1 1 2 , 142 c ; 7E, 92, 1 1 2 , 142

Three isomers (197) of leucotriene A methyl ester were isolated from the Wittig reaction of the phosphonium salt (195) and the enal epoxide (196); the composition of the isomeric mixture was ~olvent-dependent.~~~ A new synthesis of natural leucotriene A, (198), and hence of C,, D,, and Ed,involves the extensive use of the Wittig reaction (Scheme 21),130as does the synthesis of analogues, e.g. (199), of leucotriene A.131The first stereospecific synthesis of the (12R)128 129

130

131

N. Cohen, B. L. Banner, and R. J. Lopresti, Tetrahedron Lett., 1980, 21, 4163. S. R. Baker, W. B. Jamieson, S. W. McKay, S. E. Morgan, D. M. Rackham, W. J. Ross, and P. R. Shrubsall, Tetrahedron Lett., 1980, 21, 4123. J. Rokach, R. N. Young, M. Kakushima, C.-K. Lau, R. Sequin, R . Frenette, and Y. Guindon, TetrahedronLett., 1981, 22, 3979. E. J. Corey, A. Marfat, and G . Goto, J. Am. Chem. Soc., 1980, 102, 6607.

Ylides and Related Compounds

255

(198) Reagents: i, 2Ph3P=CHCHO; ii, Ph,P=-CH

Scheme 21

and (12s)-compounds (200) and (201), which are among the products of nonenzymic hydration of leucotriene A, has been achieved through use of the Wittig reaction (Scheme 22).132

(200) R' (201) R' Reagents: i, 2BunLi, THF, at

- 78 " C ; ii,

a

0

011r \ \

2

= =

M

OH, R2= H H, R2= OH

e

, lOHMPT

Scheme 22

The total synthesis of leucotriene B (202)133and of its 6-trans,lO-cis-and 6-~rans,8-cis-isomers~~~ has been reported. The key steps in the synthesis of (202) are shown in Scheme 23. 132

133

134

E. J. Corey, A. Marfat, and D. J. Hoover, Tetrahedron Lett., 1981, 22, 1587. E. J. Corey, A. Marfat, G. Goto, and F. Brion, J. Am. Chem. SOC.,1980, 102, 7984; see also E. J. Corey, A. Marfat, J. Munroe, K. S. Kim, P. B. Hopkins, and F. Brion, Tetrahedron Lett., 1981, 22, 1077. E. J. Corey, P. B. Hopkins, J . E. Munroe, A. Marfat, and S. Hashirnoto, J. Am. Chem. SOC.,1980, 102, 7986.

256

Organophosphorus Chemistry

OH

0

H"

\

'SiMe,Bu'

H OH - * Y C 5 : ; :

OSiMe,Bu'

lii

-

' H\

CH,fiPh,

OH C0,H

\

(202) Reagents : i, Ph3P=CHCOzMe, DME,PhCOzH, reflux for 6 hours; ii, Ph3P=CH(CH2)4Me, 9THF: 1 HMPT, at -78 "C;iii, 2BuLi, THF, at -4OOC; iv, HMPT, at -78 "C;

Scheme 23

(203)

I

I

H

(204)

i-iii

,CO,Me

CH,CHCONHCH,CO,H

I

NHCOCH,CH,CHCO,H

I

NH2

(205) Reagents: i, LiI, at 0 "C,4 ether: 1 THF; ii, glutathione, EhN, MeOH; iii, chromatography

Scheme 24

Ylides and Related Compounds

257

11-trans-Leucotriene C (205) has been synthesized by carrying out the Wittig reaction of the ylide (203) with the aldehyde (204) in the presence of lithium iodide, so that a mixture of isomers at C-11, rather than entirely cis, is Separation of the trans-isomer (205) was most easily achieved at the final stage (Scheme 24). (SS,6R)-LeucotrieneA (207),and hence 6-epi-leucotrienes-C(208)and -D (209), have been synthesized by a Wittig reaction of the (Z)-non-3-enylidene ylide (206).13sThe 6-epi-leucotrienes are less active as slow-reacting substances than their natural analogues. Standard use has been made of thecarbanion of methyl 4-(dimethy1phosphono)crotonate and carbomethoxymethylenetriphenylphosphoranein the stereospecific

(207) R =

H O & ‘C,

H OzMe

I

CH,CHCONHCH,CO,H

I

NHCOCH,CH,CHCO,H

I

NH,

(209) R =

&C02H

I

CH,CHCONHCH,CO,H NH2 135

136

E.J. Corey, D. A. Clark, A. Marfat, and G. Goto, Tetrahedron Lett., 1980,21, 3143. E.J. Corey and G. Goto, Tetrahedron Lett., 1980, 21, 3463.

258

Orgaiiophosphorus Chemistry

synthesis of the 'right wing' (210) of the ionophore antibiotic X-14547A.13' An alternative to (210) involves the use of the 2-pyrroloylmethylylide (21 1 ) to give the tetraene (212), which can cyclize to (210).

137 138

K. C. Nicolaou and R. L. Magolda, J. Org. Chem., 1981, 46, 1506. W. R. Roush and A. G . Myers, J. Org. Chem., 1981, 46, 1509.

11 Physical Methods BY J. C. TEBBY

The abbreviations n2,n3,n4,n5,and ns refer to the co-ordination number of phosphorus, and the compounds in each subsection are usually dealt with in this order. In the formulae, the letter R represents hydrogen, alkyl, or aryl, X represents an electronegative substituent, Ch represents chalcogenides (usually oxygen and sulphur), and Y and Z are used to indicate groups of a more varied nature. The terminology apical and radial has been retained for the stereochemical description of substituents on n5 atoms that possess trigonal-bipyramidal geometry, so that the terms axial and equatorial can be reserved to describe the conformational preferences of substituents on n4 atoms in six-membered rings. The nomenclature ‘phosphane’ is used for n3 phosphorus compounds in general, reserving the term ‘phosphine’ for phosphanes which possess three carbon or hydrogen substituents and the term ‘phosphite’ for phosphanes which possess three alkoxy or aryloxy substituents. Some relevant theoretical and inorganic studies are included in this chapter. One such study is a further example of the use of a computer for the design of a synthetic route to the cyclic phosphine (l).l

1 Nuclear Magnetic Resonance Spectroscopy Biological Applications and Instrumental Techniques.-The application of n.m.r. spectroscopy to the study of phosphorus-containing biological systems continues to grow, but space now limits coverage to noting the reviews.2 It has been found that instruments that are set for 31Pn.m.r. studies of aqueous systems can be conveniently tuned, using the water lH signal, which can also be used as an internal reference. The l H signal of H 2 0 is insensitive to the variations in pH and in ionic strength that are normally encountered in biological ~ystems.~ Chemical Shifts and Shielding Effects.-Phosphovus-~~.Positive shifts are downfield of 85 % phosphoric acid, and are usually given without the appellation p.p.m. 1 2

3

C. Laurenco and G. Kaufmann, Tetrahedron Lett.. 1980, 21,2243. T. Glonek, Phosphorus Chem. Directed Biol., Lect. Int. Symp., 1979, 1980, 157; D. P. Hollis, ZEEE Trans. Nucl. Sci.,1980, 27, 1250; P. E. Hanley, Chem. Br., 1981, 17, 374. J. J. H. Ackerman and D. G. Gadian, J. Magn. Reson., 1981,42,498.

259

Organophosphorus Chemistry

260

a~ of n2 compounds. Quite a large number of two-co-ordinate compounds have now been prepared. Those compounds which have two carbon atoms bound to phosphorus can resonate as far upfield as 49, as has been recorded for the amine (2),4 and yet as far downfield as 262, as observed for the sulphur compound (3).5 On the other hand, the diazo-cations (4) can resonate as low as 451.s P

h

(2)

P a N Me

PhP=C /SSiMe3

+

RJ-=P=-NR,

‘SSiMe,

(3)

(4 )

d~ ofn3 compounds. There have been further studies on the inter-relation of n.m.r. parameters and valence angles of phosphanes.’ In studies of the ethylphosphanes (3,the deshielding that is caused by increasing the bond angles is offset by inductive shielding effects when silane and stannane groups are present.8 Large downfield shifts for the iodides ( 5 ; Y = I) have been rationalized in terms of a greater distribution of values of the bond angles within the molecules producing a larger electron imbalance at phosphorus, and a consequential increase in paramagnetic effects. The chemical shifts of the (dimethy1amino)phosphanes ( 5 ; Y =NMe,) have been explained in terms of inductive effects, but, for the chlorophosphanes (6), P-N multiple bonding was invoked.1° The prediction of 8~ values of chiral phenylphosphines (7) has been achieved, using a second-order pairwise additivity schemnll A most extraordinary deshielding of a n3phosphorus atom has been observed in the spectra of the syn-7-phosphatrinorbornanes (8), and signals for the bridging phosphorus atom appear in the range 100-147.12

H. Oehme, E. Leissring. arid H. Meyer, Tetruhedron Lett., 1980, 21, 1141. G. Becker, G . Gresser, and W. Uhl, Z . Anorg. Allg. Chem., 1980, 463, 144. A. H. Cowley, M. C. Cushner, M. Lattman, M. L. McKee, J. S. Szobota, and J. C. Wilburn, Pure Appl. Chem., 1980, 52, 789. V. E. Bel’skii, G. V. Romanov, V. M. Pozhidaev, and A. N. Pudovik, Zh. Obshch. Khim., 1980,50, 1222. * J. P. van Linthoudt, E. V. van den Berghe, and G . P. van der Kelen, Spectrochim. Acta, Part A , 1980, 36, 17. J. P. van Linthoudt, E. V. van den Berghe, and G. P. van der Kelen, Spectrochim. Acta, Port A , 1979, 35, 1307. l o J. P. van Linthoudt, E. V. van den Berghe, and G. P. van der Kelen, Spectrochim. Acta, Part A , 1980,36, 315. l1 N. C. Payne and D. W. Stephan, Can. J . Chem., 1980, 58, 15. 1 2 L. D. Quin and K. A. Mesch, J . Chem. Soc., Chem. Commun., 1980, 959.

Physical Methods

261

The precise origin of this remarkable effect remains to be identified. A pronounced effect is also observed for the bis-n4-derivatives of (8).13 The BIJ values of the trinorbornyl compounds (9) are to higher field when the phosphorus groups are A study of the aromatic phosphines exo (as shown) than for their endo-is~mers.~~ (10) has indicated that through-space interactions play a part in determining &.15 6p ofn4 compounds. The chemical shifts of the chalcogenides of the phosphines (10) appear to be influenced by the large polarizability of the P-Ch bond. The contribution of the cc-lone-pair tends to reverse the substituent effect.15 Phosphorus-3 1 n.m.r. anisotropies have been calculated for phosphine, trimethylphosphine oxide, POF3, and POCI, by a Hartree-Fock formalism and a pseudopotential method.16 In another theoretical study, using CND0/2, E.H.T., and empirical calculations, it was shown that the distribution of p-electrons about the phosphorus atom is of considerable importance in its contribution to the paramagnetic screening constants.17 It is interesting to note that whilst tetra-t-butylphosphonium salts (1 1) have chemical shifts (BP= 56) that are not very different from that of tri-t-butylphosphine,18 the di-t-butyI(ch1oro)methylenephosphorane (12; X = C1) has BP = 116.5,l which is well downfield of most ylides. In a manner characteristic of n4 compounds, the five-membered-ring ylides (13) resonate But ,h X -

(1 1)

X

But ,P=CH,

(12)

c

P-CY,

I

Me

Ph,P=NAr (14)

+

Ph,P-N

/Me

~.

'A* (15)

(13)

downfield (Bp ca 25) of their acyclic analogues (BP ca O).20 A study of the substituted N-aryl-iminotriphenylphosphoranes(14) showed a good correlation of SP values with Hammett substituent constants, and as such was used to estimate u and u- values for some new groups.21The importance of &bonding to transmit the substituent effects was clearly demonstrated by the insensitivity of the BP values of the N-methylated compounds (15) to changes in the aryl substituents.22 A series of papers on the oxygen-isotope shifts of cyclic phosphates have appeared.23*24 The line-broadening that is caused by the presence of an oxygen-17 atom that is bound to phosphorus, combined with different oxygen-18 isotope L. D. Quin and K. A. Mesch, Org. Magn. Reson., 1979, 12, 442. L. D. Quin, M. J. Gallagher, G. T. Cunkle, and D. B. Chesnut, J. Am. Chem. SOC., 1980, 102, 3136. l 5 N. Inamoto, Koen Yoshishu - Hibenzenkei Hokozoku Kagaku Toronkai (Oyobi) Kozo Yuki Kagaku Toronkai, 12th, 1979, 325 (Chem. Absrr., 1980, 92, 180 512). l6 T. Weller, D. Deininger, and R. Lochmann, Z. Chem., 1981, 21, 105. l7 R. Wolff and R. Radeglia, 2. Ph-vs. Chem., 1980, 261, 726. l a H. Schmidbaur, G. Blaschke, B. Zimmer-Gasser, and U. Schubert, Chem. Ber.. 1980, 113,

l3

l4

1612. l9 2o 21

22 23 24

0. 1. Kolodiazhnyi, Tetrahedron Lett., 1980, 21, 3983. H. Schmidbaur and H. P. Scherm, 2. Anorg. Allg. Chem., 1979,459, 170. J. Boedeker, P. Koeckritz, H. Koeppel, and R. Radeglia, J. Prakt. Chem., 1980, 322, 735. E. M. Briggs, G. W. Brown, P. M. Cairns, J. Jiricny, and M. F. Meidine, Org. Magn. Reson., 1980, 13, 306. S. L. Buchwald and J. R. Knowles, J. Am. Chem. SOC.,1980, 102, 6601; R. L. Jarvest, G. Lowe, and B. V. L. Potter, J. Chem. SOC., Chem. Commun., 1980, 1142. D. G. Gorenstein and R. Powell, J. Am. Chem. SOC.,1980, 102. 6165.

Organophosphorus Chemistry

262

shifts (dependent on whether the oxygen-18 atom participates in a P=O bond or in a P-OR bond), allows an unambiguous assignment of the absolute configuration of chiral phosphate When the phosphate group is incorporated into a six-membered ring, the oxygen-18 atom exerts a different isotope shift, depending on whether it is axially or equatorially ~ r i e n t a t e d . ~ ~ dp of n6 compounds. Several hexaco-ordinated phosphorus compounds that contain trifluoroethoxy-groups, e.g. (16; X = OCH,CF,), have been prepared.25 It appears that the deshielding effect of including n4 and n5 phosphorus atoms in five-membered rings also applies to n6 compounds. Carbon-13. There is a linear relationship between the SC values of phosphanes or phosphonium salts and those of the corresponding hydrocarbons; a-, 8-, y-, and 6-effects of the PH, group have also been discussed.26Assignments of chemical shifts have been made for various phosphole derivatives, using partially relaxed inversion-recovery spectra and by utilizing the field dependence of the The spectrum of the cyclic phosphine (17) has the C-6 signal at higher field than the C-2 signal. The 13Cspectra of the n4 derivatives aided the conformational analysis.,*

1 x

0

II

(M eO),PNH Ar

p* P oh/ Ph

(18)

(M eO),P =N Ar (19)

Nitrogen-15. Several studies of P-N compounds have 3 0 The spectra of the phosphoramidates (18) and iminophosphoranes (19) indicated that N-aryl conjugation was more important than P-N c o n j ~ g a t i o n . ~ ~ Chlorine-35. The parameters for a range of chlorophosphanes, together with data on phosphoryl trichloride and thiophosphoryl trichloride, have been rep~rted.~' Studies of Equilibria, Shift Reagents, and Liquid Crystals.-The transfer of selenium from phosphine selenides to phosphines can occur at a rate that is suitable for n.m.r. The n4+n5 tautomeric equilibria involving the oxyphosphoranes (20) and (21) are other such examples.33 The effects of lanthanide shift reagents upon coupling constants have been 25 26 27

28

29

30 31

3, 33

D. B. Denney and D. Z. Denney, J. Am. Chem. Soc., 1981, 103, 1785. J. Koketsu, Nippon Kagaku Kuishi, 1980. 12, 1834. G . A. Gray and J. H. Nelson, Org. Magn. Reson., 1980, 14, 14. ( a ) J. B. Rampal, G. D. MacDonell, J. P. Edasery, K. D. Berlin, A. Rahman, D. van der Helm, and K. M. Pietrusiewicz, J. Org. Chem., 1981, 46, 1156; (h) J. B. Rampal, K. D. Berlin, J. P. Edasery, N. Satyamurthy, and D. van der Helm, ihid., p. 1166. B. Thomas, G. Seifert, and C. Grossmann, Z. Chem., 1980, 20, 217; A. I. Rezvukhin and G. G. Furin, J. Fluorine Chem., 1981, 17, 103. G . W. Buchanan, F. G. Morin, and R. R. Fraser, Can. J. Chem.. 1980, 58, 2442. K. Barlos, J. Kroner, H. Noeth, and B. Wrockmeyer, Chem. Ber., 1980, 113, 3716. S. W. Carr and R. Colton, A m . J. Chem., 1981, 34, 3 5 ; D. H. Brown, R. J. Cross. and R. Keat, J. Chem. SOC.,Dalton Trans., 1980, 871. M. M. C. F. Castelijns, P. Schipper, D. van Aken, and H. M. Buck, J. Org. Chcm., 1981, 46, 47; H. B. Stegmann, R. Haller, A. Burmester, and K. Schettler, Chem. Ber., 1981, 114, 14.

Physical Methods

263

studied.j4It has been found that the counter-ions of phosphonium salts can act as binding sites for shift reagents, their effectiveness decreasing in the order Cl- > Br- > I-.35Europium shift reagents were used to establish the configuration of the oxazaphospholidines (22)36and to show that the two phosphorus atoms of the P-P bond in the cyclotriphosphazene (23) are nearly isochronous. Shift reagents increased the shift differentialbetween the two phosphorus atoms by a factor of ten.37Shift reagents have also been used to assist conformational studies ~ ~ to identify ( E ) -and (2)-isomers of of phosphor in one^^^ and p h o ~ p h e p i n sand the vinylphosphonates (24; Y, Z = R or CN).40The shift mechanisms of a variety

OR (20)

/’\

Me

PMe,

II

s (23)

of lanthanide shift reagents on triethyl and tributyl phosphates have also been in~estigated.~~ Nickel and cobalt acetylacetonates have been used to study the conformational preferences of the phosphorinans (25).42 Phosphorus-31 and 13Cn.m.r. studies of 13C-labelledtribenzoylphosphine that is orientated in a liquid crystal gave a PCP bond angle of 96” and a 31Pchemicalshift anisotropy of 75 15 ~ . p . r n . ~ ~ Variable-temperature Studies.-Pseudorotation. Variable-temperature 13C n.m.r. spectroscopy has been used to study the pseudorotation of some caged oxaza-

*

34 35 3e

37 38 39

40 41 42

43

B. 1. Ionin, V. I. Zakharov, G. A. Berkova, V. Ya. Komarov, Yu. P. Sigolaev, and A. A. Petrov, Magn. Reson. Relat. Phenom., Proc. Congr. AMPERE ZOth, 1978 (publ. 1979), 500. K. B. Lipkowitz, T. Chevalier, and B. P. Mundy, Tetrahedron Lett., 1980, 21, 1297. Yu. Yu. Samitov, A. A. Musina, R. M. Aminova, M. A. Pudovik, A. I. Khagarov, and M. D. Medvedeva, Org. Magn. Reson., 1980, 13, 163. J. Hoegel and A. Schmidpeter, 2. Anorg. Allg. Chem., 1979,458, 168. L. P. Krasnomolova, 0. V. Agashkin, A. P. Logunov, Yu. B. Bosyakov, and B. M. Butin, Zh. Fiz. Khim., 1980, 54, 1447. Y. Segall, E. Shirin, and I. Granoth, Phosphorus Sulfur, 1980, 8, 243. A. Preiss, St. Dietzel, H. Fedgenhauer, and B. Hesse, J . Prakt. Chem., 1980, 322, 569. 0. V. Galaktionova, E. N. Lebedeva, V. V. Yastrebov, and S . S. Korovin, Zh. Neorg. Khim., 1980,25, 2660. B. A. Arbuzov, 0. A. Erastov, S.Sh. Khetagurova, T. A. Zyablikova, R. P. Arshinova, and R . A. Kadyrov, Zzu. Akad. Nauk SSSR, Ser. Khim., 1980, 1626. A. Cogne, L. Wiesenfeld, J. B. Robert, and R. Tyka, Org. Magn. Reson., 1980, 13, 72.

2 64

Organophosphorus Chemistry

phosphoranes (26).44It has been concluded that the constraints which govern the Berry mechanism also govern the multiple turnstile-rotation process, although the latter was originally proposed as a means of by-passing high-energy structures. Ab initio calculations have indicated that the pseudorotational isomers of the Wittig intermediates (27) have unexpected small energy differences, and that the small ring reduces the apicophilicities of the phosphorus l i g a n d ~ .Another ~~ theoretical study indicated that the Wittig intermediate (27; R = H) is formed and cleaved by what is basically a concerted process.46The transition states that are involved in pseudorotation processes have also been discussed in terms of self-inverse and non-self-inverse degenerate i ~ ~ m e r i ~ a t iDynamic o n ~ . ~ ~31Pn.m.r. studies of a variety of benzoxaphospholidines (28) detected pseudorotational proce~ses.~~

R

(30)

R

(32)

Restricted Rotation. Natural-abundance 13C,15N,and 31Pn.m.r. spectra of aminophosphanes have been used to study the electronic structure and restricted rotation concerning the P-N bond.49 In the cases of the aminophosphanes (29) and (30) the temperature dependence of lJ(PC) was attributed to restricted rotation about the P-N bond, with a preference for conformers with the lonepairs of electrons on nitrogen and on phosphorus anti to each other.60 The variable-temperature 13C spectra of simple and strongly sterically hindered alkylenephosphoranes, together with their borane adducts (3 l), have been interpreted in terms of hindered rotation in the ylides which was relieved on forming the ad duct^.^^ In the case of the aminophosphorane (32), which has minimal steric hindrance at 215 K, the NH, group prefers to lie in a plane perpendicular to the radial plane.52 The variable-temperature spectra of some 44

45 46 47

48 49 50 51

D . B. Denney, D. Z . Denney, D. M. Gavilivic, P. J. Hammond, C. Huang, and H. S. Tseng, J. Am. Chem. SOC.,1980,102, 7072; D. B. Denney, D. Z . Denney, P. J. Hammond, C. Huang, and K-S. Tseng, ibid., p. 5073. H. J. Bestmann, J. Chandrasekhar, W. G . Downey, and P. von R. Schleyer, J. Chem. SOC., Chem. Commun., 1980, 978. R. Hoeller and H. Lischka, J. Am. Chem. SOC,, 1980, 102, 4632. J. G. Nourse, J. Am. Chem. SOC., 1980, 102, 4883. K. Schemer, A. Burmester, R. Haller, and H. B. Stegmann, Chem. Ber., 1981, 114, 23. J. P. Gouesnard, J. Dorie, and G . H. Martin, Can. J. Chem., 1980, 58, 1295. G. A. Gray and J. H. Nelson, Org. Magn. Reson., 1980, 14, 8. H. Schmidbaur, G . Mueller, and G. Blaschke, Chem. Ber., 1980, 113, 1480. D . W. H. Rankin and J. G. Wright, J. Chem. SOC.,Dalton Trans., 1980, 2049.

Physical Methods

265

bicyclic n6 compounds have been attributed to the interconversion of stereoisomers.53 Studies of Configuration.-The inversion barrier for formylphosphine (33) has been estimated by an ab initio method to be 108 kJ m01-l.~~In the case of . ~ ~ n.m.r. acylphosphines, the inversion barriers correlate with 8 ~ Multinuclear studies of diphosphines (34) showed that bulky groups lower the inversion barrier.56 In addition to further studies of the extent of non-equivalence that is induced in enantiomers by optically active phosphinothioic acids5’ there has also been an investigation of the effects of concentration on the diastereoisomeric anisochronicity of the phosphonates (35).5B Double-resonance experiments involving the configurational assignment of phosphinate enantiomers have been described.59A further example of possible misinterpretation of 31Pn.m.r. spectra due to accidental equivalence was avoided by recording the spectra at high and at low temperatures.6oAn interesting configuration inversion of the phospholan (36) has also been studied by variable-temperature n.m.r. spectroscopy. The intermediate (37) was invoked in the mechanistic explanation.‘jl H,PCHO (33)

R’ \ /P--P

R2

0 /R’ ‘R2

R0,II /OR ,P-C-CO,R X ‘Cl

(34)

(36)

(35)

(37)

Spin-Spin Coupling.--J(PP) and J(PM). Negative direct coupling constants have been found for the chalcogenide derivatives of a series of diphosphines as well as for the diphosphines (34) themselves. The different magnitude of the couplings has been attributed to the changes in the s-overlap integrals of the P-P bond.62 Theoretical values of P-P and P-C couplings for n2- and n3-phosphorins and diphosphines correlate satisfactorily with observed values whether d-orbitals are included or not. Both angular dependence and changes in electronic effects have been taken into The dependence of lJ(PP) on the dihedral angle of 53

54 55 56 57

58

T. von Criegern and A. Schmidpeter, Phosphorus Suvur, 1979, 7 , 305; J. J. H. M. Font Freide and S. Trippett, J. Chem. Soc., Chem. Commun., 1980, 934. J. R. Damewood, jun., and K. Mislow, Monatsh. Chem., 1980, 111, 213. I. I. Chervin, M. D. Isobaev, Sh. M. Shikhaliev, L. V. Bystrov, Yu. I . El’natanov, and R. G. Kostyanovskii, Fiz.-Khirn. Protsessy Gazov. Kondens. Fasakh, 1979, 52. A. A. M. Ali, G. Bocelli, R. K . Harris, and M. Fild, J . Chem. SOC.,Dalton Trans., 1980,638. M. J. P. Harger, J. Chem. SOC.,Perkin Trans. 2, 1980, 1505. B. N. Kozhushko, Yu. A. Paliichuk, L. Ya. Bogel’fer, and V. A. Shokol, Zh. Obshch. Khirn., 1980, 50, 1273.

59 6o

61

e2

G. Haegele, D. Wendisch, R. Luckenbach, and H. H. Bechtolsheimer, Z . Naturforsch., Teil. B, 1980, 35, 1182. B. Thomas and L. Riesel, 2. Chem., 1980, 20, 335. C. Muegge, H. Weichmann, and A. Zschunke, J. Organomet. Chem., 1980,192,41. H. C. E. McFarlane, W. McFarlane, and J. A. Nash, J. Chem. SOC.,Dalton Trans., 1980, 240.

63

V. Galasso, J. Magn. Reson., 1979, 36, 181.

0rganophosphorus Chemistry

266

the phosphorus substituents is strongly evident in the spectra of triph~sphines.~~ Geminal P-C-P couplings are subject to similar effectss5 The n.m.r. data of selenides in liquid-crystalline media show that lJ(PSe) is highly anisotropic.66 Vicinal P-Se couplings in cyclic biphosphorus compounds (38) are sensitive to stereochemistry. Thus 2J(PSe) is -6 Hz for the cis-isomer (38; Z = OMe, Y = NBut) but - 14.2 Hz for the trans-i~omer.~~ The magnitude of ‘J(PN) for the phospholan (40) is also strongly dependent on steric factors,68and it assisted the determination of the absolute configuration of cyclic amidates (39) since IJ(PN) is lower when the amino-group is axially ~ r i e n t a t e d . ~ ~ It is interesting to note that the P(n3)-N-P(n4) coupling constant is positive in acyclic compounds but negative in most cyclic compounds, and furthermore is related to the conformation that is adopted about the P(n3)-N bond.70 Values of lJ(PSn) are in the range 538-724 for the stannylphosphanes (41).71

y-4

x

(42)

(44 1

J(PC). The direct P-C coupling constants in cyclic and bicyclic phosphines are believed to be strongly dependent on the flexibility of the bond angles.72This coupling is also temperature-dependent (0-9 Hz) for the aminophosphanes (29).50 There is an appreciable difference in lJ(PC) for the exo- and endo-cyclic bonds in the n5-phosphorane (42).73 The larger values of lJ(PC) for the (alkoxymethy1)phosphonium salts (43 ;Y = OR) as compared to those of the normal quaternary salts (43; Y = R) have been attributed to donation of a lone-pair from the oxygen atom to the phosphonium atom.74The stereochemical assignments of epoxidized 64 65

66

67 68

69 70

71 72

73 74

M. Baudler and G. Reuschenbach, Phosphorus Sulfur, 1980, 9, 81 : M. Baudler, G. Reuschenbach, D. Koch, and B. Carlsohn, Chem. Ber., 1980, 113, 1264. I. J. Colquhoun, S. 0. Grim, W. McFarlane, and J. D. Mitchell, J. Mugn. Reson., 1981, 42, 186; S. 0. Grim, L. C. Satek, and J. D. Mitchell, Z . Nuturforsch., Teil. B, 1980. 35, 832; S. 0. Grim and E. D. Walton, Phosphorus Sulfur, 1980, 9, 123. (a ) A. Cogne, A. Grand, J . Langier, J . B. Robert, and L. Wiesenfeld, J . Am. Chenz. SOC., 1980, 102, 2238; (b) J. P. Albrand and J . B. Robert, Pure A p p l . Chem., 1980, 52, 1047. I. J. Colquhoun, H. C. E. McFarlane, W. McFarlane, J. A. Nash, R. Keat, D . S. Rycroft, and D. G. Thompson, Org. Magn. Reson., 1979, 12, 473. J. P. Gouesnard and J. Dorie, J . Mol. Struct., 1980, 67, 297. W. J. Stec and W. S. Zielinski, Tetrahedron Letr., 1980, 21, 1361. G . Bulloch, R. Keat, D. S. Rycroft, and D. G. Thompson, Org. Mugn. Reson., 1979, 12, 708. J. D. Kennedy, W. McFarlane, G. S. Pyne, and B. Wrackmeyer, J . Organomet. Chem., 1980,195,285. A. Zschunke and+H. Meyer, Phosphorus Sulfur, 1980, 9, 117. H. Schmidbaur and P. Holl, 2. Anorg. Allg. Chem., 1979, 458, 249. Y.Yamamoto and Z. Kanda, Bull. Chem. SOC.Jpn., 1980, 53, 3436.

Physical Methods

267

p h o ~ p h o l e n sand ~ ~ isomeric 1,3-dioxan and 1,3-dioxolan phosphates were assisted by measuring vicinal P-C couplings. J(PH). The direct coupling constants in n4 compounds are in the region 450600 H z . The ~ ~ low value of lJ(PH), i.e. 266 Hz, for the n5-phosphorane(44)was evidence for an apical hydrogen, as shown, since the coupling does not fit 'the relationship lJ(PH)/Hz = 306{C.[o1(radial) 0.505 apical)]}+ 595 (ITI is the Taft parameter) for radial hydrogens, which is based on data from 52 phosp h o r a n e ~ The . ~ ~ equation indicates that radial substituents are almost twice as effective as apical substituents with regard to their influence on values of 'J(PH) for radial hydrogen.

+

J(PCnH) and J(PXC,H). The geminal P-C-Ha coupling constant of the trans cyclic phosphine oxide (45) is zero, in accordance with the known dependence of this coupling on bond angle, where J passes through zero at 80" and 180°.79 Other values of J(PCH) in these oxides varied from - 16 to + 6 Hz. In some n2 compounds this coupling varies from 22 to 45 HZ.~OThe decrease in absolute values of geminal and vicinal P-H coupling constants when a thiophosphoryl group is replaced by a phosphoryl group has been attributed to an increase in the transmission of coupling effects through the d-orbitals of phosphorus. This additional coupling mechanism is believed to have an appreciable, negative contribution.81 Another interesting hypothesis, this time concerning J(POCH), is that the s-character and the extent of d,-p, bonding in the P-0 bond determine the magnitude of the vicinal couplings for the phosphazenes (46; Y = OCH2CF2X).82 The coupling has also been used in the conformational analysis The abc subspectra of vinylphosphonium of a number of cyclic salts have been analysed, using spectral

(45) (46) L. D. Quin, G. Symmes, jnr., E. D. Middlemas, and H. F. Lawson, J . Org. Chem., 1980, 45, 4688. 76 (a) G . Adiwidjaja, B. Meyer, and J. Thiem, 2.Naturforsch., Tei.'. B, 1979, 34, 1547; (b) Y.Wedmid, C. A. Evans, and W. J. Baumann, J. Org. Chem., 1980, 45, 1582. 77 M. J. Gallagher and H. Honegger, Aust. J. Chem., 1980, 33, 287; 0. I. Kolodyazhnyi, Zh. Obshch. Khim., 1980, 50, 1485. ' 8 M. R . ROSSand J. C. Martin, J. Am. Chem. Soc., 1981, 103, 1234. 79 K. Moedritzer, Z . Anorg. Allg. Chem., 1979, 458, 183. a0 J. H. Weinmaier and G. Brunnhuber, Chem. Ber., 1980, 113, 2278. 81 V. Ya. Komarov, V. I. Zakharov, Yu. V. Belov, and B. I. Ionin, Zh. Obshch. Khim.,1980, 50, 1262. 82 V. N. Prons, N. B. Zaitsev, V. P. Sass, and A. L. Klebanskii, Zh. Obshch. Khim., 1980, 50, 17. ~43 D. Bouchu and J. Dreux, Tetrahedron Lett., 1980, 21, 2513; J. P. Dutasta, J. Martin, and J. B. Robert, Heterocycles, 1980, 14, 1631; D. G. Gorenstein, R. Rowell, and J. Findlay, J. Am. Chem. Soc., 1980,102, 5077; C . Bonningue, D . Houalla, M. Sanchez, and R. Wolf, J . Chem. Soc., Perkin Trans. 2, 1981, 19; J. A. Gerlt, N. I. Gutterson, R. E. Drews, and J. A. Sokolow, J . Am. Chem. SOC.,1980,102,1665. 84 H. Dolhaine, M. Engelhardt, G. Haegele, and W. Kueckelhaus, J . Magn. Reson., 1980, 41, 1. 75

10

Organophosphorus Chemistry

268

Studies of Relaxation, CIDNP, and N.Q.R.-The 31Pspin-lattice relaxation data of various compounds have been studied,85 as has the optimization of paramagnetic relaxation to reduce line-broadening of 31Psignals.86 Laser-induced CIDNP has been used as a probe for non-aromatic amino-acid residues in The 1 7 0 n.q.r. spectra of triphenylphosphine oxide and triphenyl phosphate support the postulate of substantial n-bond order in the phosphoryl bonds.88 Chlorine-35 n.q.r. data of the phosphines (47) showed non-equivalence of the three trichloromethyl groups and of each chlorine atom within each

(47)

(49)

Conformational and electronic transmission effects in trichlorophosphazenes (48) have also been studied.g0 N.q.r. (35Cl)spectra have also been used to show that the C-Cl group in the phosphorin (49) is substituted before the PCI, groupg1 and to determine the preferred orientation of trichloromethyl groups in n5-phosphoranes. 92 2 Electron Spin Resonance Spectroscopy

The phosphinyl radical (50) gives an e.s.r. spectrum with a(P) = 9.63 mT (96.3 G); this is in the upper range for n2 radicahg3The parameters for the trimesitylphosphine radical cation indicate that the unpaired electron occupies a o - ~ r b i t a l . ~ ~ A knowledge of the preferred orientations of substituents on phosphorus in phosphoranyl radicals is important for an understanding of radical-scission reactions. 95 By recording the e.s.r. spectra of a pyrrolephosphoranyl radical at low temperatures, it was possible to observe an equilibrium involving structures in which the pyrrole ring occupies both apical and radial The caged radical (51) provided a unique study because the unpaired electron is forced into 85 86

87 88

89 90

91 92

93 94

95

96

R. K. Nanda, A. Ribeiro, T. S. Jardetzky, and 0. Jardetzky, J. Magn. Reson., 1980, 39, 119; K. Rarnarajan. Diss.Abstr. Int. B, 1980, 41, 2186 (Chem. Abstr., 1981, 94, 156 900). T. M. Carr and W. M. Ritchey, Spectrosc. Lett., 1980, 13, 603. C. L. Lerman, and M. Cohn, Biochem. Biophys. Res. Commun., 1980, 97, 121. C. P. Cheng and T. L. Brown, J . Am. Chem. SOC..1980, 102, 6418. I. A. Kyuntsel, G . B. Soifer, E. S. Kozlov, A . V. Solov’ev, and M. I. Povolotskii, Zh. Obshch. Khim., 1980, 50, 822. Yu. P. Egorov and M. I. Povolotskii, Teor. Eksp. Khim., 1981, 17, 5 2 ; Yu. G . Shermolovich, E. A. Romanenko, T. D . Petrova, M. I. Povolotskii and G . G. Furin, Izv. Sib. Otd. Akad. Nnuk SSSR, Ser. Khim. Nuuk, 1980, No. 9, p. 141 ; I. A. Kyuntsel, Yu. I. Rosenberg, G . B. Soifer, N. Ainbinder, G . A. Volgina, G . E. Kibrik, andV. A. Mokeeva, Mapn. Reson. Relat. Phenom., Proc. Congr. AMPERE ZOth, 1978 (pub]. 1979), 195. P. P. Kornuta, L. S Kuz’rnenko, and V N. Kalinin, Zh. Obshch. Khim., 1980, 50, 1313. V. I. Dmitriev, E. S. Kozlov, and B. V. Tirnokhin, Zh. Obshch. Khim., 1980, 50, 2230. M. J . S. Gynane, A. Hudson, M. F. Lappert, P. P. Power, and H. Goldwhite, J . Chem. SOC.,Dalton Trans., 1980, 2428, A. V. Il’yasov, Yu. M. Kargin, E. G. Nikishin, A. A. Vafina, G . V. Romanov, A. Sh. Mukhtarov, 0. V. Parakin, A. A . Kasakova, and A. N. Pudovik, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 189. B. P. Roberts and K. Singh, J. Chem. SOC.,Perkin Trans. 2, 1980, 1549. J. A. Baban, and B. P. Roberts, J . Chem. SOC.,Perkin Trans. 2, 1980, 876.

2 69

Physical Methods

an apical siteg7E.s.r. spectroscopy has been used in a number of stereochemical studies involving arylenedioxy-groups,98 a-ketylphosphonate anions,99organosilyl radicals,loo and novel thiophosphoranyl radicals.lol In addition to several studies of nitroxyl and iminoxyl radicals,lo2aryloxyl radicals,lo3a hydrazidinyl radical,lo4 and quinodimethanides,lo5 there have been studies of additions of alkyl radicals to vinylphosphonates lo6and an example of ‘wandering’ valences,1o7 using e.s.r. spectroscopy. 3 Vibrational and Rotational Spectroscopy Band Assignments and Absorptivity.-Further work on the vibrational spectra of methylphosphines108*109 has led to the assignment of bands in the 1020500 cm-l region of dimethylphosphine to coupled d(PH), p ( C H 3 ) , and skeletal modes.lo9 Assignments have also been reported for the spectra of the diphosphanes (52; Y = H, D, or Li),ll0 various n3-iminomethylenephosphoranes (53),ll1 a (silylimino)phosphorane,112the unusual phosphazeno carbenium ion (54),113 and some metal complexes of diphosphine di~u1phide.l~~ The molar absorptivity of tributyl phosphate, at various concentrations, has also been measured, for qualitative ana1~sis.l~~ R’,N (Ph,P),NY

( 5 2)

‘P=CR’Me

R~NH (53)

(C13P=N),6

SbC1,

(54)

J. H. H. Hamerlinck, P. Schipper, and H. M. Buck, J. Am. Chem. SOC.,1980, 102, 5679. S. P. Solodovnikov, N. N. Bubnov, and A. I. Prokof’ev, Usp. Khim., 1980, 49, 3 . V. Cerri, P. Fuerderer, F. Gerson, and P. Tordo, N o w . J. Chim., 1980, 4, 109. 100 T. Newman and R. West, J. Organomet. Chem., 1980, 199, C39. lol J. C. Evans, S. P. Mishra, and C. C. Rowlands, Chem. Phys. Lett., 1980, 72, 168. l o 2 A. V. Il’yasov, A. Sh. Mukhtarov, and A. A. Barley, Magn. Reson. Relat. Phenom., Proc. Congr. AMPERE 20th, 1978 (publ. 1979), 176: A. A. Barlev, A. V. Il’yasov, and B. M. Odintsov, Deposited Document, 1979, VINITI 1129,23; J. Skolimowski, R. Skowronski, and M. Sirnalty, Tetrahedron Lett., 1979, 4833; B, M. Odintsov, A. A. Barlev, and A. V. Il’yasov, Teor. Eksp. Khim., 1980, 16, 392. 1 0 3 B. B. Adeleke and 3. K. S. Wan, J. Chem. SOC., Perkin Trans. 2, 1980,225. 104 F. A. Neugebauer and H. Fischer, Z. Naturforsch., Ted. B, 1980, 35, 250. 1°5 L. Komorowski, R. Kowal, S. Jerzak, and S. Waplak, Potsdamer Forsch. Paedagog. Hochsch. ‘Karl-Liebknecht’ Potsdam. Reihe B. 1979, 19, 141. l06 J. A. Baban and B. P. Roberts, J. Chem. Soc., Perkin Trans. 2, 1981, 161. l o 7 M. I. Kabachnik, Pure Appl. Chem., 1980, 52, 859. l 0 8 S. A. Katsyuba, I. S. Pominov, and B. P. Khalepp, Deposited Document, 1980, VINITI g7

9s 99

546, 33. D. C. McKean and G. P. McQuillan, J. Mol. Struct., 1980, 63, 173. J. Ellerman and M. Lietz, 2. Naturforsch., Teil. B, 1980, 35, 64. ll1 E. Niecke and D.-A. Wildbredt, Chem. Bet-., 1980, 113, 1549. 112 J. C. Wilburn, P. Wisian-Neilson, and R. H. Neilson, Znorg. Chem., 1979, 18, 1429. 113 U. Mueller, Z. Anorg. Allg. Chem., 1980, 463, 117. 1 1 4 G. P. McQuillan and 1. A. Oxton, J. Mol. Struct., 1980, 64, 173. 115 V. P. Tomaselli, H. Zarrabi, and K. D. Moeller, Appl. Spectrosc., 1980, 34, 415. 109

270

Orgarlophosphorus Chemistry

Bonding.-There have been further studies of the inductive and mesomeric effects of substituents on Y(PO),~'~ and a measurement of thef(PS) force-constant of the dithiophosphinate ion ( 5 5 ) supports a structure possessing a n-delocalized anion.117Studies of hydrogen-bonding by i.r. spectroscopy have been extended to proton-donor and -acceptor properties of phosphines.ll* It is interesting to note that bonding between phenol and aminophosphanes involves the nitrogen as the sole donor for the P-ethyl compounds, as shown in (56), but it involves the phosphorus atom as donor, as shown in (57), as well as the nitrogen atom, for the Fphenyl corn pound^.^^^ Studies of hydrogen-bonding involving phosphoryl groups have been extended to quinolylmethyl compounds,120 cc-aminophosphonates121(cf CND0/2 studies of the hydration of aminomethyl-phosphonic and -phosphinic acids122), the oxazaphospholines (58),123 and phosphorussubstituted aliphatic A L.F.E.R. study found that v(0H) for phenol

0

II

ArPR,

Ph,P'

\

RO,C "=I\,

(59)

(58)

(60)

and (substituted ary1)phosphine oxide systems correlates best with the G O and 0 substituent constants125for the oxides (59; R = Me) and (59; R=Ar), respectively. In another investigation, using a wide range of phosphoryl compounds, A[v(OH)], K(eq.), and - AH were found to decrease in the order (Me,N),PO > Me,PO > Ph3P0 > (MeO),PO > (ArO)3P0.126An i.r. and n.m.r. study of the enol (60) showed it to be favoured over the keto-form, regardless of the nature of the anion X-.127 V. E. Bel'skii and L. Kh. Ashrafullina, Zh. Prikl. Spektrosk., 1980, 33, 361. I. Silaghi-Dumitrescu and I. Haiduc, Rev. Roum. Chim., 1980, 25, 815. 11s E. V. Ryl'tsev, A. K. Shurubura, Yu. P. Egorov, and V. Ya. Semenii, Teor. Eksp. Khim., 1980, 16, 497. ll9 V. 1. Shibaev, A. V. Garabudzhin, A. N. Lavrent'ev, and E. G . Sochilin, Zh. Obshch. Khim., 1980, 50, 309. 120 V. Jagodic, B. Bozic, L. Tusek-Bozic, and M. J. Herak, J . Heterocycl. Chem., 1980, 17, 685. 121 G . Zuchi and V. Zotta, Farmacia (Bucharest), 1980, 28, 31 ; M. G. Zimin, A. R. Burilov, R. G. Islamov, I. S. Pominov, and A. N. Pudovik, Zh. Obshch. Khim., 1980, 50, 2203. 1z2 Z . Latajka, H. Ratajczak, J. Barycki, and R. Tyka, J . Mol. Struct., 1981, 70, 49. 1 2 3 G. A. Kalyagin, I. E. Boldeskul, Yu. P. Egorov, and Yu. V. Balitskii, Teor. Eksp. Khim., 1980. 16, 815. 124 N. A. Bondarenko, E. I. Matrosov, E. N. Tsvetkov, and M. I. Kabachnik, Zzu. Akad. Nauk SSSR, Ser. Khim., 1980, 106. lZ5L. V. Goncharova, A. A . Shvets, Yu. I. Sukhorukov, 0. A. Osipov, and L. N. Talanova, Zh. Obshch. Khim., 1980, 50, 321. 1 z 6 V. S. Pilyugin, Zh. Obshch. Khim., 1980, 50, 835. 1 2 7 I. M. Aladzheva, P. V. Petrovskii, T. A. Mastryukova, and M. I. Kabachnik, Zh. Obshch. Khim., 1980, 50, 1442. 116 117

Physica I Methods

27 1

Stereochemistry.-The i.r. spectra of the 3-phospholen (61) and its deuterium analogue, in the vapour phase, indicated that P-H inversion is strongly linked with ring-puckering.128On the other hand, v(PH) for a variety of phosphanes has been found to correlate with bond angle and with 31Pn.m.r. parameter^.^ Vibrational spectroscopy has been used in the conformational analysis of trimethyl phosphite,lZ9 difluoromethoxyphosphane,130and methylmercaptophosphanes,131 and the split fundamental bands in the spectra of trimethyl phosphite-borane adducts have been interpreted in terms of certain rotamer preferences.132 Similar studies of n4 organophosphorus compounds involve (trichloromethy1)phosphonates (62),133phosphinic methyl dimethylp h ~ s p h i n a t e ,and ~ ~ ~tetra-allyldiphosphine disulphide (63).136 A transannular 0

II

C1, CP(0R ),

(H,C=CHCH,),P-P(CH,CH=CH,),

interaction across an eight-membered ring, involving a heteroatom and a phosphoryl group, has been invoked on the basis of infrared spectral evidence.13’ The intensities of v(P0) bands of some 1,3,2-dioxaphosphorinanswere used to calculate the thermodynamic parameters for the conformational whilst steric effects which widen the C-P-C bond angles of triarylphosphine oxides are thought to lower v(P0) and v(PC) through a change of the hybridization of the phosphorus atom.139 The long-standing problem of the conformational preferences of myo-inositol hexakisphosphate has been resolved by the combined use of Raman and n.m.r. spectroscopy, the former being responsive to both acid dissociation and ring conformation, in addition to permitting comparisons between aqueous solutions and s01ids.l~~ n5-Phosphoranes which possess P-H bonds that occupy radial positions exhibit v(PH) bands in the region 2360-2430 cm-l whereas the apical P-H bond in the phosphorane (44)has v(PH) at 2256 (in CCl,) or 2150 cm-l (in N ~ j o l ) . ~ ~ 128

129 130

131 132 133

134 135 136 137 138

139

140

L. W. Richardson, P. W. Jagodzinski, M. A. Harthcock, and J. Laane, J. Chem. Phys., 1980,73, 5556. 0 .A. Raevskii, Yu. A. Donskaya, and L. P. Chirkova, Izu. Akad. Nauk SSSR, Ser. Khim., 1980, 817. J. R. Durig and B. J. Streusand, Appl. Spectrosc., 1980, 34, 65. I. 1. Patsanovskii, E. A. Ishmaeva, A. B. Reniizov, and F. S. Bilalov, Dokl. Akad. Nauk SSSR, 1980,254,414. K. Hassler, Bey. Bunsenges. Phys. Chem., 1980, 84, 285. B. J. van der Veken, M. A. Herman, and P. Stevens, C.R. ConJ Int. Spectrosc. Raman, 7th, 1980, 256. 0. A. Raevskii, N. G . Mumzhieva, N. P. Anoshina, and B. Ya. Teitel’baum, Izv. Akad. Nauk S S S R , Ser. Khim., 1980, 930. B. J. van der Veken, R. Odeurs, and M. A. Herman, C.R. Conf. Znt. Spectrosc. Raman, 7th, 1980,258. A. J. Blake, G. P. McQuillan, and 1. A. Oxton, Spectrochim. Acta, Part A, 1980, 36, 501. R. K. Sharma, K. Sampath, and R. Vaidyanathaswamy, J . Chem. Res. ( S ) , 1980, 12. R. Vilceanu and 1. Neda, Phosphorus Sulfur, 1980, 8 , 131. R. R. Shifrina, J. P. Romm, E. N. Gur’yanova, and N. A. Rozanel’skaya, Z h . Prikl. Spektrosk,, 198 1 , 34, 1 1 1 . L. R. Isbrandt and R. P. Oertal, J. Am. Chem. SOC.,1980, 102, 3144.

Organophosphorus Chemistry

21 2

Rotational Data.-The characterization of C-cyanophosphaethyne (64) by microwave spectroscopy is based largely on the value of the rotational constant r(C=P) of 154.4, which gives p = 3.5 D.14' The microwave spectra of methylenephosphine (65) and of 3-phospholen (61) 143 have also been analysed and structural parameters calculated. Inelastic neutron-scattering spectra of partially deuteriated dimethyl methylphosphonate have been used to estimate the barriers to rotation about the P-methyl bond.144 P=C-CEN

H,C=PH

(64)

(65)

4 Electronic Spectroscopy

Absorption Spectroscopy.-The U.V.spectra and the Faraday effects of a wide range of phenylphosphanes (66; Y = H , Ph, Et, C1, or OEt) and diphosphanes (67; Y = Ph, Et, CF3, or NPr,) have been compared and discussed in terms of the interactions of n-electrons of phenyl and of lone-pairs with the phosphorus atom.145The effects of solvent and of the extent of n-delocalization on the U.V. spectra of the triazaphosphorines (68) have been i n ~ e s t i g a t e d land ~ ~ a comparison has been made between the chromophores 1,4-oxaphosphorin and A spectral study of aryltetrachlorophosphoranes has also been 4H-pyran0ne.~~~ re~0rted.l~~

Photoelectron Spectroscopy.-The electronic structure of phosphacymantrene has been studied, using p.e. spectroscopy and E.H.T. ~alculations,'~~ and a word of warning has been expressed about the bias that can be introduced when matching model calculations with experimental data, using linear regressions.15o The spectra and proton affinities of phosphiran (69) have been compared with those of the corresponding sulphur and nitrogen analogues and of dimethylphosphine. The lower proton affinities of the small-ring heterocycles were attributed to the high s-character of the lone-pair of electrons and to increased 141 142

143

T. A. Cooper, H. W. Kroto, J. F. Nixon, and 0. Ohashi, J . Chem. SOC.,Chem. Commun., 1980, 333. H. W. Kroto, J. F. Nixon, K. Ohno, and N. P. C. Simmons, J . Chem. SOC., Chem. Commun., 1980, 709. J. R. Durig, B. J. Streusand, Y . S. Li, L. Richardson, and J. Laane, J. Chem. Phys., 1980,

73, 5564. B. J. van der Veken, D. H. C . Harris, and G. Haines, J. Chem. SOC., Faraday Trans. 2, 1980,76, 1485. 145 D. Troy, R. Turpin, and D. Voigt, Bull. SOC.Chim. Fr., Purt I , 1979, 241. 146 E. A. Romanenko, S. V. Iksanova, and Yu. P. Egorov, Teor. Eksp. Khim., 1980, 16, 308. 147 H . G. Henning and R. Krueger, 2. Chem., 1980, 20, 261. 148 L. M. Sergienko, G . V. Ratovskii, V. I . Dmitriev, and B. V. Timokhin, Zh. Obshch. Khim., 1980,50, 1958. 1 4 9 C. Guimon, G. Pfister-Guillouzo, and F. Mathey, Nouu. J . Chim., 1979, 3, 725. 150 E. Heilbronner and A . Schmelzer, Noua. J . Chirn., 1980, 4, 23.

144

Physical Methods

273

ring strain in the protonated species.lS1Studies have also been carried out on three- and four-membered ring systems that contain two or three phosphorus atoms 152 and on a heptapho~phanortricyc1ene.l~~ The binding energies of the core electrons of the phosphorus of some phosphanes (mainly dialkylaminocompounds and phosphites) have been determined.154Some substituted diphosphine disulphides have been investigated by U.V. photoelectron spectroscopy 155 and the ionization potentials of a range of phosphoryl compounds measured from their p.e. Parametrization and MIND0/3 calculations on the ionization potentials of compounds with P-0, P-F, and P-CI bonds have also been described.15' X-Ray Fluorescence Spectroscopy.-In keeping with the main body of evidence X-ray fluorescence spectroscopy supports the postulate that there is a greater degree of d-orbital participation in P=O bonds than in P-OR 5 Diffraction X-Ray Diffraction.-The number of structures of organophosphorus compounds that has been determined over the past year has now exceeded one hundred, X-Ray diffraction studies showed that the n2-cyanophosphinidene (70) 159 and the lithium salt (7l)lSo both have C-P-C bond angles of 101.8", whilst the diaminophosphenium cation (72) has a bond angle for N-P-C of 114.8".6

(70)

(71)

(7 2)

There have been several studies of diphosphines, including those of the phenylene (73) and its monoprotonated tetrafluoroborate salt,161 the bis(acy1)diphosphine (74),162and the diphospheten (75).lS3Despite the possible 6n-electron delocalized system, the structure of the diphospheten exhibited no evidence of D. H. Aue, H. M. Webb, W. R. Davidson, M. Vidal, M. T. Bowers, H. Goldwhite, L. E. Vertal, J. E. Douglas, P. A. Kollman, and G. L. Kenyon, J . Am. Chem. Soc., 1980, 102, 5151. 1 5 2 R. Gleiter, M. C. Boehm, and M. Baudler, Chem. Ber., 1981, 114, 1004 H. Rock, B. Solouki, G . Frits, and W. Hoelderich, Z . Anorg. Allg. Chem., 1979, 458, 53. 1 5 4 T. H . Lee, W. L. Jolly, A. A. Bakke, R. Weiss, and J. G . Verkade, J. Am. Chem. SOC., 1980, 102, 2631. l 5 5 L. Alagna, C. Cauletti, M. Andreocci, C. Furlani, and G . Haegele, 2. Naturforsch., Teil. A , 1981, 36, 68. 1 5 6 V. V. Zverev and J. Villem, Zh. Strukt. Khim.,1980, 21, No. 1, p. 30. 15' G. Frenking, F. Marschner, and H. Goetz, Phosphorus Sulfur, 1980, 8, 337; G. Frenking, H. Goetz, and F. Marschner, ibid., 1979, 7 , 295. l 5 8 V. D. Yumatov, L. N. Mazalov, and E. A. Il'inchik, Zh. Strukt. Khim., 1980, 21, No. 5 , p. 24. 159 A. Schmidpeter, W. Gebler, F. Zwaschka, and W. S . Sheldrick, Angew. Chem., Inr. Ed. Engl., 1980, 19, 722. 160 G . Becker, M. Birkhahn, W. Massa, and W. Uhl, Angew Chem., Inr. Ed. Engl., 1980, 19, 74. 161 N. K. Roberts, B. W. Skelton, and A. H . White, J. Chem. Sac., Dalton Trans., 1980, 1567. 1 6 2 G. Becker, 0. Mundt, and M. Roessler, Z. Anorg. Allg. Chem., 1980, 468, 5 5 . 163 C. Charrier, J. Guilhem, and F. Mathey, J. Org. Chem., 1981, 46, 3. 151

274

Organophosphorus Chemistry

delocalized bonds. The structure of the phosphole (76) is interesting in that, upon conversion into its sulphide, the geometry is almost unchanged.lB4Some unusual ring systems have been studied, such as a dithiatetra-azadipho~phocin,l'~ an azaphospha-adamantane,166 and a trioxatriph~sphorin,'~~ the latter possessing the boat conformation (77; R = Pri). The crystal structure of the oxaphosphocin (78) indicated that there is a weak transannular P-N interaction, which CND0/2 calculations and n.m.r. spectroscopy suggested was of an electrostatic character.lae Ph

,COBu*

Ph, P

Ph

PPh

Me

PhKbPh

Q C 0 2 M e Ph

(75)

P h i P \ C 0 But

Me

Me

(76)

(74)

(73)

(77)

(7 8)

(79)

The molecular structures of the dioxaphosphorin (79),ls9 a phenylphosphinyli d o p y r a n ~ s e , ' and ~ ~ the phosphite derivatives of two xylitans171 and of two f u r a n ~ s e shave l ~ ~ also been determined. As usual, there have been numerous studies of n4 compounds. In addition to several triphenylphosphonium acyclic and cyclic and ylides 175 R. D.Knott, H . Honneger, A. D. Rae, and G. de Lanzon. Cryst. Struct. Commun., 1980, 9 , 905. 165 H. W. Roesky, S. K. Mehrotra, C. Platte, D. Amirzadeh-Asl, and B. Roth, Z . Nuturforsch., Teil. B, 1980, 35, 1130. 166 0 .J. Scherer, K. Andres, C. Kriiger, Y.-H. Tsay, and G. Wolmershauser, Angew. Chem., Int. Ed. Engl., 1980, 19, 571. 16' E. Niecke, H. Zorn, B. Krebs, and G. Henkel, Angew. Chem., Inr. Ed. Engl., 1980, 19, 709. 168 J. Devillers, D.Houalla, J. J. Bonnet, and R. Wolf, Nouu. J . Chim., 1980, 4, 179. 169 J. von Seyerl and G. Huttner, Z . Naturforsch., Teil. B , 1980, 35, 1373. 170 P. Luger, M. Yamashita, and S. Inokawa, Carbohydr. Res., 1980, 84, 25. 171 L. A. Aslanov, S. S. Sotman, V. B. Rybakov, V. I. Andrianov, Z. Sh. Safina, M. P. Koroteev, L. T. Elipina, and E. E. Nifant'ev, Zh. Strukt. Khim., 1979,20, 1122. 172 L. A. Aslanov, S. S. Sotman, V. B. Rybakov, V. I. Andrianov, Z . Sh. Safina, M. P. Koroteev, and E. E. Nifant'ev, Zh. Strukt. Khinr., 1979, 20. 1125. 173 M. Yu. Antipin, A. E. Kalinin, Yu. T. Struchkov, and M. Aladzheva, T. A. Mastryukova, and M. I. Kabachnik, Zh. Srrukt. Khim., 1980, 21, No. 4, p. 175; R. J. Fleming, M. A. Shaikh, B. W. Skelton, and A. H. White, Aust. J. Chem., 1979, 32, 2187; J. C. J. Bart, I. W. Bassi, and M. Calcaterra, J . Organomet. Chem., 1980, 193, 1 . 174 D. W. Allen, I. W. Nowell, and P. E. Walker, Phosphorus SuIfur, 1979,7, 309; Mazhar-ulHaque, W. Horne, S. E. Cremer, P. W. Kremer, and J. T. Most, J . Chem. SOC.,Perkin Truns. 2, 1980, 1467; T. A. Mastryukova, I. M. Aladzheva, and I. V. Leont'eva, Pure Appl. Chem., 1980, 52, 945; J. C. Galluci and R. R. Holmes, J. Am. Chem. Soc., 1980, 102, 4379; R. 0. Day, S. Husebye, J. A. Deiters, and R. R . Holmes, ibid., p. 4387. 1 7 5 H . Schmidbaur and U. Deschler, Chem. Ber., 1980, 113, 902; J. Bojes, T. Chivers, A. W. Cordes, G. MacLean, and R. T. Oakley, Znorg. Chem., 1981, 20, 16; J. Weiss and B. Nuber, 2. Anorg. Allg. Chem., 1981,473, 101 ; H. Schmidbaur, T. Costa, B. MilewskiMahrla, and U. Schubert, Angew. Chern., 1980, 92, 557.

164

Physical Methods

275

have been studied. The group of quasiphosphonium salts 176 included some unusual azo-deri~atives.~~~ Amongst the large number of phosphine oxides that diphenylcycl~hexenyl,~~~ and have been investigated are tri~yanoethyl,~’~ (cc-hydroxybenzyl)diphenyl,la0and oxides of phosphepin,lsl phosphorin,182and phosphetan la3 derivatives, together with several phospholan oxides la4 and a have been studied. Several other phosphine chalcodihydrophosphole genides have been studied, reports appearing on a phosphorinanone sulphide,28a a phosphole sulphide,la6and three selenides.66a~ la7All of the phosphinic derivatives examined were acyclic compounds.188In the case of the chloride (SO), the benzene rings were distorted into boat conformation^.^^^ Of the phosphonic derivatives,lgO two possessed azaphospholidine structures lgl and one was a camphene Reports have appeared on phosphate acid esters l g 2and Structures for a number of phoson related thioJg3 and amino-derivati~es.~~~ K. Henrick, H. R. Hudson, and A. Kow, J. Chem. Soc., Chem. Commun., 1980, 226; G. Maas and R. Hoge, Liebigs Ann. Chem., 1980, 1028. 1 7 7 C. Roemming and J . Songstad, Acta Chem. Scand., Ser. A , 1980,34, 631 ; M. Halstenberg, R. Appel, G. Huttner, and J . von Seyerl, 2. Naturforsch., Teil. B, 1979, 34, 1491. 178 A. J. Blake, R. A. Howie, and G. P. McQuillan, Acta Crystallogr., Sect. B, 1981, 37, 997. 1 7 9 M. L. Glowka and Z . Galdecki, Acta Crystallogr., Sect. B, 1980, 36, 1728. 180 M. Dankowski, K. Praefcke, S. C . Nyburg, and W. Wong-Ng, Phosphorus Sulfur, 1979,7, 275. 181 D. W. Allen, I. W. Nowell, and P. E. Walker, 2. Naturforsch., Tcil.B, 1980,35, 133. 1 8 2 J. B. Rampal, K. D. Berlin, N. S. Pantaleo, A. McGuffy, and D. van der Helm, J. Am. Chem. Soc., 1981, 103, 2032. 183 E. Vilkas, M. Vilkas, J. Sainton, B. Meunier, and C. Pascard, J . Chem. Soc., Perkin Trans. I , 1980, 2136. 184 Z. Galdecki and M. L. Glowka, Acta Crystallogr., Sect. B, 1980,36,2191,2809; ibid. 1981, 37, 459, 461; F. Cavagna, U. H. Felcht and E. F. Paulus, Angew. Chem., Inr. Ed. Enel., 1980, 19, 132. 185 Z. Galdecki and M. L. Glowka, Acta Crystallogr., Sect. B, 1980, 36, 2188. 1 8 6 D. C. Craig, M. J. Gallagher, F. Mathey, and G. De Lanzon, Cryst. Struct. Commun., 1980, 9, 90 1. 187 Z. Galdecki and M. L. Glowka, Int. Semin. Cryst. Chem. Coord. Organomet. Compd. (Pruc.), 3rd, 1977, 206; D. H. Brown, R. J. Cross, P. R. Mallinson, and D. D. MacNicol, J . Chem. SOC.,Perkin Trans. 2, 1980, 993. 188 G. Oliva, E. E. Castellano, and L. R. Franco-de Cavalho, Acta Crystallogr., Sect. B , 1981, 37,474; W. Wong-Ng, S. C. Nyburg, and T. A. Modro, J . Chem. Soc., Chem. Commun., 1980, 195; Yu. P. Belov, G. B. Rakhnovich, V. A. Davankov, N. N. Godovikov. G. G . Aleksandrov and Yu. T. Struchkov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1125; Z . Galdecki, M. L. Glowka, S. Musierowicz, aad J. Michalski, Pol. J . Chern., 1980, 54, 539; D. Schomburg, 0. Stelzer, N. Weferling, R. Schmutzler, and W. S . Sheldrick, Chem. Ber., 1980, 113, 1566; M. L. Glowka and Z . Galdecki, Acta Crystallogr., Sect. B, 1980,36, 2312. 189 M. Yoshifuji, I. Shima, N. Inamoto, K. Hirotsu, and T. Higuchi, Angew. Chem., Int. Ed. Engl., 1980, 19, 399. 1 9 0 V. V. Tkachev, L. 0. Atovmyan, N. A . Kardanov, N. N. Godovikov, and M. I. Kabachnik, Zh. Strukt. Khim., 1980, 21, No. 2, p. 106. 191 Yu. V. Balitskii, Yu. G. Gololobov, V. M. Yurchenko, M. Yu. Antipin, Yu. T. Struchkov, and I. E. Boldeskul, Zh. Obshch. Khim., 1980,50,291; G. L’abbe, J. Flemal J. P. Declercq, and M. Van Meerssche, Bull. Soc. Chim. Belg., 1979, 88, 737. 1 9 2 G. G. Aleksandrov and Yu. T. Struchkov, Cryst. Struct. Commun., 1980, 9, 493; M. Yu. Antipin, A. E. Kalinin, Yu. T. Struchkov, A. A. Kryuchkov, E. A. Matrosov, and M. I . Kabachnik, Zh. Strukt. Khim., 1980, 21, No. 4, p. 168. 193 M. W. Wieczorek, Phosphorus Sulfiw, 1980, 9, 137; Z. Galdecki and M. L. Glowka, Cryst. Struct. Commun., 1981, 10, 137; R. L. Lapp and R. A. Jacobson, J . Agric. Food Chem., 1980, 28, 755. 194 3. Jernow, J. Blount, E. Oliveto, A. Perrotta, P. Rosen, and V. Toome, Tetrahedron, 1979, 35, 1483; M. P. Du Plessis, T. A. Modro, and L. R. Nassimbeni, S . AJi.. J . Chem., 1980, 33, 124. 176

276

Organophosphorus Chemistry

phazenes,lg5 related sulphur analogues,l 96 phosphazanes,lg7 and a borane adduct of a caged phosphanelg8have also been established. Most of the n5-phosphoranes that have been investigated are bicyclic or caged aza-lg9 or oxaza-compounds;200 however, diazadifluoro- and diazadichlorophosphoranes 201 and a difluoro-oxazaphosphorane 202 have also been examined. Full details of the structures of bis-biphenylenephosphoranes203 have also appeared. Electron Diffraction.-t-Butyldichlorophosphane has been shown to adopt a staggered symmetrical conformation, with the P-C and P-Cl bonds longer than for less crowded p h o ~ p h a n e sThere . ~ ~ ~ have been studies of several derivatives

of aminodifluoroph~sphanes,~~~ which may be compared with recent MNDO/ SCF MO calculations on the parent compound (81).206The phosphonium ylide (82), in the gas phase, prefers a conformation which has the Si-C bond twisted 195

196

197 198

199

200

201 202

203 204

205

206

K. D. Dhathathreyan, S. S. Krishnamurthy, A. R. V. Murthy, T. S. Cameron, C. Chan, R. A. Shaw, and M. Woods, J . Chern. SOC.,Chem. Cornmun., 1980, 23 1 ; T. S. Cameron, C. Chan, J. F. Labarre, and M. Graffeuil, Z . Naturforsch., Teil. B, 1980, 35, 784; Y. S. Babu, H. Manchar, and R. A. Shaw, J . Chem. SOC.,Dalton Trans., 1981, 599; A. G. Scopelianos, J. P. O’Brien, and H. R. Allcock, J . Chem. SOC.,Chem. Commun., 1980, 198. N. Burford, T. Chivers, and R. T. Oakley, J . Chem. SOC.,Chem. Commun., 1980, 1204; F. Van Bolhuis, C. Cnossen-Voswijk, and J. C. Van d e Grampel, Cryst. Struct. Commun., 1981, 10, 69. G . J. Bullen, S. J. Williams, N. L. Paddock, and D. J. Patmore, A m Crysrallogr., Sect. B, 1981, 37, 607: W. Zeiss, W. Schwarz, and H. Hess, Z . Naturforsch., Teil. B, 1980,35, 959. D. Grec, L. G. Hubert-Pfalzgraf, J. G. Riess, and A. Grand, J. Am. Chem. SOC.,1980,102, 7133. J. E. Richman, R. 0. Day, and R. R. Holmes, J. Am. Chem. SOC.,1980, 102, 3955; D. Hellwinkel, W. Blaicher, W. Krapp, and W. S. Sheldrick, Chem. Ber., 1980, 113, 1406; H. W. Roesky, K. Ambrosius, and M. Banek, ibid., p. 1847; L. Vande Griend and R. G. Cavell, Inorg. Chern., 1980, 19, 2070; A. Schmidpeter, W. Zeiss, D . Schomburg, and W. S. Sheldrick, Angew. Chem., Int. Ed. Engl., 1980, 19, 825; D. Lux, W. Schwarz, H. Hess, and W. Zeiss, Z . Naturforsch., Teil. B, 1980, 35, 269. W. S. Sheldrick, D. Schomburg, and A. Schmidpeter, Acta Crystallogr., Sect. B, 1980,36, 2316; D. Van Aken, I. I . Merkelbach, A. S. Koster, and H. M. Buck, J. Chem. SOC.,Chem. Commun., 1980, 1045. R. 0. Day, R. R. Holmes, H . Tautz, J. H. Weinmaier, and A. Schmidpeter, Inorg. Chem., 1981, 20, 1222. Yu. V. Balitskii, Yu. G. Gololobov, V. M. Yurchenko, M. Yu. Antipin, Yu. T. Struchkov, and I. E. Boldeskul, Zh. Obshch. Khim., 1980, 50, 291. R . 0. Day and R. R. Holmes, Inorg. Chem., 1980, 19, 3609; R. 0. Day, S. Husebye, and R. R. Holmes, ibid., p. 3616. V. A. Naumov, R. N. Ziatdinova, G . V. Romanov, and A. N. Pudovik, Dokl. Akud. Nuuk SSSR, 1980, 253, 167. G. S. Laurenson and D. W. H. Rankin, J. Chem. SOC.,Dalton Trans., 1981, 425; C. M. Huntley, G. S . Laurenson, and D. W. H. Rankin, ibid., 1980, 954; S. Cradock, G. S . Laurenson and D. W. H. Rankin, ibid., 1981, 187. W. B. Jennings, J. H. Hargis, and S. D. Worley, J . Chem. SOC.,Chem. Cornmun., 1980, 30.

27 7

Physical Methods

25" from eclipse with a P-C bond,207and the phenyltetrafluorophosphorane(83) adopts the conformation shown, which may be due to intramolecular hydrogenbonding involving the ovtho-protons and apical fluorine atoms.208

6 Dipole Moments and the Kerr Effect A comparative study (using CND0/2 calculations) of the dipole moments and ionization potentials of methylphosphines and methylamines indicated that the methyl group acts as an electron acceptor to n3 nitrogen but as an electron donor to n3 phosphorus, the change being largely due to the availability of the 3d-orbitals for Whilst the conformational preferences of dioxa-210 and diaza-phosphorinans211 (84; X = 0 or NR) have been estimated, using dipole moments and n.m.r. spectroscopy, the influence of a cyanide group upon the conformations adopted by phosphanes was studied by the combined use of dipole moments and Kerr constants.212The higher dipole moments of mixed halogenophosphanes PX12X2,as compared with the non-mixed type PX3, have been attributed to the asymmetric orientation of the lone-pairs on phosphorus with respect to the bonding orbitals of Z

In another interesting study, the polarity of the P=N bond of iminophosphoranes was found to be nearly five times more sensitive to the inductive effects of phosphorus substituents than the P-0 bond of phosphine The conformational analyses of a wide variety of phosphorinans (85; Y=CH2, NR, S, or 0) have been investigated, using dipole usually with the aid of measurements of the Kerr effect.21s 207 208 209 210

211 212 213 214

215

216

E. A. V. Ebsworth, D. W. H. Rankin, B. Zimmer-Gasser, and H. Schmidbaur, Chem. Ber., 1980, 113, 1637. C. Dittebrandt and H. Oberhammer, J. Mol. Struct., 1980, 63, 227. V. V. Zverev, Z. G. Bazanova, and Yu. P. Kitaev, Zh. Obshch. Khim., 1980, 50, 47. B. A. Arbuzov, 0. A. Erastov, S . Sh. Khetagurova, T. A. Zyablikova, R. P. Arshinova, and R. A. Kadyrov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1630. B. A. Arbuzov, 0. A. Erastov, G. N. Nikonov, T. A. Zyablikova, R. P. Arshinova, and R. A. Kadyrov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1571. I. I. Patsanovskii, E. A. Ishmaeva, G. V. Romanov, V. N. Volkova, E. N. Stralkova, and A. N. Pudovik, Dokl. Akad. Nauk SSSR, 1980, 255, 383. J. P. van Linthoudt, E. V. van den Berghe, and G. P. van der Kelen, J. Mol. Struct., 1980, 67,269. Yu. Ya. Borovikov, Zh. Ohshch. Khim., 1979, 49, 2649. E. A. Ishmaeva, E. N. Ofitserov, T. A. Faskhutdinova, T. A. Zyablikova, L. P. Ivanteva, I. V. Konovalova, and A. N. Pudovik, Zh. Ohshch. Khim., 1980, 50, 30; I. I. Patsanovskii, E. A. Ishmaeva, A. P. Logunov, Yu. G. Bosyakov, B. Butin, S. K. Shishkin, and A. N. Pudovik, Tr. Inst. Khim. Nauk, Akad. Nauk Kaz. SSR, 1980, 53, 175; B. A. Arbuzov, 0. Erastov, G. N. Nikonov, R. P. Arshinova, and R. A. Kadyrov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 721. I . I. Patsanovskii, E. A. Ishmaeva, A. P. Logunov, Yu. G . Bosyakov, B. M. Butin, S. K. Shishkin, and A. N. Pudovik, Zh. Obshch. Khim., 1980, 50, 527; R. P. Arshinova, R. A. Kadyrov, Zh. B. Robert, and J. Martin, ibid., p. 829; R. P. Arshinova, R. N. Gubaidullin, and E. T. Mukmenev, ihid., 1979, 49, 2661.

278

Organophosphorus Chemistry

7 Mass Spectrometry Mass spectrometry was a useful tool in the characterization of the n2 azaphosphole (86)217 and aroyldiphenylphosphines,218but various 3-0x0-2-butyl phosphates all showed the occurrence of thermal reactions.219The low volatility of phosphonium salts is normally a major problem; however, spectra have been obtained by purely thermal desorption, and the recording of intact positive ions has been reported.220 High-precision l80/l6O isotope ratios have been determined for thiophosphoryl anhydrides by repetitive scanning on a routine spectrometer.221The very stable benzodiazaphosphole unit was present in many of the ions in the mass spectra of the esters (87).222 Whilst the electron-impact-induced fragmentation of diastereoisomeric phosphorinans is characterized by multiple hydrogen rearrangement^,^^^ the intensity differences of the [ M - HS]f peaks for

the diastereoisomeric thioamides (88) have bem attributed to the interaction of the axial proton at position 4 with the axial sulphur atom for the isomer A study of the high-resolution mass spectra of a cubane-like n6-PN compound included the investigation of transition signals for the fragmentation of the metastable ions.225 Ion cyclotron resonance spectroscopy has been used to study the nucleophilic reactions of anions with trimethyl phosphate,22sand also the proton affinities of trimethyl phosphite, trimethyl phosphate, and trimethyl p h o s p h o r o t h i ~ n a t e . ~ ~ ~ 8 pKa and Thermochemical and Kinetic Studies The relative acidities of protonated phosphines and phosphine oxides have been compared with those of other acids. The acidities increased in the order R 3 P H z + + + + R3NHc ArN=OH < R2C=OH c R3POH.228L.F.E.R. studies of the basicities of phosphine oxides in nitromethane showed them to have a linear relationship with substituent constants.229In another study, the weakening effect of phosi

217

218 219 220

221

222 223 224

225 226

2z7 229

A. Schmidpeter and H. Tautz, 2. Naturforsch., Teil. B, 1980, 35, 1222. M. Dankowski and K. Praefcke, Phosphorus Tulfur, 1980, 8, 105. S. Meyersen, E. S. Khan, F. Ramirez, J. F. Marecek, and H . Okazaki, J. Am. Chem. SOC., 1980, 102, 2398. R. Stoll and F. W. Roellgen, J. ChPm. Soc., Chem. Commun., 1980, 789. W. Reimschussel and P. Paneth, Org. Muss Spectrom., 1980, 15, 302. M. S. R. Naidu, C. D. Reddy, and P. S . Reddy, Indian J . Chem., Sect. B, 1979, 17, 458. 2. J. Lesnikowski, W. J. Stec, and B. Zielinska, Org. Muss Spectrom., 1980, 15, 454. W. J. Stec, B. Zielinska, and B. van de Graaf, Org. Mass Spectrom., 1980, 15, 105. K. Utvary, M. Kubjacek, and K. Varmuza, Z . Anorg. A l g . Chem., 1979, 458, 281. R. V. Hodges, S. A. Sullivan, and J. L. Beauchamp, J . Am. Chem. SOC., 1980,102, 935. R. V. Hodges, T. J. McDonnell, and J. L. Beauchamp, J . Am. Chem. Soc., 1980,102,1327. B. A. Korolev, Zh. Obshch. Khim., 1980, 50, 841. V. V. Yakshin, M. I. Tymonyuk, L. I. Sokal’skaya, I. A. Volodin, and B. N. Laskorin, Radiokhimiya, 1980, 22, 517.

Physical Methods

27 9

phony1 groups on the basicities of imino-ester groups was shown to decrease with the number of intervening methylene groups.23oThe three pKa values of some phosphinocarboxylic acids were determined by colorimetric titration and the deprotonation sequence was found by slP and 13C n.m.r. The acidities of 1-hydroxyethylidene-1,1-diphosphonic acid a32 and the bicyclic phosphorane (89) 233 have been reported. 0

II,OMen

PhP,

Cl (8%

(90) Men = menthyl

The enthalpy of formation of triphenylphosphine oxide has been estimated, using the oxidation of triphenylphosphine by The kinetics of the reactions of phosphonyl chlorides with oxirans 235 and of the racemization and hydrolysis of the phosphonyl chlorides (90) 236 have been studied. For a series of phosphinyl chlorides and phosphonyl chlorides, an additive substituent effect was The L.F.E.R. for the hydrolysis238 and e t h a n o l y s i ~of~ ~aryl~ phosphonates have been reported and the catalytic effects of arninesz4Oand the catalytic effects of micelles241 investigated; cf. related solvation and catalysis effects in the reaction of imidazole and benzoate ions with diphenylphosphinate^.^^^ The steric effects of ortho-substituents on the hydrolysis of aryl esters of phosphinic acids can be taken into account by using CT$ constants.243The nucleophilic reactivities of phosphinic hydrazides have been and the hydrol y s i and ~ ~ the ~ ~ stabilities towards acids 246 of phosphoramides and phosphoramidates have been augmented by M.O. calculations on stereoelectronic L.F.E.R. studies of the hydrolysis of thiophosphinates248 have been 230 231

232

233 234

235 236 237 238

239 240 241

242 243 244 245 246

247 248

V. E. Shishkin, E. V. Mednikov, B. I. No, and N. V. Shishkina, Zh. Obshch. Khim., 1979, 49, 2720. P. H. C. Heubel and A. 1. Popov, J. Solution Chem., 1979, 8, 615. T. Mioduski, Talanta, 1980, 27, 299. A. Munoz, B. Garrigues, and M. Koenig, Tefrahedron, 1980, 36, 2467. V. G . Tsvetkov, Yu. A. Aleksandrov, V. N. Glushakova, N. A. Skorodumova, and G. M. Kol’yakova, Zh. Obshch. Khim., 1980, 50, 256. A. P. Khardin, 0. I. Tuzhikov, K. A. V’yunov, T. V. Khokhlova, and L. N. Rygalov, Zh. Obshch. Khim., 1980, 50, 1733. R. J. P. Corriu, G. F. Lanneau, and D. Leclercq, Tetrahedron, 1980, 36, 1617. M. G. Gubaidullin, Zh. Obshch. Khim., 1980, 50, 1012. B. I. Istomin, G. D. Eliseeva, and A. V. Kalabina, Zh. Obshch. Khim., 1980, 50, 1186. G. D. Eliseeva, B. I. Istomin, and A. V. Kalabina, Zh. Obshch. Khim., 1980, 50, 1901. V. E. Bel’skii, L. A. Kudryavtseva, K. A. Derstuganova, S. B. Fedorov, and B. E. Ivanov, Zh. Obshch. Khim., 1980, 50, 1997. A. V. Begunov and G. V. Rutkovskii, Zh. Org. Khim., 1980, 16, 1607. G. Wallerberg and P. Haake, J. Org. Chem., 1981, 46, 43. M. P. Ponomarchuk, L. F. Kasukhin, I. Yu. Budilova, and Yu. G. Gololobov, Zh. Obshch. Khim., 1980, 50, 1937. N. Yanchuk, Org. React. (Tartu), 1979, 16, 421. J. Rahil and P. Haake, J. Am. Chem. SOC.,1981,103, 1723. M. J. P. Harger, J. Chem. SOC.,Perkin Trans. 2, 1980, 154; T. A. Modro, J. Chem. SOC., Chem. Commun., 1980,201. D. Gorenstein, B. A. Luron, and E. M. Goldfield, J. Am. Chem. SOC., 1980, 102, 1757. B. I. Istomin, G. D. Eliseeva, and A. V. Kalabina, Org. React. (Tartu), 1979, 16, 468; B. I. Istomin and G. D. Eliseeva, ibid., p. 457.

280

Organophosphorus Chemistry

interpreted in terms of a rectangular pyramidal transition Iodide ions react with quasiphosphonium salts by first-order kinetics only at high concent r a t i o n ~ Kinetic . ~ ~ ~ studies of the formation and decomposition of dioxaphos~ ~ ~ also been pholans 251 and the epimerization of s p i r o p h o ~ p h o r a n e s have reported. 9 Chromatography Gas-Liquid Chromatography.-Chiral phosphorus compounds have been chromatographed, using peptide and amino-acid amide stationary The and of the cis- and transdetermination of cyclophosphamide in blood isomers of substituted styryl phosphates 255 by g.1.c. has been reported. RF values of Thin-layer Chromatography and Paper Chromatography.-The aliphatic phosphates on t.1.c. are generally lower than those of aryl Ascending paper chromatography has been used to determine various phosphorus compounds in High-performance Liquid Chromatography.-A detector for phosphorus has been described which utilizes a primary air-into-hydrogen flame with a photometric measurement of the HPO emission.25s Column Chromatography.-Anion-exchange resins have been used for the rapid analysis of phosphorus-32- and rubidium-86-labelled plant

249 250 251

252

253 254

255 256 257

258 259

B. 1. Istomin and G . D. Eliseeva, Org. React. (Tartu), 1979, 16,478. L. V. Nesterov and N. A. Aleksandrova, Zh. Obshch. Khim., 1980, 50, 36. A. L. Baumstark, C. J. McCloskey, T. E. Williams, and D. R. Chrisope, J. Org. Chem., 1980,45, 3593. A. Klaebe, M. Sanchez, G. Caruana, and R. Wolf, J. Chem. SOC.,Perkin Trans. 2, 1980, 976. T. Oi, H. Shimada, 0. Hiraoki, M. Horiba, and H. Kitahara, Jpn. Kokai Tokkyo Koho 80 23 481 (Chem. Abstr., 1980, 93, 145 823). N. van den Bosch and D. de Vos, J. Chromatogr., 1980,183, 49. V. F. Koval’skaya, Khim. Prom-st. Ser. Metody Anal. Kontrolya Kach. Prod. Khim. Prom-sti, 1980, 9 (Chem. Abstr., 1980, 93, 179 106). I. V. Komlev, P. P. Dakhnov, and L. M. Troitskaya, Vestn. Mosk. Univ., Ser. 2, Khim., 1980, 21, 197. J . R. Trimm, L. A. Stumpe, J. E. Lawrence, R. D. Duncan, and F. J. Johnson, J. Assoc. O f . Anal. Chem., 1980, 63, 859. T. L. Chester, Anal. Chem., 1980, 52, 1621. D. D. Lefebvre and A. D. M. Glass, Int. J. Appl. Radiat. hot., 1981, 32, 116.

Author Index

Abbad, E. G., 183 Abdel-Rahman, M. O., 111 Abel, E. W., 89 Abel, G., 172 Abramova, A. M., 83 Abushanab, E., 17 Acher, F., 118 Ackerman, J. J. H., 259 Ackles, D., 195 Adamiak, D. A., 159, 161, 185 Adams, P. M., 170 Adeleke, B. B., 269 Ademola, J. I., 140, 141 Adiwidjaja, G., 158, 267 Afanaset, M. M., 117 Agafonov, S. V., 54, 56, 63 Agashkin, 0. V., 263 Agawa, T., 79, 82, 104, 243 Agol, V. I., 193 Ahlers, H., 245 Ainbinder, N., 268 Aizenshtat, Z., 85 Ajiro, K., 141 Akiba, K., 76 Akita, T., 144 Aklayan, Zh. A., 26 Aktalay, Y.,6 Akutsu, H., 220 Aladzheva, I. M., 222, 270, 274 Alagna, L., 71, 273 Alarcon, R. A., 148 Alatortseva, G. I., 193 Albrand, J. P., 266 Aleksandrov, G. G., 109, 275 Aleksandrov, Yu. A., 279 Aleksandrova, N. A., 28,280 Ali, A. A. M., 265 Ali, M. F., 16 Ali, S. F., 75 Aliev, N. A., 25 Alkabets, R., 40 Allaudeen, H. S., 195 Allcock, H. R., 276 Allen, D. W., 29, 274, 275 Allen, L. M., 152 Alparova, M.V., 129 Ambartsumyan, N. S., 214 Ambrosius, H. P. M. M., 7 Ambrosius, K., 276 Amemiya, Y., 229 Aminova, R. M., 263 Amrhein, N., 138 Andreae, S., 111 Andreetta, A., 20 Andreocci, M., 273 Andres, K., 88, 96, 274 Andriamizaka, J. D., 12 Andianov, V. I., 274

Angeletti, E., 27 Angelici, R. J., 14, 239 Angelov, C. M., 121, 123 Angelov, Kh., 121, 123 Anoshina, N. P., 271 Ansell, M. F., 249 Antipin, M. Yu., 54, 71, 75, 99, 274, 275, 276 Antoniadis, A., 57 Antonovich, E. G., 208 Antonovich, V. A., 3 Aoki, K., 96 Appel, R., 5 , 12, 15, 16, 50, 60,275 Appler, M., 172 Aradi, J., 212 Araki, S., 114 Araya, A., 199 Arbuzov, B. A,, 9, 22, 28, 68, 83, 263, 277 Arduengo, A. J., 44, 53 Arentzen, R., 204, 208 Aristoff, P. A,, 242 Arjunan, P., 228 Armatis, F. J., jun., 219 Armizadeh-Asl, D., 34,274 Arnold, B., 236 Arnold, H., 146, 148 Arrieta, A., 118 Arshinova, R. P., 22,28,263, 277 Ash, D. K., 18, 86 Ashrafullina, L. Kh., 270 Aslanov, L. A., 274 Asseline, U., 177 Atabekov, 1. G., 214 Atanasov, P., 54 Atherton, F. R., 52 Atkinson, T. C., 207 Atovmyan, L. O., 71, 275 Aue, D. H., 273 Augk, J., 131 Avoeva, S. M., 141 Awasarkar, P. A., 53 Axelrod, J., 137 Ayi, A. I., 59 Baban, J. A,, 268, 269 Babin, B., 233 Babu, Y. S., 276 Babushkina, T. A., 29 Baccolini, G., 79 Bachmann, P., 55 Badanyan, Sh. O., 123 Baert, F., 22 Baggaley, K. H., 249 Baglioni, C., 211 Baier, H., 31 Bajwa, G. S., 93, 184 Baker, M . H., 172 Baker, S. R., 254

28 1

Bakke, A. A., 273 Bakke, J. E., 147 Bakuleva, N. P., 141 Baldwin, J. E., 157 Balgobin, N., 205 Balitskii, Yu. V., 54, 99, 102, 110, 270, 275, 276 Ball, D. J., 186 Ballou, C. E., 135 Balogh-Nair, V., 25 1 Balthazor, T. M., 31, 80, 105 Balzarini, J., 198 Banek, M., 276 Banks, R. E., 17 Banner, B. L., 254 Barahona-Naranjo, S., 227 Baraniak, J., 183 Barbier, C., 204 Bardos, T. J., 212 Barenholz, Y., 137 Barlev, A. A,, 269 Barlos, K., 262 Barrans, J., 30, 35 Bart, J. C. J., 274 Bartholomew, J 1 C., 216 Bartlett, D. L., 161 Bartlett, P. A., 138 Bartlett, P. D., 39 Bartolli, G., 79 Barycki, J., 270 Bass, A. D., 240 Bassett, J.-M., 238 Bassi, I. W., 274 Bateson, J. H., 252 Baudler, M., 6, 51, 55, 266, 273 Baumann, W. J., 267 Baumstark, A. L.,19, 280 Baxter, A. J. G., 252 Baxter, S. G., 24, 56 Baykov, A. A., 141 Bazanova, Z. G., 277 Beaucage, S. L., 93, 201 Beauchamp, J. L., 278 Becher, H. J., 4 Bechtolsheimer, H. H., 265 Beck, W., 20 Becker, G., 4,11, 12, 13,260, 273 Becker, K. R., 226 Beechey, R. B., 193 Begasse, B., 231 Begley, M. J., 243 Benunov. A. V.. 279 BeLe, M:, 220 ' Belkin, Yu. V., 14 Belov, Yu. P., 109, 275 Belov, Yu. V., 267 Bel'skii, V. E., 112, 260, 270, 279 Benckhuysen, C., 120, 166

Author Index

282 Benes, J., 3 Benkovic, S. J., 191 Benner, S. A., 111 Bennett, M. A., 1 Bennett, W. S., jun., 140 Benninghoven, A., 221 Bensoam, J., 60 Bentrude, W. G., 86,93, 169, 183, 184 Berdnikov, E. A., 23 Berenblyum, A. S., 20 Berghus, K., 245 Bergin, V., 214 Berkova, G. A., 263 Berlin, K. D., 7,22,26,68, 71, 228, 230, 262, 275 Bernal, I., 7 Berrigan, M. J., 149 Bertelo, C. A., 4 Bertino, J. R., 195 Bessman, S. P., 143 Bessodes, M., 17 Bestmann, H. J., 33, 222, 225, 226, 234, 235, 236, 247, 264 Bezpal’ko, G. K., 29 Bhuta, A., 181 Bianchini, C., 5 Bichlmayer, K.-P., 237 Bielicki, L., 150 Bigge, C. F., 179, 198 Bilalov, F. S., 271 Billets, S., 146 Biosca, J . A., 185 Birch, N. J., 131 Birkhahn, M., 4, 273 Bisson, R., 137 Black, M. J., 186 Blackburn, G. M., 107 Blaicher, W., 276 Blake, A. J., 71, 271, 275 Blanquet, S., 200 Blaschke, G., 154. 238, 261, 264 Blau, H., 239 Blocker, H., 205 Blount, J. F., 4, 25, 62, 275 Blum, J., 85 Bobst. A. M.. 212 Bobst; E. V.,’212 Bocelli, G., 265 Bochkarev, M. N., 20 Bock, H., 273 Bock, J. L., 197 Bodalski, R., 62, 63, 240 Bodor, N., 164 Boedeker, J., 261 Bohme, M. C., 142,273 Bohme, R., 235 Boer,V. I., 236 Bogatyreva, E. V., 108 Bogdanov, A. A., 214 Bogel’fer, L. Ya., 104, 265 Bohlmann, F., 235 Bohn, E. W., 150 Boisdon, M. T., 35 Bojes, J., 274 Boland, W., 228 Boldeskul, 1. E., 54, 99, 270, 275, 276 Bondarenko, N. A., 71, 270 Bondy, P. K., 165 Bonnet, J. J., 274 ,

,

~

~,

Bonningue, C., 95, 267 BOOS,K.-S., 197 Borovikov, Yu. Ya., 277 Borun. T. W.. 141 Bosnich, B., 3 Bosyakov, Yu. G., 71, 263, 277 Bouchu, D., 267 Bourseaux, F., 146, 148 Bowers, G. N., 141 Bowers, M. T., 273 Boyandina, E. V., 127 Boyd, V. L., 156 Bozic, B., 270 Bradford M. M., 143 Bradley, D., 213 Bragg, P. D., 199 Brahmana, H. R., 251 Bramson, H . N., 141 Brandt, J. A., 159. 166 Branson, H. N., 194 Brassfield, H. A., 161 Brauer, M., 220 Braunstein, P., 20 Brawn, K., 216 Brazier, J. F., 35 Bredenbrocker, B., 194 Bredenkamp., M. W., 26, 172

LLJ

Bredikhina, Z. A., 123 Brel, V. K., 121, 122 Bridges, A. J., 96 Bridson. P. K.. 210 Briggs, E. M.,’261 Briggs, S. P., 249 Brightly K. E., 7, 66, 68 Brimacombe, R., 217 Brion, F., 255 Britton, H. G., 189 Brocas, J., 58 Brock, N., 146, 148, 149 170 Brody, R. S., 175, 190 Broekhof, N. L. J. M., 242 Broger, E. A., 9 Broka, C., 204 Brousseau, R., 204, 208 Brown, D. H., 75, 262, 275 Brown, G. L., 212 Brown, G. W., 261 Brown, J. M., 116 Brown J. R., 187 Brown, R. S., 2 Brown, T. L., 268 Browning, J., 20 Bruck, M. A., 219 Brundrett R. B., 172 Brunks, N., 225 Brunner, H., 7 Brunngraber, E. F., 141 Brunnhuber, G., 92, 267 Bruzik, K., 116 Bryant, B. M., 172 Bryant, F. R., 191 Bubnov, N. N., 269 Buchanan, G. W., 262 Buchwald, S. L., 114, 261 Buck, H. M., 40, 98, 128, 262, 269, 276 Budilova, I. Yu., 116, 279 Buina, N. A., 106 Bukachuk, 0. M., 23 Bullen, G. J., 276

Bulloch, G., 266 Bunick,D., 193 Bunton, C. A., 116 Burford, N., 276 Burgada, R., 35, 85 Burger, K., 86 Burgers, P. M. J., 192 Buriliov, A. R., 82, 270 Burkert, H., 145, 149 Burmester, A., 44, 46, 262, 264 Burnaeva, L. A., 82,98, 100, 103, 111 Burnett, M. G., 233 Burton, D. J., 25, 106, 232 Burzlaff, H., 235 Busch, H., 141 Bushnell, G. W., 20 Buss, A. D., 72 Butch, P., 176 Butin, B. M., 71, 263, 277 Butke, G., 180 Butsugan Y . , 114 Buttero, P. D., 20 Butterworth, P. J., 193 Bynum, J. W., 187 Byrd, R. A., 137 Byrn, S. R., 215 Bystrov, L. V., 265 Cabelli, D. E., 57 Cabre-Castellri, J., 118 Cainelli, G., 249 Cairns, P. M., 261 Calabresi, P., 136 Calcaterra, M., 274 Calvin, M., 216 Cameron, T. S., 276 Campbell, M. M., 77, 139 Cane, D. E., 142 Cantor, C. R., 218 Capka, M., 4 Caplar, V., 3 Cardillo, G., 249 Carlsohn, B., 266 Carr, M. C., 182 Carr, S. W., 19, 66, 262 Carr, T. M., 268 Carruthers, N., 77, 139 Carter, S. K., 145, 152 Caruana, G., 280 Caruso, A. J., 229 Caruthers, M. H., 93, 201, 205 Cassidy,F., 249 Castel, A., 20 Casteliins. M. M. C. F.. 40. 128,262 Castellano, E. E., 275 Castellanos, L., 249 Castro, B., 85 Cates. L. A.. 102 Caton, M. P. L., 249 Cauletti, C., 71, 273 Cavagna, F., 275 Cavalieri d’Oro, P., 20 Cavell, R. G., 276 Cavender, P. L., 143 Cavezzan, J., 20, 57 Cenini, S., 20 Cerri, V., 269 Chaki, H., 136 Challberg, M. D., 217 I

,

Author Index Chamberlin, M. J., 197 Chan, C., 276 Chandra, B. P., 238 Chandrasekahar, J., 33, 226, 264 Chandrasekaran, S., 169 Chang, C., 215 Chang, C. C., 131, 190 Chang, C. T.-C., 175, 198 Chang, T.-T., 190 Chapleur, Y., 85 Chapman, T. M., 176 Charbonnel, Y.,30 Charrier, C., 9, 31, 68, 273 Charubala, R., 211 Chassignol, M., 204 Chastel, C., 77 Chatterjee, C. L., 220 Chattopadhyaya, J. B., 205, 21 1 Chauvet-Monges, A. M., 134 Chauzov. V. A.. 54. 56. 63 Chen, C.‘ H., 7; 66, 68, 81, 236, 243 Chen, C. T., 156 Chen, H.-W., 238 Chen, R., 220 Chen, Y.-C. 150 Chene, A., 23 Cheng. C. P.. 268 Cheng; D. M.,179 Cherkasov, R. A., 111, 112, 117 Cherkasov, V. M., 105 Cherkina, M. V., 82, 111 Chernokalskii, B. D., 59, 72 Chernov, B. K., 208 Chernyuk, I. N., 23 Chervin, I. I., 265 Chesnut, D. B., 261 Chester, T. L., 280 Cheung, A., 193 Chevalier, T., 263 Chichkova. N. V., 214 Chiles, M. S., 27 Chirgwin, J. M., 139 Chirkova, L. P., 271 Chivers, T., 274, 276 Chladek, S., 180, 181 Choder, M., 195 Chodkiewicz, W., 3 Choi, K.-Y., 100 Choi, S.-K., 100 Chojnowski, J., 114 Chou, S.-S. P., 4, 64, 104 Chmutova, M. K., 76 Chrisope, D. R., 19, 280 Christenson, P. A., 250 Christol, H., 23 Christov, V., 121 Chu, H.-K., 39 Chu, M. Y., 136 Chunin, E. D., 121 Ciampolini, M., 4 Ciardelli, T., 132 Clardy, J. C., 158 Clark, D. A., 257 Clark, V. M., 52 Claus, T. H., 135 Clausen, K., 110, 128 Clausen, U., 170 Cleland, W. W., 140, 194, 218

283 Cleophax, J., 249 Cline, S., 213 Clonis, Y. D., 185 Cnossen-Voswijk, C. 76 Coates, R. M., 143 Coburn. W. C.. 154 Cocivera, M., 141 Coderre, J. A., 181 184, 191 Cogne, A., 263, 266 Cohen, J. S., 220 Cohen, L. H., 141 Cohen, N., 254 Cohen, R. E., 135 Cohn, M., 193,219,220,268 Colin, J., 77 Collignon, N., 77, 107 Collins, R. L., 24, 56 Collis, C. H., 170 Colman, R. F., 200 Colquhoun, I. J., 8, 76, 266 Colton, R., 19, 66, 262 Colvin, M., 145, 146, 172 Comisso, G., 3 Conia, J. M., 232 Connolly, B. A., 193 Connors, T. A., 147, 149 Constantin, E., 137 Cooke, M. P., jun., 237 Cooper, D., 124 CooDer. T. A.. 272 Copper; K., 243 Corbel, B., 120 Cordes, A. W., 274 Corey, E. J., 5,232,254,255, 257 Cornelius, R. D., 140 Corriu, R. J. P., 116, 279 Costa, T., 21, 224, 274 Costisella, B., 44, 78, 242 Couchie, D., 183 Couffignal, R., 8, 71 Couret, C., 12, 20, 57 Coutelle, C., 186 Cowley, A. H., 24, 56,51, 59, 89, 260 Cox, P. J., 147, 149, 152, 157, 159, 165, 172, 173 Crabbk, P., 249 Cradock, S., 276 Craig, D. C., 71, 275 Crea, R., 211 Creaven, P. J., 152 Cremer, S. E., 25, 274 Crevat, A., 134 Cristau, H. J., 23 Crocker, C., 10 Crombie, L., 228, 250 Crombie, W. M. L., 228 Cross, R. J., 75, 262, 275 Cseh, G. Y., 249 Cuchillo, C. M., 185 Cullis, P. M., 114, 181 Cumming, D. A., 135 Cummings, S. C., 11 Cunkle. G. T.. 261 Curatoio. w.,’I 37 Curtis, N. J., 2 Cushner, M. C., 260 Cutbush, S. D., 120 Dabkowski, W., 109, 126 Darr, E., 6 Dahms, R., 151

Dakhnov, P. P., 280 D’Alessandro, S. B., 211 Daly, J. W., 166 Dameshe, W., 146 Damewood, J. R., jun., 265 D’Andrea, A. D., 216 Danenberg. P. V.. 178 Dangyan,-Yu. M.; 123 Danion, D., 236 Dankowski, M., 21,65,275, 278

Dapporto, P., 4 Darst, K. P., 231 Dash, K. C., 30, 238 Daskalov, H. P., 182 Davankov, V. A., 109, 275 Davidson, R. M., 134, 247 Davidson, W. R., 273 Davies, D. I., 249 Davis, P., 252 Day, R. O., 24, 34, 274, 276 Dean, P. A., 76 De’Ath, N. J., 52, 64 Dechter, J. J. 219 De Clercq, E., 175, 195, 198 Declercq, J. P., 275 Deeming, A. J., 2 Deger, H. M., 252 de Grado, W. F., 141 De Groot, E. J., 197 Dehmlow, E. V., 227 Dehnert, P., 20 Deininger, D., 261 Deiters, J. A., 24, 274 de Lauzon, G., 29,71,274 275 Delmas, M., 227 Dembek, P., 207 Demou, P. C., 184 den Hartog, J. A. J., 211 Denis, J. N., 54 Denney, D. B., 16,34, 37,41, 42, 86, 87, 88, 94, 95, 262 264 Denney, D. Z., 34,37,41,42, 86, 87, 94, 95, 262, 264 Depres, J.-P., 249 De Riemer, L. H., 198 Derstuganova, K. A., 112, 279 Descamps, J., 175 Deschamps, B., 29 Deschler, U., 240, 274 Desiderio, S. V., 217 Deslauriers, R., 137 Dess, D. B., 44 Dev, S., 247 Devilliers, J., 274 Devine, H. L. 175 De Vos, D., 280 Dewar, M. J. S., 57 Dhathathreyan, K. D., 276 Diaz, A. F., 96 DIaz, S., 116 Dickerson, R., 166 Dietzel, St., 263 Dirnroth, K., 31 Dittebrandt, C., 277 Dittrich, R., 79 Di Verdi, J. A., 220 Dixit, V. M., 100 Dixon, D. A., 222 Dixon, K. R., 20

284 Djarrah, H., 34 Dmitriev, V. I., 38, 268, 272 Dmitrieva, N. V., 58 Dmitrieva. T. M.. 193 Dobrynin,‘V. N.,’208 Doetsch, P., 211 Dogadina, A. V., 104, 121, 177 1L A

Doi, T., 213 Dolhaine, H., 267 Dolinnava. N. G.. 211 Dombrchskii, A. V., 236 Domcheva, Z., 123 Domeyer, B. E., 149, 150 Donini, P., 197 Donis-Keller, H., 214 Donskaya, Yu. A., 271 Doolittle, R. E., 249 Doorakian, G. A., 14 Dorgan, L. J., 197 Dorie, J., 264, 266 Dormoy, J. R., 85 Dose, K., 198 Dotson, M. J., 22 Douglas, J. E., 273 Downey, W. G., 33,226,264 Drabble, W. T., 200 Drach, B. S., 28, 121 Drengler, K. A., 143 Dreon, N., 209 Dreux, J., 267 Drews, R. E., 267 Drinkwater, N. R., 215 Dubac, J., 20, 57 Dubenko, L. G., 38 Duckworth, M. L., 207 Dudchenko, T. N., 116 Dudnikova, V. N., 16 Dumm, H. V., 46 Dumont, J. E., 183 Du Mont, W.-W., 57, 72, 225 Duncan, R. D., 280 Duncan, R. E., 187 Dunogues, J., 233 Du Plessis, M. P., 275 Duquette, L. G., 14 Durham, D. L., 39 Durig, J. R., 271, 272 Durst, T., 252 Dutasta, J. P., 105, 267 Dutheil, J.-P., 116 Dyess, B. T., 197 Dzhemilev, U. M., 7 Ebel, J. P., 215 Ebsworth, E. A. V., 55, 277 Eccleston. J. F.. 195 Eckes, H.; 73 ’ Eckstein, F., 192, 193 Edasery, J. P., 7, 71, 262 Edes, R. A., 222 Edge, M. D., 207 Edmondson, D. E., 133 Edmundson, R. S., 87, 100 Edwards, M. P., 245 Efamov, V. A., 104 Efremov, Yu. Ya., 40 Effenberger, F., 100 Egan, W., 157, 159, 160, 166 Egli, H., 228 Egorov, Yu. P., 268,270,272

Author Index Eicke, A., 221 Eidels, L., 199 El-Barbary, A. A., 128 El-Dareer, S., 146, 152 El-Deek, M., 59 El-Hamshary, S., 59 Elipina, L. T., 274 Eliseeva, G. D., 128, 279, 2x0

ElIKateb, A. A., 42, 79 Ellermann. J.. 269 El-Moghrabi,‘ M. R., 135 El’natanov. Yu. I., 265 Elmer, G.; 6 Elstner, E. F., 142 Enda, J., 243 Ene. R.. 27 Engel, W. D., 131 Engelmann, M., 12, 91 Engels, J., 113, 21 1 Englehardt, M., 267 Enqvist, J., 100 Erastov, 0. A., 9,22, 28, 68, 263, 277 Erdmann, V. A., 212 Eremeeva, T. P., 193 Erneux. C.. 183 Errington, ’R. J., 10 Esaki, Y., 251 Escudie, J., 12, 20, 57 Eshtiagh-Hosseini, H., 11 Eto. M.. 103 Evans, C. A., 267 Evans, C. T., 141, 199 Evans, J. C., 269 Faber, W., 6 Fabre, G., 77, 107 Fabricant. J. D.. 170 Facchinetti, T., 156 Fackler, J. P., jun., 238 Fankhauser. H., 178 Farber, S., 147 Farmer, P. B., 147, 149, 152 154, 156, 157, 159, 161, 165. 172. 173 Faskhutdinova, T. A., 98, 277 Fasold, H., 217 Fastenakel, D., 58 Fauduet, h., 85 Favorova, 0. O., 200 Fayat, G., 200 Fedgenhauer, H., 263 Fedin, E. I., 222 Fedorov, S. B., 112, 279 Fedorova, F. D., 126 Feil, V. J., 147, 154 Felcht, U., 114 Felcht, U.-H., 49, 275 Felsenfeld, G., 220 Fenselau, C., 146, 166, 172 Fenske, D., 4 Ferro, M. P., 27 Feser, R., 14 Fickentscher, K., 154 Figuly, G. D., 44 Fild, M., 265 Filimov. E. A.. 76 Fillhgame, R. H., 131 Finch, N., 17 Findlay, J., 115, 267 Fink, G., 217

Flay, R’. B., 29 Flemal, J., 275 Fleming, R. J., 274 Floss, H. G., 133 Fluck, E., 120 Flynn, R. M., 106 Fohlisch, B., 18 Foley, G. E., 147 Font Freide, J. J. H. M., 48, 265 Fortes, P. A. G., 197 Forth, C. I., 87, 100 Foss, V. L., 66 Foster, A. B., 147, 149, 154, 157, 1.60, 159, 161, 165 Fothergill, J. E., 141 Fothergill, L. A., 141 Foulon, M., 22 Fourrey, J. L., 92, 202 Franceschi, G., 251 Franco-de Cavalho, L. R., 275 Franek, U., 197 Franklin, R. M., 220 Franks, S., 1 Frankston, J., 116 Fraser, R. R., 262 Freeman, A. I., 170 Frenette, R., 254 Frenking, G., 273 Fresneda, P. M., 105 Frey, G., 30, 75 Frey, H., 225 Frey, P. A., 182, 190 Fridland, S. V., 58 Fridovich, I., 216 Friedman, 0. M., 145, 146 147, 149, 166 Friedman, R. M., 186 Frits, G., 273 Fritschel, S. J., 4 Fuerderer, P., 269 Fujimori, K., 17 Fujino, S., 32 Fujita, T., 19 Fuke, M., 214 Fukui, T., 133, 204 Fukushima, A., 14, 61 Fukushima, M., 3 Fukuzumi, K., 20 Funnun, J. L., 93 Furin, G. G., 262, 268 Furlani, C., 71, 273 Furukawa, I., 233 Furukawa, S., 132 Fuzhenkova, A. V., 83 Gadian, D. G., 259 Gait, M. J., 207 Galaktionova. 0. V.. 263 Galardy, R. E., 143 Galasso, V., 265 Galdecki, Z., 69, 106, 120, 155, 275 Gallagher, M. J., 71, 261, 267, 275 Gallicano, K. D., 59 Gallucci, J. C., 24, 274 ’

285

Author Index Galy, J., 98 Galyatdinov, N. I., 83 Gamayurova, V. S., 59, 72 Gamon, N., 12 Gamper, H. B., 216 Gandolfi, C., 251 Garabudzhin, A. V., 270 Garber, L. J., 178 Garcia-Blanco, S., 158, 161 Gareev, R. D., 82, 9 8 ~100, 111

Garegg, P. J., 17, 61 Garrigues, B., 35, 36,46,279 Garth, B. H., 16, 88 Gaset. A.. 227 Gassmann, P. G., 222 Gasteiger, J., 79, 107 Gaston, J. L., 120, 157 Gateau-Olesker, A., 249 Gatilov, Yu. F., 72 Gaudin, D., 221 Gavrilovic. D. M.. 42. 94. 264 Gazizov, M. B., 98, 102 Gazizov, T. Kh., 40, 102 Gdaniec, M., 161 Gebler, W., 12, 273 Gedye, R. N., 27 Geeves. M. A.. 189 Gehrke, S. H.,'116 Gerhard, J., 27 Gerlt, J. A., 181, 184, 191, 267 Gero, S. D., 249 Gerson, F., 269 Giamalva, D., 245 Gibbs. D. E.. 169 Gibson, D. R., 139 GiegC, R., 215 Gilbert, C. S., 211 Gilbert, H. J., 200 Gilbert, J. C., 245 Gilbert. W.. 215 Gilby, 8. D., 157, 165 Gilfanova, N. B., 58 Gilham, P. T., 187 Gilman, A., 146 Gilyarov, V. A., 98, 103 Gioeli, C., 211 Giyasov, K., 25 Gizatullina, I. Kh., 102 Glasel, U., 16 Glasel, V. I., 60 Glass, A. D. M., 280 Glass, D. B., 141 Glebova, Z. I., 98 Gleiter, R., 273 Gloede, J., 38 Gloede, V. J., 44 Glonek, T., 259 Glowka, M. L., 69, 106, 120 155, 275 Glukhikh, V. I., 104 Glushakova, V. N., 279 Godovikov, N. N., 109, 275 Goelet, P., 207 Goetz, H., 273 Gohda, N., 18, 60 Golander. Y.. 175 Goldberg; N.'D., 144, 185 Gol'dfarb, E. I., 21, 68 Goldfield, E. M., 220, 279 Goldwhite, H., 268, 273 I

,

,

Golinski, B., 69 Gololobov, Yu. G., 17, 54, 99, 102, 105, 110, 116,275, 276, 279 Gomes, J. D., 215 Gomori, G., 146 Gompper, R., 237 Goncalves, H., 85 Goncharova, L. V., 75, 270 Goodman, L. S., 146 Goodman, M. F., 213 Goodman, M. J., 146 Goody, R. S., 219 Gopinathan, C., 53 Gopinathan, S., 53 Gordeev, V. K., 59, 72 Gorenstein, D. G., 115, 158, 220, 261, 267, 279 Goss, N. H., 141, 199 Goswami, R., 246 Goth, H., 86 Goto, G., 254, 255, 257 Gotoh, H., 243 Gottstein, W., 18 Gouesnard, J. P., 264, 266 Grabiak, R. C., 80 Grachev, M. A., 209 Gracy, R. W., 139 Graff, G., 144, 185 Graffeuil, M., 276 Graham, D. A., 119 Graham, D. R., 216 Grand, A., 95, 266, 276 Granot, J., 194 Granoth, I., 38, 39,40, 5 5 , 69, 79, 126, 263 Grapov, A. F., 120 Graves, D. E., 221 Gray, G. A., 262, 264 Grec, D., 95, 276 Green, D. E., 131 Green, G. R., 249 Greene, A. E., 249 Greene, A. R., 207 Gregorio, G., 20 Greiger, P. J., 143 Gren, E. J., 214 Gresser, G., 12, 260 Griffiths, D. V., 33, 81, 84, 126 Griggs, L. J., 159, 165 Grim, S. O., 8, 22, 76, 266 Grimm, A., 111 Grishkun, E. V., 43 Grisolia, S., 189 Grobe, J., 20 Groner, Y., 195 Gros, L., 167 Gross, H., 38, 78, 242 Grossmann, C., 262 Gruber, L., 249 Grubmeyer, C., 190 Grunberg, S. M., 217 Grutzmann, H., 186 Grzeskowiak, K., 113, 178 Gubaidullin, L. Yu., 7 Gubaidullin, M. G., 279 Gubaidullin, R. N., 277 Gubaidullinova, R. Sh., 51, 65 Gubnitskaya, E. S., 108 Gudi,.N. M., 76 Guedj, R., 59

Gunther, U., 149 Guilhem, J., 9, 273 Guimon, C., 272 Guindon, Y., 254 Gupta, C. M., 137 Gupta, 0. D., 29 Gupta, R. K., 219 Gupta, T. R., 76 Gurevich, P. A., 85 Gurtoo, H. L., 149, 150, 151 Gur'yanova, E. N., 271 Guseva, F. F., 102 Guthrie, R. D., 18 Gutterson, N. I., 267 Gynane, M. J. S., 268 Haake, P., 128, 129, 279 Hadida, M., 134 Haegele, G., 71, 79,265, 267, 273 Hahn, J., 6 Haiduc, I., 270 Haines, G., 272 Hakam, A., 212 Hakimelahi, H. G., 107 Halazy, S., 227 Hall, C. D., 43 Hall, C. R., 109, 112 Hall, E. A. H., 27 Hallab, M., 51 Haller, R., 44, 262, 264 Halstenberg, M., 275 Hamada, A,, 96 Hamada, Y., 3 Hamana, H., 32 Hamanaka, N., 249 Hamashima, Y., 147 Hamberger, H., 18 Hamerlinck, J. H. H., 269 Hamlet, A. B., 252 Hammerschmidt, F., 98, 101 Hammond, P. J., 34, 37, 41, 42, 43, 86, 87, 94, 95, 264 Hampl, B., 109 Handler, A. H., 147 Hanifin, J. W., jun., 16, 88 Hanley, P. E., 259 Hansen, A., 245 Hansen, P.-E., 13, 223 Hansen, T. M., 170 Hanzawa, Y., 32 Harbers, E., 152 Hardt, S. L., 131 Hardy, G. E., 238 Harger, M. J. P., 265, 279 Hargis, J. H., 83, 276 Harper, D. P., 9 Harper, S. D., 44, 53 Harpp, D. N., 18, 86 Harris, D. H. C., 272 Harris, G. S., 16 Harris, R. K., 39, 265 Harris, S. H., 23 Hart, D. A., 199 Harthrock, M. A., 271 Hartley, F. R., 1 Hartman, R. F., 212 Hasegawa, A., 211 Haseltine, W. A., 216, 217 Hashimoto, C., 135 Hashimoto, M., 233 Hashimoto, S., 233, 255 Hashimoto, T., 47, 178

286 Haskins, N. J., 172 Hassan, M. A., 59 Hassler, K., 271 Hata, T., 84, 107, 113, 125, 182, 194, 202, 205 Hathway, D. E., 216 Hayashi, M., 249 Hayashi, S., 232 Hayashi, T., 3, 4 Hayatsu, H., 178 Headley, J. A., 25 Heath, R. R., 249 Heathcliffe, G. R., 207 Hebel, P., 252 Hecht, J., 170 Heerschap, A., 220 Heilbronner, E., 272 Heinicke, J., 3 1 Heissler, D., 228 Hellmann, J., 6 Hellwinkel, D., 9, 238, 276 Helmreich, E. J. M., 133 Henderson, J. Y . , 141 Henichart, J.-P., 22 Henkel, G., 12, 90, 91, 274 Hennawy, I. T., 42, 79 Henning, H. G., 272 Henrick, K., 275 Herak, M. J., 270 Hercouet, A., 23 Herman, M. A., 271 Hermoso, J. M., 217 Hernandez, A., 231 Hershberger, J., 79 Herzig, C . , 79, 107 Hess, H., 276 Hesse, B., 263 Hetflejs, J., 3 Heubach, G., 110 Heubel, P. H. C . , 279 Heuschmann, M., 111 Heusinger, J. H., 166 Hevia, E., 199 Hewson, M. J. C., 36, 39, 59 Heymer, G., 6 Hickling, R. I., 252 Higuchi, T., 275 Hilbers, C . W., 220 Hill, D. L., 145, 146, 152 Hillman, G. R., 22 Himes, V. L., 156 Hipkens, J. H., 149, 150, 151 Hirai, H., 119 Hiraiwa, H., 144 Hirano, T., 166, 167 Hirao, T., 79, 104 Hirata, F., 137 Hiroaki, O., 280 Hirotsu, K., 275 Hirsch, H. L., 247 Ho, L., 245 Ho, N. W. Y., 187 Ho, Y.-K., 212 Hobbs, J. B., 182 Hochleitner, R. H., 53 Hodges, R. V., 278 Hoefer-Janker, H., 149 Hoegel, J., 263 Hoelderich, W., 273 Holler, R., 226, 264 Hofer, B., 213 Hofmann, G., 51 Hofstetter, F., 218

Author Index Hogan, M. E., 220 Hoge, R., 113, 275 Hohorst, H.-J., 146, 147, 149 150, 165, 172 Holl. P.. 266 Holmes,’ R. R., 24, 34, 274, 276 Holy, A., 177, 185 Hon, C., 199 Honda, S . , 205 Honegger, H., 71, 267, 274 Hong, C . I., 195 Hong, G. F., 207 Hoover, D. J., 255 Hope,. H . , 5 Hopkins, P. B., 255 Hopper, D. J., 133 Horak, A., 193 Horiai, H., 233 Horiba, M., 280 Horigan, E. A., 170 Horigane, A., 138 Horiguchi, N., 138 Horne, W., 25, 274 Horner, L., 27, 97 Houalla, D., 95, 267, 274 Hountondji, C . , 200 Houssin, R., 22 Hoving, H., 134 Howard, J. G., 170 Howells, R. D., 25 Howie, R. A., 275 Hoye, T. R., 229 Hozumi, T., 204, 207 Hsiung, H. M., 204, 208 Hsu, Y. F., 34 Huang, C., 41, 42, 94, 95, 264 Huang, K.-S., 137 Huang, S. L., 131, 190 Huang, S.-P., 252 Huang, T., 207, 208 Hubert-Pfalgraf, L. G., 95, 276 Hudson, A., 268 Hudson, H. R., 275 Hueber, R., 137 Hughes, A. N., 13 Hultin, T., 187 Humiliere, M., 60 Hunger, H.-D., 186 Huntley, C . M., 276 Hursthouse, M. B., 2 Hurtley, L. H., 148 Husebye, S., 24, 274, 276 Hutchison, D. J., 55 Hutchinson, D. W., 140,141, 173 Huttner, G., 30, 92, 274, 275 Hwang, W.-S., 95 Ignat’ev, V. M., 122 Ignat’eva, S. N., 22, 68 Ignateva, T. I., 76 Ihara, M., 252 Ihara, Y., 116 Iida, T., 19 Iimori, T., 19 Iio, H., 244 Ikehara, M., 179, 204, 207, 211, 213 Iksanova, S. V., 272 Il’inchik, E. A., 273

Il’yasov, A. V., 20, 268, 269 Imai, H., 4 Inage, M., 136 Inamoto, N., 261, 275 Inanaga, J., 251 Inch, T. D., 109 Indzhikyan, M. G., 22, 23, 26, 28 Inoguchi, Y . , 1 Inokawa, H., 105 Inokawa, S., 274 Inouye, Y., 25 Ionin, B. I., 104, 109, 121, 122. 263. 267 Isbrandt, L. R., 271 Ishida, M., 117 Ishikawa, N., 232 Ishmaeva, E. A., 71,271,277 Islamov, R. G . , 270 Ismagilova, N. M., 51, 65 Isobaev, M. D., 265 Issleib, K., 11, 13, 31, 50 Istomin, B. I., 128, 279, 280 Itakura, K., 204, 207, 208 Ito, K., 19 Ito, T., 2 Ivanov, B. E., 112, 279 Ivanova, E. M., 177 Ivanova, T. M., 29 Ivanteva, L. P., 277 Ives, D. H., 182 Iwata, T., 147, 152, 166, 168 Iwata, Y . , 197 Iyengar, R., 139, 142 Izawa, T., 19 Izawa, Y . , 71 Jackson, D. D., 27 Jacobsen, N. E., 138 Jacobson, R. A., 14, 161, 239, 275 Jaenicke, L., 228 Jagodic, V., 270 Jagodzinski, P. W., 271 Jahngen, J. H., 195 Jain, J. C . , 193 Jamieson, S. V., 228 Jamieson, W. B., 254 Jankowski, K., 221 Jansone, I., 214 Janzen, A. F., 38 Jardetzky, O., 220, 268 Jardetzdy, T. S., 268 Jardine, I., 172 Jarman, M., 147, 149, 152, 154, 156, 157, 159, 160, 161, 165, 172, 173 Jarrell, H. C., 137 Jarvest, R. L., 114, 181, 261 Jastorff, B., 183 Jaud, J., 98 Jay, E., 207 Jayaraman, K., 210 Jeck, R., 132 Jeffery, J. C . , 11 Jenkins, I. D., 18 Jenkins, J. A., 140 Jennings, L. J. A., 249 Jennings, W. B., 276 Jerina, D. M., 166 Jernow, J., 275 Jerris, P. J., 232

Author Index Jerushalmy, P., 85 Jerzak, S., 269 Jiricny, J., 261 Jo, S . , 23 Joergensen, K . A., 128 John, J. K., 186 Johnson, A. E., 200 Johnson, F. J., 280 Johnson, K. K., 3 Johnson, L. N., 140 Johnson, L. P., 221 Johnson, M. R., 244 Johnson, W. S., 228 Johnston, M. I., 186 Jolly, W. L., 273 Jones, C. E., 141 Jones, M. E., 186 Jones, R. L., 220 Jones, S. S., 206 Jonkers, F. L., 242 Jordan, M., 97 Josephson, S., 205 Joshua, A. V., 216 Juliani, M. H., 198 Juodka, B., 182 Jurkschat, K., 105 Juroda, T., 233 Just, G., 107, 227 Kabachnik, M. I., 21, 66, 71, 75, 103,222,274,269,270, 275 Kabachnik, M. M., 127 Kachroo, P. L., 75 Kadryov, Ch. Sh., 25 Kadyrov, R. A., 28,263,277 Kagan, H. B., 8, 71 Kagotani, M., 3 Kaiser, E. T., 141, 194 Kakushima, M., 254 Kalabina, A. V., 38, 128,279 Kalaritis, P., 198 Kalbitzer, H. R., 219 Kal’chenko, V. I., 24 Kalinin, A. E., 75, 274, 275 Kalinin, V. N., 268 Kalinov, S. M., 68 Kalshik, M. P., 104 Kalyagin, G. A., 270 Kamai, G. Kh., 51 Kamaike, K., 113 Kamba, H., 76 Kametani, T., 252 Kamimura, T., 107 Karnpmeier, J. A., 23 Kan, L. S., 179 Kan, M.-N., 146, 172 Kanda, Z . , 266 Kanno, T., 76 Kant, R., 75 Kapp, D. C., 176 Kardanov, N. A., 275 Kargin, Yu. M., 20, 23, 268 Karle, I. L., 159 Karle, J. M., 159 Karran, P., 218 Karpova, G . G., 201 Kartha, P. K., 76 Kasai, K., 168 Kasakova, A. A., 268 Kashirskaya, I. M., 51, 65 Kaska, W. C., 238 Kasper, C. B., 144

287 Kasukhin, L. F., 17, 116,279 Katada, T., 117 Kataev, E. G., 23 Katagiri, K., 152, 166, 168 Katagiri, N., 73 Kato, M., 19, 208 Kato, S . , 117 Kato, T , 73 Kato, Y . , 71 Katritzky, A. R., 81, 105 Katsuki, T., 251 Katsuvama. K.. 251 Katsybba, S . A:, 269 Kauffmann, T., 245 Kaufmann, G., 195, 259 Kavan, V., 4 Kawakami, S., 3 Kawasaki, T., 18, 60, 134 Kawashima, T., 98, 160 Kayasuga-Mikado, K., 178 Kazakova, A. A., 20 Kazimierczuk, Z . . 183 Kaziro Y . , 220 . Kearns, D. R., 219, 220 Keat, R., 262,266 Keav. J. G.. 81. 105 Keitkl, I., 242 ’ Kellner, K., 7, 10 Kelly, T. J., jun., 217 Kernp, W., 252 Kende, G . , 170 Kennedy, J. D., 266 Kent, D. E., 107 Kentamaa, H., 100 Kenyon, G. L., 134,247,273 Kerlavage, A. R., 198 Kern, D., 215 Kerr, 1. M., 211 Kertscher, P., 23 Kerwin, J . F., jun., 15 Kesling, H. S., 232 Keubler, M., 20 Khabarova, M. I., 208 Khachatryan, R. A., 26 Khagarov, A. I., 263 Khairullin, R. A., 98 Khairullin, R. S., 51 Khalepp, B. P., 269 Khan, B. T., 75 Khan, E. S . , 278 Kharchenko, A. V., 120 Khardin, A. P., 279 Khaskin, B. A., 112, 117 Khatri, H. N., 143 Khayarov, A. I., 82, 11 1 Khetagurova, S. Sh., 28,263, 277 Khokhlova, T. V., 279 Khorana, H. G . , 137 Khrarnov, A. S., 58 Khristov, Kh., 123 Khusainova, N. G., 123 Kibardin, A. M., 40, 102 Kibrik, G. E., 268 Kikuchi, H., 233 Kilduff, J. E., 89 Kim, K. S., 255 Kinas, R. W., 154, 157, 159, 160, 161, 165, 172, 173 Kingston, R. E., 197 Kinoshita, M., 229 Kinting, A., 49 Kirilov, M., 123 241

Kirk, M. C., 146, 149, 152, 154, 217 Kirkegaard, K., 217 Kirsanov, A. V., 105 Kirsch. M.. 197 Kishi, Y . , 244 Kiso, Y . , 144 Kisselev, L. L., 200 Kita, Y . , 18, 60 Kitaev, Yu. P., 277 Kitahara, H., 280 Kitchin, K . T., 170 Klaebe, A., 35, 280 Klautke, S., 6 Klebanskii, A. L., 267 Klein, C . , 198 Klein, H. O., 149 Klejn, H. W., 133 Kleiner H.-J.. 49 Kleinrok, Z.,7170 Klenk, H., 100 Klesse, W., 166 Klingenberg, M., 98 Klose, W., 235 Kluger, R., 141 Klyagina, V. P., 2 2 Kneen. G.. 250 Knolinski,’E. A., 219 Knorre, D. G., 177, 201 Knott, R. B., 71, 274 Knowles, J. R., 114, 131, 132, 173, 261 Knutson, K.. 164 Kobayashi, S., 19, 47 Kobayashi, Y . , 18, 32 Kobets, N. D., 200 Koch, D., 266 Kodama, K., 179 Koeckritz, P., 261 Kohler, F., 154 Konig, G., 100 Koenig, M., 46, 279 Koenigkramer, R. E., 246 Koeppel, H., 261 Koster, H., 205, 213 Kohli, V., 205 Koiro, 0. E., 76 Kois, P., 177, 185 Koizumi, T., 106, 119 Kojima, T., 76 Kok, R. A., 160 Koketsu, J., 262 Kolar, G. F., 216 Kolbina, V. E., 104 Kolesnik, N. P., 48 Kolesnikov, V. T., 79 Kollman, P. A., 273 Kolodiazhnyi, 0. 1. 14 56, 65, 126,225, 230, 261, 267 Kolosov, M. N., 208 Kol’yakova, G . M., 279 Kolyvanova, T. V., 76 Koma, Y., 233 Komarov, V. Ya., 263, 267 Komarova, M. P., 76 Komlev, I. V., 280 Komorowski, L., 269 Kondrat’ev, P. V., 3 Konieczny, M., 98, 169 Konishi, M., 3 Konovalova, I. V., 82, 98, 100, 103, 111, 123, 277 Konstantinova, M., 76

288 Konya, S., 194 Koob, R., 132 Kopel’tsiv, Yu, A., 79 Kormina. T. V.. 85 Korn, E.’D., 197 Kornfeld, S., 135 Kornuta, P. P., 268 Korobeinicheva, I. K., 177 Korolev, B. A., 278 Koroleva, T. I. 117 Koroteev, M. P., 274 Korovin, S. S., 263 Korp, J., 7 Koshushko, B. N., 265 Koslov, E. S., 9 Koster, A. S., 276 Kostyanovskii, R. G., 265 Kosuge, S., 249 Koszuk, J., 63 Kotova, L. V., 76 Kottmair, N., 219 Kotynski, A., 102, 107 Kovacs, J., 17 Koval, I. V., 120 Kovalenko, M. A., 76 Kovaleva, G. K., 200 Koval’skaya, V. F., 280 Kovar, K., 220 Kow, A., 275 Kowal, R., 269 Kowalik, J., 107 Kowalski, J., 114 Kozarich, J. W., 195 Kozhushko, B. N., 104 Kozlov, E. S.,38, 65, 268 Kozlowski, J. F., 131, 190 Kraemer, R., 98 Kraft, H. P., 154 Krahmer, U., 113 Krapp, W., 9, 238, 276 Krasnomolova, L. P., 263 Kraszewski, A., 117, 178 Kraus, J. L., 77 Krause, H. W., 49 Krause, L. J., 3 Krawiecka, B., 127 Krebs, B., 12, 90, 91, 274 Krebs, E. G., 141 Kreickmann, H., 196 Kremer. P. W.. 25. 274 Kremlev, M. M., 120 Kren, R. M., 59 Krengel, H. G., 170 Krick. T. P.. 144. 185 Krief,’ A., 19, 54,,222, 227 Krishnamurthy, S. S., 276 Krishtal, V. S., 24 Kristallovich, E. L., 83 Kroher, R., 89 Kron, T. E., 21, 66 Kron, V. A,, 16 Kroner, J., 262 Kroshefsky, R. D., 160 Kroto, H. W., 11, 272 Kriiger, C., 88, 274 Krueger, R., 272 Kruge, L. I., 157 Krugh, T. R., 221 Krynetskii, E. Yu., 202 Kryuchkov, A. A., 275 Krzytanowska, B., 148 Kubjacek, M., 278 Kudinova, V. V., 66

A uthor Index Kudrya, T. N., 105 Kudryavtseva, L. A., 112, 279 Kudzin, Z. H., 107 Kueckelhaus, W., 267 Kuhn., E. S., 188 Kuivila, H. G., 20 Kukhar,V. P., 23,43,98,126 Kukhtin, V. A., 81 Kulaev, I. S., 144 Kumada, M., 3, 4 Kumadaki, I., 18, 32 Kumar, N., 75 Kumarev, V. P., 210 Kuninaka, A., 179 Kunze, U., 57 Kupczyk-Subotkowska, L., 107 Kuplennik, Z. I., 17 Kurihara, T., 186 Kuroda, K., 228 Kursanov, D. N., 3 Kusakabe, S., 76 Kusukhin, L. F., 17 Kusumoto, S., 136 Kutyrev, G. A., 117 Kuwano, E., 103 Kuz’Menko, L. S., 268 Kwiatkowski, M., 21 1 Kyand’zhetsian, R. A., 14 Kyba, E. P., 4, 64, 104 Kyuntsel, I. A., 268 Laane, J., 271, 272 Labarre, J. F., 276 L’abbe, G., 102, 275 Lacey, C. J., 135 Lalancette, R. A., 71 Lam,. K. S., 144 Lambert, G., 166 Lamoureux, C. J. H., 154 Langier, J., 266 Lanneau. G. F.. 116. 279

Latajka, z., 270 Lattman, M., 260 Lau, C.-K., 254 Lauer, M., 8 Laurenco, C., 2.59 Laurenson. G. S .58. 276 Lavrent’ev; A N ’:270 Law, J. H., 137 Lawesson, S Q., 110, 128 Lawrence, J E., 280 Lawson. H. F.. 9. 73. 267 Leader,‘H., 38; 126 ’ Le Baron, H., 23 Lebedeva, E. N., 263 Le Bigot, Y., 227 Leclercq, D., 279 Le Corre, M., 23, 231 Lee. C.-G.. 215 Lee; J.-S., 21, 65 Lee, T. H., 273 Lefebvre, D. D., 280 Legator. M. S.. 170 Le-Goffic, F., 132

Legros, J.-P., 30 Leidl, E., 20 Leissring, E., 13, 14, 260 Lemire, A. E., 38 Leont’eva, I. V., 222, 274 Lerman, C. L., 219, 268 Lerner, D. B., 219, 220 Leroy, J., 60 Lesch, J. S., 26, 223 Lesiak, K., 102 Lesko, S. A., 216 Lesnikowski, Z. J., 185, 204 278 Lessen, U., 172 Letham. D. S.. 221 Letsinger, R. L., 93 Le Van, D., 20 Lever, 0.W.,jun., 54,63,240 Levin, Y. A., 21 Levv. G. C.. 219 Lev?; H. M:, 188 Lex, J., 252 Ley, S. V., 245 Li, V.-S., 102 Li, Y. S., 272 Licandro, E., 20 Liebenow, H., 230 Liebl, R., 31 Lietz, M., 269 Light, R. W., 17. 87 Lim, N. M., 3 Limassett, J.-C., 232 Lin, T.-S., 178 Lindahl, T., 218 Lindemann, H., 152 Lindig, C., 15, 61 Lindner, E., 30, 53, 75 Lipkowitz, K. B., 263 Lischka, H., 226, 264 Lister, S. G., 245 Little, R. D., 229 Litvak, S., 199 Litvina, M. N., 76 Liu, F., 213 Liu, H.-J., 114 Livingstone, L R., 186 Livneh, Z., 218 Lloyd, D., 17 Lloyd, J. R., 43 Lo, K. M., 216 Lobana, T. S., 76 Lobanov, 0. P., 28, 121 Lobe, C. G., 5 Lochmann, R., 261 Loew, L. M., 135 Loewus, D. I., 124 Logunov, A. P., 71,263,277 Lohrmann, R., 210 Lolkema, J. S., 134 Lombardi, P., 251 Longo, A,, 251 Lopresti, R. J., 254 Lopusinki, A., 109, 127 Lorentzen, R. J., 216 Lothar, W., 16 Louzon, F., 135 Lowe. C. R.. 185 Lowe; G., 114, 181, 189,261 Lown, J. W., 216 Luckenbach, R., 265 Lucsak. L.. 127 Ludeman, 8. M., 156, 157, 160, 161, 166

Author Index Ludlum, D. B., 151, 217 Luckoff, M., 31 Lutkecosmann, P., 6 Luger, P., 274 Lukin, P. M., 81 Lulukyan, R. K., 22 Lunardi, J., 198 Lutsenko. I. F.., 1.. 6._66 Lux, D., 276 Luxon, B. A., 220, 279 Lyttle, M. H., 233 M aah, M. J., 11 M aas, G., 275 M cAllister, P. R., 22 M cClard, R. W., 186 M ccloskey, C. J., 19, 280 M cClure, H. M., 170 M cComb, R. B., 141 M ccurry, S. D., 131 M acDiarmid, J. E., 7, 66, 73 M acDonald, E. K., 55 M acDonell, G. D., 71, 262 M acDonnell, G. C., 7 M cDonnel1, T. J., 278 M acDougall, A. J., 187 M acDougall, J. J., 29 M cFadden, G., 141 M cFarlane, H. C. E., 265, 266 M kFarlane, W., 8, 76, 265, 266 M 'cGuffy, A., 68, 275 M [achida, H., 179 M IcIntire, W., 133 M jcKay, S. W., 254 M cKean, D. C., 269 M cKee, M. L., 260 M IcKeever, B., 48 M ackie, R. K., 17 M 'cLaughlin, L. W., 216 M 'acLean, G., 274 M [acleod,J. H., 149 M [acLeod, J. K., 221 M clennan, M., 146 M cManaman, J., 141 M 'cMillan, C., tert., 213 M acNeil, P. A., 3 M acNicol, D. D., 75, 275 M cParland, K. B., 209, 210 M'cQuillan, G. P., 71, 269, 271, 275 M cRorie, R. A., 143 M cVicker, E. M., 39 M addock, C. L., 147 M adoyan, I. A., 200 M adsen, N. B., 134 M aercker, A., 228 M arkl, G., 10, 31 M agdesieva, N. N., 14 M agid, R. M., 16 M agolda, R. L., 258 M ahrau, M. R., 79 M aier, G., 12, 50 M aier, L., 108 M aiorana, S., 20 M aiorova. L. P., 20 M ajoral, J. P., 98 M akino, I., 168 M alavaud, C., 35 M aleki, M., 54, 63, 240 M alherbe, J. S., 26, 223 M alik, K. M. A., 2

289 M alisch, W., 239 M allinson, P. R., 75, 275 M altseva, T. V., 177 Manchar, H., 276 M anchester, K. L., 134 M andl, J. R., 238 M aniwa, S., 229 M aracek, J. F., 48 M archenko, A. P., 29 M arco, A., 71 M arcus, A,, 195 M arecek, J. F., 116, 187, 188, 278 M areva, S., 76 M arfat, A., 254, 255, 257 M arinello, A. J., 149 M arino, J. P., 27 M ark, E., 18 M arkham, A, F., 207 M arkham, R., 10 M ark6, L., 10 M arkovskii, L.N., 24,37,48, 49,. 65, 66, 77, 79, 89, 104 M arlier, J. F., 191 M arschner, F., 273 M arshall, D. R., 17 M arshall. L. E.. 216 M artin, C., 31 ' M artin, G. H., 264 M artin, J., 105, 267, 277 M artin, J. C., 35, 39, 44, 5 5 , 65. 79. 267 M artyn'yuk, A. P., 28 M aruta, H., 197 M arx, A., 6 M ason, J. S., 249 M ass, G., 113 M assa, W., 4, 273 M astalerz, P., 107 M astryukova, T. A., 222, 270, 274 M asuda, S., 247 M asuda, T., 4 M asui, M., 20 M asumaga, T., 79 M asunarra. T.. 104 M atevogan, G. L., 81, 105, 126 M athey, F., 8, 9, 29, 30, 31, 60, 68, 71, 272, 273, 275 M atrosov., E. I., 71, 75, 270, 275 M atsuda, A., 176 M atsukage, A., 197 M atsumoto, A., 3 M atsumoto, M., 228 M atsumoto, S., 152, 166, 168 M atsumoto, T., 138 M atsunami, N., 197 M atsuzaki, N., 82 M att, D., 20 M atteucci, M. D., 205 M attingly, P. C., 15 M attson, G. A., 83 M atveev, I. S., 12 M atyushicheva, R. M., 126 M avrin, V. Yu., 117 M ayer, A., 198 M ayer, B., 158 M ayerle, J. J., 29 M azalov, L. N., 273 M azhar-ul-Haque, 25, 274 M azo, A. M., 214

M Iazerolles, P., 20, 57

Mleads, R. E., 2 M ealli, C., 5 M eares, C. F., 198 M ednikov, E, V., 279 M edved, T. Ya., 71 M edvedeva. M. D.. 263 M eek, D. W., 11 M egera, I. V., 23 M ehdi, S., 181, 184 M ehrotra. S. K.. 274 M ehta, J.'R., 151 M eidine, M. F., 261 M eienhofer, J., 148 M eier, G. P., 226 M eli, A., 5 M ellett, L. B., 146 M elnick. B. P.. 93 M el'nikov, N. 'N., 120 M endenhall, G. D., 39 M entzel, H., 212 M erai, K., 172 M ercier, F., 8, 71 M eresak, W. A., 135 M erkelbach, I. I., 276 M erritt, E. A., 140 M ersch, K. A., 67 M ertes, M. P., 175, 179, 198 M esch, K. A., 8, 19, 260,261 M essmer, A., 17 M estres, R., 114 M etelev, V. G., 214 M eunier. B.. 56. 66. 275 M eyer, B., 267 . . M eyer, H., 14, 260, 266 M eyer, R. B., jun., 182 M eyerson, S.,188, 278 M ichaels, F. M., 7, 68 M ichalak. R. S.. 44 M ichalski, J., 38, 88, 106, 109, 126, 127, 275 M ichalski, T. J., 240 M ichie, J. K., 52, 64, 104 M ichniewicz, J. J., 204 M iddlemas, E. D., 8, 9, 69, 73, 267 M idelfort, C. F., 188, 189 M ighell, A. D., 156 M ikhailova, N. V., 100 M ikhailova, T. S., 122 M ikoshiba, R., 243 M ildvan, A. S., 194 M ilewski-Mahrla, B., 21, 224, 238, 240, 274 M illar. D. P.. 221 M iller, A,, 240 M iller, E. G., 215 M iller, G., 152 M iller, J., 16 Miller, J. A., 51, 52, 53, 54, 63, 64, 104, 215 Miller, J. P., 182, 183 Miller, M. J., 15, 233 Miller. P. S.. 209. 210 Miller; R. L:, 195 Miller, W. H., 195 Milsted, R. A. V., 165, 172 Milyukova, M. S., 76 Minami, K., 114 Minami, T., 82 Mioduski, T., 279 Mir, Q.-C., 37 Mironova, Z. N., 21

Author Index Miroshnichenko, V. V., 29 Mise, T., 3 Mishra, S. P., 269 Misiura, K., 165 Mislow, K . , 265 Mitchell, J. D., 8, 266 Mitchell, P., 131 Mitchell, P. R., 218 Mitrenga, D., 149 Mitschler, A., 20, 29, 30 Mitsunobu, O., 18 Miura, K., 217 Miyagawa, K., 117 Miyake, T., 207 Miyamoto, T., 117 Miyashita, A., 2 Miyazaki, T., 144 Miyazawa, T., 220 Miyoshi, K., 207, 208 Mizrakh, L. I., 29 Mizuta, M., 117 Moczydlowski, E. G., 197 Modro, T., 119, 275, 279 Moedritzer, K., 267 Moeller, K. D., 269 Mortl, A., 21, 223 Mohri, A., 35 Moir, A. J. G., 141 Moiseev, I. I . , 20 Mokeeva, V. A., 268 Molina, P., 105 Moller, M. R., 219 Mollevanger, L. C. P. J., 220 Molnar, E. M., 26, 223 Monkiewicz, J., 63, 240 Montecucco, C., 137 Montrasi, G., 20 Moore, R. W., 249 Morgan, S. E., 254 Mori, K., 247 Morin, F. G . , 262 Morita, S., 32 Morita, T., 1 1 1 Moriyama, M., 127 Morozumi, M., 179 Morrison, J. A,, 3 Morrison, J. F., 194, 218 Morrison, M. A., 15 Morse, J. G., 5 Mosbach, K., 186 Mosbo, J. A., 158, 169 Moskalevskaya, L. S., 126 Mosler, G., 53, 64 Most, J. T., 25, 274 Motoyoshiya, J., 243 Motto, M. G., 251 Moudgil, V. K., 186 Moulton, C . J., 10 Muchowski, J. M., 27, 231, 248 Mucklejohn, S. A. , 89 Muegge, C., 127, 265 Muhlbach, G., 6 Mukmenev, E. T., 277 Mueller, G., 238, 264 Mueller, U., 269 Mukhtarov, A. Sh., 268. 269 Muller, G. W., 229 Mulliez, M., 36, 113, 119, 129 Mumzhieva, N . G., 271 Mundt, O., 13, 273 Mundy, B. P., 263

Munoz, A., 36, 46,279 Munroe, J. E., 255 Munson, K . B., 198 Murahashi, S.-I., 27 Murakami, A., 93, 179,202 Murata, M., 202 Muratov, A. A . , 58 Murthy, A. R. V., 276 Murthy, P. P. N., 142 Murty, M. V., 76 Musierowicz, S., 106, 275 Musin, R. Z., 40 Musina, A. A., 263 Musliniov, S. A., 85 Mustaev, A. A., 209 Myasoedov, B. F., 76 Myers, A. G., 258 Myles, A , , 145, 149, 166 Naal, N. G., 232 Nagahara, T., 252 Nagaoka, H., 244 Nagashima, N., 3, 4 Nagel, U., 20 Nagy-Magos, Z . , 10 Naidu, M. S. R., 278 Najjar, D., 228 Nakagawa, I., 194 Nakai, S., 20 Nakai, T., 232 Nakajima, Y . , 100 Nakamichi, K., 93, 202 Nakamura, H., 197 Nakamura, S., 220 Nakanishi, K . , 251 Nakano, A,, 220 Nakano, T., 18 Nakatani, Y., 137 Nall, B. T., 220 Nandu, R. K., 268 Narang, S. A , , 204, 208 Narayan G. K. A . S. S., 128 Narayanan, K. S., 26, 230 Nardi, N., 4 Narukawa, Y., 47 Nash, J. A., 265, 266 Nassimbeni, L. R., 275 Naumov, V. A., 276 Navech, J., 98 Nazarova, T. I., 141 Nechaev, A,, 195 Neda, I., 99, 271 Needham. R. J.. 16 Negishi, K.,178 Negishi, T 178 Negrebetskii, V. V., 110, I17 Neidle. S.. 120 Neilson, R, H . , 269 Nelson, J. H., 29, 262, 264 Nelson, P. H., 27, 231 Nemer, M. J., 93, 181, 202, 203, 205, 208 Nerner, M. J., 93 Nesterov, L. V., 28, 280 Neugebauer, F. A . , 269 Neumann, H., 1 Neumann, J . M., 220 Newman, T. H., 5, 269 Newton, C. R., 207 Newton, R . F., 249 Nguyen Thanh Thuong, 177, 204 Nickish, K., 235

Nickloweit-Luke, A., 12,91 Nicolaou, K . C . , 243, 258 Niecke, E., 10, 12,89,90,91, 110, 269, 274 Niedner, R., 143 Nief, F., 31, 68 Niemeyer, U . , 149 Nierman, W. C., 197 Nietzschmann, E., 2 Ni_fa_?t’ev,E. E., 102, 108,

Nikonov, G. N., 9, 277 Nikonova, L. Z . , 109 Nilsen, T. W., 21 1 Nilsson, K., 186 Nishiguchi, T., 20 Nishimura, J. S., 186 Nishimura, S., 177 Nishimura, T., 216 Nishizawa. Y..186 Nixon, J . F., 11, 272 No, B. I., 279 Noall, W. I., 100 Noeth, H., 262 Noltmann, E. A., 139 Nomoto. T.. 11 3. 202 Nordhoff, E:, 235 Norpoth, K . , 149, 152 Nourse, J. G., 264 Novikov, M. P., 76 Novikova, N . K., 98, 103 Novikova, Z . S., I , 6 Nowell, I . W., 274, 275 Noyori, R.,2 Nozaki, H., 114 Nuber, R., 274 Niirrenbach, A., 249 Nuhn, P., 23 Nunn, M. J., 52, 64 Nuretdinov, I. A . , 106, 127 Nuretdinova, 0.N., 102, 109 Nurtdinov, S. Kh., 51, 65 Nyburg, S. C., 21, 65, 275 Nygird, O., 187 Oae S. 17 Oakiey,’ R. T., 5, 59, 274, 276 Oberhammer, H., 277 O’Brien J. P., 276 o’c onnbr, T., 219 Odell, K . J., 10 Odeurs, R 271 Odintsov, B. M., 269 Oberg, R., 21 1 Ohler, E., 25 Oehme, H., 13, 14, 260 Oertel, R. P., 271 Otvos, L., 175 Ofitserov, E. N., 277 Ogilvie, K. K., 93, 181, 202 203, 205, 208 Ohler, E., 223 Ohmori, H., 20 Ohno, K., 11, 272 Ohno, M., 19, 211 Ohshiro, Y . ,79, 82, 104, 243 Ohtani, S., 194 Ohtsuka, E., 204, 207, 211, 213

A uthor Index

29 1

Ohuchida, S., 249 Oi, T., 280 Okada, H., 132 Okamoto, Y., 111 Okamura, W. H., 25 1 Okashi. 0.. 272 Okazaki, H., 278 Okimoto, K., 84 Okruszek, A., 164, 165, 169 Olehnik, K., 193 Oleksyszyn, J., 107 Olesen, S. O., 110, 128 Oliva, G., 275 Oliveto, E., 275 Olson, M. 0. J., 141 Olwin, B. B., 199 Ono, K., 197 Ono, T., 204 Onys’ko, P. P., 105 Ouella. S. J.. 220 Oiahovats, A. S., 15 Orgel, L. E., 210 Orlandini, A., 5 Osborne, A. G., 2 Oshevski, S. I., 209 Oshie, K., 211 Oshima, K., 114 Osipov, 0. A., 75, 270 Osipova, M. P., 81 Osman, F. H., 95 Oswald, T., 233 Ott, T., 181 Ottlinger, R., 86 Ourisson, G., 137 Ovakimvan. M. Zh.. 22. 23. 26, 2 8 ‘ Ovchinnikov, V. V., 117 Owens, P. W., 64, 104 Oxton, I. A., 17, 269, 271 I

,

,

Pace, B., 187 Pace, N. R., 187 Paddock, N. L., 59, 276 Padgett, C. A,, 146 Padyukova, N. Sh., 180 Pagani, G., 20 Paine, R. T., 17, 87 Pakulski, M., 38, 88 Paliichuk, Yu. A., 104, 265 Palomo, C., 114, 118 Palomo-Coll, A. L., 118 Paneth, P., 278 Pankiewicz, K., 154,156,159, 160, 161, 165, 167, 172 Panne-Jacolot, F., 249 Panosyan, G. A., 123 Pantaleo, N. S., 68, 275 Panzica, R. P., 17 Pao, C. C., 197 Paparizos, C., 238 Parakin, 0. V., 20, 23, 268 Park, J. S., 175 Parker, C. W., 221 Parkin, A., 157 Parnes, Z. N., 3 Parry, R. W., 49 Pascard, C., 56, 66, 275 Pastor, R., 59 Patel, A. N., 28 Patel, H. A., 247 Patil, S. K., 76 Patmore, D. J., 276 I

Patsanovskii, I. I., 71,271, 277 Pattenden, G., 243, 250 Patzelt-Wenczler, R., 196 Paugam, J. P., 120 Paul, W., 230 Pauls, H., 194 Paulsen, H., 158 Paulus, E. F., 275 Paust, J., 249 Pavia, M. R., 243 Pavlenko, N. G., 23 Payette, D. R., 227 Payne, N. C., 260 Peake, S. C., 39 Peattie, D. A., 215 Pelka, H., 200 Penefsky, H. S., 190 Penningroth, S. M., 193 Perales, A., 158, 161 Perov, V. A., 72 Perozzi, E. F., 44 Perrotta, A., 275 Peter, G., 147, 165, 172 Peters, J., 5 Peters, J. A. M., 228 Petraud, M., 233 Petrenko, V. A., 209 Petridis. G.. 183 Petrov,‘A. A., 104, 109, 121, 122, 263 Petrov, A. I., 218, 221 Petrov, K. A., 54, 56, 63 Petrova, J., 241 Petrova. T. D.. 268 Petrovskii, P. V., 3, 222, 270 Pezzano, H., 218 Pfister-Guillouzo, G., 272 Pfleiderer, W., 142, 21 1 Phelps. M. E., 178 Phillips, B. J., 149 Pickering, R . A., 14, 239 Pieronczyk, W., 7 Pietrusiewicz, K. M., 7, 62, 63. 71. 262 Pilkis, J.; 135 Pilkis, S. J., 135 Pilyugin, V. S., 270 Pinchuk. A. M.., 17., 29 Pinter, I:, 17 Pirrung, M. C., 232 Pisareva, S. A., 71, 76 Planck, S. R., 150 Planta, R. J., 220 Platte, C., 274 Platz, H., 247 Plumbridge, T. W., 187 Podlaha, J., 3 Podlahova, J., 3 Podo, F., 218 Pogosyan, A. S., 23, 26 Pohl, J., 149 Poizat, O., 30 Polensek, L., 76 Polezhaeva, N. A., 14 Polonskaya, L. Yu., 29 Polushina, V. L., 23 Pominov, 1. S., 269, 270 Pon, R. T., 205 Ponomarchuk, M. P., 17, 116, 279 Ponomarenko, I. V., 209 Ponsford, R. J., 252

Popov, A. I., 279 Popov, S. G., 207 Porter, N . A., 228 Posen, S., 141 Posthumus, T. A. P., 228 Potenza, J. A., 71 Potter. B. V. L.. 114. 181.261 ‘ Pougeois, R., 140 ’ Poulter, C. D., 100 Povolotskii, M. I., 268 Power, P. P., 268 Pozdnyakov, P. I., 209 Pozhidaev, V. M., 260 Praefcke, K., 21,65,275,278 Prakash, A., 17 Prasad, K., 18 Prasad, V. A., 48 Pratt, R. M., 170 Preiss, A., 263 Priester, W., 3 Prieto, J. A., 231 Prijs, B., 218 Prishchenko, A. A., 1, 6 Proia, R. L., 199 Prokof’ev, A. I., 269 Prokofiev, M. A., 209 Prokscha, H., 4 Promonenko, V. K., 112, 117 Prons, V. N., 267 Prusoff, W. H., 178 Przybylski, M., 151, 172 Pudovik, A. N., 20, 23, 40, 58, 71, 82, 98, 100, 102, 103, 111, 112, 117, 123, 260, 268, 270, 276, 277 Pudovik, M. A., 263 Pulford, S. M., 209 Pushparaja, S. M., 76 Pyne, G. S., 266 Qazi, T. U., 15 Quast, H., 111 Queen, A., 38 Quiggle, K., 181 uin L. D 7 8 9 19 56 66,’ 67, 64, 53: 2k0, 561: 267 Rachon, J., 78, 107, 244 Rackham, D. M., 254 Raddatz, P., 243 Radeglia, R., 261 Radhakrishna, A. S., 22 Radhakrishnan, R., 137 Radionova, N. P., 214 Radziejewski, C., 109, 126 Radzikowski, C., 170 Rae, A. D., 71, 274 Raevskii, 0. A,, 271 Rahil, J., 129, 279 Rahman, A., 7, 71, 262 Raidt, H., 152 Rakhnovich, G. B., 109, 275 Ramakrishna, V. V., 76 Ramarajan, K., 268 Ramdal, J. B., 71 Ramirez, F., 48, 52, 98, 116, 187. 188. 278 Ramos, S.,’23 Rampal, J. B., 7, 68, 262, 275 Rankin, D. W. H., 34, 55, 58, 264, 276, 277

292

Author Index

iao, B. D. N., 220 iao, V. M., 76 iaphalen, A. P., 107 iasmussen, J. B., 128 iatajczak, H., 270 iathgeber, G., 198 iatovskii, G. V., 38, 272 iauchfuss, T. B., 11
L43

Reznik, G., 170 Rezvukhin, A. I., 262 Rheinwald, M., 247 Ribeiro, A., 268 1Xicard. L.. 20. 30

1 1 Richter, H., 120 Richter, W. J., 142 Riehl, J.-J., 228

Ringer, D., .181. Ringsdorf, H., 166, 167, 172 Rios-Mercadillo, V. M., 131 Ritchev. W. M.. 268 Riviere,’ P., 20 ’ Rivkin, M. I., 210 Rizkalla. B. A., 135 Robbins, R. J., 221 RcQcrt, J. B., 105, 263, 266,

Robillard, G. T., 134 Robins, R. K., 182 Rockley, M. G., 228 Rodaway, S., 195 Rodebaugh, R., 17 Rodehorst, R. M., 23 Roellgen, F. W., 278 Roemming, C., 275 Rosch, P., 219 Roschenthaler, G.-V., 59 Roesky, H. W., 34, 274, 276 Rossler, M., 11, 13, 273 Rokach, J., 254 Rolfes, A. I., 198 Romakhin, A. S., 23 Romanenko, E. A., 268,272 Romanenko. V. D.,_ 49._ 65,_ 66, 89 Romanov, G. V., 20,23,260, 268, 276, 277 Romm, I. P., 271 Rommel. W.. 217 Romsted, L. ’S., 116 Ronkov, V. I., 108 Rose. I. A,, 139, 140 Rose; J. P.,’ 71 . Rose, S. D., 212 Rosen. P.. 275 Rosen; W:, 23 Rosenberg, I., 185 Rosenberg, Yu. I., 268 Ross, M. R., 35, 44, 5 5 , 65,254,267 Rossomando, E. F., 195 Roth, B., 274 Roth, K., 236 Rothe, S., 10 Rothwell, I. P., 2 Rothwell, W. P., 220 Roush, W. R., 258 Rowell, R., 115, 261, 267 Rowlands, C. C., 269 Roy, S., 200 Rozanel’skaya, N. A., 271 Rozhkova, N. K., 83 Rozinov, V. G., 104 Ruban, A. V., 89 Rubin, C. M., 213 Rubio, V., 189 Rudavskii, V. P., 43 Rudnik, S. R., 126 Rudolph, G., 225 Rueger, H. J., 23 Ruger, R., 12, 91 Runova, L. M., 108 Rupprecht, A., 220 Russell, G. A., 79 Ruther, F., 228 Rutkovskii, G. V., 279 Rutkowska-Olma, E., 62 Rutsch, W., 244 Rybakov, V. B., 274 Rybakov, V. N., 210 Rycroft, D. S., 266 Rygalov, L. N., 279 Ryl’tsev, E. V., 270 Ryte, A. S., 201

LO I

Robert, Zh. B., 277 Roberts, B. P., 89, 268, 269 Roberts. D. H.. 228 Roberts: N. K.; 3, 273 Roberts, P. M., 252

Saalfrank, R. W., 230 Sabesan, S. I., 114 Sacconi, L., 5 Sadana, Y. N., 27 Sadkova, D. N., 127

Sadler, P. J., 131 Saegusa, T., 47 Saenger, W., 159, 185 Safina, Z. Sh., 274 Sagi, J., 175 Sagina, E. J., 23 Sahara, H., 105 Saiton, J., 56, 66, 275 Sakurai, H., 111 Salakhov, I. S., 58 Salakhutdinov, R. A., 51,65, 85, 129 Salas, M., 217 Salemink, P. J. M., 220 Samitov, Yu. Yu., 263 Sammes, M. P., 81, 105 Sampath, K., 271 Samuel, O., 8, 71 Samuelsson, B., 17, 61 Sanchez, M., 95, 267, 280 Sandhu, S. S., 76 Sandmeier, D., 235 Sanemori, H., 134 Saneyoshi, M., 177, 179 Sanger, A. R., 5 Santi, D. V., 176 Santini, C., 8, 29,71 Santonastaso, V., 197 Sanyal, M. K., 170 Sarma, R., 48 Sartori, P., 53, 64 Sasnauskiene, S., 182 Sass, V. P., 267 Sastri, M. N., 76 Sastry, C. V. R., 128 Satake, H., 220 Satek, L. C., 8, 76, 266 Satgt, J., 12, 20, 57 Sato, N., 54 Sato, R., 73 Sato, T., 164 Satoh, M., 125 Satomi, M., 144 Satre, M., 198 Satterthwait. A. C.. 101 Satyamurthy, N., 7, 7 1, 262 Saucy, G., 3 Sauveur, F., 77, 107 Saval, I. H., 9 Savignac, P., 77, 107 Sawada. Y.. 211 Sawai, H., 211 Scanlon, D., 207 Scanlon, L. G., 11 Schaal, M., 20 Schade, G., 234 Schaefer, H.-J., 198 Scheef, W., 149 Schemer, G., 149 Schemer, K. 44, 46, 264 Scheibye, S., 110, 128 Scheit, K. H., 175, 197 Scheller, K. H., 218 Scherer, 0. J., 88, 96, 274 Scherm, H. P., 261 Schettler, K., 262 Scheurich, P., 198 Schidbaur, H., 224 Schiff, J. A., 178 Schipper, P., 40, 262, 269 Schlak, O., 39 Schlimme, E., 197 Schmelzer, A,, 272

Author Index Schmid, B. P., 170 Schmid, C. W., 213 Schmid, G., 222, 234, 235, 244

Schmidbauer, H., 1, 17, 21, 30, 223, 225, 238,240,261, 264. 266. 274. 277 Schmidpeter, A.: 12, 30, 34, 45, 88, 92, 263, 265, 273 276? 278 Schmidt, C. L., 175 Schmidt, H., 11, 13, 50 Schmitz, R., 5 Schmutzler, R., 34, 36, 39, 59, 275 Schnackerz, K. D., 139 Schneider, D. F., 26, 223 Schneyder, E., 101 Schnitker, J., 149 Schoeller, W. W., 10, 90 Schollkopf, U., 78, 107, 244 Schonhammer, B., 7 Schomburg, D., 34, 45, 88, 275 Schoner, W., 194, 196 Schore, N. E., 5 Schrors, H. J., 170 Schubert, U., 224, 239,261, 274 Schugar, H. J., 71 Schulman, J. I., 4 Schulman, L. H., 200 Schulten, H. R., 120, 166 Schultz, G., 18 Schultz, H.-J., 7 Schup, H., 167 Schuster, S. M., 197 Schutzbank, S. G., 94 Schwarz, W., 120, 276 Scopelianos, A. G., 276 Secor, H. V., 156 Sedelnikova, E. A., 208 Seela, F., 175, 212 Seeliger, A., 132 Sega; A., 3 Segall, Y., 38, 40, 69, 126, 263 Seidel, P., 113 Seifert, G., 262 Seifert, J.-M., 205 Seitz, S. P., 243 Sekine, M., 84, 125, 182 Sekine, T., 76 Seligman, A. M., 146 Semashko, Z. T., 108 Semenii, V. Ya., 270 Sena, S. F., 24, 56 Sequin, R., 254 Sergeeva, N. F., 202 Sergienko, L. M., 38, 272 Serve, D., 23 Seth, A. K., 207 Sevrin, M., 19 Shabana, R., 17, 110, 128 Shabarova, Z. A., 198, 200, 202, 209, 211, 214 Shaikh, M. A., 274 Shaikhullina, R. F., 83 Shand, F. L., 170 Sharma, R. K., 251,271 Sharma, S. D., 149 Shaw, B. L., 10 Shaw, R. A., 276

293 Shcherbina, T. M., 103 Sheldrick, W. S., 9, 12, 34, 45, 88, 238, 273, 275, 276 Shelest, V. V., 23 Sheluchenko, 0. D., 112, 117 Shermolovich, Yu. G., 37, 48, 79, 268 Shestakova, T. G., 108 Shevchuk, M. I., 23 Sheves, M., 251 Shiao, M.-S., 142 Shiba, T., 136 Shibaev, V. I., 270 Shibahara, S., 204 Shibata, T., 21 1 Shida, T., 179 Shifrina, R. R., 271 Shigetomi, Y., 76 Shih, Y. E., 156 Shikhaliev, Sh. M., 265 Shima, I., 275 Shimada, A., 251 Shimada, H., 280 Shimidzu, T., 93, 179, 202 Shimomura, S., 133 Shindo, H., 220 Shin-Ya, S., 25 Shirahashi, K., 18 Shiratori, O., 152, 168 Shirazi, S. P., 193 Shire, D. J., 92, 202 Shirin, E., 38, 69, 126, 263 Shishkin, S. K., 71, 277 Shishkin, V. E., 279 Shishkina, N. V., 279 Shoham, M., 140 Shokol, V. A.. 104, 265 Shreeve, J. M., 37 Shreeve, R. W., 37 Shridhar, D. R., 128 Shriver, J. W., 220 Shrubsall, P. R., 254 Shtepanek, A. S., 105 Shubina, T. N., 209 Shugar, D., 183 Shukla, K. K., 188 Shulman, S. D., 141 Shumate, R. E., 3 Shurubura, A. K., 270 Shvets, A. A., 75, 270 Shymasundar, N., 228 Sibanda, S., 206 Sibgatullina, F. G., 106 Sichtermann, W., 221 Sicsic, S., 132 Sidky, M. M., 17, 42, 79 Sigel, H., 218 Sigman, D. S., 216 Sigolaev, Yu. P., 263 Silaghi-Dumitrescu, I., 270 Silberman, L., 157 Silverman, R. H., 211 Simalty, M., 26, 31, 68, 269 Simmons, N. P. C., 11, 272 Simoncsits, A., 214 Simpson, J. M., 176 Singer, B., 213 Singer, T. P., 133 Singh, E. B., 76 Sjngh, K., 89, 268 Singh, M., 207 Singh, R. K., 76

Singh, S. K., 76 Sinitsa, A. D., 24 Sinitsyna, N. I., 129 Sinyavskaya, E. I., 76 Sirkin, S. R., 170 Sirvio, L. M., 249 Sivolobova, G. F., 209 Skelton, B. W., 273, 274 Skolimowski, J., 26, 269 Skorodumova, N. A., 279 Skowronska, A., 38, 88 Skowronski, R., 269 Skrzypczynski, Z., 126 Skuballa, W., 249 Skvortsov, N. K., 121 Sladek, N. E., 148, 149, 150 Slobin, L. I., 200 Slusarska, E., 128 Smagowicz, W. J., 197 Smale, T. C., 252 Smalley, M. V., 59 Smirnov, V. D., 202 Smirnov, V. N., 111 Smirnova, E. I., 102 Smith, A. B., tert., 232 Smith, D. J. H., 53 Smith, G. F., 20 Smith, I. C. P., 137 Smith, I. E., 172 Smith, L. T., 193 Smith, M. J., 108 Smith, P. H., 8 Smith, R. A., 18, 86 Smolyaninova, 0. A., 208, 212 Smrt, J., 180 Smyth, J. F., 172 Snatzke, G., 159 Snoble, K. A. J., 226 Snowden, R. L., 250 Snyder, M., 213 Sobanova, 0. B., 58 Sochilin, E. G., 270 Socol, S. M., 165 Soifer, G. B., 268 Sokal’skaya, L. I., 278 Sokolov, L. B., 109 Sokolov, V. I., 4 Sokolova, N. I., 198, 200, 209 Sokolow, J. A., 267 Soliman, F. M., 17 Solodovnikov, S. P., 269 Solouki, B., 273 Solov’ev, A. V., 37, 268 Solov’eva, N. P., 3 Songstad, J., 275 Sonnett, P. E., 249 Sopchik, A. E., 86, 93, 183, 184 Sosnovsky G., 98, 169 Sotman, S. S., 274 Souchi, T., 2 Sourisseau, C., 30 Souther, S. K., 16 Southgate, R., 252 Spadaro, A., 197 Spande, T. F., 136 Spena, A., 197 Spengler, S., 213 Sperling, J., 218 Sproat, B. S., 189 Sreekumar, C., 231

Author Index Srivastava, S . P., 135, 136 Stachel, H. D., 109 Stackhouse, J., 130 Stahl, J., 200 Stalick, J. K., 156 Stammer, C . H., 143 Standring. D. N.. 132 Stan-Lotter, H., 199 Stawinski. J.. 117. 178 Stec, W. J., 98, 102, 116, 148, 154, 156, 158, 159, 160, 161, 165, 170, 172, 173, 183, 185, 204, 266, 278 Stegmann, H. B., 44,46, 262, 264 Steim, J. M., 136 Stein,’J., 238 Steinrucken, H. C., 138 Steitz, T. A., 140 Stekar. J.. 149. 152 Stelzer, O’., 275 Stepanova, T . Ya., 23 Stephan, D. W., 260 Stephan, H. W., 6 Stephanovitch, L. E., 201 Stephenson, D . S., 31 Stephenson, J. H., 185 Stevens, P., 271 Stevenson, W. H., tert., 44 Stewart, C. J., 132 Stewart, D., 52, 53, 64 Steyer, E. M., 10 Still, W. C., 231 Stille, J. K., 4 Stock, P., 4 Stoll, R., 278 Stoodley, R. J., 251 Storhoff, B. N., 9 Storm, D. R., 199 Storzer, W., 59 Stralkova, E. N., 277 Strecker, M., 143 Streitwieser, A.. iun., 233 Streng, K., 7 Streusand, B. J.. 271, 272 Strotmann, H., 197 Struchkov, Yu. T., 54, 71, 75, 99, 109, 274, 275, 276 Struck. R. F.. 146. 149. 150. 152,’154, 165, 166 ’ Stubbe, J., 195 Stukalo, E. A., 77, 104 Stumpe, L. A., 280 Stura, E. A., 140 Sturtz, G., 77, 107 Sturz, G., 120 Stutz, P., 18 Subotkowska, L., 107 Suda, M., 14, 61, 232 Sueiras, J., 251 Sugimoto, R., 3 Sugimoto. T.. 23 Sugimoto; Y.’,132 Suguro, T., 247 Suhadolnik, R. J., 211 Sukhorukov. B. I.. 218. 221 Sukhorukov; Yu. I., 75, 270 Sullivan, S. A., 278 Sun, R. C., 3, 4 Sundaralingam, M., 140 Sung, W. L., 208 Sunjid, V., 3 Suzuki, H., 54, 216 ,

I

-

I

‘

Swanson, S . , 142 Sykes, B. D., 134, 220 Symmes, C., jun., 9, 56, 73, 267 Szabolcs. A., 175 Szamosi, J., 187 Szego, F., 17 Szemzo., A., 175 Szobota, J. S., 260 Szpala, A., 84, 126 Tacke, R., 143 Tadeusiak, E., 127 Takagi, H., 106, 119 Takagi, M., 133 Takahashi, Y., 186 Takai, K., 114 Takaishi, N., 4 Takaku, H., 19, 100, 113, 202, 206, 208 Takamizawa, A., 147, 152, 166, 168 Takase, S., 168 Takashima, H., 207 Takata, S., 71 Takaya, H., 2 Takeda, A,, 18 Takeno, H., 233 Talanova, L. N., 75, 270 Talent, J. M., 139 Talley, B. G . , 16 Tampieri, M., 20 Tamura, Y., 18, 60 Tanaka, K., 20, 21, 238 Tanaka, N., 216 Tanaka, Y., 197 Tangour, B., 35 Tanigawa, Y., 27 Tanimoto, S., 23 Taniyama, Y., 213 Tantasheva, F. R., 23 Tarasova, R. I., 129 Tatsuta, K., 229 Tautz, H., 30, 45, 92, 276, 278 Tawata, S., 103 Taylor, B. F., 29 Taylor, G. N., 120, 157 Tavlor. M. J.. 11 Tailor; S. S.,’198 Tebby, J. C., 33, 81, 84, 126 Teichmann, H., 225 Teitel’baum, B. Ya., 271 Tellev, G., 137. Temesvari-Major, E., 249 Teranishi, A., 243 Theil, F., 15, 61 Theriault, N. Y., 205 Thewissen, D. H . M. W., 7 Thiem, J., 158, 267 Thomas, B., 262, 265 Thomas, N., 141 Thomas, P., 149 Thomas, P. R. M., 170 Thomas, R. C . , 157 Thompson, D . G., 266 Thompson, T. E., 137 Thorpe, M. C., 154 Thuong, N. T., 204 Tibbetts, L. M., 136 Tikhonina, N. A., 103 Tilhard, H.-J., 245 Tilichenko, M. N., 68

Timokhin, B. V., 16, 38, 268, 777

L f L

Ting, L. P., 139 Titmas, R. C., 207 Tius, M. A., 5, 232 Tkachev, V. V., 71, 275 Tobias. R. S.. 219 Tochino, Y.,‘147, 152, 166, 168 Toda, F., 21, 238 Todd, A. R., 52 Todesco, P., 79 Todhunter, J. A., 166 Tomoskozi, I., 249 Togo, H., 17 Tolstikov, G . A., 7 Toman, K., 11 Tomaselli, V. P., 269 Tomioka, H . , 71 Tong, W. P., 217 Toome, V., 275 Toppet, S., 102 Tordo, P., 269 Torgasheva, N. A., 112, 117 Torgomyan, A. M., 23, 26, 28

Toriumi, K., 2 Torrence, P. F., 186 Toth. G.. 17 Tothi K.: 3, 25, 62 Tovstenko, V. I., 9, 49, 65, 66 Townsend, J. M., 4 Traficante, D. D., 184 Tran-Dinh, S., 220 Tran-Thi, 0.-H., 175, 212 Trentham, D. R., 189, 190 Tretyakova, S. S., 198 Trifonov, L. S., 15 Trimm, J. T., 280 Trippett, S., 48, 53, 124, 230, 231, 265 Troitskaya, L. L., 4 Troitskaya, L. M., 280 Trost. B. M.. 228 Troy,’D., 272 Takatsuka, Y., 179 Tsai, M.-D., 131, 182, 190 Tsao, Y.-Y., 11 Tsav. Y.-H.. 88. 274 Tse: Y.-C.. 217’ Tseng, K.-’S., 41, 42, 87, 94, 95, 264 Tsivunin, V. S., 51, 65 Ts’o, P. 0. P., 179, 210, 216 Tsokur. N. 1.. 76 Tsubuhari. K:. 100 Tsui, W.-C., 141 Tsuji, S., 19 Tsujimoto, K., 251 Tsvetkov, E. N., 21, 66, 71, 270 Tsvetkov, V. G . , 279 Tu, S. C . , 132 Tucker, P. A., 11 Tulloch, C. D., 252 Tumlinson. J. H.. 249 Tundo, P.,’27 ’ Tupchienko, S. K., 116 Turcotte, J. G., 135, 136 Turkova, T. V., 20 Turpin, R., 272 Tusek-Bozic, L., 270

Author Index

295

Tuzhikov, 0. I., 279 Tyka, R., 263, 270 Tymonyuk, M. I., 278 Tyrrell, A. W. R., 249 Tzschach, A., 2, 7, 10, 20, 31 Ubasawa, A., 181 Uchida, N., 168 Udenfriend, S., 166 Ueda, T., 217 Ueki, H., 134 Uemura, H., 213 Uesugi, S., 179 Ugi, I., 113 Uhl, W., 4, 11, 12, 260, 273 Uhlig, W., 20 Ulanovskaya, N. V., 29 Ulmer. W.. 120 Uno, H., 182 Urabe, I., 132 Utvary, K., 278 Uzleva, L. A., 98 Vachkov, K., 123 Vafina, A. A., 20, 268 Vaidyanathaswamy, R., 104, 27 1 Valceanu, R., 99 Valentine, D., jun., 3, 4, 25, 62 van Aken. D.. 40. 128, 262, 276 van Boeckel, C. A. A., 135 Van Bolhuis, F., 276 van Boom, J. H., 135, 208, I

,

,

~,

21 1

van-de Graaf, B., 278 Van de Grampel, J. C., 276 Van d e Griend, L., 276 van den Berghe, E. V., 260, 277 van den Bosch, N., 280 Van Den Goorbergh, J. A. M., 62 Van Der Gen, A., 62, 242 van der Helm, D., 7, 22, 68, 71,262,275 Van der Kelen, G. P., 260, 277 van der Marel, G., 208 van der Steen, J., 120, 166 van der Veken, B. J., 271,272 van Lier, J. J. C., 40 van Linthoudt, J. P., 260, 277

van'Maanen, J. M. S., 157, 160. 165 Van Meerssche. M.. 275 Van Vliet, N. P., 228 Varki, A., 135 Varlet, J. M., 77, 107 Varmuza. K.. 278 Vasilev, G., 123 Vaught, J. B., 151 Vedejs, E., 226 Vederas, J. C . , 133 Veeneman, G., 208 Venayak, N. D., 17 Venczel, A., 22 Venturello, P., 27 Venugopalan, B., 252 Venuti, M. C., 248 Verbruggen, A., 102

Verhoeven, T. R., 228 Verkade, J. G., 158, 160, 161, 164, 165, 169, 273 Vertal, L. E.. 273 Vidal,'M., 273 Vignais, P. V., 140, 198 Vilceanu, R., 22, 271 Vilkas, E., 56, 66, 275 Vilkas. M.. 56. 66. 275 Villa, A. C., 20 ' Villafranca, J. J., 143, 189 Villem, J., 273 Vincent, C., 132 Vincent, E. J., 134 Vinogradova, L. V., 198 Viola, R. E., 194 Vishwakarma, L. C., 128 Vlasova, M. M., 102 Vlassov, V. V., 215 Vodovatova, S. N., 81, 105 Voelcker, G., 147, 150, 172 Vogel, E., 252 Vogel, F. G. M., 249 Voigt, D., 272 Voigtmenn, R., 149 Volgina, G . A., 268 Volkin, E., 187 Volkova, V. N., 277 Vollmer, R., 31 Volodin, I. A., 76, 278 Volynskaya, E. M., 23 von Criegern, T., 265 Von der Haar, F., 193 von Jagow, G., 131 von R. Schleyer, P., 33, 226, 264 von Seyerl, J., 30, 92, 274, 275 Vorkunova, E. I., 21 Voskanyan, M. G . , 123 Vostrowsky, O., 247 Vutz, H . , 132 Vysotskii, V. I., 68 V'Yunov, K. A., 279 Wada, M., 76 Wadsworth, W. S., 116 Wagner, T., 147, 172 Waid, K., 15 Wakabayashi, T., 204 Wakatsuki, J., 3 Wakselman, C., 60 Wakselman, M., 118, 129 Walker, B. J., 95, 230, 233, 252 Walker, P. E., 274, 275 Walkowiak, U., 107 Wallerberg. G.. 128. 279 Walseth, TI F.,' 144,' 185 Walt, D. R., 131 Walton, E. D., 8, 76, 266 Wan. J. K. S.. 269 Wang, G.-H.,'213 Wang, J. C., 217 Wang, J . H., 139 Wang, J. S., 156 Wang, Y.-P., 37, 86 Waplak, S., 269 Warren, S., 72, 240 Warwick, P. E., 212 Watanabe, S. M., 213 Watarai, H., 117 Wataya, Y., 176

Waugh, J. S., 220 Waysbort, D., 38, 126 Wazeer, M. I. M., 39 Webb, H. M., 273 Webb, M. R., 188, 189, 190 Weber, R., 184 Weber, W., 31 Wedmid, Y., 267 Weerasooriya, U., 245 Weferling, N., 34, 275 Weichmann, H., 127, 265 Weiner-Fedorak, J. E., 5 Weinmaier, J. H., 92, 267, 276 Weinmann, R., 193 Weise, G., 114 Weiss, E., 225 Weiss J., 274 Weiss, R., 273 Weissermel, K., 49 Weitzberg, M., 85 Weller, T., 261 Wells, B. D., 218 Wells, J. A., 201 Wendisch, D., 265 Werber, M. M., 201 Werner, H., 14 Werner, L. H., 17 West, C. R., 195 West, R., 5, 269 Westcott, K. R., 199 Westerhaus, A., 12, 50 Westermann, P., 187 Westheimer, F. H., 101, 130, 175 Westra, J. G., 120, 166 Wharton, C. J., 108 White, A. H., 273, 274 White, D. W., 169 Whiteley, R. H., 2 Whitesides, G . M., 131 Whybrow, D., 250 Wiechman, B., 245 Wieczorek, M. W., 275 Wieland, T., 132 Wiesenfeld, L., 263, 266 Wijnands, R. A., 211 Wilburn, J. C., 89, 260, 269 Wildbredt, D.-A., 10, 90, 110, 269 Wilhelm, E., 235 Wilk, A. L., 170 Wilkie, C. A,, 49 Willetts. S. E., 81 Williams, N. E., 112 Williams, S. J., 276 Williams, T. E., 19, 280 Williams, T. R., 249 Willis, B. J., 250 Wilson, I. B., 141 Wilson, K. S., 140 Wilson, S, H., 150 Wilson, W. D., 220 Winkeler, H.-D., 175 Winkle, S. A., 221 Wintel, T., 78, 107, 244 Winterfeldt, E., 243 Wintrobe, M. M., 146 Wirkner, C., 11, 13, 50 Wise, W. B., 220 Wisian-Neilson, P., 269 Withers, S. G., 134 Witkop, B., 166

Author Index Witt, M. H., 149 Wodinskv. I.. 149 Woenckhaus,‘ C., 132 Woggan, W.-D., 228 Wolf, R., 35,95,267,274,280 Wolff, R., 261 Wolmerhauser. G.. 88. 274 Woltermann, A., 245 ’ Wood, H. G., 141, 199 Woodman, P. W., 178 Woods, M., 276 Wooten, J. B., 220 Wooton, G., 249 Wong, C.-H., 131 Wong-Ng, W., 275 Worley, S. D., 276 Worstell, J. H., 9 Wrackmeyer, B., 262,266 Wray, S. K., 199 Wreschner, D. H., 211 Wrigglesworth, R., 108 Wright, J. G., 34, 55, 264 Wroblewski, A. E., 164, 165 Wu, J. M., 211 Wu, R., 208 Wuhrmann J. C., 53 Wunz, T. P., 135 Yagi, M., 216 Yagodinets, P. I., 23 Yagura, T. S., 182, 183 Yakovlev, V. N., 126 Yakshin, V. V., 278 Yamada, K., 84 Yamada, R., 119 Yamagata, H., 125 Yamaguchi, K., 107, 152, 166, 168 Yamaguchi, M., 251 Yarnaguchi, R., 19, 208 Yamamoto, I., 117, 243 Yamamoto, K., 3 Yamamoto, Y., 266 Yamana, K., 93, 202 Yarnasaki, R., 18 Yamashita, M., 274

Yamazaki, H., 96 Yanchuk, N., 279 Yankov, L., 54 Yaouanc, J. J., 77 Yarbrough, L. R., 197 Yarkova, E. G., 58 Yarus, M., 213 Yastrebov, V. V., 263 Yasuda, A., 2 Yasuda, H., 18, 60 Yasufuku, K., 96 Yoke, J. T., 95 Yokohama. S., 252 Yoshida, M., 19, 113, 206, 208 Yoshifuji, M., 275 Yoshihara, K., 197 Yoshii, E., 106, 119 Yoshino, H., 179 Young, R. N., 254 Yount, R. G., 201 Yuan, C. Y., 128 Yuan, J.-G., 213 Yuan, Q., 128 Yudelevich, V. I., 109 Yu Jin, G., 10 Yumatov, V. D., 273 Yurchenko. V. G.. 15 Yurchenko; V. hi., 54, 99, 275, 276 Yur’eva, E. M.,77, 104 Yushok, W. D., 219 Yusupov, M. M., 83 Zabirov, N. G., 111, 112 Zaharko, D. S., 167 Zaitsev, N. B., 267 Zakharov, V. I., 122, 263, 267 Zaltzman-Nirenberg, P., 166 Zanobini, F., 4 Zanotti, G., 140 Zarrabi, H., 269 Zarytova, V. F., 177 Zavalishina, A. I., 102 Zavlin, P. M., 81, 105, 126

Zawadzki, S., 120 Zawoiski, S., 4 Zayed, M. F., 42, 79 Zaylskie, R. G., 147 Zbiral, E., 18, 25, 98, 101, 223 Zeelan. F. J., 228 Zeiss, W., 45, 88, 276 Zelenova, L. M., 7 Zentova, V. N., 120 Zewail, A. H., 221 Zhang, L.-F., 213 Zhang, S. Y., 8 Zhdanov, Yu. A., 98 Zhenodarova, S. M., 208, 212 Zhmurova, I. N., 15, 17 Zhu, L.-Q., 213 Ziatdinova, R. N., 276 Ziegler, C. B., jun., 228 Zielinska, B., 278 Zielinski. W. S.., 185., 204., 266 Zimin, M. G., 82, 111, 112, 117, 270 Zimrner, H., 246 Zimmer-Glasser, B., 238, 240. 261. 277 Zimmerman, S. B., 220 Zinin, V. H., 40 Zink, J. I., 238 Zon, G., 156, 157, 159, 160, 161, 166, 172 Zon, J., 109 Zorn, H., 12, 90, 91, 274 Zotta. V.. 270 Zschunke, A., 127, 265, 266 Zuchi, G., 270 Zverev, V. V., 273, 277 Zwaschka, F., 12, 273 Zwierzak. A.. 120. 128 Zyablikova, T. A.,22, 28, 68, 263, 277 Zygmunt, J., 107 Zykova, T. V., 51, 65, 85, 129