Organophosphorus Chemistry
Volume 30
A Specialist Periodical Report
Organophosphorus Chemistry
Volume 30
A Review of the Literature Published between July 1997 and June 1998 Senior Reporter D. W. Allen, Sheffield Hallam University, Sheffield, UK J. C. Tebby, Staffordshire University, Stoke-on-Trent, UK Reporters N. Bricklebank, Sheffield Hallam University, Sheffield, UK C . D. Hall, King's College, London, UK T. F? Kee, University of Leeds, UK M. Salt, Staffordshire University, Stoke-on- Trent, UK R. Slinn, Staffordshire University, Stoke-on- Trent, UK J. C. van de Grampel, University of Groningen, The Netherlands J. S. Vyle, The Queen's University of Belfast, UK B. J. Walker, The Queen's University of Belfast, UK
RSmC ROYAL SOCIETY OF CHEMISTRY
ISBN 0-85404-324-1 TSSN 0306-0713
0The Royal Society of Chemistry 2000 AN rights reserved
Apart from any fair dealing for the purposes of reseurch or private study, or criticism or review as permitted under the terms of the UK Copyright, Designs and Patents Act, 1988, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry, or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright Licensing Agency in the UK, or in accordunce with the terms of the licences issued by the appropriate Reproduction Rights Organizution outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this puge.
Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 OWF, UK For further information see our web site at www.rsc.org Typeset by Computape (Pickering) Ltd, Pickering, North Yorkshire, UK Printed by Athenaeum Press Ltd, Gateshead, Tyne and Wear, UK
Introduction
Further changes to our team of authors have taken place. We welcome Terry Kee (Leeds) and Joe Vyle (Queen’s, Belfast) as new contributors for the areas of ‘tervalent phosphorus acid derivatives’, and ‘nucleotides and nucleic acids’, respectively. We hope that they will continue to contribute to future volumes in this series. Organophosphorus chemistry continues to be a very active field, the number of publications showing no sign of decline. Interest in the synthesis of new phosphines continues unabated, the area still being driven by a need for improved homogeneous catalyst systems. Perhaps the most unusual reagent system of the year is the in situ preparation of alane (AlH3), for the reduction of phosphine oxides to phosphines, by the addition of concentrated sulfuric acid to lithium aluminium hydride in THF. Also noteworthy is the long overdue development of a simple procedure for the separation of the mixture of isomeric phosphabicyclononanes obtained on addition of phosphine to cyclo-1,5-octadiene. There has also been a resurgence of interest in the chemistry of the zwitterionic adducts of tertiary phosphines with acetylenic esters, initially explored more than thirty years ago, and which now have growing potential as reactive intermediates in synthesis. Tervalent phosphorus acid derivatives continue to be a focus of activity in nucleotide chemistry, with many new reagent systems being reported. Studies related to therapeutic applications continue to dominate nucleic acid and nucleotide chemistry, with a growing interest in reactions having the potential for scale-up to the kilogram level, using only limited reagent excesses. Some of the most rapidly developing areas of research relate to the fabrication of devices based on surface-immobilised DNA, and the number of publications in this area looks set to increase significantly. A notable anniversary in 1997 was the centenary of the birth of George Wittig. The continued exploitation of the Wittig reaction in the synthesis of a variety of new biologically active molecules provides a fitting tribute to the man and his research work. Phosphonium ylides also continue to provide new challenges for synthetic and structural chemists as illustrated by recent investigations of their coordination chemistry which have led to a variety of novel metal complexes involving unusual bonding modes. Hypervalent phosphorus chemistry, this year, has been dominated by a series of X-ray crystallographic publications especially in terms of their systematic study of (a) the formation of hexacoordinated phosphorus compounds via donor interaction and (b) the relevance of this chemistry to enzymatic intermediates. Other highlights include the preparation of derivaV
vi
Introduction
tives of calixarenes containing pentacoordinate phosphorus and the first corrole derivative containing pentacoordinate phosphorus. A most unusual compound containing phosphorus in a mixed valence (P1I1-PV-P1I1)chain may afford entry into a highly novel series of compounds. Biological aspects of quinquevalent phosphorus acid chemistry, quite separate from nucleotide chemistry, are increasing in importance - tetracoordinate phosphorus compounds being a major source of transition state analogues for the generation of abzymes, etc. A wide variety of natural and unnatural phosphates, especially those of carbohydrates, and their phosphonate and phosphinate, particularly fluorinated, analogues have been synthesised, usually with some biologically-related purpose, and the enormous interest in phosphorus analogues of all types of amino acids continues. The importance of enantiomeric synthesis is illustrated in many of these reports. A recent patent addresses the reduction of undesirable tastes in foods, pharmaceuticals, etc. by the addition of phosphates, thiophosphates, and phosphonates, which act as inhibitors of intramolecular phosphatase enzymes of taste cells. There has been continuing and increasing interest in approaches to easierkafer nerve gas hydrolysis (particularly metal cation-catalysed and biological approaches), in dendrimers, and in both cyclic and acyclic ligands containing phosphorus(V) acid-functional groups. In the phosphazene field there have been interesting advances in the main group chemistry area. Synthetic uses of phosphoranimines (iminophosphoranes) have been extended to the formation of the diazo (N=N) group by their reaction with NOBF4. Cationic polymerisation of phosphoranimines has been proven to be a facile tool for the preparation of a large variety of polyphosphazenes. Also notable is the extended use of phosphazene bases as deprotonating agents. As usual, applications of cyclic phosphazenes as flame retardants receive considerable attention. It has been shown that phosphazene dendrimers can undergo reactions at internally situated sites as well as at their surface. The latter reaction mode offers the possibility to synthesise polydendritic macromolecules. The incorporation of cyclophosphazenes into membranes has led to a variety of useful properties. These include removal of colorants in sugar solutions as well as enantioselective membranes for aminoacids Trp, Phe, and Tyr. The application of phosphazene based polymers in the biological field is expanding and includes biomaterials, and drug delivery. Noteworthy is the use of dicarboxylic amino ester substituted polyphosphazenes as carriers for antitumour diamine Pt" complexes. Organic backbone polymers with pendant cyclophosphazene groups are the subject of various investigations. Such polymers have the ability to significantly increase the fluorescence intensity of Eu3+, and a styrene based polymer has been shown to exhibit a strong selectivity for the extraction of Ag+ ions from aqueous solution. The range of physical methods being applied to the study of phosphorus compounds continues to widen. Thus particle-beam LC-MS was used for separation of diphosphine-substituted selenido Fe and Ru clusters. A novel headspace G C method for 'semivolatiles' was utilised for the analysis of butyl
Introduction
vii
phosphate and phosphonates. In addition microwave spectroscopy enabled the detection of the CH2CP radical and FT-ICR mass spectrometry was used to generate and study stable carbon phosphide anions. There have been renewed efforts to rationalise phosphorus NMR chemical shifts and there has been a steady increase in the incorporation of theoretical predictions to aid the interpretation of results.
Contents
Chapter 1 Phosphines and Phosphonium Salts By D. W. Allen
1
1 1
1. Phosphines 1.1. Preparation 1.1.1 From Halogenophosphines and Organometallic Reagents 1.1.2. Preparation of Phosphines from Metallated Phosphines 1.1.3 Preparation of Phosphines by Addition of P-H to Unsaturated Compounds 1.1.4 Preparation of Phosphines by Reduction 1.1.5 Miscellaneous Methods of Preparing Phosphines 1.2 Reactions of Phosphines 1.2.1 Nucleophilic Attack at Carbon 1.2.2 Nucleophilic Attack at Halogen 1.2.3 Nucleophilic Attack at Other Atoms 1.2.4 Miscellaneous Reactions of Phosphines
12 16 16 18 19 20
2 Phosphine Oxides 2.1 Preparation 2.2 Reactions 2.3 Structural and Physical Aspects 2.4 Phosphine Chalcogenides as Ligands
23 23 24 27 27
3 Phosphonium Salts 3.1 Preparation 3.2 Reactions
28 28 29
4 p,-Bonded Phosphorus Compounds
31
5 Phosphirenes, Phospholes and Phosphinines
36
References
40
Organophosphorus Chemistry, Volume 30 0The Royal Society of Chemistry, 2000 ix
1
4 9 10
Cont en ts
X
Chapter 2 Pentaco-ordinated and Hexaco-ordinatedCompounds By C.D. Hall
59
1 Introduction
59
2 Acyclic and Monocyclic Phosphoranes
60
3 Bicyclic and Tricyclic Phosphoranes
64
4 Pentaco-ordinate/Hexaco-ordinate Compounds
69
References Chapter 3 Tervalent Phosphorus Acid Derivatives By T . P . Kee
74
76
1 Introduction
76
2 Reactions Involving Nucleophilic Phosphorus
76
3 Reactions Involving Electrophilic Phosphorus
82
4 Miscellaneous Reactions
84
References Chapter 4 Quinquevalent Phosphorus Acids By B.J. Walker
86
88
1 Introduction
88
2 Phosphoric Acids and their Derivatives 2.1 Synthesis of Phosphoric Acids and their Derivatives 2.2 Reactions of Phosphoric Acids and their Derivatives 2.3 Selected Biological Aspects
88
3 Phosphonic and Phosphinic Acids 3.1 Synthesis of Phosphonic and Phosphinic Acids and their Derivatives 3.1.1 Alkyl, Cycloalkyl, Aralkyl and Related Acids 3,1.2 Alkenyl, Alkynyl, Aryl, Heteroaryl and Related Acids 3.1.3 Halogenoalkyl and Related Acids
99
88 95 99
99 99 100 103
x1
Contents
3.1.4 Hydroxyalkyl and Epoxyalkyl Acids 3.1.5 Oxoalkyl Acids 3.1.6 Aminoalkyl and Related Acids 3.1.7 Sulfur- and Selenium-containing Compounds 3.1.8 Phosphorus-Nitrogen Bonded Compounds 3.1.9 Phosphorus-containing Ring Systems 3.2 Reactions of Phosphonic and Phosphinic Acids and their Derivatives 3.3 Selected Biological Aspects 4 Structure References
Chapter 5 Nucleotides and Nucleic Acids By J.S. Vyle
104 106 108 113 113 115 115 122 123 126 135
1 Introduction
135
2 Mononucleotides 2.1 Nucleoside Acyclic Phosphates 2.1.2. Mononucleoside Phosphate Derivatives 2.1.3. Polynucleoside Monophosphates 2.2 Nucleoside Cyclic Phosphates
136 136 136 142 145
3 Nucleoside Polyphosphates
147
4 Oligo- and Poly-nucleotides 4.1 DNA Synthesis 4.2 RNA Synthesis 4.3 The Synthesis of Modified Oligodeoxynucleotides and Modified Oligoribonucleotides 4.1.4. Oligonucleotides Containing Modified Phosphodiester Linkages 4.3.2 Oligonucleotides Containing Modified Sugars 4.3.3 Oligonucleotides Containing Modified Bases
157 157 160
5 Linkers
182
6 Interactions and Reactions of Nucleic Acids with Metal Ions
198
161 161 172 177
Contents
xii
7 Nucleic Acid Devices
20 1
8 Nucleic Acid Structures
203
References
205
Chapter 6 Ylides and Related Species By N. Bricklebank
219
1 Introduction
219
2 Phosphonium Ylides 2.1 Theoretical and Mechanistic Studies of Phosphonium Ylides and the Wittig Reaction 2.2 Synthesis and Characterisation of Phosphonium Ylides 2.3 Ylides Coordinated to Metals 2.4 Reactions of Phosphonium Ylides 2.4.1 Reactions with Carbonyl Compounds 2.4.2 Reactions of Aza-Wittig Reagents 2.4.3 Miscellaneous React ions
219
3 Synthesis and Reactions of Phosphonate Anions
235
4 Structure and Reactivity of Lithiated Phosphine Oxide Anions
238
5 Selected Applications in Synthesis 5.1 Compounds with Potential Biological Properties 5.2 Solid Phase Synthesis 5.3 Tetrathiafulvalenes and Related Organic Materials 5.4 Synthesis of Miscellaneous Compounds References Chapter 7 Phosphazenes By J. C. van de Grnmpel 1 2 3 4 5
Introduction Linear Phosphazenes Cyclophosphazenes Polyphosphazenes Crystal Structures of Phosphazenes and Related Compounds
219 220 223 228 228 232 233
239 239 245 246 247 249 255
255 255 262 269 275
...
Contents
xi11
References
284
Chapter 8 Physical Methods By R. N. Slim and M. C. Salt
291
1 Theoretical and Molecular Modelling Studies 1.1 Studies Based on Semiempirical Methods 1.2 Studies Based on Ab initio and Density Functional Methods
29 1 29 1
2 Nuclear Magnetic Resonance Spectroscopy 2.1 Biological and Analytical Applications 2.2 Applications of 31PNMR Chemical Shifts and Shielding Effects 2.2.1 One-coordinate Compounds 2.2.2 Two-coordinate Compounds 2.2.3 Three-coordinate Compounds 2.2.4 Four-coordinate Compounds 2.2.5 Five-coordinate Compounds 2.2.6 Six-coordinate Compounds 2.2.7 Other Nuclei/Multinuclear/General NMR 2.3 Studies of Equilibria, Configuration and Conformation 2.4 Spin-Spin Couplings
294 294
292
295 295 296 296 298 300 30 1 303 303 305
3 Electron Paramagnetic (Spin) Resonance Spectroscopy
307
4 Vibrational and Rotational Spectroscopy 4.1 Vibrational Spectroscopy 4.2 Rotational Spectroscopy
309 309 310
5 Electronic Spectroscopy 5.1 Absorption Spectroscopy 5.2 Fluorescence and Chemiluminescence Spectroscopy 5.3 Photoelectron Spectroscopy
310 310 31 1 3 12
6 X-Ray Structural Studies 6.1 X-Ray Diffraction (XRD) 6.1.1 Two-coordinate Compounds 6.1.2 Three-coordinate Compounds 6.1.3 Four-coordinate Compounds 6.1.4 Five- and Six-coordinate Compounds
3 12 312 3 12 3 12 313 315
Conten ts
xiv
6.2 X-Ray Absorbtion Near Edge Spectroscopy (XANES) 6.3 Electron Diffraction
315 316
7 Electrochemical Methods 7.1 Dipole Moments 7.2 Cyclic Voltammetry and Polarography 7.3 Potentiometric Methods
316 316 316 3 16
8 Thermochemistry and Thermal Methods
316
9 Mass Spectroscopy
317
10 Chromatography and Related Techniques
10.1 Gas Chromatography and Gas ChromatographyMass Spectroscopy (GC-MS) 10.2 Liquid Chromatography 10.2.1 High-performance Liquid Chromatography and LC-MS 10.2.2 Thin-layer Chromatography (TLC) 10.3 Capillary Electrophoresis (CE) and Micellar ElectrokineticChromatography (MEKC)
11 Kinetics References
Author Index
3 19 319 320 320 321 32 1 32 1 323 331
Abbreviations
Benzamide adenine dinucleotide Cyclodiphospho D-glycerate Capillary electrophoresis Creatine kinase Controlled potential electrolysis 1-(2-chlorophenyl)-4-methoxylpiperidin-2-y1 Cyclic volt ammet ry cv DETPA Di(2-ethylhexyl)thiophosphoric acid Dimethyl acetylenedicarboxylate DMAD Dimethylformamide DMF Dimyrist oylphosp hatidylcholine DMPC DRAMA Dipolar restoration at the magic angle Differential scanning calorimetry DSC DTA Differential thermal analysis Energy resolved mass spectrometry ERMS ESI-MS Electrospray ionization mass spectrometry EXAFS Extended X-ray absorption fine structure FAB Fast atom bombardment 1-(2-fluorophenyl)-4-rnethoxylpiperidin-2-y1 FPmP High-performance liquid chromatography HPLC LA-FTICR Laser ablation Fourier Transform ion cyclotron resonance Matrix assisted laser desorption ionization MALDI Micellar electrokinetic chromatography MCE Mass-analysed ion kinetic energy MIKE Polycyclic aromatic hydrocarbons PAH Hydroquinone- 0,0’-diacetic acid QDA 9-[2-(Phosphonomethoxy)et hylladenine PMEA S-Acyl-2-thioethyl SATE Secondary ion mass spectrometry SIMS Spermidine/spermine-N 1-acetylt ransferase SSAT Static secondary ion mass spectrometry SSIMS Thiazole-4-carboxamide adenine dinucleot ide TAD tert - Butyldimet hy lsilyl tBDMS Trifluoroacetic acid TFA Thermogravimetric analysis TGA Thin-layer chromatography TLC Time of flight TOF X-Ray absorption near edge spectroscopy XANES
BAD cDPG CE CK CPE CPmP
xv
1
Phosphines and Phosphonium Salts BY D. W. ALLEN
1
Phosphines
1.1
Preparation
I . I . I From Halogenophosphines and Organometallic Reagents - The addition of mesitylmagnesium bromide to phosphorus trichloride in THF at - 78 "C provides an improved route to tri(mesity1)phosphine (1, R = Me), free of contamination by the related tetraaryldiphosphine (2, R = Me). However, applying the same procedure for the synthesis of (1, R = E t ) gave only the diphosphine (2, R = Et). Related Grignard procedures have also been developed for the synthesis of functionalised mesitylphosphines, e.g., (3)'. Grignard and organolithium routes to perfluoroalkyl-substitutedtriarylphosphines and diphosphines, e.g., (4)and (5), have also been developed, the perfluoroalkyl groups promoting the solubility of related catalytically active metal complexes in perfluorinated solvent^^.^ and supercritical carbon dioxide4. Sequential substitution reactions of the amino(ch1oro)phosphines (6) using Grignard and organolithium reagents provide a route to chiral phosphines which may have
potential for solid phase synthetic procedures5. In a related approach, sequential treatment of phosphorus trichloride with a bulky alkyl Grignard reagent, followed by methylmagnesium halides, has given the phosphines (7). After Organophosphorus Chemistry, Volume 30 0The Royal Society of Chemistry, 2000 1
2
Organophosphorus Chemistry
protection at phosphorus with borane, these can then be metallated at a methyl group in the presence of butylithium and (-)-sparteine, and undergo C-C coupling in the presence of copper(I1) to provide the chiral diphosphines (8), after deprotection with trifluoroacetic acid6. A range of new menthylphosphine ligands, e.g., (9), has been prepared by the reactions of lithiated Me R-P \ Me (7) R = But, Et3C, I-adarnantyl,
c-C5H9,or c-C6H1
aPR2
R-r-\-Me Me
(8)
(9) R'
=
PRp2
menthyl, R2 = Ph or menthyl
arylphosphines with bis(menthyl)chlorophosphine7. The reactions of pentamethylcyclopentadienyllithium with phosphorus trihalides have provided the monohalophosphines (lo), which undergo the expected reactions with reagents such as methyllithium or lithium aluminum hydride to give related secondary and tertiary phosphines*. The cyclopentadienylphosphines (1 1) have been prepared by treatment of dihalogenophosphines with alkylcyclopentadienyllithium reagents. Subsequent quaternisation at phosphorus, followed by deprotonation of the cyclopentadienyl systems, has given novel phosphoniumbridged alkali- and alkaline earth metallocene complexes, e.g., ( ~ 2 )Lithiation ~. of iodomethyltriphenylstannane, followed by treatment with a chlorodiorganophosphine, has given the stannylmethylphosphine (13), which has been converted into the phosphino-stibine (14) by a second lithiation, and the subsequent reaction with a diorganohalogenostibine''.
+
(10) X
=
CI or Br
Ph3SnCH2PR2' (13) R' = Cy or Pr'
(1 1) R = Me or But Rq' PCH2SbR22
(14) R2 = Pr' or But
(12) M"+ = Li+, K+ or Ba2+
0 II Ph2PCH2C-CH=PPh3
(15)
The phosphinoylide (15) has been obtained by C-lithiation of the related stabilised ylide and subsequent treatment with chlorodiphenylphosphine' I . The organolithium-halogenophosphine route has continued to be applied in the synthesis of ferrocenylphosphines bearing other functional groups12-14, e.g., (16)13 and (17)14.C-metallation of (1R)-(+)-camphor azine is the key step in the synthesis of the chiral diphosphine (18)15. Improved routes to pyridylphosphines (e.g., 19), have been developed. The key modification is lithiation
1: Phosphines and Phosphonium Sults
3
CHO
I
of a bromopyridine with butyllithium in the presence of TMEDA at low temperatures, followed by treatment with the appropriate halogenophosphine16. A low temperature halogen-lithium exchange has also been used in the synthesis of a range of alkoxypyridylphosphines, e.g., (20)17. Treatment of 1,2-bis(dichlorophosphino)ethane with aryllithium reagents has been used in the synthesis of the new diphosphines, (21)18 and (22)19. Arylation of 1,lbis(dich1orophosphino)ferrocene using organolithium reagents has given a
2
series of new ferrocenyldiphosphines (23). The same group has also reported an organolithium reagent route to the diphosphines (24)20.This approach has also been used in the synthesis of the chiral ferrocenyldiphosphines (25)2’,the 1,8-bis(phosphino)naphthalenes (26)22,and in an improved large scale route to 2,2’-bi~(diphenylphosphino)diphenylmethane~~. A wide range of functionalised
&PPh2
%
PPh2
Ar2P PAr2 (24) Ar = 0-tolyl, X = H,H or CMe2
R.-2
NMe2 (25) R = Me, Pent or Ph
(26) R = Me, Pr‘, Cy or Ph
4
Organophosphorus Chemistry
phosphines has also been prepared by the organolithium-halogenophosphine route, including the arylazophenylphosphine (27)24, the heterocyclic system (28)25, the phosphinoaminoalcohol (29)26, the phosphinoacyloxazolidinone (30)27, the chiral aminophosphines (3 1)28 and the phosphinophenols (32)29. Phosphines functionalised with crown ether groups (33)30 and related N ,Smacrocyclic systems, e.g . , (34)3l , have also been prepared by conventional organolithium-halogenophosphine routes.
(31) R = Me or Et
Ph2P 3-X
(33) x = O , 1 or2, R = H o r M e
(34)
A ‘microreview’ of the use of organozinc reagents in the synthesis of functionalised phosphines has appeared3*. The reactions of organozirconium reagents (formed by addition of dicyclopentadienylzirconium(ch1oro)hydride to vinyl- and allyl-silanes) with chlorophosphines have been used in the synthesis of silylalkylphosphines, e.g., (35)33.In a similar vein, cycloaddition of dicyclopentadienylzirconium to vinyl- and alkynyl-phosphine oxides, followed by treatment with a dichlorophosphine, provides a novel one-pot route to mono or bicyclic phosphiranes, e.g., (36), and phosphirenes, e.g. (37)34. 1.1.2 Preparation of Phosphines from Metallated Phosphines - The displacement of halogen, commonly fluorine, from aromatic and heteroaromatic
(35) n = 0, 1 or 2; x = 0 or 1
5
1: Fhosphines and Phosphonium Salts
substrates, using metallophosphide reagents, has been widely employed in the past year in the preparation of a range of new systems. Among heteroarylphosphines prepared in this way are the ‘two-layer’ chiral quinolylphosphine (38)35, the phosphinoterpyridyl (39)36, and the diphosphinoacridine (40, X = N)37. 1)isplacement of fluorine from benzenoid systems has been the method of choice for the diphosphinoanthracene (40, X = CH)38, phosphines bearing chiral oxazolinyl systems, e.g., (41)39, the phosphonate-functionalisedphosphines (42)40,and a wide range of functionalised, amphiphilic phosphines, e.g., (43>41,The generation of alkynylphosphide reagents by treatment of elemental phosphorus with an alkynyllithium, followed by addition of an alkyl halide, has been used as a route to alkynylphosphine~~~. Further examples of ring opening of three- and four- membered cyclic ethers and thioethers by Me
Ph
I
Ph2Pe!(OR)2 (42) R = Et or Pri
phosphide reagents have been reported. The reaction of lithium diphenylphosphide with cyclohexane epoxide provides a one-pot route to the chiral, ftinctionalised, phosphine (44)43. A related ring-opening of a,P-epoxysilanes, followed by quaternisation of the initially formed phosphinosilane with iadcimethane, and a subsequent Peterson elimination, results in the formation of vinylphosphonium salts4. The reagent (45) is formed on treatment of tl-iiirane with lithium diphenylphosphide, and has found use for the synthesis of new polydentate, mixed donor ligands, e.g., (46)45. Phosphide-induced ringopening of functionalised oxetanes has been used in the synthesis of a range of mixed donor, tripod-like, phosphine l i g a n d ~ ~e.g., ~ - ~(47)48. ~ , The phosphinomethyloxetane (48), prepared by a conventional mesylate-lithium diphenylphosphide route, has been shown to undergo aminolytic cleavage, leading to other types of functionalised, mixed donor, tripod ligands, e.g., (49)49. The
Organophosphorus Chemistry
6
yiz p
Ph2PnS
<2
PPh2
(47)
Li
(48)
NEt2
(49)
Ph2P
OSO3Li
(50) R1,R2 = H or Me,
n = 1 or 2
ring-opening of cyclic sulfate esters by phosphide reagents has provided a new route for the synthesis of amphiphilic and water-soluble ligands, e.g., (50)50.A 31PNMR study of the cleavage of 5-phenyldibenzophospholewith lithium in THF at 20 "C has shown that the resulting 5-lithiodibenzophospholide reagent exists as an apparent complex with the other cleavage product, phenyllithium, having lj3'P= 15 ppm. This complex is only destroyed on heating under reflux in the presence of t-butyl chloride, to give the free lithiophospholide, having lj3'P= 0.5ppmsl. This reagent has found use in the synthesis of the new chiral diphosphines (5 lyl and (52y2.Lithium-cleavage of the triphosphines (53) has
provided triphosphide reagents which have been used in the synthesis of the new chiral, tripod ligands (54)53. The reaction of a diarylphosphide reagent obtained by deprotonation of the related diarylphosphine with lithium disopropylamide, with the trihalide CH3C(CH2Br)3, has been employed in the synthesis of the triphosphine (55)54. Among other phosphines prepared via the 4 R
p
A
r
2
'-PAr2 PAr2
(53) R = H or Ph
Rl
PAr2
(55)Ar = mCF3C6H4
use of lithiophosphide reagents are the bipyridyl (56)55,the diphosphinobutadiene (57)56,and the aminophenylphosphine (58), from which new multidentate P, As, N ligands have been derived57. Lithium diphenylphosphide has found use for the demethylation of arylmethyl ethers5g. Metallophosphide reagents have also found extensive use for the synthesis of compounds involving bonds from phosphorus to boron, silicon, or tins9-65.
1: Phosphines and Phosphonium Salts
f
7
PPh2
Although not as popular as the lithium analogues, sodium- and potassiumorganophosphide reagents continue to be employed in phosphine synthesis. Reactions of sodioorganophosphide reagents with alkyl halides and alkyl sulfonate esters have found use in the synthesis of the new chiral systems (59)66, (60)67,and (61)68,and also for the chiral polydentate ligand (62)69.Attempts to prepare o-chloroalky(pheny1)phosphines (63) from the reactions of monosodiumphenylphosphide with a,w-dichloroalkanes met with only moderate success, with several other products being formed70.A route to alkylcyclopolyphosphines is provided by the reaction of red phosphorus with metallic sodium in dimethoxyethane, followed by treatment of the resulting sodium phosphide
. Ph2P (59) R = Me or Pr'
(60)
OMe PPh2
reagent with alkyl halides71. The phosphide reagent (64) has been used in the synthesis of a range of diphosphines bearing the 3,5-bis(trifluoromethyl)phenyl substituent, e.g., (65)72. Potassium diphenylphosphide was the reagent of choice for the synthesis of the chiral amidinoalkylphosphine (66)73, and the aminlophosphine (67), although development of the latter system was frustrated by the formation of aziridines in the reactions of precursor aminoethyl tosylates with the p h ~ s p h i d e ~Deprotonation ~. of a borane-protected chiral secondary phosphine with potassium t-butoxide has given a protected phosphide: reagent which has been used in a conventional reaction with a haloalkane to give the chiral system (68)75. Deprotonation of phosphine or primary phosphines under superbase conditions (DMSO-KOH), followed by treatment with bis(chloroethyl)amines, has given a route to the phosphines (69)76.
8
Organophosphorus Chemistry
PAr2 Ar = PAr2
,But (PhCH2)2N
PPh2
H 3 ~ &‘“ph
(67)
R’-N(CH2CH2PHR2)2 (69) R’ = H, Bu or ptol, R2 = H, Me or Ph
Interest in the structural characterisation of metallophosphide systems has continued unabated, with particular emphasis on the characterisation of phosphide derivatives of the less familiar metals. In addition to reports of lithium-77and sodium-78organophosphide systems, structural diversity in the solid state of rubidium and calcium salts of 2,6-dimesitylphenylphosphinehas been explored79.The dynamic behaviour and structure of alkaline earth metal bislbis { trialkylsilyl}phosphides] has been revieweds0 and new studies in this area have appeareds1. Further studies of gallium- and indium- organophosphides have been p ~ b l i s h e d ~and ~-~ studies ~ , of lanthanide organophosphides have also been r e p ~ r t e d ~Organophosphide ~?~~. units bonded to titanocenes7 and z i r c o n ~ c e n e ~ systems ~ * ~ ~ have also received attention, and a series of clusters involving tin-phosphido and copper-phosphido units has been characterisedgO.A copper-diphenylphosphide reagent has been employed in the synthesis of functionalised phosphines, e . g , , (70), and (71)91.
Applications in synthesis of phosphines metallated at carbon have also continued to appear. The lithium salts (72) are formed by treatment of fulvenes with lithium diarylphosphide reagents, and, on subsequent reaction with zirconium tetrachloride, give the zirconocene system (73), which involves two
@-(;PAr* C12Zr w - : P A r2 (72) R’ = Me, Bu‘ or Ar, R2 = H or Me
(73)
9
I : Phosphines and Phosphonium Salts
chiral centres9*. Similarly, the phosphinocyclopentadienides (74) have been used in the synthesis of polyphosphin~ferrocenes~~. The C-lithiated phosphine (75) reacts with a chloro(amino)borane to give the phosphine (76)94. The borane-protected system (77) is the key intermediate in the synthesis of the chiral diphosphines (78)95. Structural studies of phosphinoalkyllithium compounds have also a ~ p e a r e d ~ ~ q ~ ~ . PPh2
I
(74) R = Me or PPh2
Ar
I
H3B--P--CH2Li A Ph (77) Ar = &MeOC6H4
Ph, .P Ar'
,Ph
P' 'Ar
(78) X = N or CH, Ar = &MeOC6H4
1.1.3 Preparation of Phosphines by Addition of P-H to Unsaturated Compounds The course of photochemical addition of ammonia, phosphine, and silane, to alkenes and alkynes has been compared, phosphine invariably adding in the pposition to electron-withdrawing substituent groups9*.Photochemical addition of primary or secondary phosphines to enantiomerically pure deltacyclenes provides a route to a series of new chiral phosphines, some of which are easily isolable in one chiral form, e.g., (79)99. Addition of the phosphines (80) to cycloalkenes provides a route to new chiral diphosphines (8 1) with four stereogenic centresIo0. An improved route to the partially perfluorinated phosphines (82) has been developed, involving addition of phosphine to perfluorohexylethene". Full details of a study of catalysis by platinum group complexes of the addition of phosphine to acrylonitrile have now appearedlo2, and, in related work, similar catalysis of phosphine addition to ethyl acrylate has now been demonstrated, giving (83) in a much purer form than from related AIBN-promoted additionslo3. A detailed study of the radical-pro-
(79) R = Ph, oanisyl (80) R = H or Me or C H V ~ ~ O C H ~ C H ~ C ~ H ~
(81) R' = H or Me, R2 = cycloalkyl
Organophosphorus Chemistry
10
moted, anti-Markovnikov addition of secondary phosphines to vinyl ethers has been reportedlw. Base-promoted additions of phosphine to vinyl pyridineslo5, and also to styrenelo6, have been investigated, the latter providing a convenient route to tris(2-phenylethy1)phosphine. The base-catalysed addition of diphenylphosphine to substituted diphenylacetylenes has been shown to proceed in two stages with some stereoselectivity. The extent of addition and the stereochemistry is controlled by the bulk of the substituents on the alkyne. With very bulky groups, the addition stops at the vinylphosphine stage (84), involving addition cis to the olefinic hydrogen, the phosphorus becoming attached to the least hindered carbon. Less hindered alkynes give rise to the trans isomer initially, but this then reacts further to give rnesolerythrobis(dipheny1phosphino)alkanes (85)lo7. Additions of secondary phosphines to propargylphosphines, both of which are coordinated by phosphorus to a molybdenum carbonyl acceptor, have given the diphosphine (86)'08. The enolisable phosphine (87) is the initial product of addition of phosphine to a fluorinated p-diketone; further addition of the diketone to (87) can then occur to give the cage system (88)lo9. Further examples of the synthesis of watersoluble hydroxymethylphosphines, (89)"O and (90)' by addition of primary phosphines to formaldehyde, have been described, and the synthesis of functionalised phospholanes and phosphorinanes from the reactions of 1,4and 1,5-diketones with P-H bonded compounds (phosphines and phosphonous acid derivatives) has been reviewed' 12.
'
Ph2P-C(R')=CHR2
(84)
Q
(87)
1.1.4 Preparation of Phosphines by Reduction - The use of trichlorosilane for the reduction of phosphine oxides in the final stage of the synthesis of phosphines continues to be a popular choice, and the past year has seen its application in the preparation of the new planar chiral diphosphine (91)'13, the bicyclic diphosphines (92)' l 4 , ] 5 , the tetraphosphine (93)116, the atropisomeric systems (94)'17 and (95)'18, and the biferrocenyl system (96)*19.Full details have also appeared of the use of phenylsilane in the final stage of the synthesis of calixarenes bearing pendant phosphino groups 20. Reduction of
I : Phosphines and Phosphonium Salts
I1
(92) X = C02H or NEt2, n
=
1 or 2
rnPAr2
Q N
'
\
(94) Ar = mtolyl, 3,5dimethylphenyl or 2-fury1 Ar2P = dibenzophosphole
(95)
phosphinic acids with phenylsilane, diphenylsilane, or lithium aluminium hydride, respectively, provides a convenient route to secondary phosphines. Among new systems obtained in this way are (97) and (98)121. A mixture of polymethylhydrosiloxane and titanium isopropoxide has been employed in the reduction of the dioxide of the chiral diphosphine (99)122.A novel means of reducing phosphine oxides to phosphines is provided by the use of alane (AlH3), prepared in situ by the addition of concentrated sulfuric acid to a solution of lithium aluminum hydride in THF' 23. Lithium aluminium hydride has found further use in the reduction of halogenophosphines, giving a route to bis(pentafluor~benzyl)phosphine~~~, allylic primary p h o s p h i n e ~ ' ~and ~, and ( 101)127,the latter existing as mesovarious P-P diphosphines,
9 qp& \ /
\ /
H
(100) R = alkyl or Ph
H
(101) R = Me3Si
12
Organophosphorus Chemistry
and rac-isomers which crystallise separately. A review has appeared of the selective reduction of prochiral alkyldiphenylphosphines to chiral alkyl(cyc1ohexyl)phenylphosphines, involving niobium and tantalum homogeneous hydrogenation catalyst systems128.The Schwarz reagent, [Cp2 ZrHCl],, has been shown to reduce both phosphine oxides and sulfides to phosphines, the only problem being hydrozirconation of any alkene or carbonyl functionalities present 29. 1.1.5 Miscellaneous Methods of Preparing Phosphines - Full details have appeared of the synthesis of medium ring diphosphines, e.g . , ( 102)' 30, bridgehead diphosphines, e.g., ( 103)131, and the ferrocenylmethyl(hydroxymethy1)phosphine ( 104)132. Strategies for the synthesis of chiral hydroxyalkylphosphines have also been reviewed'33. A simple procedure has been devised for separation of the catalytically important phosphabicyclononane isomers (105) and (106), (R = H), the products of addition of phosphine to cycloocta-1,Sdiene. On treatment with formaldehyde and hydrochloric acid, the respective bis(hydroxymethy1)phosphonium salts (107) are formed. The key point is that on treatment of the mixture of salts with aqueous alkali, (0.5 mole), the salt derived from (106, R = H) is decomposed selectively to give the phosphine (106, R = CH20H) which is then extracted into pentane, the salt from (105, R = H ) remaining in the aqueous phase. Subsequent treatment of
(106, R=CH20H) with further alkali and sodium bisulfite affords the pure secondary phosphine (106, R = H). Similar treatment of the aqueous phase containing the salt from (105, R = H ) affords the latter in a pure state. The separation can be effected on a multigram scale and the pure secondary phosphines have been used in the synthesis of a range of new diphosphines, largely by metallophosphide routes134.A new route to aryl-, benzyl-, and vinyl-phosphines is provided by the reaction of the appropriate halide or triflate ester with chlorodiphenylphosphine in the presence of (diphos)NiC12 and metallic zinc, in DMF at ca. 1 10 "C.The reaction tolerates the presence of amide and ester functionalities within the organic substrate, but fails if a carboxylic acid group is present' 35. The related nickel-catalysed reactions of
I : Phosphines and Phosphoniurn Salts
13
diphenylphosphine (and its oxide) with aryltriflates have been used in the synthesis of a range of new chiral systems, e.g., the bis(steroida1) diphosphine ( the diphosphine-monoxide (109)137, and the phosphine-arsine A route to new chiral binaphthyl phosphinooxazoline ligands (e.g. (1 1 1 1) has also been developed139.New chiral aminophosphines, e.g., (1 12), have been prepared via nucleophilic aromatic substitution reactions by chiral lithium amide reagents on 1-methoxy-2-(diphenylphosphinoy1)naphthalenes, followed by reduction of the phosphinoyl functional Routes to a series of new amphiphilic diphosphines bearing basic groups, e.g., (1 13), have been developed for application in homogeneous catalysis, the protonatable groups enabling easy separation of the catalyst from the products141.The new
(108)
'
atropisomeric system (1 14) has been prepared from related o-aminophenyldiphenylphosphines, and resolved via a chiral palladium complex142.A regiospecific synthesis of the 2,3-bis(diphenylphosphino)naphthalenes (1 15) is afforded by a double insertion of alkynyldiphenylphosphines into nickel(0)-benzyne complexes143.Various routes to o-phosphinophenols, e.g., (1 16), have been described. These compounds are easily protonated at phosphorus, as a result of the hydrogen-bonding with the ortho-phenolic substituent. Metallation, acylation, and silylation also take place preferentially at phosphorus, and these compounds have also been ~ s e d in ~the~ synthesis ~ , ~ of~ new ~ heterocyclic
Organophosphorus Chemistry
14
systems. The heterocyclic system (1 17), readily accessible from the reaction of 1-phenyl-2-phospholene with a benzynezirconocene dichloride complex, is a versatile intermediate for the synthesis of new heterocyclic phosphines. With dihalofunctional antimony and tin reagents, the ring system (1 18) results, and with chlorodiorganophosphines, the phosphinophospholanes ( 1 19) are formed146.
(1 17)
(118) X = SbPh or Me2Sn
(1 19) R = Et or Ph
A review of the asymmetric synthesis of organophosphorus compounds contains much of relevance to phosphines, covering asymmetric induction at phosphorus, and asymmetric induction in the transfer of chirality from phosphorus to other centres147.The regio- and stereo-chemistry of nucleophilic attack by organolithium reagents at the P-chiral centre of a dioxaphospholane borane complex, the first step in a route to chiral phosphines, has been explored14*. The reactions of 1,l'-dilithioferrocene with borane-protected chiral phosphinites has given the chiral diphosphines (120) after deprotect i ~ n 'The ~ ~first . example of crystallisation-induced asymmetric transformation of a phosphorus compound has enabled a practical synthesis of phenyl(oanisy1)methylphosphine in chiral form. Recrystallisation of a 1:1 mixture of the diastereoisomers of the acylphosphine (121) results in a dramatic change in the diastereoisomer ratio to 25-32:l. This also occurs on storing the solid at room temperature for several weeks or more rapidly on warming, and the ultimate ratio of diastereoisomers can approach 99: 1. Subsequent methylation of phosphorus, followed by hydrolysis of the acylphosphonium salt, and protection with borane, affords the aforementioned chiral p h o ~ p h i n e ' ~The ~. diphosphine (1 22), having non-racemisable bridgehead phosphorus centres, has been resolved into chiral forms151.Both isomers of the chiral phosphine
Fe
ph:P-@ Ai (120) Ar
=
eMeOC6H4or a-naphthyl
,P Ar' A Ph
I : Phosphines and Phosphonium Salts
15
(123) have been prepared' s2. Quaternisation of secondary phosphines (usually, but not always followed by treatment with a base ) has been employed in the synthesis of the new chiral phosphine (124)lS3, the phosphine (125)Is4, and the diphosphine (1 26)Is5. Dimethylsulfonium methylide has been shown to methylate primary (and some secondary) phosphines, to give corresponding methylphosphines in high yieldis6. Routes to the chiral aminoethylphosphines (127) have been described, starting from optically pure primary amines' s7. The arylaminobisphosphines (128) have been prepared by the reaction of primary arylamines with bis(hydroxymethy1)diphenylphosphonium c h l ~ r i d e ' A ~ ~den. drimer, with sixteen outer bis(diphenylphosphinomethy1)amino end groups,
W TeC PPh2 p H
CHzCH2PR2' RI-N:
/-PPh2 Ar-N
CH~CH~PR~~ (127) R' = Bus or Ph(Me)CH R2 = Ph or Cy
LPPhp (128) Ar = Ph, P C F ~ C ~ H ~ Of pMe2NC6H4
has been prepared in one step by phosphinomethylation (using diphenylphosphine and formaldehyde) of a commercially available polyamino-dendriiner 59. Applying the same approach to a dendrimer having chiral secondary amino groups at the surface has given the related chiral aminomethylphosphinofunctionalised systemi60.New polyphosphino-building blocks, e . g . , (129), have been developed for novel approaches to the synthesis of phosphino-functionalised dendrimers and their related metal complexes161.Several reviews of the synthesis of phosphorus-containing dendrimers have also appeared 62-164. Interest has also continued in the synthesis of phosphine-systems bound to polymers of various typesi6s-167, including a water-soluble polymeric systemi6*.Strategies for the synthesis of water-soluble phosphines have shown further development 169-i71, among new systems reported being the tripodal phosphine (1 3O)l7O, and the diphosphine (1 3 l ) I 7 l . Schiff's base condensation reactions of o-aminophenyldiphenylphosphinehave been used in the synthesis of new mixed donor ligands, e.g., (1 32)i727173and related reactions of aromatic amines with o-diphenylphosphinobenzaldehyde have given the iminophosphines (133)i74. Shaw's group has continued to develop the chemistry of phosphino-azine ligands. Among new systems described is (1 34)i759176.Alcohols and pyrroles have been shown to add to the double bond of 1,l'bis(diphenylphosphino)ethene, coordinated to ruthenium, to give the diphosphines (135)'77. Interest has also continued in the synthesis of phosphines
16
Organophosphorus Chemistry
NCCH2
0 0
MeO(CH2CH20)&H2 p ~ ~ H 2 ( O C H 2 C H 2 ) f i M e CH2(0CH2CH2)#Me
(130)
Ph2PH2C
(129)
bearing bonds from phosphorus to a Group 13 (usually boron)178or a Group (14) element (in particular, germanium)179-'8'. 1.2 Reactions of Phosphines 2.2.I Nucleophilic Attack at Carbon - Interest has continued in the reactions of phosphines with acetylenic esters, with particular reference to the reactions of the initial zwitterioinc adducts which may be trapped or become involved as catalytically active species in other synthetic schemes involving carbon-carbon bond formation. Thus, e.g., stable crytalline phosphonium betaines (136) are formed when the initial adduct of triphenylphosphine and ethyl propiolate is trapped with the aid of a strong carbon acid such as indan-1,3-dione, or Meldrum's acid 182. Protonation of the 1:l adduct of triphenylphosphine and dimethyl acetylenedicarboxylate with phenols leads to vinylphosphonium phenate salts which react further to give 4-carboxymethylcoumarins in good yeild 83. A similar sequence involving N-hydroxyphthalmides provides a route to trimethyl 5-arylpyrrole-2,3,4-tricarboxylates84. A route to spirolactones is provided by the reation of the triphenylphosphine-dimethyl acetylenedicarboxylate aduct with ortho-quinones 185. Trost's group has also reported further
I : Phosphines and Phosphonium Salts
AN)TJ
PPh2
N JQ
fN
b""
Ph2P
( 132)
A
17
(133) Ar = Ph, eMeOCsH4 or pMeOCeH4 R' = H, Me or Ph, R2 = H, CI or OMe
NcNH
But
(134)
(Ph2P)2CHCH2R
PPh2
(135) R = OCH2Ph,
OCH2CH2
applications of triphenylphosphine acetylenic ester adducts in synthesis' 86. Isomerisation of acetylenic pentafluorophenyl esters in the presence of triphenyphosphine results in the formation of activated dienoic acids, which undergo coupling with amines and alcohols in a simple procedure, providing a synthesis of conjugated unsaturated amides and esters187.Treatment of the phosphinozirconaindene (137) with methyl propiolate or dimethyl acetylenedicarboxylate results in the formation of the zwitterionic system (138)188.Both 1:1 (139) and 1:2 (140) adducts of tributylphosphine with ethoxyacetylene have been characterised. Related adducts of other phosphines have been shown to act as carbon nucleophiles, undergoing C-alkylation on treatment with ally1 bromide'89. Further work on the chemistry of the tributylphosphine<arbon disulfide adduct has also been reported. The adduct has been shown to undergo cycloaddition to strained double bonds, as present in norbornene, to give new zwitterionic systems which react further on addition of acetylenic
0 (138) R = H or C a M e
OEt ( 139)
OEt OEt (140)
18
Organophosphorus Chemistry
dipolariphiles to give dihydrotetrathiafulvalene derivatives, together with loss of tributylphosphine' 90. 1.2.2 Nucleophilic Attack at Halogen - The nature of tertiary phosphinehalogen adducts continues to attract attention. The adducts of tris-isopropylphosphine with chlorine and bromine have been shown to exist as monomeric ion-pairs in the solid state. Structural studies show that the halogen of the halogenophosphonium ion is involved in an interaction with the related halide ion, with a corresponding lengthening of the halogen-phosphorus bond191.A structural study of the tri-n-propylphosphine
I: Phosphines and Phosphonium Salts
19
cyclohexadien-1-one as a new positive halogen reagent system for the nucleophilic bromination of alcohols2w, and for the conversion of primary and secondary alcohols to the respective azides, in the presence of zinc azide, a reaction which proceeds in excellent yield with the expected inversion of configuration2 O. 1.2.3 Nucleophilic Attack at Other Atoms - The anomalous fluorescence spectroscopic properties of solutions of triarylphosphines in non-deaerated solvents at room temperatures are consistent with the formation of the related phosphine oxides21l. The course of the reactions of triphenylphosphine with peroxides derived from polymers proceeds via a concerted insertion of the phosphine into the peroxo bond to give a phosphorane intermediate, the fate of which depends on conditions212.A theoretical approach has been used to compare the oxidation of trimethylphosphine by peroxynitrous acid with that in the presence of other peroxy compound^^'^. A polymerisation initiator system based on the in situ cleavage of diphenyl disulfide by triarylphosphine has been developed for the ring-opening polymerisation of bisphenol Acarbonate cyclic 01igomers~'~. The kinetics of reduction of dialkyldisulfides with triphenylphosphine have been studied in various solvents215. Diorganotellurides and -ditellurides have been shown to undergo a nickel(0)-catalysed detelluration to give biaryls in high yield216. Triphenylphosphine has found further use in desulfurisation reactions converting a-(alky1thiomethyl)acrylates to the related a-alkylacrylates, via a radical-chain mechanism2'7. Treatment of the thione (142) with triphenylphosphine results in the formation of the heterocyclic system ( I 43)21*. Solutions of trialkylphosphines (but not triarylphosphines) develop a yellow coloration over several hours when treated with sulfur in the presence of carbon disulfide, attributable to the formation of the polysulfur betaines ( Borane complexation of trimethylphosphine has been shown to increase the gas-phase acidity of carbon-hydrogen bonds220. Phosphine-borane adducts have also found use as de-oxygenating reagents221. Cyclic cationic phosphinoborane systems, e.g., (145), have been isolated from the reactions of chelating diphosphines with dimethyl sulfide adducts of bromoboranes222. Adducts of phosphine with alane (AlH3) and gallane (GaH3) have also been ~ h a r a c t e r i s e d ~ as~have ~ , related complexes of trialkylg a l l i ~ r n ~ ~ -thallium225 ~and acceptors. S
(141) Ar = 2,4,6-But3C&I2
SBu'
Ar.
r-l
Buts
(1 43)
n3r
-CI \
Ar
s-s,
( 144)
Ar ASBut (142) Ar = Ph or P-thienyl
h' \
,Ph
Ph
Ph
1
'Br
Q::
(145) X = H or Br
Organophosphorus Chemistry
20
Interest in the synthetic applications of the triphenylphosphine-diethyl azodicarboxylate system continues and Mitsunobu procedures have been applied in amino acid and peptide chemistry226-228,in the 0-acetylation of deoxynucleosides and n u c l e ~ s i d e s ~in~ , the synthesis of enantiopure 2,4dideoxysugar lac tone^^^^, and as the key step in the macrolactonisation of saturated s e c ~ a c i d s ~Mitsunobu ~l. chemistry has also been used to promote stereochemical inversion of unbiased cyclic allylic alcohols232,and for the synthesis of phenolic ethers derived from chiral alcohols233.A solid phase procedure for the synthesis of benzoxazoles has also been developed234. Further examples of Mitsunobu promoted C-N bond formation using a new cyclic azodicarboxamide have a ~ p e a t e d A ~ ~one-pot ~. procedure has been developed, based on the Mitsunobu and Staudinger reactions for the preparation of 3-aminocholan-24-oic acid esters from the related 3-hydroxycholanoic esters, via initial formation of the 3-azido system via Mitsunobu reaction with diphenylphospharyl azide, and subsequent Staudinger reduction using triphenylphosphine in the presence of water236.The Staudinger reduction has also been used for the selective reduction of a symmetrical diazide to an aminoazide in high yield237,and for the transformation of an azido group to an N-(tbutoxycarbony1)amino Formation of phosphinimines by the Staudinger reaction has been utilised in the design of new ligand systems, e.g., (146)239and (147)240.An unusual outcome of a Staudinger reaction between an azidosugar and triphenylphosphine has been noted, with the formation of a phosphazide, RN=N-N=PPh3, rather than the expected ph~sphinimine~~'. The reactions of diazoindanes and diazoindanones with triphenylphosphine have also been explored242.
(9c02Et N=p,
ph2((342)" 'PPh2
(146) n = 1-4
s
II Ph2P-
NMAr II PPh2
(147) Ar = ptolyl or panisyl
I .2.4 Miscellaneous Reactions of Phosphines - Triphenylphosphine has found use as a sacrificial electron donor in a visible light-initiated photosensitised electron trasfer cyclisation of aldehydes and ketones to tethered ap-unsaturated esters243.Photolytic cleavage of tri-m-tolylphosphine244and tetraphenyld i p h ~ s p h i n e has ~ ~ ~been investigated. The electrochemical oxidation of ferrocenylphosphines, and their oxides, has received The functionalised ferrocenylphosphine (148) has been shown to bind to an activated silicone surface via a hydroxymethyl group to form a phosphine-modified surface247. Further applications in synthesis have been reported for the functionalised phosphine (149)248.Treatment of the phosphinonaphthol (150, X = H) with a pre-isolated aryldiazonium salt in acetonitrile results in azo-coupling to form (150, X = ArN=N-), and avoids the usual oxidation at phosphorus that occurs in the presence of nitrous acid249.The reactivity of the phosphino-2H-azirine
I : Phosphines and Phosphonium Salts
21
Q
PPh2
Fe
(15 1) has been explored. Electrochemical oxidation leads to the four-membered ring phosphonium heterocycle ( 152)250,and with borane ring-expansion occurs to give (153)251.Catalytic amounts of triphenylphosphine have been shown to promote the isomerisation of propargyl bromide to 1-bromopropadiene252,and tributylphosphine has found use in a mild, catalytic decarboxylation of a - i m i n ~ a c i d sThe ~ ~ ~reactions . of diarylphosphines with 2-hydroxy-1Me3Si\
~ N \ 1
1
R2P
‘Ph
I<
I*N-P+NR2 SiMe3 F HN BF4Ph
Me3siHph R2P< G,NH / \
H H
naphthaldehyde and an ester of phenylboronic acid result in the formation of the phosphino-dioxaboraphenanthrenes (154)254. Cleavage of the oxindole ring occurs when isatins are treated with triphenylphosphine, giving rise to 2-aminobenzonitriles and triphenylphosphine Further consideration of the factors affecting the reactivity of phosphine and related donors towards metal acceptors has led to a revised set of basicity parameters256.The general reactivity and coordination chemistry of 1,2-bis(diphenylphosphino}-1,Z-dicarbon-closo-dodecaborane(12) has been explored. A reaction with dicyclopentadienyl(dimethy1)zirconium leads to cleavage of the diphosphino units from the ~ a r b o r a n eThere ~ ~ ~ .have been some interesting developments in the area of heterocyclic phosphine chemistry. Treatment of dialkynylphosphines with zirconocene results in the formation of zirconacyclopentadienephosphiranes (155), the reactivity of which has also been explored. This new heterocyclic system is the source of a variety of unsaturated phosphines, giving, e.g., the phospharadialene system (156) on treatment with hydrogen chloride in ether258.The reactivity of the 1,2-dihydrophosphete system (157) has been explored. As might be expected, its chemistry is dominated by its nucleophilic character; in addition, metal coordination of phosphorus appears to reduce the tendency of the system to undergo electrocyclic ring-opening to the corresponding 1- p h o ~ p h a b u t a t r i e n e ~The ~ ~ *phosphapyrazoline ~~~. system (158) rearranges on photolysis to give the zwitterionic system (159) which, on further prolonged photolysis, is converted into the other compounds, including a phosphindole261. Photochemical and thermally-induced biradical pathways have been explored for the rearrangement of the W(CO)5-complexed 7-
Organophosphorus Chemistry
22
Ph 'H >P-R Ph (155) R = Ar, But or NPt$
( 156)
phosphanorbornadiene (160) to the related complex (161)262.The macrocyclic triphosphorus system (162) is f o k t d on treatment of phenylbis(0-trimethylsiloxypheny1)phosphine with phosphirus pentachloride in toluene263.A theoretical treatment of the reaction of alkyllithium reagents with organodk(2pyridyl)phosphines, which results in the formation of 2-methylpyridine and
lithiophosphide reagents, has shown that the postulated phosphoranide intermediates, R4P- Li+, are not on the pathway for C-C coupling, although they do play a role in the established exchange of groups at phosphorus. The coupling reaction is considered to be an intramolecular nucleophilic substitution, involving the attack of an essentially free carbanion on the 2-position of the pyridyl group, aided perhaps by coordination of the pyridine nitrogen to Two groups have shown that the chelating diphosphines (163) undergo cleavage of the ring-R2 carbon<arbon bond in the presence of rhodium(1) c o r n p l e ~ e s ~Interest ~ ~ * ~ in ~ .methods for the resolution of chiral phosphines has also continued at a high level. A variety of new approaches based on the use of palladium and related complexes of chiral amines have been d e s ~ r i b e dl , ~and ~ ~ the - ~ general ~ area reviewed272.Potential ambiguities in the assignment of absolute stereochemistry of complex paracyclophanes, including (91), have been addressed, and solutions A procedure has been described for the direct enantiomeric resolution of diphosphines and the related oxides, by HPLC on chiral columns274.The reactions of boraneprotected P-chiral lithiophosphide reagents with benzylic halides, in the presence of (-)-sparteine, have been shown to proceed via dynamic resolution,
1: Phosphines and Phosphonium Salts
(1 63) R1= P i or But. R2 = CH3 or CF3, R3 = H or Me
23
OMe (164)
enabling the isolation of chirdl phosphines, e.g., (164) in high yield, and with 95% ee275.An X-ray structural study of tris-(9-anthracenyl)phosphine ( 165) shows ‘edge to face’ interactions between the anthracenyl units which are somewhat different to those previously observed in triphenylph~sphine~~~. Further modes of ‘phenyl-embrace’ have been recognised in some metal complexes of triphenylph~sphine~~~. The in situ formation of hydroxymethylphosphonium salt derivatives of ferrocenylphosphines and of silver(1) adducts of sulfonated arylphosphines allow a means of characterising such compounds by electrospray mass spectrometry278.
2
Phosphine Oxides
Preparation - The scope and limitations of the palladium-catalysed reactions of secondary phosphines with aryl triflates, giving arylphosphine oxides, have been explored. The mechanism of oxidation at phosphorus is, as yet, unknown279.An improved, ‘one-pot’, route to the dibenzophosphepin oxide system (166) has been developed involving sequential lithiation of obromobenzyl bromide280.The tertiary phosphine oxides (167) act as masked secondary phosphine oxides, and can be metallated and subsequently alkylated at the methylene carbon adjacent to phosphorus, allowing the synthesis of new tertiary phosphine oxides whicn can then be deprotected to give the related secondary phosphine oxides. This approach has been used for the preparation of tertiary phosphine oxide-modified DNA2*’. Procedures have been developed for the selective introduction of phosphine oxide groups to the upper282 and lower282rims of calix[4]arenes, and also to related resorcinarene cavitand systems284.The first enantiomerically pure P,P-diphosphine dioxides ( 168) have been isolated from the reaction of a lithiated secondary phosphine oxide with the related phosphinyl bromide. Treatment of the lithiated secondary phosphine oxide with copper(I1) chloride provides the meso-form of the above system285. Diorganovinylhosphine oxides have been prepared by heating 2.1
(166) R = Ph or P i
(168) R’
=
Bu‘, R2 = Ph
Organophosphorus Chemistry
24
secondary phosphine oxides with vinylsulfoxides or divinylsulfone in the presence of potassium hydroxide286.The phosphine oxides (169) are formed by the addition of the P-H bond of secondary phosphine oxides to carbonyl compounds, imines, and some alkenes, in an uncatalysed process under neutral conditions in THF. The P-H bond is activated by the presence at phosphorus of vinyl or phenylethynyl s u b s t i t ~ e n t s ~Addition ~~. of dimethylphosphine oxide to 3-thiazolines under various conditions has given the phosphine oxides ( 170)288. Palladium-catalysed addition of diphenylphosphine oxide to an alkyne normally gives the vinylphosphine oxides (17 1). However, addition of 0
(169) X = 0, NH or CHR
one drop of diphenylphosphinic acid causes a reversal of the regiospecificity of the addition, giving the isomeric system (172)289.The phosphine oxides ( 173) have been obtained from the reaction of the ylide derived from 1,l- diphenylphospholanium perchlorate with a series of acrylate esters290.The triphosphine (174) can be selectively oxidised to its monoxide or dioxide by oxygen in the CH
e
, K b PIIh 2
0
(1 72)
!
P
h2
EtO
(173)R'
=
R2 Me, Pr, Pr' or Ph, R2 = H or Me
xPp PPh2 h2
PPh2 (1 74)
presence of colbalt(I1) chloride291.Hydrogen peroxide oxidation of the parent diphosphine has been used for the synthesis of ( 175)292.A route to phosphonic acids bearing phosphine oxide groups at carbon adjacent to phosphorus (176) has been developed293.Macrocyclic phosphine oxide-disulfoxides ( 177) have been obtained by oxidation of the corresponding macrocyclic dithioethers with rn-chloroperbenzoic acid294.Difunctional phosphine oxides of type (178) have been used as reactive intermediates in the synthesis of a range of polymeric phosphine oxides in which phosphorus is part of the back-bone of the polymer295-300. Other phosphine oxide-containing polymeric systems have also been described with particular reference to their flame-retardant properties30 1 - 303 2.2 Reactions - Perfluoro cis-2,3-dialkyloxaziridineshave been shown to be effective reagents for the stereoselective transformation of thio- and selenophosphoryl groups into phosphoryl groups under mild conditions304.Treatment of a polymer-bound diisopropylarylphosphine oxide with phosgene has given the related dichlorophosphorane, used subsequently as a polymeric reagent for conversion of alcohols to chloroalkanes, but in lower yield than
1: Phosphines and Phosphonium Salts
PPh2 II
25
II PPh2
(175)
0 0 R,l I IO ,I H P-CH2Hd P\OH (176) R = Me of Ph
X
Q,S/R\SOQ (177) Q=(CH2),,, n - O o r l R = o.and mxylene or (CH2)n x = 2,3 or 4
Q
1p\\
D
X
R O (178) R = Me or Ph, X = F, CI, NCO or NH2
those previously reported using polymer-bound dichlorotriarylphosphoranes305.Halogen and interhalogen adducts of phosphine-sulfides and -selenides have been revisited. Three groups have reported the characterisation of 1:1 molecular charge transfer complexes involving iodine or iodine monohalides308.Structural studies reveal that all involve discrete molecular units. The reactions of dibenzylphosphine oxide with positive halogen sources have been
[email protected] radical anion, Me3PS’-, has been characterised by EPR studies, following exposure of trimethylphosphine sulfide to ionising radiation in aqueous media. This species has a trigonal bipyramidal structure, characteristic of a phosphoranyl radical3I0. Further studies have appeared of the photolysis of acylphosphine oxides, resulting in the formation of acyl and phosphorus-based radicals3’ll3l2. S-methyl dithiocarbamates of alcohols have been shown to undergo deoxygenation in the present of di-n-butylphosphine oxide and various radical initiators, the phosphine oxide acting as a hydrogen atom donor313.Vinylic systems involving electron-withdrawing groups have been shown to insert into the carbon-manganese bond of the cyclometallated triarylphosphine chalcogenides (179), giving the functionalised systems (1 80)314.The reaction of allenylphosphine oxides with o-aminobenzonitriles, followed by treatment with sodium hydride, results in formation of the quinolylphosphine oxide (18 l), via cyclisation of an intermediate p-enamino-
(179) X
= 0, S or Se
(180) R = CQMe, CN or COMe
A
R’
(181)
”
26
Organophosphorus Chemistry
phosphine oxide (182)315 . Formation of the methacrylate of the phosphine oxide (183) enables its incorporation into a copolymer with methyl methacrylate, which exhibits significant second order non-linear optical properties316. Alkylaminomethylphosphine oxides and sulfides (184) have been shown to react with sulfinyl and sulfonyl halides to form the related N-sulfamido systems3I7. Sulfanolysis of tris(2-cyanoethy1)phosphine oxide has given the amido-functional systems (185), which, on subsequent alkaline hydrolysis, are converted into the sodium salt of tris(2-carboxyethy1)phosphine oxide3'8. The P-thiophosphinoyl carbene (186) has been obtained by photolysis of the related diazomethylene compound, and its reactivity studied3lg.Several groups have explored the carbofunctional reactivity of 2- and 3-phospholane chalcogenides. Catalytic cis-hydroxylation with osmium tetraoxide has given phosphanyl sugar derivatives, e.g., (187)320.Keglevich's group has continued to
If
H J-(
M@PCH2(
R' R2
(184) X = 0 or S, R' = H or Me3Si R2 = Me or PhCH2
X It O=P+CH2CH2CNH2)3
(185) X = 0 or S
S II PhC-CH2-PPh2 (186)
,\
Ph 0
(187)
explore the chemistry of dichlorocarbene adducts, e.g., (188), of 3-phospholene and other partially unsaturated cyclic phosphine chalcogenides. Of particular interest is their behaviour on reduction or on heating which can lead to ringexpanded systems, e.g., (189) and (190)321-324. Metallation of the phospholane oxide (191, R = H), using a chiral lithium amide, has enabled the synthesis of new enantiomerically pure phospholanes (19 l), which are capable of reduction to the related chiral p h ~ s p h i n e sTreatment ~~~. of the dibromocarbene adducts (192) of allenylphosphine oxides with butyl lithium results in the formation of the comulated trienylphosphine oxide system (193)326.Warren's group327-329 and have continued to explore the alkyl side-chain reactivity of alkyldiphenylphosphine oxides, particularly with regard to the synthetic
(192)
(193) Ar = Ph, pCICgH4,pBrG3H4 or p5u'C~H4
1: Phosphines and Phosphonium Salts
27
applications of such compounds in Horner-Wittig procedures, details of which can be found elsewhere in this volume.
2.3 Structural and Physical Aspects - The lithiated phosphine oxide (194) has been structurally characterised by x-ray techniques. In the solid state it exists as a cubane-like tetramer in which the lithium atom is involved in a very definite association with the carbon 01 to phosphorus, rather then the more usual association with phosphoryl oxygen333.X-ray structural studies have also been reported for various tetracyclic phosphine chalcogenides, e.g., ( 195)334,tris(3chloropheny1)phosphine various peptides containing phosphine sulfide side chains366,and a phosphine oxide derivative of a g l u c ~ p y r a n o s e ~ ~ ~ . New crystalline modifications of bis(dimethy1phosphino)methan d i ~ e l e n i d e ~ ~ ~ and l,1'-bis(diphenylphosphino)ferrocene339 have also been characterised. Interest in hydrogen-bonded adducts of phosphine oxides has continued, adducts of triphenylphosphine oxide with various carboxylic and with diisopropyl hydrazocarboxylateU2having been structually characterised. A structural study of an adduct of triphenylphosphine oxide with triphenylsilylacetylene has revealed the existence of a short hydrogen bond (1.99 between the oxygen of the phosphine oxide and the alkynyl hydrogenM3.An exceptionally short hydrogen bond has also been characterised between the oxygen of water, hydrogen-bonded to two triphenylphosphine oxide molecules, and the terminal alkynyl hydrogen of 1,4-bis(ethynyl)benzenew. Intraand inter-molecular hydrogen-bonding in 2-phosphinoylphenol(196) has been investigated by quantum chemical computational techniquesM5. Interest has also continued in studies of the conformation of systems bearing diorganophosphoryl s ~ b s t i t u e n t s ~A~ theoretical - ~ ~ ~ . study of the carbon acidities of the tetraphosphacubane chalcogenides (197) has revealed that they are strongly acidic, the tetra-oxide having an acidity comparable with that of a strong protic aicd. The related anion is highly d e l o c a l i ~ e d Calculations ~~~. also reveal that such systems involve large ring strain energies350.
A)
0
S
s
(197) X = Oor S
(198)
x
II II PbPCH2-CNR2 (199) X = 0 or S, R = H or Et
2.4 Phosphine Chalcogenides as Ligands - Complexes of silver with the diphosphine disulfide (198)351and with the amido-functional phosphine
28
Organophosphorus Chemistry
sulfides (199)352? 353 have been characterised. The disulfide (198) has also been shown to form complexes with gold(III), which activates the double bond towards nucleophilic addition354.The ligand properties of the tris(dipheny1thiophosphinoy1)methanide ion towards various metal ions have also been explored355. 3
Phosphonium Salts
3.1 Preparation - A route to the lipophilic phosphonium salts (200) has been developed using well established methodology. These compounds show good thermotropic liquid crystalline phase ranges356.A new route to the 3-alkoxycarbonyl-2-oxopropylphosphoniumsalts (20 1) has also been described357.The synthesis of pyridylphosphonium salts by nucleophilic attack of tervalent phosphorus compounds at the 2- or 4-positions of pyridine, in the presence of triflic anhydride, has been extended to include mixed phosphonio-phosphonate systems, e.g., (202)358.Phosphonium betaine systems have continued to attract interest. The phosphonium and arsonium analogues (203) of the biologically significant trimethyammonioacetate betaine have been prepared and their biological activity explored359. The phosphonato-functional phosphonium salts (204) are converted into the betaines (205) on heating in chloroform or
(200)
R = Clo, C14or Cls-alkyl
(2011
0
Me3iCH2C02-
(203) E = P or As
II (MeO)2P- C- CH26R' 2 R2 II C H ~ cr (204) R',R2 = Ph or Bu
(202)R = Et or Pr'
0
II MeO-P- C-CH$R1 #I2 I II 0- CH2
(205)
THF360. A range of 2-(phosphonioaryl)benzimidazolide betaines (206) has been obtained by deprotonation of the related phosphoniophenylbenzimidazoles with aqueous alkali. Detailed 'H, 31P,and 13C studies reveal significant differences in electronic properties between the salts and corresponding betaines. The latter also exhibit negative solvatochromism361.Chiral alkaliand alkaline earth etallocene complexes have been obtained from the phosphonio-bis(cyc1opentadienide) system (207)362.A patent has claimed the use of ethylene glycol as useful high boiling solvent in the Homer synthesis of arylphosphonium salts from aryl halides, instead of the usual b e n ~ o n i t r i l e ~ ~ ~ . A route to the vinylphosphonium salt (208) has been developed, involving the palladium(0)-catalysedreaction of triphenylphosphine with P-bromostyrene. A palladium complex of the salt has also been characterised, and shown to act as
1: Phosphines and Phosphonium Salts
29
a catalyst in the formation of the salt364.Arylphosphonium salts have also been observed as intermediates in aryl-aryl exchange reactions undergone by arylpalladium-triarylphosphine complexes365, and tetraarylphosphonium chlorides, rather than bromides or iodides, have been shown to be the most effective promoters of palladium catalysis in the Heck reaction, again becoming involved in the formation of arylpalladium intermediate^^^^. The reactions of phosphonium ylides with secondary amines and phopshines have Tetraethylphosprovided a route to the unusual salts (209)367and phonium azide has been prepared from the reaction of the corresponding
(206) R' = Ph or Bu, R2 = Ph R2,R2 = benzo- or 9,lO-phenanthro-
phosphonium bromide with silver a ~ i d e Butyltriphenylphosphonium ~~~. dichromate, obtained by trating the phosphonium bromide with chromium trioxide, has been shown to be a useful selective oxidising agent370.Phosphonium salts of diacetoxyiodine(1) anions, R,P+ I(OAc)2-, are accessible by the reactions of phosphonium iodides with phenyliodine diacetate, and behave essentially as sources of acetyl hypoiodite, 'I-OAc', for additions to double bonds371.Interest in phosphonium salts of TCNQ-related radical anions has continued372,and phosphonium cations have again been used to stabilise a wide range of unusual 'inorganic' anions373-379.
3.2 Reactions - The effects of solvent composition on the kinetics of alkaline hydrogen have been compared for 3-bromopropyltriphenylphosphonium bromide and tetraphenylphosphonium bromide. As has been demonstrated in other systems, the third order rate constant increases steadily as the water content of the solvent decreased, the dominant effect being the extent of solvation of the hydroxyl ion. The rate of decomposition of the 3-bromopropylphosphonium salt is greater than that of its phenyl counterpart under similar conditions, attributable to the inductive effect of the bromine380.A study has also been made of the kinetics and mechanism of protonation of the dipolar system (21 1). Protonation occurs at the cyclopentadiene ring, leading to three isomeric salts, but this is not the rate-limiting step, which involves intial protonation at the quinone unit3*'. Treatment of the silylalkynylphos-
30
Organophosphorus Chemistry
phonium salt (212) with fluoride ion results in the formation of the phosphonio-acetylide (213), a new type of betaine, only stable at low temperature. It behaves, as expected, as a carbon n u ~ l e o p h i l e ~The ~ ~ .chemistry of the tributylphosphine-carbon disulfide adduct has undergone further development. Treatment with norbornene results in cycloaddition to form the ylide (214), subsequently used in the Wittig reactions to form new bis- and trisd i t h i ~ l a n e sA ~ ~study ~ . has been made of the metallation of alkylphosphonium salts by g ~ l d ( I ) ~ Additions *~. to unsaturated phosphonium salts have continued to attract attention. Oxazolones and Munchnones have been added to vinyltriphenylphosphonium bromide to give pyrroles as the main products385. Addition of hydroxylamines to propargylphosphonium salts gives a route to p-
(21 1) X = F, CI, Br or I H H
functionalised o ~ i m e s Enaminophosphonium ~~~. salts (the products of addition of secondary amines to propargylphosphonium salts) undergo hydroboration with the formation of azaboretidinium salts, e.g., (219, which, on alkaline hydrolysis provide a route to the chiral P-aminoalkylphosphine oxides (216)387. Further applications of methyltriphenylphosphonium tetrahydroborate as a reducing agent have been reported3". Lipophilic phosphonium salts, e.g., (217), and a lipophilic derivative of cytidine, have been used as cocarriers for the transport of guanosine 5'-monophosphate at neutral pH389. Acyloxyphosphonium salts, e.g., (2 18), (obtained by a previously published route from the reaction of triphenylphosphine, N-bromosuccinimide, and a carboxylic acid), have found use as chemoselective acylating agents390. Polymer-supported phosphonium salts have been used as phase-transfer catalysts in the oxidation of benzyl alcohol with hydrogen peroxide39'. The use of phosphonium salts as phase-transfer catalysts in asymmetric synthesis has been reviewed392.Combination of the tetraphenylphosphonium cation and the
31
I : Phosphines and Phosphonium Salts
triphenylmethanide anion gives an initiating system for the living polymerisation of methacrylates which probably involves a phosphorylide species393. Fast-atom bombardment mass spectrometry of a series of o-hydroxyalkyltriphenylphosphonium bromides has been i n v e ~ t i g a t e dand ~ ~ , ionisation under fast-atom bombardment and electrospray conditions has been compared for some bis(phosphonium) salts395. 4
p,-Bonded Phosphorus Compounds
The transition metal coordination chemistry of a wide range of p,-bonded two-coordinate phosphorus compounds has been reviewed396.Further examples of sterically protected diphosphenes (219) have been described. These compounds have been shown to form stable radical anions on treatment with alkali metals397.A radical anion is also formed on reduction of the phosphaarsene (220) with sodium398. The ylidyl-functionalised diphosphenes (221) have been shown to undergo dimerisation to form two types of product, (222) and (223), depending on substituent A tungsten carbonyl complex
of the reactive diphosphene (224) (obtained from the thermal decomposition of the 7-pheny1-7-pho~phanorbornadiene-W(CO)~ complex) has been shown to undergo a [2+2] cycloaddition reaction with alkynes to form 1,2-dihydro-l,2diphosphete complexes (225)400.The reactivity of the two-coordinated phosphorus atom in the phosphetes (226) has been exploredm*.The main products R!
-R2
Pi?
W(C0)S
ph\ P=P, Ph (224)
(225) R'
=
Ph or Me, R2 = H, Ph or C a M e
X But2P- P=P(-But But
(227)
Bu$P-P=P-PBu$ (228)
(226) R = Pri2N
32
Organophosphorus Chemistry
of thermal decomposition of the triphosphorus system (227, X = Me) are di-tbutyl(methy1)phosphine and the cyclopolyphosphine P4(PBut2)4. Trapping experiments indicate the intermediate formation of the diphosphene (228)m2. The coordination chemistry of (227, X = Br) has also received attention403. Three groups have described routes to phosphafulvenes, e.g., (229)404and (230)404-m6,and the related system (231)406.Radical-anions have been characterised following electrochemical or chemical reduction of (229) and (230)4". The reactions of (230, R = H) and (231) with sulfur have also been
(229) Ar = 2,4.6-6ut&H2
(230) Ar = 2.4,6-8Ut&H2,
R = H or Bu'
(231) Ar = 2,4,6-But&H2
studiedM6. The ability of phospha-alkenes and -alkynes to undergo 'ene' reactions has been reviewedm7, and several new aspects have also been reported. Thus, e.g., treatment of the phosphines (232) with base gives a transient phospha-alkene (233) which undergoes a [4+2] cycloaddition to form the phosphabicyclo[4.3.0]-non-4-enesystem (234)M8. Ene-reactions between
p.:- [pR] - (yR, \
\ R2
(232) R' = H or CI, R2 = H or Ph
(233)
pL R2
(234)
differently substituted phospha-alkenes have provided a route to 3-amino-1,2dihydro- 1,2-diphosphetes (235)409.Treating the phospha-alkene (236) with tbutyllithium results in the initial formation of a cyclic biradicaloid species which rearranges to give the 1,2-dihydr0-1,2-diphosphete(237)410.The same diphosphete system is also formed by treating the phospha-alkene (236) with CI
/
CI
R2' (235) R' = Ph or Mes, R2 = Me, R3 = H, Me or tms
Me (236)
(237) R2N = 2,2,6,6-tetramethylpiperidino
either titanocene or z i r c ~ n o c e n e ~At ~ room temperature, C-lithiated phosphaalkenes (238) undergo a-elimination to form an intermediate phosphinidenecarbenoid species which subsequently undergoes intramolecular insertion to form the heterocyclic system (239)412.The same group has also shown that treatment of (238) with copper(I1) chloride, followed by oxygen, gives rise to
I : Phosphines and Phosphonium Salts
33
the 1,4-diphosphabutatriene system (240)4'3. The effects of halogen-substitution at either phosphorus or carbon on the molecular and electronic structures of halogen-substituted phospha-alkenes have also been discussed414.Beckertype phospha-alkenes (241) have been shown to undergo 1,2-hydrostannylation to form the corresponding stannylphosphines (242)415.The coordination chemistry of the bis(phospha-alkene) (243) has proved to be of interest, the system behaving as a 4 0 + 67r donor to tungsten acceptors416.Further work has appeared on the chemistry of phospha-alkenes bearing a complexed
AT\
P=C,
/x
AT\ P=C=C=PeAr
Li
(240) AT =2.4,68Ut3C6H2 AT
I
Me3Si-
P=(
R'
OSiMes R' = But,CH~BU', 1-adamantyl or cyclohexyl
Me3Si-~-CH(R1)(0SiMe) SnR23 (242) R2 = Bu or Ph
pH:: PI
AT (243) AT= 2,4,6-Pr'&H~
metallo-substituent at p h o ~ p h o r u s ~ ' ~The -~~ first ' . examples of phosphavinylidene-phosphorane [R3P=C=PR] and phosphavinylphosphonium [RP=CHPR3]+systems have been characterised as ligands in nickel complexes obtained by oxidative addition of phospha-alkenes to zerovalent nickel complexes422.A review has appeared on the chemistry of trigonal planar phosphonium cations, which includes much coverage of methylenephosphonium cations423.A room temperature-stable 1,3-diphosphaallyl radical (244) has been described424.Diphosphaallenic radical cation425and anion426systems have also been characterised by EPR studies. A l-phosphaallyl anion system has been used as a versatile building block in reactions with alkynes and Fischer-type alkynyltungsten carbene complexes427.The species HCCP has been studied by microwave spectroscopy428.The first stable arsaphosphaallene (245) has been prepared and fully characterised, both in solution and by X-ray cry~tallography~~~. The phosphaketene Mes*P=C=O (Mes* = 2,4,6-But3C6H2) undergoes palladium-catalysed decarbonylation to give the related diphosphene Me~*P=pMes*~~*. Further chemistry of the diphosphonio-iso-
NR R2N-PAL-NR2 (244) R = Pr'
AT-P=C=AS-AT (245) AT = 2,4.6-BUt&H2
34
Organophosphorus Chemistry
phosphindolide system (246) has been reported43'. A structural comparison of the diphenylphosphido-boratabenzene complex anion (247) with the related diphenylamido-boratabenzene complex has revealed little evidence of P=B interactions432.The phosphasilene (248) undergoes a [1,3]-sigmatropic shift of fluorine above 40 "C. Treatment of (248) with lithium results in addition to the Si=P double bond, followed by elimination of lithium fluoride, to give, after hydrolysis, the phosphadisilacyclopropane system (249)433. The stabilised iminophosphene (250) has been prepared and its reactivity explored434.
A review has appeared of transition metal-assisted synthesis of rings and cages from phosphaalkenes and p h ~ s p h a a l k y n e s New ~ ~ ~ .work continues to appear on the cyclooligomerisation reactions of phosphaalkynes which are promoted by metal complexes. Evidence of cyclodi- and tri-merisation, and the formation of triphospholide systems, has been obtained in studies of the reactions of the phosphaalkyne Bu'C =P with molybdenum complexes436. Cyclooligomerisation of kinetically stabilised phosphaalkynes also occurs in the presence of organoaluminium compounds, with the inclusion of aluminium in the resulting c a g e - s t r u ~ t u r e sThe ~ ~ ~chemistry . of phosphaalkyne cyclooligomers also continues to develop, many undergoing transformations to new polycyclic systems4389439, including the new triphospha Dewar benzene (251)440.The reactions of phosphaalkynes with boron and gallium halides have been reviewed4', and further transition metal coordination chemistry of the stable phosphaalkyne But3C6H2C=P has been reported442943.A route to new unsaturated phosphines is provided by ene-reactions of phosphaalkynes with alkylidenecyclopropanes and allenesW. The kinetics of the Diels-Alder addition of tetracyclone with Bu'C E P have been investigatedu5. A theoretical study has appeared of the Diels-Alder reaction of the ene-phospha-yne (252) with alkenes, to give the cyclic phosphacumulene (253)446. The phosphaalkyne Me3SiCE P undergoes cycloaddition on treatment with 1,3-dipoles, e.g., diazomethyl compounds, to form heterocyclic systems, e.g., 1,2,4-diazaphospholesU7. Both hydrostannylation448 and h y d r o z i r c ~ n a t i o nof ~ ~ phosphaalkynes have been reported. Photochemically generated silylenes have been shown to add to the triple bond of stable phosphaalkynes to form initially the silaphosphirene (254), which then undergoes photochemical transformation to give the phosphadisilacyclobutane system (255)450. Stable phosphaalkynes
35
I : Phosphines and Phosphonium Salts
(251)
.
.
(252) Me@-SiMes;!
b=h (255)
(2%)
(254) R = l-adamantyl or 2-methylcyclohexyl 'PPeSePh PhSe (256) R = But or 1-adamantyl
have also been shown to undergo phenylselenation at both phosphorus and carbon on treatment with phenylseleniumfluoride,to give the seleno-functional phosphaalkenes (256)45'. The chemistry of terminal phosphinidene complexes and their heavier congeners has been reviewed452.The reactivity of platinum-phosphinidene complexes has been explored453.The more familiar phenylphosphinidenetungsten carbonyl complex has been shown to undergo a range of cycloaddition reactions, e.g., with allenes (to form 2-alkylidenephosphiranes (257)454), with butadiynes (to afford a general route to cis-l,2-dihydro-1,2-diphosphetes (258)455),and, remarkably, with the benzene ring of a 5-metacyclophane, to form the 7-phosphanorbornadiene system (259)456.Phosphinidene complexes also promote the o-phosphination of azobenzene, to give the complexed phosphinous acids ( 2 6 0 ) ~Free, ~ ~ . but transient, alkylphosphinidenes have been shown to form in the flash vacuum pyrolysis of alkyldichlorophosphinesover magnesium at 500-600°C. These species readily undergo CH insertion and other reactions458.
. ..
(257) R'R2 = H or Me
(258)
A review has also appeared of the chemistry of phosphenium cations, and also that of the isophosphindolide anion (246) discussed above459.New routes to the cyclic 6n: phosphenium (261) and related arsenium ions have been d e ~ e l o p e d ~A~ chiral . diaminophosphenium ion (262) has also been prepared&'. The reactions of a tungsten-complexed phosphenium cation with carbenoid reagents have been studied462.Controlled pyrolysis of an azaphosphirene-tungsten carbonyl complex provides a route to the nitrilium-phosphide ylide complex (263), which has been shown to react with dimethyl acetylenedicarboxylate to give a 2H- 1,2-azaphospholecomplex463. Recent developments in the chemistry of three-coordinate pentavalent (03h5-phosphoranes) have been revieweda, and routes to the P-halogeno
36
Organophosphorus Chemistry
functional systems, (264)465and (265)466described. Systems bearing ferrocenyl substituents at phosphorus, e.g., (266), have also been prepared467, and the reactivity of the ferrocenyldithioxophosphorane(267) explored468. The 03hSsystem (268) has been identified as a transient intermediate in eliminationaddition reactions undergone by a related P-chloroph~sphonamide~~~. The methylenephosphoranes (269) have been shown to undergo C-lithiation at the methylene group on treatment with butyllithium, thus providing versatile reagents for the synthetic elaboration of these systems470. Methylenediyl(t hioxo)- and methylenediy I(se1enoxo)-03h5-phosphoranes have been assembled in the coordination sphere of transition metal complexes containing isophosphaalkene ligands by direct oxidation with sulfur or selenium47* .
Fe
NMes'
x-P
(264) R = Me&,
X = CI or I
//
(265) X = halogen, R = MesSi, Mes' = 2,4,6-But3&H2
(266) R = Me3Si
E
Mes'-P
//
(269) E = NMes' or C(SiM%)2
5
Phosphirenes, Phospholes and Phosphinines
An ab initio theoretical investigation of the formation of phosphirenylium ions (270) from l-halo-l-phosphirenes (271) has shown the former to be an aromatic, delocalised system^^*. P,P-Diphosphirene complexes, e.g., (272), have been obtained by treating 1-chlorophosphirenes with iron carbonyl reagents473. Alkylation of 1H-phosphirenes with alkyl triflate reagents has provided the phosphirenium salts (273)474. Routes to 2H-azaphosphirene complexes (274) have been developed475477.Thermal decomposition of these
37
I : Phosphines and Phosphonium Salts
-!A<
( W 4 F e Fe(C0)4 R)P+ R
(270) R = H, Me, SiH3, CN, NH2 or OH
3'
R)P-x
R
(271) X
But) =
F or CI
Ph
(272)
Ph
But
F0 OTS 'R2 Ph (274) R = aryl, 2-fury1, 2-thienyl or (273) R' = Me, But, CH2SiMe3, NR2 2-(l-methylpyrrolyl), M = Cr or Mo or OMe, R2 = Me or CH2SiMe3
(275)
systems has given the first 2H-1,3,2-diazaphosphole complex478.New routes to free and coordinated 1H-diphosphirenes (275) have also been developed479i480. A simple one-pot synthesis of the 1-chlorophospholes (276) and (277) is afforded by the reaction of the appropriate dilithiated system with phosphorus t r i ~ h l o r i d e.~A~ route to blue light-emitting polymers involving biphenylylphosphole repeat units, (278), has also been developed482.Interest has continued to develop in studies of the effects of introducing bulky substituents
'
into phosphole systems, particularly at the tricoordinated phosphorus. Oxidation at phosphorus of the phosphole (279) is inhibited by steric hindrance at phosphorus483.An X-ray study of the crowded triphosphole (280) has shown that the system is fully delocalised, containing a planar tricoordinated phosphorus atom. It is considered to be the most aromatic of all the known phosphole heterocycles484.There has also been much interest in the catalysis by chiral palladium complexes of Diels-Alder reactions of 1-phenyl-3,4dimethylphosphole with functionalised vinylic and allenic dienophiles, giving a range of chiral, bicyclic 7-phosphanorbornene systems, including the phosphino systems (28 1)485*486, the related unsaturated system (282)487,the sulfoxide (283)488,and the carbofunctional systems ( 2 1 3 4 ) ~ Lithiation ~ ~ ~ ~ ~ .at a ring methyl group of the borane complex of 1-phenyl-3,4-dimethylphosphole, followed by treatment with N-bromosuccinimide, has resulted in the formation of the unusual dimeric structure (~35)~''.Intramolecular [4+2] Diels-Alder cycloaddition of a 2H-phosphole (derived from 1-phenyl-3,4-dimethylphosphole by thermal isomerisation) with coordinated, unsaturated phosphines,
38
Organophosphorus Chemistry
"9"
Me&i
1
(279)
D'
Ph
Ph
Ph
Me IYlU
(283)
Me
(284) R = C02Et or 2-(l-methylpyrrolyl)
arsines, and other phospholes, has given a new class of conformationally rigid bidentate ligands containing the 1-phosphanorbornene bicyclic system, e.g., (286)492. Thermal isomerism of a P,P-diphosphole has given the bis(2Hphosphole) (287), which has been shown to undergo a cycloaddition with diphenylacetylene to form the new chiral system (288), subsequently resolved via a chiral palladium complex493.The chemistry of 2H-phospholes has also been reviewed494.
phwph .Me
M
e
/ \
/
Ph
\
(288)
Ph
Ph
a
/ \
(289)
Ph
The coordination chemistry of phospholes and related phospholide ligands continues to attract much interest. A palladium(I1) complex of the diphosphole (289) has been characterised by X-ray ~ r y s t a l l o g r a p h yPalladium(I1) ~~~. complexes of the tetraphosphole (290) have also been characterised and shown to have favourable catalytic properties in the Heck reaction, being resistant to degradation496.Several new chiral phosphaferrocene systems have been prepared, including the enantiomerically pure (29 and the C2-symmetric diphosphaferrocene (292)498. Several phosphaferrocenes bearing additional donor groups, e.g., (293)499,(294)500and (295)50',have also been prepared, and their coordination chemistry studied. Phospholyl Ir-complexes of rutheniumso2, and zirconium5" have also been described. Related complexes of
I : Phosphines and Phosphonium Salts
39 Ph
Me)&NM" Me
Fe
Me
Fe
Me
Fe
(293) R = Ph or Cy
diphospholide ligands have been prepared, including the first stable scandocene (296)'05v506. Cage systems containing phosphorus and antimony have been obtained by coupling of 1,4,2-diphosphastibolyl anions in the presence of transition metals507. The coordination chemistry of 1,2,4-triphospholes has also received 509. The chemistry of azaphosphole systems has shown further development. The chiral system (297) has been prepared and its coordination chemistry studied5", and new routes to heterofused 1,3-azapho~pholes~~ and 1,3benzazapho~pholes~'~ developed. The formation of triazaphosphole systems bound to a pyridine nucleus by the reaction of azidopyridines with t-butylphosphaacetylene has received a quantum chemical study513.The role of 1,2,3diazaphosphole intermediates generated in situ in the synthesis of aza-heterocycles from the reactions of hydrazones and phosphorus trichloride has been
t
40
Organophosphorus Chemistry
reviewed5I4.The reactivity of triazaphosphole systems to bromine has also been investigated” 5 . Theoretical treatments of the phosphinine system continue to Full details are now available of routes to new functionalised 2-substituted phosphinines, involving zirconium complexes of the phosphabenzyne (29Q5I8. Phosphino substituted phosphinines, e.g., (299), act as bridging ligands in transition metal carbonyl ~hemistry”~, and phosphinine-rhodium complexes have found use as catalysts for the efficient hydroformylation of terminal and internal alkenesS2’. A route to polyfunctional phosphinines and arsinines, e.g., (300), is afforded by the reactions of 1,3,2-diazaphosphinines (and diazaarsinines) with a l k y n e ~ ~and ~ ’ , this approach has also enabled the synthesis of macrocyclic systems, e.g., (301)522.The h5-phosphinine area has also seen further activity. The azadiphosphinine (302) has been prepared523.Treatment
phy-Jph
Me2Si
SiMQ
ph+si+ph
(299)
Ph
Me2
(301)
Ph
of the h5-triphosphinine system (303) with the acid HBF4 yields the unusually thermally stable trication (304)524. The 1,2-dihydrophosphinine oxide (305) undergoes selective hydroboration on treatment with the dimethylsulfideborane adduct, to give the 1,2,3,6-tetrahydrophosphinineoxide (306)525.
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53
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1: Phosphines and Phosphonium Salts
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Organophosphorus Chemistry
G. Heckmann, E. Jones, E. Fluck and B. Neumuller, 2.Naturforsch., B, 1998, 53,443. 524 E. Gorbunowa, G. Heckmann, E. Fluck, M. Westerhausen and R. Janoschek, Angew. Chem., Int. Ed. Engl., 1997,36,2349. 525 G . Keglevich, Z. Bocskei, K. Ujszaszy and L. Toke, Synthesis, 1997, 1391. 523
2 Pentaco-ordinated and Hexaco-ordinated Compounds BY C.D. HALL
1
Introduction
The year includes a whole volume of Phosphorus Sulfur and Silicon dedicated to Professor Robert Wolf on his seventieth birthday and in recognition of his outstanding contributions to main group chemistry.' It contains several articles on hypervalent phosphorus chemistry which will be reported at appropriate points in the Chapter. Two important review articles have also appeared. The first, by Gloede et a1.,2deals essentially with calixarene phosphates but contains one example of a bridged dioxotrichlorophosphorane detected during the phosphorylation of t-butylcalix[8]arene. In the second, Robert Holmes discusses the formation of hexacoordinated phosphorus compounds v i a donor interaction and the relevance of the chemistry to enzymatic reaction intermediate^.^ The donor atoms include N, 0 and S and interactions with tri-, tetra- and penta-coordinated phosphorus are considered by a series of X-ray crystallographic studies. The increase in coordination results in tbp structures for the tri- and tetra-coordinated phosphorus compounds and octahedral geometries from pentacoordinated species. With sulfur as the donor atom the degree of coordination and hence displacement towards the higher coordination geometry follows the order: oxyphosphoranes > phosphites > phosphates [e.g. (I), (2) and (3)]; a similar order was found with nitrogen as the coordinating donor atom. With oxygen as the donor, the displacement towards higher coordination, although still apparent, was generally lower than with sulfur. The subject of coordination by N, 0 or S leading to hypervalent structures has received extensive treatment by Holmes et al. and
(1)
P-s = 2.367A
(2)
P-s
OrganophosphorusChemistry, Volume 30
0The Royal Society of Chemistry, 2000
59
= 2.876 A
CI
(3) P-S
= 3.174
A
60
Organophosphorus Chemistry
further details of this work form a substantial proportion of this year's report (vide infra, Section 4). 2
Acyclic and Monocyclic Phosphoranes
Reduction of tetraphenylphosphonium bromide (Ph4P+Br-) with LiAlH4 at room temperature affords Ph4PH as the initial product followed by the dihydrophosphoranate anion (Ph4PH2-) which decomposes to the dihydrophosphorane Ph3PH2.4The products were identified by 31PNMR and reductions of the other phosphonium compounds appeared to follow similar pathways. Ph46 B r
Ph3PH2 (+ PhH)
1 - t LiAIH4
LiAIH4
Ph4PH
[Ph4PH21-
In a study of the synthesis of organoguanidinyl-substituted phosphorushalogen compounds, Schmutzler et al. showed that the reaction of PC15 with trimethylsilyltetramethylguanidine (4) generated the phosphorane (9,which on reduction with magnesium gave (6).5
The perphosphoramide (8) is formed in quantitative yield by the direct reaction of the stable imidazol-2-ylidene (7) with PhPF4 in THF solution.6 The 31PNMR spectrum shows a quintet = 850.7 Hz) at - 141 ppm, some 91 ppm upfield from PhPF4 and hence consistent with a hexacoordinate (octahedral) structure as confirmed by X-ray crystallography.
I;;] -
hP$ - $ f [
Mes
i PhPF4
Mes I
THF
F Mes
The reaction of tricoordinated phosphorus compounds (9) with sulfenate esters (10) is a well established route to a wide range of pentacoordinated phosphorus compounds ( l Z).7 Product analysis, kinetic order, activation parameters, Hammett data and solvent effects were used to elucidate the twostep mechanism involving arylthiophosphoranes (1 1).* The collective data
2: Pentaco-ordinated and Hexaco-ordinated Compounds
61
indicate initial nucleophilic attack by phosphorus on the sulfur atom of (10) probably by a biphilic transition state to form the oxythiophosphorane (11), which subsequently either disproportionates or reacts with a second molecule of (10) to form the oxyphosphorane (12), with diphenyl disulfide as the byproduct.
Reaction of the bis-phenol (1 3) with PC15 gave the trichlorodioxaphosphorane (14), which was also obtained by the reaction of (13) with PC13 to give (1 5), followed by reaction of (15) with C12.9
PClB D
An interesting exchange reaction between trichlorodioxaphosphoranes [e.g. (16)] and triethyl phosphate (17) resulted in the formation of the chlorophosphates (18) and (20), with the latter being formed via the pentacoordinated intermediate (20), detected by 31PNMR as a weak signal at - 13 ppm.IO
The ozonisation of N-phenyliminophosphoranes (2 1 a,b) leads to the corresponding phosphorus oxides (22a,b), with concomitant formation of complex adducts (23a,b) which precipitate at room temperature. In the case of (21b)
62
Organophosphorus Chemistry
when the reaction was carried out at - 78 "C, intermediate phosphoranes, (24) and (25), were detected by 31PNMR.' R3P=NPh
+ nO3
(21a) R = Ph (21b) R = EtO
CH2C12
R3P(O)
+
(22a) R = Ph (22b) R = EtO
R3P(0):(CgH5NOx)y
(23a) R-Ph (23b) R = EtO
In an extension of known chemistry12 Ganoub et al. have shown that the monoxime (26) reacts with trialkyl phosphites to form oxazaphospholes (27), which are stable, crystalline materials with sharp melting points.13 OH
(26)
(27) R = Me, Et or Pr'
Mono- and bis(diethy1amido)phosphites (28) and (29) react with hexa(30) and (3 l), fluoroacetone to give a series of 1,3,2-h505-dioxaphospholanes, and single-crystal X-ray crystallography of (3 Id, R' = C6F5) revealed a slightly distorted tbp geometry at phosphorus. l4
(Et2N)nP(OR1)3-n + 2 (cF&Co
(28a) R' = CF3CH2. n = 1 (28b) R' = PhCH2. n = 1 (29a) R' (29b) R' ( 2 9 ~ )R' (29d) R'
= CF3CH2. n = 2 = (CF&CH. n = 2 = PhCH2. n = 2 = cgF5. /I= 2
(30a) R' = CF3CH2, R2 = OR' (30b) R' = PhCH2, R2 = OR' (31a) R' = CF3CH2, R2 = Et2N (31b) R' = (CF&CH, R2 = Et2N ( 3 1 ~ )R' = PhCH2, R2 = El2N (31d) F?' = cgF5, R2 = Et2N
Oxidative additions of various tricoordinated phosphorus compounds (33a-m) to 2,3-pentanedione (32) gave a series of novel 1,3,2,h5a5-dioxaphospholenes (34a-m), including the first example of a phosphorane containing a phosphorus-isocyanate group. l 5 Reaction of the diketone (35) with (33e), however, gave the bicyclic phosphorane (36) by interaction with the isocyanate group. The kinetics of ester exchange reactions between monocyclic phos-
2: Pentaco-ordinated and Hexaco-ordinated Compounds
cF31; +
(cF3)2cF
(32)
R' R2R3P
63
-
(33a) R'
CF3 R? .?+CF(CFs)2 RIfY-0
R2 (34)
= CF3, R2 = R3 = Me (33b) R' = CF3, R2 = R3 = Pr' (33C) R' = CF3, R2 = R3 = NEt2 (33d) R' = NCO, R2 R3 = OMe (336) R' = NCO, R2 = R3 = OEt (331) R' = NCO, RLR3 = OCH2CHiO (33g) R' = NCO, R2 = = OCMe2CMeO (33h) R' = OSiMe3, R2 = R3 = OEt (33i) R' = NEQ, R2 = R3 = OCH2CF3 (33j) R' = R2 = NEt2, R3 t OCH2CF3 (33k) R' = R2 = NEt2, R3 = OCH(CF& (331) R' = R2 = NEt2, R3 = OCH2Ph 133m) R' = R2 = NEk. R3 = OCRFc, P
phoranes, (37)-(39), and ethylene glycol in the presence of pyridine were studied by observing the appearance of phosphoranes (40)-(42) using 31P NMR.The second order rate constants for the formation of (40),(41) and (42) are 5.37 x 10-4,.3.00 x and 4.17 x M-'s- respectively. The results are rationalised in terms of a mechanism involving hexacoordinate intermediates (i.e associative, addition-elimination mechanism) with the lower rate constant for (39) being associated with the lower stability of the hexacoordinated intermediate from the cis-isomer relative to that from the trans-isomer (38).
'
Me
Ph
I
64
3
Organophosphorus Chemistry
Bicyclic and Tricyclic Phosphoranes
Reaction of bromotris(fluoroa1koxy)phosphonium bromides (43) with glycidol (44)in the presence of triethylamine gave only small quantities of the expected epibromohydrin (45) (pathway l), but considerable quantities of the phosphorane (46) (pathway 2) together with substantial quantities (40-50Y0) of the phosphates (47) and minor amounts of the bicyclic phosphorane (48).17 A feasible mechanism to account for the products involves the intermediate (49). Further effort has been devoted to phosphorus derivatives of calix-[4]resorcinols and amongst the compounds synthesised were two, (51) and (52), containing pentacoordinate phosphorus prepared by the reaction of (50) with tetrachloro-o-benzoquinioneand hexafluoroacetone respectively.'* Although alternatives were considered, force field calculations (using SYBIL) indicated that (51) and (52) conformed to minimum energy structures for the compounds. In a somewhat different approach, Konovalov et al. have shown that phosphorylation of (53) with (54) leads to ( 5 9 , which is in equilibrium with 5% of the hydrophosphorane (56), with lj3'P, - 18.3 ppm and J P H = 715 Hz.19 Contreras et al. have reported the synthesis and characterisation of four novel tricyclophosphoranes (61)-(64) derived from ligands (57)-(60)*' by reaction with P(NMe2)3. The formation of (63) and (64) was completely stereoselective and gave only one epimer in each case [helix A for (63) and helix A for (64)]. The phosphorus configuration for each was established by multinuclear NMR (including HECTOR studies) and confirmed by X-ray crystallography. Single crystal X-ray diffraction studies of bis(bicyc1ic)phosphoranes (67) and (68) prepared from the hydridophosphoranes (65a,b) and glycols (66a,b), revealed tbp structures at phosphorus. Molecular mechanics calculations using the Biosym Program V95 showed close agreement between the calculated and experimental structures of (67) and (68) and several analogues.21,22 The first example of coordination by a tricyclic hydrophosphorane with Pt(I1) has been reported by Mikhel et al. on reaction of (69) with bis(cyc1ooctadieny1)platinum dichloride in CDC13 at 10°C. The complex (70) was charac-
2: Pentaco-ordinated and Hexaco-ordinated Compounds
65
terised by mass spectrometry, elemental analysis, IR and a combination of 31P ('JPt = 5105 Hz) and I3C NMR. Increasing the temperature to 60 "C led to ring opening of the phosphorane structure and formation of complex (71), again characterised by MS, elemental analysis, IR and NMR.23 Reaction of the 1,3,2-0xazaphosphorinane(72) with phenyl isocyanate (73) gave the tricyclic bisphosphorane (76) via (74) and (75). The key feature of this reaction is the 1,4-migration of the N,N-diethylamino group of (74) to form (75) which then dimerises to (76).24 Reaction of the bisphosphine (78) with cyclen (77) at 100°C in a closed system gave the cyclenphosphorane (81). The first stage of the reaction forms (79) by the elimination of dimethylamine which is essential to the second stage of the reaction in forming intermediate (80) which then eliminates
Organophosphorus Chemistry
66
a
O
'
H N\H
z-z
HOD
PhxOH
H O P h I
H/N
R2.. R'
IjN
(57) Z=CH2 (58) Z = C O
/
N\H
z-z
.R'
R2
(59) Z = CHp, R' = Me, R2 = H (60) Z = CO, R1 = H, R2 = Me
H Ph
(61) Z=CH2 (62) Z = CO
67
2: Pentaco-ordinatedand Hexaco-ordinated Compounds
HonYAo" (6Sa) X = 0 (65b) X=NPh 2 EkNICCl, in Me
I
(66a) Y = S (66b) Y = NBd
(67) X = 0, Y = S (68) X = NPh, Y = NBu'
Me
C P P h
+
I
60 "C(-COD)
PhNCS (76)
t
bis(dimethy1amino)methylphosphine (81) to form (82). If the dimethylamine is allowed to escape the reaction follows a different route to give a polymer of general formula (83).25 The novel phosphatrane (85) was synthesised in
Organophosphorus Chemistry
68
+
(Me2N)2PCH2P( NMe)2
100°C
-
-2 Me2NH
n
CN\
HN ("N,PcH2P(NMe2)2
I
+ Me2NH
50-60% yield by the reaction of (84) with KOBut in THF. The 31PNMR spectrum of (85) in CD3CN showed a singlet at 109.3 ppm [for (85)l plus a 1:l:l triplet (ca. 15%) at 5.1 ppm ( ' J ~ = 7 6Hz) which was assigned to deuteriated (87) formed via (86). Thus (85) behaves as a superbase capable of deprotonating acetonitrile to generate zwitterionic structures containing fivecoordinate phosphorus. The optimised conditions for the preparation of N,N'di-isopropyltren [an essential precursor to (84)] are also reported in this paper.26 DA
Pr'
(85)63'P = 109.3
The synthetic utility of the non-ionic superbase (89) has been illustrated by the monoalkylation of diethyl malonate and acetylacetone in the presence of 1.1 equivalents of (89). Yields of 85-98% were achieved in 30 min at room temperature and an analogous set of reactions with ethyl acetoacetate at 0°C gave mono-alkylation in yields of 50-88Y0.~~ It is, of course, the protonated form of the superbase which is pentacoordinate and C-alkylation over 0alkylation is promoted by the steric bulk of the base and protection of the negatively charged oxygen atoms by the superbase counterion. The first non-metal derivative of a corrole has been obtained by reaction of
69
2: Pentaco-ordinated and Hexaco-ordinated Compounds
FIX
YCH2Z
YCHRZ + YCR2Z
(X = Br, I)
R = Me, ally1or aralkyl
(88) Y = Z = C02Et Y = Z = COMe Y =CO;IEt, Z - COMe
the diethylhexamethylcorrole (90) with POC13 under reflux in pyridine. Formation of a complex (91) was indicated by changes in the UV spectrum and by MS and multinuclear ('H, I3C and 31P)NMR studies, all of which suggested pentacoordination. The structure of (91) was confirmed by X-ray crystallography which revealed pentacoordinate (sqp) geometry with the phosphoru: atom lying 0.4 out of the corrole plane and a P-0 bond distance of 1.531 A consistent with a single P-OH bond.28
A
Et
Et
Et
POCI&H5N
Et
m
(91) S3'P -102.5
4
Pentacoordinate/Hexacoordinate Compounds
The division between pentacoordinate and hexacoordinate phosphorus structures has recently become less well defined as research groups have considered the coordination of the sixth ligand to pentacoordinate phosphorus in either an inter- or intra-molecular fashion. As an introduction to this subject, ab initio calculations of the interaction of pyridine with PF5 show that the initial tbp geometry isomerises to sqp before forming an octahedron as pyridine enters the coordination sphere.29 The calculated trajectory for pyridine coordination mimics that found for sulfur donor interaction in cyclic pentaalkoxyphosphoranes where a range of geometries from sqp towards octahedral are found as the P-S interaction increases (vide infra). Thus it seems that incorporation of a sixth donor atom within a cyclic system does not, in itself, control the geometrical changes progressing from five- to six-coordinate phosphorus. X-ray crystallographic structures on the cyclic phosphites (92)-( 94) indicate an increase in coordination to a pseudo-tbp due to donation by sulfur towards the phosphorus atom. Phosphates (95) and (96) experience a similar increase in coordination to form tbp structures. The displacement towards pseudo-tbp or
70
Organophosphorus Chemistry
tbp increased from 31% to 55% as the P-S bond distance decreased from 3.177
A for (96) to 2.818 A for (92).30aA similar study using the salicylate ester
function as the donor group gave a pseudo-tbp for (97) but no evidence of coordination by the salicylate ester function in either (98) or (99).30b
+
:-
(92)R = CI (93)R = NMe2
R
(95) R = CI
R=(96)0
m y
Ho
OMe
CI
I
0-P'
Ph
: '1
(97)oMe
tq '
R
(99)
The donor ability of the sulfone group towards pentacoordinated phosphorus has been examined in some detail.31a*b In summary, phosphoranes of type (loo)-( 102) show hexacoordinate character due to donor interaction by sulfonyl oxygen whereas phosphoranes of types (103)-( 105) remain pentacoordinate. For (103) and (105) the eight-membered ring is di-equatorial in an antichair conformation whereas in (104) the ring occupies axial-equatorial sites in a syn twist-boat form. Both structures clearly prohibit coordination by sulfonyl oxygen. Donation from the sulfone group in (100) and (102), however, led to displacement from a sqp configuration towards an octahedron to the extent of 28% for (100) but 82% for the highly fluorinated (102). Hexacoordination via sulfur donor interaction has been observed in several bicyclic oxyphosphoranes (106- 109). X-ray crystallographic studies indicated various degrees of displacement along a coordinate from sqp towards an octahedron and a linear correlation was observed between the P-S bong distance and the percentage oct$hedral character.32Extreme values at 2.373 A (70.8% octahedral) and 3.041 A (23.8% octahedral) were reported for (1 10) and (1 11) respectively and in general sulfur donor atom coordination was found to increase in the order phosphates < phosphites < oxyphosphoranes. In an extension of this work, the influence of pentafluoro substitution in
71
2: Pentaco-ordinated and Hexaco-ordinated Compounds
(101a) R = Me (101b) R=Bu'
0 II
(10s) R = M e (105b) R = Bu'
R
phenoxy ligands on sulfur atom donation within oxyphosphoranes has been investigated by X-ray crystallography studies of (1 12)-( 114).33 The electron withdrawing effect of the fluorine substituents increases the electrophilicity of phosphorus as evidenced by the P-S bond distances (shown below the structures) relative to the aFalogous unsubstituted phosphorane (1 15) with a P-S bond distance of 2.880 A . In a subsequent X-ray crystallographic study of a series of tetraoxy-phosphoranes, sulfur atom donation to pentacoordinate phosphorus was again 9bserved in (1 16) (containing a P-C bond) where a P-S bond distance of 2.562 A indicated displacement towards an octahedral configuration to the extent of 60.7% even though the electrophilicity at phosphorus is reduced relative to that in pentaoxy-phosphoranes.34 The reactivity of a series of oxyphosphoranes containing the sulfonyl group [(lOla,b), (105a,b)] and a second series containing a sulfur donor atom (117) and a methylene group (1 18) towards catechol and 4-nitrocatechol has been investigated by 31PNMR.35 The reactions were found to proceed by an associative mechanism with an order of reactivity in the sequence (1 18) >
72
Organophosphorus Chemistry
(107)
'
t
(117b) > (117a) > (101a) > (101b) >> (105a,b). In fact (105a,b) were both found to be inert towards displacement by catechols and it was suggested that the 'looseness of P-O bonds that reside in either octahedral formulations or in axial positions of a tbp' is the crucial factor controlling reactivity. For the octrahedral geometries, the order of reactivity parallels the extent of octahedral character, Le. (117b) > (117a) > (1Ola) > (101b). Finally, a most unusual six-coordinate phosphorus compound (120) has been reported containing a mixed valence P(II1)-P(V)-P(II1) chain.36It was prepared by the reaction of (1 19) with PCI5 in toluene and was isolated as an off-white crystalline solid which was insensitive to moisture or oxygen. X-ray crystallography showed the P(V) centre in a nearly perfect octahedral environment with two faciaZZy bonded di-anionic bis(o-phen0xy)phenylphosphane ligands with P-0 bond lengths of 1.726 A. The C1symmetry of the cation confirmed the trans P(II1)-P(II1) fac orientation of the ligands deduced from solution NMR and the axial P(II1)-P(V) bond distance was reported at 2.2023
A.
2: Pentaco-ordinated and Hexaco-ordinated Compounds
R
(117a) R = M e (117b) R = But
73
74
Organophosphorus Chemistry
ct
(120) S3'P = -34.8 (P"'),-107.8 'Jpp = 512 HZ ( A h )
(P")
References 1
2 3 4 5 6
7 8 9 10 11
12 13
14 15
16 17 18
Phosphorus, Sulfur, Silicon, 1997,123. J. Gloede, Phosphorus, Sulfur, Silicon, 1997,127,97-11 1. (a) R.R. Holmes, Acc. Chem. Res., 1998,31,535; (b) R.R. Holmes, A. Chandrasekaran, R.O. Day, D.J. Sherlock, P. Sood and T.K. Prakasha, Phosphorus, Sulfur, Silicon, 1997,124/!5,7. N. Donoghue and M.J. Gallagher, Phosphorus, Sulfur, Silicon, 1997,123,169. R. Schmutzler, Phosphorus, Sulfur, Silicon, 1997,123,57. A.J. Arduengo 111, R. Krafczyk, W.J. Marshall and R. Schmutzler, J. Am. Chem. SOC., 1997,119,3381. (a) D.B. Denney, D.Z. Denney, P.J. Hammond, C. Huang and K.S. Tseng, J. Am. Chem. SOC.,1980,102,5073 and references cited therein; (b) D.B. Denney, D.Z. Denney and D. M. Gavrilovic, Phosphorus, Sulfur, 1987,1 1,l. C.D. Hall, B.R. Tweedy and N. Lowther, Phosphorus, Sulfur, Silicon, 1997,123,
341. J. Gloede and I. Keitel, Phosphorus, Sulfur. Silicon, 1998,132,9.
N.G. Khusainova, G.R. Reshetkova and R.A. Cherkasov, Russ. J. Gen. Chem., 1998,68(3), 367. F. El Khatib, J. Bellan and M. Koenig, Phosphorus, Sulfur, Silicon, 1998,134-5,
391. M.M. Sidky, M.F. Zayed, A.A. El-Kateb and I.T. Hennaway, Phosphorus, Sulfur, Silicon, 1981,9,343. M.A. Ganoub, W.M. Abdou and A.A. Shaddy, Phosphorus, Sulfur, Silicon, 1998, 132,10. M. Gorg, E. Lork, A.A. Kolomeitsev and G.-V. Roschenthaler, Phosphorus, Sulfur, Silicon, 1997,127,15. M. Gorg, U. Dieckbreder, R.M. Schoth, A.A. Kadyrov and G.-V. Roschenthaler, Phosphorus, Surfur, Silicon, 1997,1245,419. N.-J. Zhang, X. Chen, Yu-Fen Zhao and R.-G. Zhong, Phosphorus, Sulfur, Silicon, 1997,126,185. V.F. Mironov, A.A. Bredikhin, Z.A. Bredikhina, V.G. Novikova and LA. Konovalova, Russ. J. Gen. Chem., 1997,67(8),1204. A. Vollbrecht, I. Neda, H. Thonnessen, P.G. Jones, R.K. Harris, L.A. Croweand R. Schmutzler, Chem. BerlRecueil, 1997,130,1715 .
2: Pentaco-ordinated and Hexaco-ordinated Compounds 19 20 21 22 23 24 25 26 27 28 29 30 31
32 33 34
35 36
75
A.I. Konovalov, V.S. Reznik, M.A. Pudovik, E.Kh. Kazakova, A.R. Burilov, I.L. Nikolaeva, N.A. Makarova, G.R. Davleschina, L.V. Ermolaeva, R.D. Galimov and A.R. Mustafina, Phosphorus, Sulfur, Silicon, 1997,123,277. M. Tlahuextl, F. Javier, M.-Martinez, M. de J. Rosales-Hoz and R. Contreras, Phosphorus, Sulfur, Silicon, 1997, 123, 5. A. Chandrasekaran, R.O. Day, R.R. Holmes and D. Houalla, Phosphorus, Sulfur, Silicon, 1997,123,219. D. Houalla, L. Moureau and C. Vidal, Phosphorus, Sulfur, Silicon, 1997, 123,
359. I.S. Mikhel, K.N. Gavrilov, D.V. Lechkin and A.I. Rebrov, Russ. Chem. Bull., 1997,46 (7), 1359. M.A. Pudovik, S.A. Terent’eva and A.N. Pudovik, Russ. J. Gen. Chem., 1997,67 (12), 1940. I.V. Shevchenko and M. Lattman, Phosphorus, Sulfur, Silicon, 1997,123, 175. B.A. D’Sa and J.G. Verkade, Phosphorus, Sulfur, Silicon, 1997,123, 301. S . Arumugam, D. McLeod and J.G. Verkade, J. Org. Chem., 1998,63,3677. R. Paolesse, T. Boschi, S. Licoccia, R.G. Khoury and K.M. Smith, Chem. Commun., 1998, 11 19. J. A. Deiters and R. R. Holmes, Phosphorus, Sulfur, Silicon, 1997, 123,329. (a) D.J. Sherlock, A. Chandrasekaran, R.O. Day and R.R. Holmes, Inorg. Chem., 1997, 36, 5082; (b) N.V. Timosheva, A. Chandrasekaran, R.O. Day and R.R. Holmes, Inorg. Chem., 1998,37, 3862. (a) A. Chandrasekaran, R.O. Day and R.R. Holmes, Inorg. Chem., 1997, 36, 2578; (b) A. Chandrasekaran, R.O. Day and R.R. Holmes, J. Am. Chem. SOC., 1997,119, 1 1434. P. Sood, A. Chandrasekaran, T.K. Prdkasha, R.O. Day and R.R. Holmes, Inorg. Chem., 1997,36,5730. P. Sood, A. Chandrasekaran, R.O. Day and R.R. Holmes, Inorg. Chem., 1998, 37, 3747. D.J. Sherlock, A. Chandrdsekardn, T.K. Prakasha, R.O. Day and R.R. Holmes, Inorg. Chem., 1998,37,93. A. Chandrasekaran, P.Sood and R.R. Holmes, Inorg. Chem., 1998,37,459. H. Luo, R. McDonald and R.G. Cavell, Angew. Chem. Int. Ed., 1998, 37 (8), 1098.
3
Tervalent Phosphorus Acid Derivatives BY T. I? KEE
1
Introduction
Significant recent work on tervalent compounds of phosphorus has been summarised in the Proceedings of the 14th International Conference on Phosphorus Chemistry, Cincinnati, 1998, much of which will not be reproduced here unless there are overriding considerations for inclusion. More comprehensive information on tervalent derivatives may be found in a previous related publication* and prior to that much relevant information has been collected in the second edition of Comprehensive Heterocyclic Chemistry. This report focuses more strongly on non-metal systems with an emphasis placed more firmly on the phosphorus atom rather than on aspects of coordination chemistry where phosphorus is commonly regarded as being of secondary importance to the metal. Exceptions are included, however, where it is deemed appropriate. Also excluded from this year's report is explicit and comprehensivechemistry of low-co-ordinate phosphorus systems.
'
2
Reactions Involving Nucleophilic Phosphorus
p-tert-Butylcalix[4]arene tetrakis(dipheny1phosphinite), ~alix[4]-(OPPh~)~ (I), and tetrakis(dimethylphosphinite), calix[4]-(0PMe& provide a phosphorus surface consisting of four co-planar tervalent phosphorus atoms capable of binding two metal ions in a close geometrical proximity. Homodimetallic complexes have been obtained in the reaction between (1) and [(COD)MC12] [COD = cycloocta-1,5-diene; M = Pd, Pt]. Characterisation has been achieved by H-1 and P-31 NMR which were particularly informative and showed how the bridging methylene of the calix[4]arene skeleton may function as a spectroscopic probe.4 Ph2PO I OPPh2
?0Pph2
Organophosphorus Chemistry, Volume 30 0The Royal Society of Chemistry, 2000 76
3: Tervalent Phosphorus Acid Derivatives
77
The conjugate addition of diethyl zinc to enones under copper catalysis is a well-known and often-used transformation in organic chemistry. In its more common forms, reaction is known to occur efficiently with copper(I1) triflate as catalyst. However, other copper salts also function as catalysts but need a phosphine or phosphite ligand to be efficient. The best combination is copper(11) triflate and triethyl phosphite. A very small amount of copper(I1) triflate (0.5%)and triethyl phosphite (1%) are sufficient for high yield^.^ The asymmetric conjugate addition of diethyl zinc to cyclohexen-2-one occurs with 0.5% copper(I1) triflate and 1% chiral phosphite. Cyclic phosphites derived from various tartrate esters of the general type (2) were found to afford moderate enantiomeric excesses. The nature of the exocyclic substituent of the dioxaphospholane ring is shown to be important, but the chiral induction is imposed by the tartrate framework.6 0
0 R = Et, NMe2, Pr'
Y
Lithium or sodium dialkylphosphites and diamidophosphites undergo addition to ( + )-(S )- benzylidene-p - toluenesulfinamide affording N-sulfinyl-aaminophosphonates in diastereoisomeric ratios from 63:37 to 94:6 (Scheme 1). The major diastereoisomers formed were separated and converted into enantiopure (+)-(R)and ( -)-(S)-a-aminobenzyl phosphonic acids re~pectively.~ P,N-ligands with a binaphthyl phosphite group and an oxazoline ring as chiral co-ordinating units are efficient ligands for the enantioselective copper-catalysed 1,4-addition of organozinc reagents to enones. The best enantio-selectivities (e.e.) are obtained with cyclohexenone (87-96%). The enantio-selectivities in reactions of cyclopentenone (72% e.e.) and cycloheptenone (77-80% e.e.) are moderate but significantly higher than with other catalysts.8 The reactions of a-peroxy lactones with a variety of carbon, nitrogen, phosphorus, and sulfur nucleophiles yield, on SN2 attack at the more electro-
18
Organophosphorus Chemistry 0 Tol’
S
0
H Ph
)i ,OMe
‘N H
ssRc
PLOMe II
0
+
I
sssc
?
(MeO)2POLi
H
(Et2N)2POLi
* Tol’
Tol’s\NAPh
(+)-(a
Separation of major diastereoisomer by column chromatography
$
H
PLOMe II
Tol’
0
)i
NEt2 PLNEt2 II 0
ssRc 0
)i ,OMe
‘N H
‘N
+
Separation of major diastereoisomer by column chromatography
0 Ph’ H Tol’
H Ph
$
$
I
sssc
H Ph
)i
‘N H
NEt2 PLNEt2 II
0
Scheme 1
philic alkoxy oxygen of the peroxide bond, diverse addition and oxygen transfer products, together with the catalytic Grob-type fragmentation. Tervalent phosphorus nucleophiles such as phosphines and phosphites prefer biphilic insertion, as demonstrated by the fact that the nucleophilicity rather than the steric demand of these reagents controls their rea~tivity.~ The synthesis of the 2,3-bisphosphite derivatives of phenyl 4,6-0benzylidene-P-D-glucopyranoside leads to new chelating ligands such as (3). A variety of rhodium(1) and platinum(I1) complexes have been prepared and tested as catalysts for the asymmetric hydroformylation of vinyl acetate, ally1 acetate and p-methoxystyrene. Good regioselectivity (>go% branched product), but an enantioselectivity of only less than or equal to 36% e.e. were found under mild reaction conditions (25-40 “C,40-70 bar syngas).l o
A new chiral trisphosphite ligand, (S,SYS)-2,2’,2’’-tris(2,4,8, 10-tetratert-butyl- dibenzo [d,fJ[ 1,3,2]-dioxaphosphepin-6-y1-6-oxy) tri -2-propylamine, (S,S, S)-TRISPHOS (4), has been synthesised and its co-ordination chemistry
79
3: Tervalent Phosphorus Acid Derivatives
investigated. Certain Rh(1)-(S,S, S)-TRISPHOS complexes ( 5 ) were found to be effective catalysts for the enantioselective hydrosilylation of ketones.
R P- .CI +
R=H.Me
-0T;
The reactions of p-02NC6H4CH2Cl with [(R0)2PO-] in Me2S0 with R = Me, Et, Pr, Bu, CF3CH2, i-Pr or Ph involve the formation of p-02NC6H4CH2P(O)(OR)2 by S N substitution ~ followed by a further S R N 1 p-nitrobenzylation of p-O2NC6H4CH[ P(0)(OR)z]- and p-02NC6H4C(CH2C6H4N02-p)[P(O)(OR)2]-. With p-02NC6H4CH2Br, reaction proceeds mainly to form p-O2NC6H&H2-, which subsequently undergoes reaction with p 0 2 NC6H4CHzBr to form p-02NC6H4CH2CH2C6H4N02-p. Halophilic reaction of [(RO),PO]- with p-o2NC6H&H(CH3)X (X = C1, Br) leading to the bis-benzyl is the preferred reaction course. Reactions of [ (R0)2PO]- or p-o~Nc6H4cH[P(o)(OR)2]- with p-02NC6H4CH2X in Me2SO do not form significant amounts of p-02NC6H4CHX- that would yield p-02NC6H4CH = CHC6HqNo2-p. However, p-ClC6H4CH[P(0)(OEt)2]-
80
Organophosphorus Chemistry
readily abstracts a benzylic proton from p-o2NC&I&H2X to form the stilbene, although p-02NC6H4CH2Br reacts with p-02NC6HqCH[P(0)(OR)2]- to form p-02NC6H4CH(CH2C6H4N02-~)P(0)(OR)2 in a reaction mixture not inhibited by ( ~ - B u ) ~ N O . ' ~ rl-Ethoxy-l,l, l-trifluoro-3-buten-2-one reacts with triethyl phosphite on heating to afford a [4+2] cycloaddition product 2,2,2-triethoxy-2,3-dihydro-3ethoxy-5-trifluoromethyl- 1,2-h5-oxaphospholene. This molecule is hydrolytically sensitive, ultimately yielding upon hydrolysis a 2-0x0-2-hydroxy-2,3dihydro-3-hydroxy 5-trifluoromethyl- 1,2-h5-oxaphospholene. A simple and general one-pot method has been developed to synthesise aaminophosphonates from aldehydes, amines and dimethyl phosphite, a variant of the Kabachnik-Fields reaction. Optically active a-amino-phosphonates were synthesised using (R)-(+),(S)-( -)-a-methylbenzylamine, (R)-( - ),(S)-(+)-2phenylglycinol. (R)-(+)-a-methylbenzylamine affords predominantly (S)-aaminophosphonates and (R)-(-)-2-phenylglycinol leads predominantly to (R)-a-aminophosphonates (Scheme 2). Reaction presumably proceeds through a phosphorus(II1) phosphite intermediate. I4 Ph
R
Me
+
0 II ,P--0Me 'OMe
-
2.0 M lithium perchlorate dirnethylether -15
"C,0.5 h
PhANH2
yNV Me
(RR) 0 II P--0Me 'OMe
phvNy H
Me
Scheme 2
0 II P--0Me 'OMe
H
R
(R, s)
Tetramethylguanidine-catalysed addition of dialkyl phosphites to unsaturated carbonyl compounds, alkenenitriles, aldehydes and ketones constitutes a practical route to a variety of phosphonate synthons. The very mild conditions employed, together with the short reaction times, make the procedure highly versatile and tolerant to a range of functionalities (Scheme 3).15 The reaction of 3-( 1-bromobenzyl)coumarin with trialkyl phosphites afforded the corresponding Arbuzov reaction products, dialkylphosphonates (6), in good yields. The interaction of trialkyl phosphites with 3 - ( 0 bromoacety1)coumarin gave the corresponding dialkyl vinyl phosphates (7) as the only isolated products, whereas dialkyl phosphites reacted under phase transfer catalysis and gave vinyl phosphates or dialkyl 1,2-epoxy-ethylphosphonates @ ) . I 6 Direct synthesis of free (a-hydroxyalky1)phosphinicacid amphiphiles (9) can be readily realised upon sonication of a heterogeneous mixture of 50% aqueous hypophosphorous acid and long-chain aldehydes in the presence of catalytic amounts of hydrochloric acid. Reaction is presumed to proceed through the corresponding intermediate tervalent phosphorus species. Oxida-
81
3: Tervalent Phosphorus Acid Derivatives
tion of these phosphinic acids by DMSO in the presence of catalytic amounts of iodine quantitatively leads to the corresponding phosphonic acids.l7
R2
Scheme 3
Ph
Ph
HP(0)(OR12
TEBA; 50% NaOH; C6H6 (TEBA = triethylbenzylammonium chloride)
R (9) R = Me(CH& R = Me(CH& R = Me(CH2)10 R = Me(CH2)12
Qj+zR 0
0 (8)
0 II
a2
3
Organophosphorus Chemistry
Reactions Involving Electrophilic Phosphorus
N-(a-Hydroxypolyhaloalky1)amides react with tervalent phosphorus chlorides to give a-(acy1amino)polyhaloalkylphosphoryl compounds via phosphorotropic rearrangement of intermediate phosphites or phosphinites. The first representatives of hydrazones having tervalent phosphorus at the azomethine carbon atom or the carbon atom vinylogous to it have been synthesised by reactions of formaldehyde and crotonaldehyde N,N-dimethylhydrazones with PBr3 and diphenylchlorophosphine in the presence of organic bases. Some properties of the compounds synthesised have been studied and reported. l 9 Data on the reactions of N-silylated amines, amides of carboxylic acids, amino acids, and their derivatives with tervalent phosphorus acid halides have been summarised. The effects of structural factors on the pathway of phosphorylation have been described in the same work.20 The scope and limitations of BHs-protected tervalent organophosphorus compounds (phosphines, aminophosphines, phosphinites, etc.) as intermediates for the synthesis of chiral phosphines has been reviewed.21These derivatives represent a class of unique ligands for homogeneous asymmetric catalysis. Several applications of BH3-protected tervalent organophosphorus compounds are surveyed ranging from simple use as air-stable derivatives involved in facile purification procedures to versatile synthetic intermediates for highly stereoselective [P-C] and [C-C] coupling reactions. Relevant properties of P-boranes including the cleavage of the P-B bond are considered also. Finally, several new pathways for the synthesis of chiral phosphine ligands are detailed such as, for example, those in Scheme 4. In selected examples, the efficiency of new ligands in asymmetric catalysis is discussed briefly.21 i. PhPCI2,Et3N,THF, 0 "C ii, BH34Me,
HO
55% yield
Ph
y43
Ph-,P, eAn'
Me
(R)-PAMP-BH3 (70% e.e.)
4
For R = 0-anisyl MeLi, Et20,-78 "C 43% yield
Scheme 4
I
Ph RLi. THF. -78 "C 82 and 80% yield
4 : 1 ratio
A kinetic analysis of the tetrazole-catalysed reaction between diisopropyl N,N-diisopropylphosphoramidite ( 10) and tert-butyl alcohol has been carried out by P-31 NMR spectroscopy in THF solvent, and the results obtained have been compared with those observed for the possible partial reactions involved, viz. the formation of diisopropyl tetrazolylphosphite (1 1) and its subsequent alcoholysis.22
83
3: Tervalent Phosphorus Acid Derivatives
A facile phosphoramidite method using a tetrazole promoter has been developed for the condensation of a nucleoside 3’-phosphoramidite and a nucleoside under catalytic conditions. This method is particularly useful for a large-scale synthesis of short oligonucleotides. For example, dinucleoside phosphates (e.g. 12) are prepared on a multi-gram scale in 92-99% yields through the reaction of nucleoside 3’-N,N-diethyl-phosphorarnidites( 1.05 equiv.) and 5’-0-free nucleosides ( 1.OO equiv.) with 5-(p-nitrophenyl)-1Htetrazole (NPT) (0.05 equiv.) in the presence of molecular sieves in acetonitrile followed by trimethylsilyltrifiate-catalysed oxidation with bis(trimethylsily1) peroxide in dichloromethane. The NPT-catalytic approach is also effective for the synthesis of longer deoxyribonucleotides such as d((S’)CTACCTGT(3’)) and 2’-5‘- or 3’-5’-linked ribonu~leotides.~~
COAO (12) All = CH24HCH2
OAOC
AOC = CH24HCH2OCO DMTr = ~ H ~ ( p M e o C & ) 2 C MMTr = pMeOC&(C6H&C
(13) X = H, Y = OMe. R = Me X = H , Y=OBn, R=Bn X=OBn, Y = H , R=Bn
A highly stereocontrolled 1,2-trans-glycosidation reaction has been developed by using glycopyranosyl phosphoramidites (13) as glycosyl donors in the presence of TMSOTf or BF,.OEt, as a promoter in a variety of solvents.24 The formation of H-phosphonate by-products from the global phosphorylation of a Thr-containing peptide resin using both di-tert-butyl and dibenzyl-N,N-diethylphosphoramiditewas identified to result from 1H-tetrazole-mediated cleavage of the tert-butyl or benzyl group from the intermediate dialkyl phosphite triester and re-arrangement of the resultant hydroxyphosphite diester to the H-phosphonate form. This side reaction was rectified by the use of aqueous iodine for the oxidation step in which the H-phosphonate is oxidised to the benzyl phosphorodiester which, on acidolytic treatment, gives the desired dihydrogen phosphate.25 New bicyclic imidazo-oxazaphosphorines have been shown to undergo a highly diastereoselective displacement of the imidazole moiety upon reaction with various alcohols, leading to chiral phosphite triesters as single diastereo-
84
Organophosphorus Chemistry
isomers. The introduction of a nucleoside on this bicyclic structure was investigated by several routes, leading to new nucleoside building blocks.26 Novel diastereoisomeric thymidine cyclic 3’,5’-threo-phosphoramidates have been prepared by the treatment of 5’-azido derivative of threo-thymidine with triphenyl phosphite as well as by treatment of the corresponding amino derivative with phenyl phosphodichloridate. Phosphoramidation of the regioisomeric 3’- and 5’-azido derivatives of erythro-thymidine by means of triphenyl phosphite afforded the open-chain 3’- and 5’-phosphoramidates.The reaction which afforded the cyclic products was assumed to proceed via the cyclic tetraoxaza-phosphorane intermediate^.^^ The synthesis of several phosphites with sterically hindered piperidine groups which are potential stabilisers for synthetic polymers is described.28 tert-Alkyl phosphoramidites are somewhat sterically hindered, but give phosphites in good yields with tetrazole catalysis when the coupling time with alcohols is prolonged. Low yields of phosphotriesters are caused by elimination of the tertiary alkyl group during the subsequent oxidation of the phosphite with iodine/water/pyridine, and can be avoided by the use of tertbutyl hydroperoxide as the oxidant (Scheme 5).29 I
I
I
. P--NPr12 BU‘O/ bO,-NE
HOCNE
tetrzole
I
fat
P--0CNE BU~O’ b m N E
~~0 slow
P--0CNE o’/’OCNE H20, pyridine
OCNE = cyanoethoxy II P--OCNE
BdOO ’OCNE
Scheme 5
4
Miscellaneous Reactions
The stereochemistry of the photo-Arbuzov rearrangement of benzylic phosphite trans-(R,R’)-(14) to the corresponding phosphonate, (15), has been determined by P-3 1 NMR spectroscopy and X-ray crystallography. Reaction is shown to occur with predominant retention of configuration at the stereogenic migratory carbon centre of configuration R’in starting trans-(R,R’)-(14) and the predominant product cis-(R,I?’)-( 15). Thus, reaction of optically active phosphoramidite (16) (96% e.e.) with 1-phenylethanol of high optical purity (94% e.e. for R isomer) gives phosphite (14) (cisltrans ratio, 97/3) almost entirely as the single enantiomer, trans-(R,R’)-(14). Irradiation of trans-(R,R‘)(14) in acetonitrile with 254 nm ultraviolet light converted it cleanly to two diastereoisomers of phosphonate cis-( 15) in 80/20 ratio (P-31 NMR). The major isomer was isolated, recrystallised, and shown by X-ray crystallography
3: Tervalent Phosphorus Acid Derivatives
85
to be cis-(R,R')-(15). The lesser product is identified, on the basis of its P-31 NMR chemical shift, as the diastereoisomer cis-(R,S)-(15). The generation of trans-(R,S)-(15) is attributed to the formation, from trans-(R,R')-(14), of shortlived, predominantly singlet, free radical pairs ( 17) that undergo combination to form cis-(R,R')-(15). To a lesser extent the 1-phenylethyl radicals of the pair (17) are converted by rotation to generate the stereochemically distinct radical pair (1 8) that then combines to form cis-(R,S)-(l5).To a first approximation, combination (kcom,,)is four times as fast as rotation (krot).During the photorearrangement the truns/cis ratios of starting phosphite (14) and product phosphonate (15) are unchanged as is consistent with the generation of a phosphinyl radical that is configurationally stable at pho~phorus.~'
R ci+(R,R)-(15)
cis(R)-( 16)
0 H Me cis(R,S)-(14)
Reactions of various types of tervalent phosphorus compounds with iron(II1) complexes in the presence of ethanol have been examined kinetically, showing that single electron transfer from the former to the latter is followed by rapid reaction of the resulting trivalent phosphorus radical cations with et han01.~ Peak oxidation potentials E-p(,,) of acyclic and cyclic phosphinites, phosphonites, and phosphites have been measured by cyclic voltammetry. The inductive effect of the ligands attached to the phosphorus is a primary factor to determine E-p(,,) of these compounds. The geometry of the compound is another important factor; E-p[,,, is lowered when the compound adopts a geometry in which the phosphorus lone-pair orbital overlaps with the adjacent oxygen p - ~ r b i t a l . ~ ~ The hydroperoxide decomposing ability and the hydrolytic stability of some HALS-phosphite stabilisers and some of their hydrolytic transformation products have been investigated by means of P-31 NMR spectroscopy. All HALS-phosphites, including those bearing sterically hindered phenolic substituents proved to be efficient hydroperoxide decomposers. HALSphosphites with tertiary HALS moieties are more effective than comparable compounds with secondary HALS groups. The hydrolytic stability of HALSphosphites is much higher than those of common phosphites. The path of hydrolysis of HALS-phosphites was established. In a first step the phenolic moieties are substituted followed by a fast removal of one hindered piperidine
86
Organophosphorus Chemistry
group to give the corresponding hydrogen phosphonates. These compounds are hydrolytically stable due to their betaine structure with increased electron density at the phosphorus atom.33
References 1
4
Proceedings of the Fourteenth International Conference on Phosphorus Chemistry, ed. F.H. Ebetino, Phosphorus, Sulfur, Silicon, 1998. 0. Dahl, ‘Tervalent Phosphorus Acid Derivatives’, in Organophosphorus Chemistry, Vol. 28, ed. D.W. Allen and B.J. Walker, Royal Society of Chemistry, Cambridge, 1998. Comprehensive Heterocyclic Chemistry II, ed.-in-chief A.R. Katritzky, C.W. Rees and E.F.V. Scriven, Elsevier Science, Oxford, 1996. M. Stolmar, C. Floriani, A. Chiesi-Villa and C. Rizzoli, Inorg. Chem., 1997, 36,
5 6
A. Alexakis, J. Vastra and P. Mangeney, Tetrahedron Lett., 1997,38,7745. A. Alexakis, J. Vastra, J. Burton and P. Mangeney, Tetrahedron: Asymmetry,
7
M. Mikolajczyk, P. Lyzwa and J. Drabowicz, Tetrahedron: Asymmetry, 1997, 8,
8 9 10 11 12 13
A.K.H. Knobel, J.H. Escher and A. Pfaltz, Synlett., 1997, 12, 1429. W.Adam and L. Blancafort, J. Org. Chem., 1997,62,1623. R . Kadyrov, D. Heller and R. Selke, Tetrahedron: Asymmetry, 1998,9, 329. S.D. Pastor and S.P. Shum, Tetrahedron: Asymmetry, 1998,9,543. G.A. Russell, J.U. Rhee and W. Baik, Heteroatom Chem., 1998,9, 201. 1.1. Gems, M.G. Gorbunova, V.P. Kukhar and R.Schmutzler, J. Fluorine Chem.,
14 15
A. Heydari, A. Karimian and J. Ipaktschi, Tetrahedron Lett., 1998,39,6729. D. Simoni, F.P. Invidiata, M. Manferdini, I. Lampronti, R. Rondanin, M. Roberti and G.P. Pollini, Tetrahedron Lett., 1998,39,7615. R. Nikolova, A. Bojilova and N. A. Rodios, Tetrahedron, 1998,54, 14407. D. Albouy, A. Brun, A. Munoz and G. Etemad-Moghadam, J. Org. Chem.,
2 3
1694.
1997,8, 3 193.
3991.
16 17
1998,90,1.
1998,63,7223.
18 19 20
P.P. Onysko, Russ. Chem. Bull., 1998,47, 1763. A.A. Tolmachev, A.S. Merkulov, A.A. Yurchenko, M.G. Semenova and A.M. Pinchuk, Russ. Chem. Bull., 1998,47, 1749. A.B. Ouryupin, LA. Rakhov and T.A. Mastryukova, Uspekhi Khimii, 1998, 67, 827.
21 22
M. Ohff, J. Holz, M. Quirmbach and A. Borner, Synthesis, 1998, 1391. E.J. Nurminen, J.K. Mattinen and H. Lonnberg, J. Chem. SOC., Perkin Trans. I ,
23 24 25 26 27 28
Y . Hayakawa and M. Kataoka, J. Am. Chem. SOC.,1997,119,11758. D.Q. Niu, M.J. Chen, H. Li and K. Zhao, Heterocycles, 1998,48,21. J.W.Perich, Lett. Peptide Sci., 1998,5,49. E. Marsault and G. Just, Nuclesides Nucleotides, 1998, 17,939. D. Katalenic and M. Zinic, Nuclesides Nucleotides, 1998, 17, 123 1. I. Bauer and W.D. Habicher, Phosphorus, Silicon, Sulfur, 1997,128,79.
1998,1621.
3: Tervalent Phosphorus Acid Derivatives 29 30 31 32 33
87
C. Scheuer Larsen, B.M.Dahl, J. Wengel and 0. Dahl, Tetrahedron Lett., 1998, 39, 8361. W. Bhanthumnavin, A. Arif and W.G. Bentrude, J. Org. Chem., 1998,63,7753. S . Yasui, K. Itoh, M. Tsujimoto and A. Ohno, Chem. Lett., 1998, 1019. S . Yasui, M. Tsujimoto, M. Okamura and A. Ohno, Bull. Chem. Soc. Jpn., 1998, 71, 927.
I. Bauer, S. Korner, B. Pawelke, S. A1 Malaika and W.D. Habicher, Polymer Degrad. Stability, 1998,62, 115.
4
Quinquevalent Phosphorus Acids BY B. J. WALKER
1
Introduction
An electronic search of the Chemical Abstracts database for the period under review produced well in excess of one thousand patents and references. In view of this the current review, although hopefully balanced, is clearly selective. Biological aspects of quinquevalent phosphorus acid chemistry, quite separate from nucleotide chemistry, continue to increase in importance. Throughout this year's report, although not pretending to offer comprehensive coverage of these aspects, there is an attempt to reflect this. Tetra-co-ordinate phosphorus compounds continue to be the major source of transition state analogues for the generation of abzymes, etc. A wide variety of natural and unnatural phosphates, especially those of carbohydrates, and their phosphonate and phosphinate, particularly fluorinated, analogues have been synthesized, usually with some biologically-related purpose, and the enormous interest in phosphorus analogues of all types of amino acids continues. The importance of enantiometric synthesis is illustrated in many of these reports. A recent patent addresses the reduction of undesirable tastes in foods, pharmaceuticals, etc. by the addition of phosphates, thiophosphates, and phosphonates, which act as inhibitors of intramolecular phosphatase enzymes of taste cells. There has been continuing and increasing interest in approaches to easierhafer nerve gas hydrolysis (particularly metal cation-catalysed and biological approaches), in dendrimers, and in both cyclic and acyclic ligands containing phosphorus(V) acid-functional groups. Perhaps it is a reflection of the extent to which organophosphorus chemistry has been investigated that, outside the above areas, little new chemistry has been reported. 2
Phosphoric Acids and their Derivatives
2.1 Synthesis of Phosphoric Acids and their Derivatives - Simple phosphorylation reactions continue to be used in many syntheses of phosphates and derivatives. A range of perfluoroalkyl- and perfluoro-alkylethersubstituted aryl phosphates (1) and phosphonates have been synthesized by reaction of the appropriate phenol with a phosphorus halide.' 0-Alkyl N , O arylphosphoramidates, e.g. (2), have been synthesized by the reaction of Organophosphorus Chemistry, Volume 30 0The Royal Society of Chemistry, 2000 88
4: Quinquevalent Phosphorus Acids
89
phenol and aniline derivatives with alkyldichloro phosphites to form phosphoramidites, followed by oxidation with 3-chloroperoxybenzoic acid.2 The method was applied to the synthesis of a N,O-arylphosphoramidatetransition state analogue for carbamate hydrolysis. Phosphate diesters (3) carrying a 4-tert-butylcalix[4]arenegroup have been synthesized and shown to selectively transport lithium cation^.^ The photolysable sphingosine 1-phosphate derivative (4)has been prepared and used in experiments which demonstrate that DNA synthesis is stimulated when caged SSP-loaded cells are ill~rninated.~ Cyclic phosphates, e.g. (6), as well as phosphites, sulfites, and sulfates, have been synthesized in good to excellent yields by room temperature reaction of phosphoryl chloride with hypervalent silyl derivatives, e.g. (5).5 The first chiral tetrathiophosphate derivative (7) has been prepared by the reaction of tetrabutylammonium camphorsulfonate with P&O, and characterized by X-ray crystallography.6
Reports of labelled terpene phosphates include two new I3C-labelled farnesyl diphosphates7 and 13C-enriched geranylgeranyl diphosphate, the latter from [4-13C]-3-methyl-3-butenyldiphosphate using coupled enzyme reactions.* The
90
Organophosphorus Chemistry
stereochemistry of the methyVmethylene elimination in the enzyme-catalysed cyclization of geranyl diphosphate (8) to give (4Qlimonene (9) has been studied by a combination of 'H and 2H NMR and radiochemical technique^.^
Numerous cyclic derivatives have been prepared. Those worthy of mention include the novel chiral phosphoric triamide (10) which, following lithiation, undergoes regio- and diastereo-selective reactions with various electrophiles.l o The chiral cyanohydrin phosphate derivative (11) offers entry into a range of optically active cyanohydrins.' Deprotonation of (1 1) followed by reaction with electrophiles gives crystalline products with high d.e.s in good yields and 0-deprotection is readily achieved without racemization. The cyclizations of L-(+)-prolinol with phosphoro- and thiophosphoro-dichloridates gave 1,2,3azaphosphaoxa-bicyclo[3.3.0loctanes ( 12) as unequal mixtures of diastereoisomers which were resolved by crystalization or chromatography. l 2 A new macrocyclic phosphate, dotriacontan- 1,32-diylphosphate, has been synthesized and its bilayer and monolayer properties investigated. Diastereoselective syntheses of 'pre-activated' analogues of the anticancer drug cyclo-phosphamide include that of the bicyclic compound (13).14 The phosphoro-diamidatesubstituted glycoside (14) has been prepared as a potential prodrug of cyclophosphamide and ifosfamide.l5 In the presence of carboxylate esterases, (14) generates the active metabolites of the drugs. The synthesis of several nitrobenzyl-based photosensitive compounds (15) carrying the phosphoramide mustard function common to all these drugs has been reported! The nitrobenzyl moiety was structurally varied to find the most promising prodrug candidates with respect to photorelease and activity of the alkylating species. Dendrimers are a topic of current interest. Examples of reports of phosphorus-containing compounds include a variety of phosphate-, phosphite-, phosphonate- and ylide-terminated structure^'^ and the first regular 'layer-block' dendrimer 1-[Gn] built by polymerizing hydroxybenzaldehyde alternatively with (16) and (17). The latter dendrimers have been characterized up to the fourth generation by 31PNMR. Chemoselective grafting of allylic and propargyl groups into the internal layers of phosphorus-containing dendrimers of generation 1 and 4 allows up to eighteen of these functionalities to be covalently incorporated when and where required.I9
'
'
'
91
4: Quinquevalent Phosphorus Acids
(12) X = 0,S; R = OEt, SEt, OPh, NEt2 etc.
(1 3)
(16) X - S (17) X = O
A large number of reports relating to inositol phosphates have appeared and the following is a small selection. Another report of the synthesis of all nine regioisomers of myo-inositol bisphosphate uses various isopropylidene and benzoyl inositol derivatives as intermediates20 3-Position modified analogues (18) of myo-inositol 1,4,5-trisphosphate have been synthesized for use in the investigation of the polyphosphoinositide pathway for cellular signalling.2’A concise synthesis of biologically active D-myo-inositol 1,4,5-trisphosphate (19) has been reported and involves only five steps from myo-inositol and minimal chromatography.22myo-Inositol 4,6-cyclic-1,5-triphosphate (20) has been prepared from myo-in~sitol.~~ No competitive inhibition of [3H] inositol 1,4,5triphosphate binding was observed over a wide range of concentration. The 1,2,6-trisphosphate (21) has synthesis of 5-deoxy-5,5-difluoro-myo-inositolbeen reported.24A number of clustered disaccharide polyphosphate analogues of adenophostin A, an agonist of-D-myo-inositol 1,4,5-trisphosphate receptor (IP3R), have been prepared as new potential ligands for IP3R.25An efficient synthesis of the enantiomers of myo-inositol 1,3,4,5-tetrakisphosphatehas been achieved by direct chiral desymmetrizationof myo-inositol orthoformate (22).26 Two enantiomeric pairs of myo-inositol 1,2,4,SY6-pentakisphosphate (23) and 1,2,3,4,5-pentakisphosphate(24) have been efficientlysynthesized by the lipase catalysed acetylation of 1,2:5,6-di-0-isopropylidene-myo-inositoland a benzoyl migration procedure.27 Both 2- (25) and 5- (26) diphospho-myoinositol pentakisphosphates, which are intracellular mediators, have been synthesized in good yield from the available bis-disiloxaamylidene derivative of myo-inositol.28A route to chiral, cyclopentane-based congeners of the second messenger 1D-myo-inositol 1,4,5-trisphosphate(27) and its metabolite, 1~ - m y o inositol 1,3,4,5-tetrakis-phosphate(28), from D-xylose has been described.29
r q
92
Organophosphorus Chemistry
ROQ
la2-
0
OH
II
2-QPO
"OH
2-02pO'
0
o'/po2z-
(18) R = Me, Et, P r , CH2C@'-
(19)
0
O
H
OH
(23) R' = H, R2 = PO(OH)2 (24) R' = PO(0H)p. R2 = H
(22)
0 II
OR'
0
OR2
(26)
! ! R' = P(O)(ONa)*, R2 = -T-O-P(ONa)2 R'
0"5(0H)2
(H0)2;0&0R1
oToo
(25)
'OH
' 0/P022-
W
!as
0
OH
0
8 : = -T-O-P(ONa)2,
ONa
0
HO (27) R = H
E
(28) R =POz2-
R2= P(O)(ONa)2
ONa
Membrane-permeable esters of various inositol polyphosphates have been synthesized and used in biological studies3*and the synthesis of 1-0-stearoyl2-O-arachidonoyl-sn-glycer-3-y-~-myo-inositol 3,4,5-tris-phosphate and its stereoisomers has been reported.31 6-0-(2-Amino-2-deoxy-a-~-glycopyranosy1)-D-myo-inositol 1-phosphate (29) and the corresponding 1,2-cyclic phosphate, which has been proposed as part of an insulin second messenger glycoinosito1 phosphate, have been synthesized.32 Numerous reports concerning phosphatidylinositols, the corresponding phosphates and related structures have appeared. 1~-3-Deoxy-(30) and 1 ~ -
93
4: Quinquevalent Phosphorus A c i h
HO
Y XQ
HO
5.4(A-5H31 Fm15H31
HO' OH
(29)
(30) X = H, Y = OH (31) X = Y = H
2,3-dideoxy- (31) phosphatidylinositols have been synthesized from protected v i b ~ r n i t o l sCompounds .~~ (30) and (31) are of interest as metabolites and as inhibitors of cancer colony formation. Substrate analogues of early intermediates in the biosynthetic pathway of glycosylphosphatidylinositol membrane anchors have been prepared.34 Examples of the synthesis of phosphatidylinositol phosphates include that of L-a-phosphatidyl-D-rnyo-inositol 5phosphate and the corresponding 3,5-bisphosphate, from methyl a-D-glycop y r a n o ~ i d e .An ~ ~ efficient synthesis of L-a-phosphatidyl-D-rnyo-inositol3,4bisphosphate (33), an intracellular messenger, in six steps from the cyclitol (32) has been reported.36 9-Fluorenylmethyl acts as a useful phosphate protecting group. The function is introduced by reaction of difluorenylmethyl phosphoramidate with the appropriate alcohol followed by oxidation (Scheme l).37This strategy has been applied to the synthesis of a dioleoyl analogue of phosphatidylinositol4,5-bisphosphate.A molecule with the currently accepted structure (34) of natural phosphatidylinositol 3,4,5-triphosphate has been ~ynthesized.~~ Dipalmitoyl derivatives (35) and (36) of 3-phosphorylated rnyoinositol phospholipids and their enantiomers have been synthesized for use as biological probes.39
0 6
0 II
OH
H H O o u o 0 (32)
OR '0-P-0
I
OH ONa (33) R = CO(CH2)&le
Dihydroxyacetone phosphate (37) and bromoacetol phosphate (38) have been synthesized from 1,3-dibromoacetone.'" Benzyl- and acetyl-protected glycosyl dimethyl thiophosphates have been conveniently prepared from the corresponding 1-hydroxy sugars in good yield!' The thiophosphates act as particularly stable but eficient glycosyl donors in the presence of various promoters. Glycosyl-N-phenyl diethyl phosphoramidates (39), which are readily available via the Staudinger reaction of glycosyl diethyl phosphites
Organophosphorus Chemistry
94
I o//P(oFm)2
0
II Reagents: i, (Fm0)2PNPr'2; ii, 1 wtetrazole; iii, CI
Scheme 1
f:
(H0)2PO' . V O H O " OR
(35) R = H
(36)R = PO(OH)2
X
L
O
,
O ,H
0
(37) X = OH (38) X = Br
NPh
II YLO-Y-OEt OEt
ROH, TMSOTf,-78 "C. EtCK
yLoR
(39)
with phenyl azide, act as useful glycodization reagents on reaction with hydroxy compounds.42Pyran analogues, e.g. (40), of GLA-60, one of several 4-O-phosphono-~-glucosamine derivatives showing the activity of liposaccharides (LPS), have been ~ynthesized.4~ Monophosphates of 3-deoxy-~mnnno-oct-2-ulosonic acid and related structures have been prepared.44These compounds provide the linkage of the core oligosaccharide in LPS. L-Glycerophosphate oxidase has been co-immoblized with catalase and the combined system used under aerobic conditions to synthesize dihydroxyacetone phosphate (42) from L-a-glycerylphosphate (4 1).45 The phosphate (42) was trapped in an aldolase reaction with glyceraldehyde to give fructose and sorbose phosphates (Scheme 2). Chemical and enzymic syntheses of 1-deoxy~-xylulose-5-phosphate(43) have been reported.46The availability of (43) will facilitate mechanistic studies on a variety of biosynthetic pathways.
4: Quinquevalent Phosphorus Aciak
95
on o
0 II
The number of reports of work on phospholipids, phosphocholines and related compounds continues to grow and the following is a small selection. A phosphotriester approach has been used to synthesize the complex phospholipid cardiolipin, specifically labelled with 2H at C-1 of the glyceryl head Novel cyclic phospholipid analogues containing thio or seleno phosphate-phosphonate linkages have been synthesized in good yield by a convenient one-pot procedure utilizing tris(diethy1amino)phosphine activated by iodine as the phosphorylating and ring-closing reagent .& Chemoenzymic methods have been used to synthesize phospholipids incorporating acetylene fatty acid side chains.49 Peracetylated a-glycosyl-H-phosphonates(44)have been prepared and used in the synthesis of phosphate diesters of 25-hydroxycholester01.~~ Phosphatidylcholines (49, carrying methyl substituents on the fatty acid side-chain, have been synthesized. The surfactant characteristics of (45) are determined by the number of substituent methyl groups. A new and practical method for the synthesis of gram quantities of the cytosolic phospholipase A2 substrate (46) has been reported.52
2.2 Reactions of Phosphoric Acids and their Derivatives - The reaction of chlorophosphates with strong nitrogen bases has been in~estigated.~~ For example, the cyclic chlorophosphate (47) reacts with DBU to give the phosphonate salt (48), the structure of which was determined by X-ray ~rystallography.~~ The reaction of phosphorus pentafluoride with phosphorodichloridic acid and its silyl ester has been studied by 19F and 31P NMR.54
96
Organophosphorus Chemistry
0-
(45) R' = R2 = R3 = R4 = Me or H
0
(46) [AA] - =
While the acid gave products which were identified, no reaction was observed for the ester.
The hydrolysis of phosphate esters is a subject of active interest, not least because of the need for improved, safe methods of nerve gas disposal. An example of this is a report of high rates of hydrolysis of phosphate diesters observed in the presence of large excesses of hafnium(1V) and zirconium(1V) ions.55 The hydrolysis of phosphate diesters is also strongly accelerated by thorium(1V) cations in Brij m i c e l l e ~ For . ~ ~ example, the rate of hydrolysis of bis(4-nitrophenyl) phosphate is increased by approximately 2.8 x lo9 fold. The 1,haphthyl phospho-triester (49) is one or two orders of magnitude more reactive to nucleophiles than 4-nitrophenyldiphenyl phosphate, the normal model used as a simulant for studies of reactions of nerve gases.57A chemical model has been reported for the enzymic mono de-alkylation of parathion (50) by glutathi~ne-S-transferase.~~ The model involves the reaction of parathion with thiophenol in the presence of triethylamine. Phosphate buffers are widely used in studies of nucleophilic substitution reactions and such buffers are known to catalyse the decomposition of various active acyl compounds. Detailed studies of the extent to which phosphate acts as a nucleophile and general base towards activated esters and thioesters has now been re-
4: Quinquevalent Phosphorus Aciak
97
The generation of energy-rich acetyl phosphate ( 5 1) by acylation of n-decyl phosphate in an aprotic solvent has been accomplished and the kinetics of the reaction investigated.6'
Trifluoromethanesulfonic acid-catalysed El reactions of secondary- and tertiary-alkyl phosphates show much higher regio- and diastereo-selectivity when carried out in smectic liquid crystalline phase media.62The reaction of bis(4-nitropheny1)phosphorazidate (52) in the presence of DBU provides a method for the one-pot conversion of alcohols to azides in good to excellent yield.63 The products of the alcoholysis of the bicyclic phosphoramidate (53) depend on P H . Compounds ~ (54) and (55) are formed under acidic and basic conditions, respectively. The conversion of P = S and P = Se functions into P = 0 with good stereoselectivity is often required. It is now reported that this can be achieved in excellent yield by reaction with perfluoro cis-2,3-dialkylo~aziridines.~~ The nucleophilic ring-opening of N-(diethoxy-phosphoryl) aziridines (56) with dianions derived from ethyl acetoacetate and 1,3-diketones has been reported.66 Acid-induced cyclization and dephosphorylation of the resulting products leads to substituted pyrrolines and pyrrolidines.
Organophosphorus Chemistry
98
Halogen-metal exchange-induced 1,3-phosphorus migration of 2-bromovinyl phosphates, e.g. (57), offers a new route to g-keto-phosphonates, e.g. (58), in moderate yields.67 The N,N,N',N'-tetramethyl-phosphorodiamidate function, e.g. in (59), can be cleaved reductively by lithium naphthalenide to give the hydrocarbon of the alkoxy group as the major product.68Palladiumcatalysed alkoxycarbonylation of ally1 phosphates (60) gives the corresponding P,y-unsaturated esters (61) stereoselectively with inversion of configuration and in good yield.69 Similar reactions using chiral catalysts give products with moderate e.e.s. The [4+2] cycloaddition reactions of N-sulfinylphosphoramidates, e.g. (62), prepared from the corresponding phosphoramidites by treatment with N-(chlorosulfinyl)imidazole, have been in~estigated.~~ Reactions with 1,3-~yclohexadieneare diastereoselective in both the absence (>90:10) and presence (>95:5) of Lewis acids.
R
ROP(NMe2)2 (59)
4 x Li+[Naphth]'
THF
-
RH + ROH Major Minor
R' ,Ft'
CO (100 at.)
-
EtOH, PdL, Pr'ZNEt
b.
(611'CQEt
A study of the laser flash photolysis of P-(phosphatoxy)alkyl radicals (63), produced from the corresponding pyridine-2-thioneoxycarbonylesters (64), has been rep~rted.~' The results are interpreted as excluding the formation of diffusively free radical cation intermediates. Sensitized photoinduced electron transfer reactions of tri- 1-naphthyl phosphate and di- 1-naphthyl methylphosphonate give 1,l'-binaphthyl but no similar reaction occurs in the case of mono-naphthyl, or di- or tri-phenyl esters.72
4: Quinquevalent Phosphorus Acids
99
2.3 Selected Biological Aspects - In view of the increasing awareness of the importance of protein phosphorylation-dephosphorylation in biological control, the appearance of a new book on the subject is particularly welcome.73 Imidazole- and triazole-substituted ether phospholipids are reported to be highly potent growth inhibitors of a number of tumour cell lines in ~ i t r oThe .~~ anti-HIV activity of a variety of complex synthetic lipids, including phosphocholine lipids, and lipid-AZT conjugates has been investigated in a structure-activity study involving both wild-type and drug-resistant HIV- 1 viruses.75The data suggest that the optimum phosphocholine lipid compounds are significantly less toxic than AZT and have high potential as novel therapeutic agents for AIDS. A 31PNMR investigation of the interaction of 6-chymotrypsin with novel, optically active, axially and equatorially substituted cis-3-(2,4-dinitrophenoxy)-2,4-dioxa-3~5-phosphabicyclio[4.4.O]decan-3ones, e.g. (65), showed that only the equatoriaily-substituted isomer was an irreversible inhibitor of the enzyme.76 Feeding experiments have provided further information on the biosynthetic origin of various structural features of the complex phosphate-containing antibiotic moenomycin A.77
3
Phosphonic and Phosphinic Acids
3.1
Synthesis of Phosphonic and Phosphinic Acids and their Derivatives
3.1.I Alkyl, Cycloalkyl, Aralkyl and Related Acids - A highly enantioselective synthesis of phosphonates (67) from alkylphosphonic dichlorides, via methanolysis of the proline intermediates (66), has been reported (Scheme 3).78 What is claimed to be the first reported example of asymmetric hydrogenation of 1-arylvinylphosphonicacids and esters has appeared.79Various chiral, homogeneous Ru(I1) catalysts are used to give 1-arylethylphosphonic acids and esters (68) with e.e.s up to 86%. The Michaelis-Becker reaction of secondary phosphite anions with alkyl halides to give phosphonates is potentially superior to the Arbusov reaction since it avoids the possibility of mixed products, but generally gives poor or even zero yields with tertiary or benzylic halides. It has now been reported that the use of diphenyl rather than dialkyl phosphites in the presence of DBU allows the synthesis of both benzyland trityl-phosphonates in good yields.** An alternative umpolung approach, involving bis-lithiation of 2-(methy1)thiophenol followed by reaction with dialkyl chlorophosphates, has been used to prepare (2-mercapto-pheny1)methanephosphonates (69).81 The recently synthesized benzylic bisphosphonates (70) represent the first artificial receptor molecules for alkylguanidinium
Organophosphorus Chemistry
100
8
i. ii
RPCh
0 N "Jf
II 0 0
iii
RP<
RY
__.t
EQC4-J (67) 93%e.e.
(66) 97% 8.8. Reagents: i, ~ c o 2 E t ii, : H
No,
Scheme 3
ions.82Compounds (70) bind by forming 1:1 chelate complexes stabilized by a planar network of electrostatic interactions and hydrogen bonds, analogous to aspects of the postulated model for RNA-protein recognition of the AIDS virus.
[Rul'
ArA!(OR,, (68)
SLi
0
R4N+
0
-':;-
CH20 - X - @ - 1 2 - $ f -
Me0
(70) X = S, SO,
R4N+ OMe
The vinylphosphonate (7 I), substituted with a chiral sulfoxide group, forms cyclopropane derivatives, e.g. (72), as single diastereomers on reaction with dimethylsulfoxoniummethylide (73) or diphenylsulfoniumisopropylide (74) or diphenyldiaz~methane.~~ The novel cyclobutyl-phosphonic acid (76) has been synthesized from diethyl 3-oxocyclobutylphosphonate (75) as a potential inhibitor of imidazole glycerol phosphate dehydrogenase for use as a herbi~ i d e . The * ~ stereochemistry of (76) was established by NOE experiments. 3.1.2 Alkenyl, Alkynyl, Aryl, Heteroaryl and Related Acids - In spite of being useful and increasingly used intermediates, methods of synthesis of vinylphosphonates are still restricted. A mild, stereoselective synthesis of pphosphonylacrylates (77) is provided by the reaction of trimethyl-silyloxy tervalent phosphorus derivatives with or-halogeno-acrylates and arylonit r i l e ~ . *It~is also reported that 1-alkyl- and 1-phenylvinyl-phosphonates(79) are conveniently synthesized by the reaction of S-(P-oxoalkyl) dithio-
101
4: Quinquevalent Phosphorus Acids
phosphates (78) with dialkyl phosphite anions.86 A one-pot ozonolysisintramolecular aldol condensation of P-oxo-w-alkenylphosphonates has been used to synthesize or-phosphonato-a$-unsaturated cycloenones, e.g. (80), in moderate to good yield.87 A Z-stereoselective synthesis of perfluoroalkylated enynylphosphonates (8 1) has been achieved via nucleophilic addition of lithium acetylides to perfluoroacylated bisphosphonates, followed by elimination of phosphonate anion.88 3,4-Bisphosphono-1,2,4,S-hexatrienes (82) have been prepared by the reaction of chlorophosphite with 2,4-hexadiyne-1,6di01s.~~ Compounds (82) undergo intramolecular [2+2]-cycloaddition to form 1,2- bis(diethylphosphonyl)-3,4-bis(isopropylenyl)cyclobutene(83).
-
(R10)2POSiMe3 + CH2=CX*
0 II
(R'0)2PCH=CHR2
(77)
= C a R , CN, X = Hal
S
II (EtOhP-S-CH2COR (78)
?
(EtO)*PNa
0
II (EtO)2PCR=CH2 (79) R = Ph, alkyl
A variety of arylphosphonates have been prepared, mostly by standard methods. Efficient phosphonylation of aryl halides, to give diethyl arylphosphonates (84), has been achieved by palladium-catalysed reaction under the influence of microwave radiation in a teflon-coated autoclave.90 New electron donor-acceptor phosphonates, e.g. (85), have been synthesized by Heck-type chemistry for use in new, non-linear optical material^.^' Similar palladium-catalysed phosphonylation has been used to synthesize racemic and optically active forms of the bis(diethoxyphosphory1)bisnaphthalenediol (86).92 Diphenylphosphinic acid can be added to terminal alkynes in the presence of a ruthenium carbonyl catalyst to provide a regioselective synthesis of alkenyl diphenylphosphinates (87).93 Three new arylphosphinate ligands, e.g. (88), based on benzimidazole have been synthesized with a view to the
102
Organophosphorus Chemistry
(EtO)zy50
M@C=C=C-C=C=CMe2 I
O=P(OEt)2
selective co-ordination of zinc(I1) in a tetrahedral e n ~ i r o n m e n t The . ~ ~ 1,8bis(diethylamino)phosphinylnaphthalene (89), prepared from 1,8-dilithionaphthalene, forms the anhydride (90) on treatment with gaseous hydrogen chloride and attempted recrystallization, presumably via oxidative hydrol y ~ i sThe . ~ ~synthesis, via phosphonylation of the corresponding phenols, of a variety of phosphonated cavitands, e.g. (91), has been reported.96The configuration of all the diastereomers produced in these reactions was determined by a combination of ‘H, 31PNMR spectra and 13CN M R relaxation times.
Examples of heteroaryl analogues synthesized include the two terdentate chelating agents (92) and (93).97Complexes of these ligands with Fe(I1) and Fe(II1) have been studied as catalysts for the air-oxidation of hydrogen sulfide to Sg. A variety of 2,2’-bipyridylbisphosphonates,e.g. (94), have been prepared, mainly using homogeneous palladium catalysts for nuclear phosphonyla t i ~ n . ~C-Phosphorylation * of N-vinylpyrroles and analogues occurs at both the vinyl group and the 2-position of the pyrrole ring.99The chemistry of the resulting phosphorylated compounds has been investigated.
103
4: Quinquevalent Phosphorus Acids
R'
(91) R'
= H, Me, Br;
R2 alkyl P
3.1.3 Halogenoalkyl and Related Acids - Due mainly to their potential biological activity, or their use in the synthesis of such compounds, the large majority of examples in this area are fluoroalkyl compounds (fluorinated amino acid analogues are discussed in Section 3.1 5). Methods involving electrophilic fluorination continue to be widely used. Examples include an investigation of the scope and limitations of the reaction of benzylphosphonate carbanions with N-fluorobenzene-sulfonimideas a route to aryl(difluor0methyl)phosphonateslO" and selective, electrophilic mono-fluorination and -chlorination in a one-pot procedure.10' The free radical addition of fluorodibromomethyl-phosphonatesand the Pd(0) and Cu(0) catalysed additions of fluoroiodomethylphosphonates to alkenes have been investigated as approaches to a-fluorophosphonates.lo2 The synthesis, characterization and reactivity of a number of derivatives of dichlorofluoromethylphosphonicacid (95) have been reportedIo3and both saturated and unsaturated (96) arylalkylmonofluorophosphonates have been prepared as potential myo-inositol monophosphatase ligands.lo4 The addition of phosphonyl or thiophosphonyl radi-
104
Organophosphorus Chemistry
(92) X=CO2H (93) X = PO(OH)2
RQ+ Y
(97)
Y
Y'
'Y (98) X = 0 (99) x = s
cals to carbohydrate-based gem-difluoroenol ethers (97) has been used as a new route to difluoromethylene-phosphonates (98) and -phosphonothioates (99) in moderate to good yields.*05 P-Ketodifluoromethylphosphonates(101) have been synthesized by acylation of the zinc difluoromethylphosphonate carbanion (1 OO), itself generated by metallation of the bromodifluoromethylphosphonate.Io6 Treatment of dibromofluoromethylphosphonate with butyllithium at low temperature affords a quantitative yield of the lithiated fluoromethyl-bisphosphonate (102).lo7 Reactions of (1 02) with alkylating and halogenating reagents or with carbonyl compounds give, respectively, substituted fluoromethylbisphosphonates or fluorovinylphosphonates. A study involving a variety of approaches to the synthesis of dichloromethylbisphosphonate monoesters (103) has been reported.I0*
E
(EtO)2PCF2ZnBr
R
(EQ2PCFBr2
BuLi
-
0 0 II It (Et012P-CF2CR
RCOX
"1 /L'
[
(Et0)2P 2C,
+ CLiFBr2 + LiBr
(102)
0
(103) R = PP, P+, hex, Ph
3.1.4 Hydroxyalkyl and Epoxyalkyl Acids - The synthesis of acids of carbohydrate derivatives is included in this section.
.
105
4: Quinquevalent Phosphorus Acids
Hydrophosphonylation of ketones and aldehydes continues to be used as a convenient and efficient route to a-hydroxyalkyl-phosphonates and -phosphinates. Asymmetric examples include a detailed examination by H and 31PNMR spectra of the the catalytic reaction with aldehydes using a diazaphospholidine-based chiral derivatizing agent log and a report of the use of various chiral binaphthol-modified lanthanide alkoxides as catalysts. lo The latter reactions give, at best, moderate e.e.s. Low-valent cobalt complexes have been used in Reformatsky-type reactions of a-halogenoalkylphosphonates with aldehydes and ketones to give a variety of P-hydroxyalkylphosphonates and amino(104). Several examples of asymmetric dihydroxylation' 12-' hydroxylation * l4 of vinyphosphonates have been reported. Dihydroxylation of 1-(E)-alkenylphosphonates (105) with a- and P-AD-mix to give threo-a,Pdihydroxy-phosphonates has been investigated. The enantioselectivity and chemical yields of the reactions were significantly improved when it was carried out with dimethyl- rather than diethyl-phosphonates. The asymmetric aminohydroxylation of P-substituted (E)-vinylphosphonates under the Sharpless protocol provided the P-substituted P-tosylamino-a-hydroxyethylphosphonate ester (106) with moderate to good enantiomeric excess.' l4 The corresponding phosphonic acid was obtained in 6 1% yield after hydrolysis.
'
'
'
''*
0 II
R'COR2 + (Et0)2PCR3R4 I X
Co(ON-4 7
0
OH
In the presence of potassium fluoride, diethyl phosphite adds preferentially to the si-face of the carbonyl group of the chiral chalcone epoxide (107) with a d.e. of 50%, to give the a-hydroxy P-epoxyphosphonate (108) as the major product. A new stereoselective route to substituted 1,2-epoxyaIkylphosphonates (109), involving oxidation of the corresponding alk- 1enylphosphonates with ethylmethyldioxirane, has been reported. I 6 There have been many reports of the synthesis of phosphonate-substituted carbohydrates and related compounds, primarily analogues of phosphate metabolites. The phosphonate analogue (1 10) of a-L-rhamnose 1-phosphate has been synthesized stereoselectively through the reaction of 2,3,4-tri-Obenzyl-L-rhamnopyranose with tetraethyl methylenediphosphonate carbanion followed by deprotection. l7 A single step approach for the diastereoselective synthesis of C-glycosidic sugar phosphonates (1 11) in moderate yield has been developed by utilizing a free radical coupling of the glycosyl radical to vinylphosphonates. l8 The method is reported to be applicable to sugars, deoxysugars, aminosugars and oligosaccharides. An efficient asymmetric synthesis of
'
'
'
106
Organophosphorus Chemistry
a water-soluble, phosphonate analogue (1 12) of phosphatidylinositol 4,5-bisphosphate has been reported and involves Michaelis-Becker coupling of the secondary phosphite of inositol diphosphate with protected 4-iodo-1,2-dihydroxybutane. l 9 Cyclic phosphonates (1 13) of ribose and arabinose have been prepared by Lewis acid-catalysed addition of trimethyl phosphite to protected D-threose. 120 Phosphonate analogues of 2-deoxyribose have been synthesized by Lewis acid-mediated reaction of the appropriate glycosyl donors with diisopropyl hydroxymethylphosphonate or triisopropyl phosphite. 121 5-Methylphosphono-D-arabinohydroxyiminolactone(1 14), an inhibitor of glucosamine-6P synthase, has been prepared in low overall yield by a long synthetic sequence.122The amine- or fluoride-catalysed addition of diethyl phosphite to 2,3-O-cyclohexylidene-~-glyceraldehyde leads to 1:2 mixtures of diethyl (1R,2R)-(115) and (lS,2R)-(116) 2,3-O-cyclo-hexyiidene-l,2,3trihydroxypropylphosphonates, which were separated by chromatography. 123 Reactions of phosphinoyl chlorides with D-glucofuranose in the presence of triethylamine give (8-phosphinate products with a uniform configuration at chiral phosphorus. 124 A short, stereoselective synthesis of three new azasugarderived phosphonates, e.g. (1 17), has been reported. 125 The new compounds are versatile intermediates for the synthesis of glycosyltransferase inhibitors. The aziridino-phosphonate (118) has been synthesized in 15 steps from D-lyxose with the ultimate aim of synthesizing new 2-amino-5-phosphonopentanoic acid analogues as potential NMDA receptor antagonists. 126 3.1.5 Oxoalkyf Acids - Although susceptible to hydrolysis, a-ketophos-
phonates (1 19) have substantial potential application in synthesis. They are readily prepared by the reaction of phosphites with acylating agents and a study of the synthesis of benzyl-a-ketophosphonates has been recently re~ 0 r t e d . One l ~ ~ of the few reported X-ray crystal structural studies of these compounds has shown the P-carbonyl bond in 2-iodophenyl-a-ketophosphonate (120) to be exceptionally long. 128
4: Quinquevalent Phosphorus Acids
107
N
I
OH
(117)
(118)
Cbz
A new route to a-fluoro-P-ketophosphonates(122), involving a-acylation of a-fluoro-P-carboxyphosphonate dianion ( 121) followed by de-carboxylation, has been r e ~ 0 r t e d .A l ~convergent ~ synthesis of the C15-C38 domain (123) of the marine natural product okadaic acid has been achieved in 19 linear steps and 0.3% yield from methyl 3-O-benzyl-a-~-altropyranoside. 30
'
0 0
II II RC-P(OR)p
0
0
II (EtO)2kF-C-0(121)
RCOCl
4%
0
0
II II (Et0)2P-CHFCR (122)
Michael addition of the carbanion of chiral hydrazone (124) to vinylphosphonates, followed by oxidation with ozone, provides a new route to 2,3disubstituted 4-ketophosphonates (125) with excellent enantioselectivity but poor to moderate diastereoselectivity (Scheme 4). 31 Alternatively the phosphonate carbanions generated in the initial Michael addition reaction can be trapped with alkylating agents to give, following oxidative cleavage, 1,2,3trisubstituted 4-ketophosphonates.
'
108
Organophosphorus Chemistry
T
O
M
e
Rl
i, 2
OEt 'OEt
(125) R'
( 124)
8
Reagents: i, LDA, THF; ii, R3*P(OEt)2;
iii, O3?CH2CI2, -78°C Scheme 4
3.1.6 Aminoalkyl and Related Acids - The Kabachnik-Fields reaction, which together with its many modifications is still widely used to synthesise aaminophosphonates, has been reviewed. 132 The review includes a discussion of the mechanism of the reaction and is followed by a report of the use of the method in the synthesis of a large number of compounds aimed at the generation of molecules with herbicide activity. A related reaction commonly used in aminophosphonate synthesis is the addition of secondary phosphites to imines. It has now been reported that both the Kabachnik-Fields reaction and the addition of phosphite to imines are catalysed by ytterbium triflate. The application of this method to asymmeteric synthesis using chiral amines has also been in~estigated.'~~ A similar approach, involving addition of phosphite to the a-ketophosphonate (126), has been used to prepare 2-amino-1-hydroxy-ethylene-1,l-bisphosphonic acid (127) and its N-methylated and N,N-dimethylated analogues. 34 N-Phosphinoylmethylaminoacid derivatives (128) have been obtained in high yield by N-halomethylation of the hexafluoroacetone-protected amino acids (129) followed by an Arbusov reaction. 135 Compounds (128) react with a wide range of nucleophiles to give unprotected N-phosphinoylmethylamino acids, amides, peptides, azapeptides, and hydroxamic acids. A new synthesis of a-aminoalkyl-phosphonates from vinylphosphonates involves aziridination using the iminophenyliodonane (130) in the presence of a copper catalyst, followed by reduction (Scheme 5). 136 The synthesis of another aziridine derivative, [2-(bromomethy1)aziridin-1-yl]methylphosphonate ( 131), has also
HNxo F3C CF3
(128)R3 and R4 = Ph or OMe
(1 29)
4: Quinquevalent Phosphorus Acids 0 II ( E t O ) 2 P w R + PhI=NTS ( 130)
1 09
i
0
(EtO)2PtjR It
ii
0 II
~
E (o'2 )pYR -
N Ts Reagents: i, CuOTf, MeCN, RT; ii, Pd/C, H2, MeOH, HC@NH4 Scheme 5
NHTs
been r e ~ 0 r t e d . lGlyphosate ~~ (132), the wide-spectrum herbicide, has been produced from glycolic acid by a chemoenzymic method.13*The biotransformation converts glycolic to glyoxylic acid and the latter is converted to glyphosate in aqueous solution by reductive amination in the presence of aminomethylphosphonic acid. 0 II
P
f P(oR)2
Br
?
(H0)2PCH2NHCH2C02H
(132)
(131)
Phosphonate analogues of tyrosine and tyrosine phosphate continue to be of substantial current interest. In the latter case this is largely due to the importance of phosphates of tyrosine-containing peptides and their interactions with phosphatases. For example, a new synthesis of fluorophosphonate analogues, e.g. (133) (Scheme 6), of phosphotyrosine by both solution and solid phase methods, has been r e ~ 0 r t e d . INew ~ ~ naphthyldifluoromethylphosphonic acids (134) and (135) designed to interact with protein-tyrosine phosphatase 1B arginine47, have been synthesized.140The new analogues show 7- to 14-fold greater binding affinity to the enzyme than the non-peptide analogue ( 136). The novel pyridone-based tyrosine analogue (137) has been designed and synthesized using a Pd-catalysed coupling of piodoalanine with N-(phosphomethy1)pyridone triflate (138) as the key step. (S)-a-Methyl-4-phosphonophenylglycine (139) has been prepared as one of a new class of selective antagonists of metabotropic glutamate receptors.142 A new synthesis, in 17 steps and 13% overall yield from (R)-pantolactone, of the NMDA receptor antagonist LY235959, (140), has been r e ~ 0 r t e d . I ~ ~
XNH
\
i,ii
MeO%
F F
Reagents: i, CH2N2; ii, CuCI, DMF, BrCdx
l(0Eth 0
Scheme 6
'NH
'
(133)
0
CF2P(OEt)2 II
Organophosphorus Chemistry
110
n
ri
(pr'o)2p>
F' 'F
BOCNH
OTf
Reports of the synthesis of analogues of acidic amino acids include a convenient preparation of the protected aspartic acid (143), in high optical purity, by addition of diallylsilyl phosphite (141) to the chiral lactone (142)? The synthesis of the diphenyl phosphonate analogues (144 of aspartic and (145) of glutamic acid has been r e ~ 0 r t e d . lThese ~ ~ analogues were found to function as irreversible inactivators of S. aureous V8 proteinase but exhibited no activity against Granzyme B.
(144) (145)
n =1 n =2
A wide variety of asymmetric and enantioselective syntheses of aminophosphonates and -phosphinates have been reported. Chiral analogues, e.g. (147), have been efficiently prepared with e.e.s of 87-92% by asymmetric hydrogenation of the prochiral N-acyl-a$-dehydroamino-phosphonates (146) Enantiomerically pure (2S,3R,4R)using PROPRAPHOS-Rh catalysts.
4: Quinquevalent Phosphorus Acids
111
ethoxycarbonylcyclopropylphosphonoglycine ( 149) has been synthesized with a key step involving a 1,4-addition of the chiral phosphonate carbanion (148) to ethyl 4-bromocrotonate (Scheme 7). 147 The addition of dialkyl phosphite anions to chiral sulfinimines (150) has been used in the asymmetric synthesis of aminophosphonates (151) and the corresponding phosphonic acids, with d.e.s up to 94%.1489’49Reductive cleavage of the nitrogen-sulfur bond in (151) gave the enantiomerically enriched aminophosphonate (152). 14* The catalytic, enantioselective hydrophosphonylation of cyclic imines to give (153) has been The most efficient catalysts are lanthanide binaphthyl-based, reported. giving e.e.s up to 98%. The lipase AP 6 hydrolysis of racemic a-chloroacetoxyphosphonates (154) gives the (S)-a-hydroxyphosphonates (155) which can be further transformed into single enantiomers of a-aminoalkylphosphonates.
i.ii
(148) Reagents: i, BrCH&H=CHC@R; ii, H,O+
Scheme 7
Phosphinic acid- (156), sulfoximine- and sulfone-based transition-state analogues have been synthesized and evaluated as inhibitors of E. coli y-glutamylcysteine synthetase. 52 The phosphinic and sulfoxime analogues were found to be potent ATP-dependent inactivators of the enzyme. A procedure for preparing novel phosphinopeptides (157) on a solid support has
112
Organophosphorus Chemistry
been d e ~ c r i b e d .The ' ~ ~ key step in the synthesis involves a conjugate addition of the tervalent form of a protected amino secondary phosphinic acid to a resin-bound acrylate. A variety of approaches to the synthesis of polyfunctionalized phosphinates, with the particular target of phosphinopeptides, have been in~estigated.'~~ The studies culminated in a successful synthesis of the phosphinic acid analogue (158) of glutathionylspermidine as an inhibitor of Gsp synthetase. Tri- and tetra-peptides (159), incorporating aminoalkylphosphinic acids, have been synthesized as transition-state analogues for D-alaD-ala-addingenzyme with a view to the development of new antibiotics.'55
Various cyclic and acyclic multifunctional derivatives of aminophosphonates have been reported, mostly for use as ligands. These include a series of calix[4]arene-based a-aminophosphonates, prepared by KabachnikFields reactions of the corresponding calixarene diamine.* The resulting compounds are highly selective carriers for the membrane transport of the zwitterion form of amino acids. New bifunctional, chelating aminophosphonic Other aminoacids, e.g. (160), have been synthesized as ligands for 153Sm.157 phosphorus acid derivatives prepared as metal radionucleotide-ligands for use in diagnostic imaging include the thiophosphinic acids (161).158The europium complexes of phosphinic acid-substituted cyclic ligands (162) have been synthesized and shown to be useful as luminescent chemosensors for measur3tP NMR and circularly ment of pH, and halide and hydroxide ions.*59*160 polarized luminescence studies on these ligdnds indicate that the configuration at the chiral carbon centre determines the helicity of the layout of the pendant arms and the macrocyclic ring conformation. lS9 Macrocyclic peptidyl
(161) R = P h , n =2; R-Me, n = 2 R=Ph, n = 3 ; R=Me, n = 3
4: Quinquevalent Phosphorus Acidrs
113
phosphonates, e.g. (163), have been designed and synthesized as inhibitors of penicillopepsin. 161v162
3. I . 7 Sulfur- and Selenium-containing Compounds - Lawesson's reagent (164) continues to be the reagent of choice for sulfurization. For example, reaction of (164) with 1,3,4-oxadiazoles and 1,2,4-triazoles at 100°C in toluene give, e.g. (165) and (166), res~ective1y.l~~ Compound (164) is reported to react with bis(alkyl/silylamino)-germanium(I1) (167) and -tin(II) (168) to give a variety of products, the structures of which were determined by X-ray crystallography in two cases.164The phosphonates (170) have been prepared from the S-methyl ketene acetal (169) and used as a synthetic equivalent of l-phosphonyl-2cyanoethene cation (17 1) to provide a new route to phosphonyl-substituted pyrazoles, isoxazoles, and pyrimidines. 65
R2N,
M
R*d
(167) M = G e (168) M = S n
3.1.8 Phosphorus-Nitrogen Bonded Compounds - 1H-Tetrazole selectively catalyses the sequential monoaddition of alcohol and amine nucleophiles to phosphonic acid dichlorides and so provides a convenient route to phosphonamidate esters (172) under mild conditions (Scheme 8).166 Monochiral N-
114
Organophosphorus Chemistry
diphenylphosphinyl aziridines (173) have been efficiently prepared from monochiral2-aminoalcohols by N-phosphinylation followed by cyclization (Scheme 9).167 Nucleophilic ring-opening reactions of (173) with a variety of nucleophiles take place in good yields.
H
Reagents: i, R'OH; ii, R2R3NH
(172)
Scheme 8
( 173)
Reagents: i, Ph2POCI. EtsN, CH2Cl2; ii, TsCI, EtsN, DMAP; iii, NaH. THF Scheme 9
A number of chiral compounds containing P-N bonds have been prepared, mainly as potential or actual catalysts for asymmetric synthesis. Examples include the diastereomerically pure 2-hydroxyphenyl-diazaphospholidineoxide (174), which has been used as a catalyst for the asymmetric addition of diethylzinc to aromatic aldehydes.168 A large range of chiral phosphinamides, e.g. (175), have been prepared and shown to act as a new class of catalyst for the asymmetric reduction of prochiral ketones with d i b ~ r a n e .The ' ~ ~ novel C2symmetric binaphthyl phosphorotriamides, e.g. (176), have been prepared and their physical properties investigated.170 Chiral N-diphenylphosphinyl-3quinolylamines (178) with up to 75% e.e. have been obtained by enantioselective alkylation of the imine (177) using dialkylzinc reagents in the presence of various chiral amino alcohols.17' The [4+2] cycloaddition reactions of Nsulfinylphosphoramidates (179), prepared by treatment of the corresponding phosphoramidates with N-(chlorosulfinyl)imidazole, and 1,3-~yclohexadieneto give (180) are reported to 'be highly diastereoselective in both the absence (90:lO) and presence (95:5) of Lewis acid. 172 Novel C-P-N rings, e.g. (182), have been prepared by cycloaddition reactions of diferrocenyl dithiadiphosphetane disulfide (18 1) with C-N multiple bonded compounds. 173
115
4: Quinquevalent Phosphorus Acids
0
R
O
3.1.9 Phosphorus-containing Ring Systems - The synthesis of a wide range of quinquevalent phosphorus acid derivatives, including many with P-containing ring systems, has been reported in the Chinese literature with the primary aim of producing new pesticides and herbicides.174In most cases these use wellestablished chemistry. The novel chiral receptors (183) and (184) have been synthesized with a view to the recognition of amino acid derivative^.'^^ Moderate levels of enantioselectivity are observed in binding experiments. The 2-phosphaindolizines (18 5 ) react with hydrogen sulfide and elemental sulfur to give new zwitterionic heterocyclic systems (186) (X = S).176 The analogous pyridinodiselenophosphinates(186) (X = Se) have also been prepared by the (187) which reaction of (185) with 1,3,2,4-diselenadiphosphetane-2,4-diselenide is a seleno-analogue of a Lawesson-type reagent. A new fused ring system (189) has been obtained from the reaction of substituted 1,2,3triazolium- 1-imide 1’3-dipoles (188) with Lawesson’s reagent. 177 Cyclic phosphonic anhydrides (190) are conveniently prepared by the reaction of phosphonyl dichlorides with bis( 0-sily1)phosphonates. 78
3.2 Reactions of Phosphonic and Phosphinic Acids and their Derivatives - The phosphonate group is reported to be stable under conditions which allow phenylsilane to reduce phosphine oxide functions to the phosphine in the same molecule.179 The reduction of phosphinic acids (191) to the corresponding
116
Organophosphorus Chemistry
R3
R4
phosphine followed by alkylation, most conveniently of the phosphineborohydride adduct, provides a route to a large variety of new phosphine and diphosphine ligands.’*O 0 II
R’R2POH
-
R’R2PH
-
[R’R2PH]BH3
R3X
R’R2PR3
PT:
QCO-C-P(OMe)2
Reactions of diazoalkylphosphonates continue to be used in synthesis. Thermolysis of (192) gives 1 -disubstituted amino-1 H-2-benzopyran derivatives
4: Quinquevalent Phosphorus Acids
117
(194) ( 195) Reagents: i, Rhz(0Ac)d; ii, DBU, CH2CI2, RCHO Scheme 10
(193) via Wolff rearrangement and ring closure.181The reaction has also been applied to heteroaryl analogues of (192). The Rh(I1)-catalysed reaction of triethyl diazophosphonoacetate with N-protected amino acid amides (194) provides or-aminoalkylphosphonates(1 95) and hence, via Wadsworth-Emmons olefination, dehydropeptides (1 96) (Scheme 10). 82 Chiral aziridino alcohols (197) can act as enantioselective-promoters for the addition of dialkylzinc reagents to N-(diphenylphosphinoy1)imines (198) to give phosphinimidates (199) and, following hydrolysis, amines with e.e.s up to 94Y0.l~~ N-Phosphinoyl imines (200) also react with allylsulfonium ylides to give trans-aziridines or cisaziridines at room or low temperatures, respectively. 84 The reactions proceed in high yields and with good stereoselectivity. The analogous, chiral phosphinoylaziridine (20 1), derived from D-norleucinol, has been used in the synthesis of (+)-monomorine (202). 85 Ring-opening reactions of enantiomerically pure N-phosphinoylaziridines (203) with carbon nucleophiles provide a route to a variety of chiral N-diphenylphosphinyl derivatives.
118
Organophosphorus Chemistry
Diastereoselectivity in the heterogeneous hydrogenation of phosphonosubstituted methylene-cyclohexanes (204) has been investigated.187 1-Seleno-2silylethene (205) undergoes stereoselective, SnCl4-promoted [2+ 11 cycloaddition to 2-phosphonoacrylates to give cyclopropylphosphonates in good yields. 88 Inverse-electron-demand,hetero-Diels-Alder reactions of a,p-unsaturated acylphosphonates (206) with enol ethers are catalysed by C2-symmetric bis(oxazo1ine)-Cu(I1) complexes to give (207) in high yield with excellent enantioselectivity (e.e.s up to 99%).' 89 The first examples of ring-closing metathesis reactions on a phosphonate template catalysed by a ruthenium alkylidene complex have been reported and used to synthesize the heterocyclic phosphonate (208).
Harger and others continue to investigate the mechanism of hydrolysis and rearrangement reactions of certain phosphonic and phosphinic acid amides. The P-bromomethylphosphonates (209) rearrange on treatment with methoxide.lg1 The mechanism is suggested to involve an intermediate azaphosphiridine oxide (210) which ring opens via P-N and P-C cleavage to give (21 1) and (212), respectively (Scheme 11). The present study investigates how steric effects influence the direction of ring opening. 0-Benzoyl N(dipheny1phosphinothioyl)hydroxylamine (2 13), on treatment with base, undergoes rearrangement with transposition of S and 0 atoms to give (215).192 The reaction is suggested to involve a three-membered cyclic intermediate (2 14) (Scheme 12). Methyl a-hydroxyiminobenzyl-N-tert-butylphosphonamidate (216) undergoes Beckmann rearrangement to give (2 17) when heated in toluene but fragmentation, probably via (218), to give the phosphoramidate
4: Quinquevalent Phosphorus Acids
119
Me I
OMe (212)
scheme 11
S
PbP(' NHOCOPh (213)
++
-
OCOPh
S-
/
Ph2?\
Ph,P
NOCOPh
Scheme 12
/
e Ph2P
\\Ns
(215)
'NSCOPh
(219) when heated in butanol (Scheme 13).193The results are interpreted to indicate a common intermediate in both reactions. The fluorenylphosphonamidic chloride (220) shows much higher reactivity towards DBUcatalysed nucleophilic substitution with secondary amines when compared to similar reactions of 2-propylphosphonamidic chloride (22 l).'94This and other evidence indicates that reactions of (220) take place via the previously postulated elimination-addition mechanism involving a phosphene intermediate (222). The base-induced rearrangement of 80-labelled N,O-bis(diphenylphosphinoy1)hydroxylamine (223) gives (224) and not (225), suggesting a concerted mechanism rather than one involving a metaphosphonimidite intermediate.195 A similar labelling approach has been used to investigate the mechanism of the reaction of carbonyl 180-labelled (226) with methoxide to give (227).196
t
?\
H20 + PhCN + [Bu&P-OMe]
-
Reagents: i, PhMe, 110 "C; ii, BuOH, 110 "C Scheme 13
0 BuO-P-OMe II I NHBU'
Organophosphorus Chemistry
120
bg
0 II,NEt2 R- P, Cl
(220)
(221)R = Me2CH 0 '80 II I1 Ph2PNHO-PPh2
(223)
KOBu'
"F
II Ph2P-NHOCPh I NHPh
! "!
PhP-O-PPh2 I NHPh
(224)
Ma-,
MeOH
0
0
II II PhP-"O-PPh
I
NHPh
(225)
0 + S + PhC-OMe
Ph2{ NH2
The equilibrium between various species generated when the phosphinate (228) is treated with nitrogen bases has been investigated using 'H and 31P NMR. 197 The synthesis of a novel class of chiral O-hydroxyarylphosphonic acid derivatives, e.g. (229), by P-O to P-C bond rearrangement has been reported. Ig8
A number of phosphorus acid and ester functionalized compounds have been used as selective ligands for a variety of purposes (see also other sections). The benzylic bis(phosphonate) (230) is reported to be a highly selective host for aromatic guanidinium ions199and the crown phosphonate (231) has been shown to efficiently transport dopamine through organic liquid membranes.200 On reaction with thionyl chloride, phosphonate monoesters (232) give aaminoalkylphosphonochloridates (233) (Scheme 14).201This reaction, and those of (233) with alcohols and amines, have been studied by 3'P NMR and intermediates in both the chlorination step and the nucleophilic substitution steps identified. Based on these results a method giving improved yields from the reaction of (233) with nucleophiles has been developed. Treatment of the 2-(3-trimethylsilyl)bisphosphonate (234) with an excess of methyllithium is
4: Quinquevalent Phosphorus Acids
i
Me
121
(230)
reported to give a mixture of the 1,3-phosphasilolane (235) and the phosphonate (236).202A mechanism involving intermediate formation of the phosphonate carbanion (237) is suggested. A new synthesis of a-fluoromalonates is provided by magnesium chloride-promoted P-C bond cleavage of the phosphonate (238).203Desulfurization of phosphoryl thioamides (239) with nickel boride, generated in situ from nickel dichloride and sodium borohydride, provides a new approach to functionalized a- and p-aminophosphonates .204
I; (EtokP-c'!
(239) II
,c02Et
CaMe
= 0,1
MgC12,
PhMe, NH&I
*
EtQCCHFaMe
122
Organophosphorus Chemistry
3.3 Selected Biological Aspects - Diphenyl phosphonate amino acid analogues have been investigated as inhibitors of trypsin-like granzyme A and K and mast cell t r y p t a ~ eThe . ~ ~most ~ potent inhibitor for granzyme K was (240). Bisphosphonate derivatives are well established as useful drugs in the treatment of various bone disorders. Bisphosphonic acid functionalized steroid structures, e.g, (241), have now been prepared and investigated for use in this 207 A variety of substituted bisphosphonate ester structures have been prepared and investigated as anti-inflammatory and anti-arthritic agents.208 An example is (242), which shows excellent inhibition of arthritis and potent anti-inflammatory effects.
Efforts continue to develop enzymes and abzymes capable of catalysing the hydrolysis of phosphorus acid esters, particularly structures with cholinesterase inhibiting properties. Such attempts include the synthesis of bifunctional aminophosphonic haptens, e.g. (243)209and (244),210 to structurally mimic Soman and the conjugation of such haptens to carrier proteins for the generation of monoclonal antibodies. In the case of (244) all four stereoisomers were synthesized and investigated. So far unsuccessful attempts have been made to elicit and isolate, from mouse hybridoma, catalytic antibodies capable of accelerating organophosphate hydrolysis.21 However, organophosphonatebinding Fabs have been isolated from a human combinatorial phage-display library.212The synthesis and conjugation to carrier proteins of phosphonate monoester analogues of cocaine benzoyl ester, and the use of these conjugates in the generation of anti-cocaine monoclonal antibodies, is described in a recent patent.2* The catalytic monoclonal antibodies are reported to degrade cocaine and block acute toxicity in rats. A library of novel phosphotyrosine mimics has been generated and screened with a view to identifying new leads for immunosuppressive Serine at position 286 of firefly luciferase has been replaced by a number of different natural and unnatural amino acids, including tyrosine phosphate and
4: Quinquevalent Phosphorus A c i h
123
phosphonate analogues of serine- and tyrosine-ph~sphate.~' In some cases the wavelength and pH dependence of the light emitted varied depending on the nature of the amino acid replacement. The antiviral properties of phosphonoformic acid and its derivatives are well known216and a recent patent contains descriptions of a large number of cyclic analogues, e.g. (245), with such properties.217 It has been reported that undesirable tastes in foods, beverages, dental compounds and pharmaceuticals can be reduced by the addition of an inhibitor of intramolecular phosphatase enzymes of taste cells.218The large number of such compounds reported include phosphates, thio-phosphates, phosphonates, bisphosphates, bisphosphonates, and various combinations and mixtures of these. The arabinose-5-phosphate oxime (246) has been reported to be the most potent currently known inhibitor of glucoamine-6P synthase, while the corresponding phosphonate is some 25 fold weaker as an inhibitor. l9
4
Structure
A number of theoretical studies have been reported. Ab initio investigations include one carried out on a variety of phosphorus(V) acids and derivatives to obtain structural and vibrational parameters220and a study of the reaction profiles for the base-catalysed methanolysis of the chiral oxathiaphospholane (247).221The latter study gives results which closely parallel those obtained
124
Organophosphorus Chemistry
from experimental work. An ab initio study of the isomerization of magnesium and calcium pyrophosphates in the gas phase has been reported.222 The involvement of metal-complexed metaphosphate and orthophosphate as intermediates in these studies was considered and it is suggested that the isomerization energies calculated may provide an explanation of why pyrophosphatases utilize magnesium, but not calcium, complexes as substrates.
(250)X = S (251) X = 0
Numerous studies of structure and conformation of 1,3,2-dioxaphosphorinanes and related heterocycles have been reported. These include conformational analysis of (248) and (249) by IR, X-ray, and 'H, 13C,and 31P NMR, including solid-state NMR studies, 223 and crystal and molecular structure determination of cis- and trans-2-morpholino-2-thioxo-4-methyl1,3,2-dioxaphosphOrinane(250) and the 2-0x0 analogue (25 l).224 Unambiguous assignment of cis- and trans-geometries in each case allows confirmation of the stereochemistry of P=S to P=O conversion using ozone (retentionp) and of formic acid-catalysed hydrolysis (inversionp) of (250). C-H- - -0hydrogen bonding and its importance in determining the solid state structure in a variety of biological molecules are now well established. X-Ray and solid-state NMR have now been used to study possible weak C-H- - .S hydrogen bonding in the 2-thioxa-1,3,2-dioxaphosphorinan-2-yl-~-~-glucopyranose (252).225 Conformational studies, based on 'H, 13C, and 31PNMR226and I5N NMR,227of the both cis- and trans-fused saturated 2-[bis(2-chloroethyl)-amino]-1,3,2-benzoxazaphosphorinane 2-oxides (253) have been reported. '.INp Coupling constants vary widely depending on the configuration at phosphorus. The 1,3,5-triaza-2phosphorine (254) has been synthesized and its structure investigated by NMR and X-ray crystallography.228Six phosphoric triamides, including (255), (256), and (257), incorporating acyclic and mono-, di- and tri-cyclic systems, have been synthesized and their crystal structures determined.229The increasing ring constraint is paralleled by a strong deshielding of the 31Pnucleus. New P-and Se-containing heterocycles, 1,3,2,6-dioxaphosphaselenacyclooctanes, e.g. (258), have been synthesized by the reaction of bis(2-hydroxyethyl) selenide with phosphorus chlorides and their structures investigated by spectroscopic and X-ray methods.230 A large number of reports concerning the structure and structurally related macroproperties of phospholipids and related compounds have appeared. 'Nearest neighbour' recognition (NNR) in phospholipid membranes has been the subject of a recent review.23*NNR analysis has been used in various studies of structurelbehaviour relationships. These include an examination of certain phosphocholine-based diluents on the mixing behaviour of phospho-
4: Quinquevalent Phosphorus Acids
s,\
IS
oNP\o
K
O\So2+Me
-
125
a 3 t P-N(CH2CH2Clh
(252)
0 (253) R = H, Me, CH2Ph
lipids232and the first demonstration that phospholipid chirality can influence the interactions between nearest neighbours in a fluid bilayer structure.233A conformational study by 13Cand 31PCP-MAS (cross-polarization magic angle spinning) NMR of phospholipids in the crystalline state and in hydrated bilayers has been reported234and the melting of self-assembled phospholipid tubules in alcohoUwater solutions has been studied by CD and ca10rirnet1-y.~~~ An investigation has been carried out on the size, structure and properties of the supramolecular aggregates formed by synthetic fatty acids and phosphatidylcholine amphipiles incorporating a trans-stilbene chromophore in the fatty acid chain.236The sodium salts of two isomeric, D-glucopyranoside-derived surfactants carrying phosphate polar head groups and differing in the anomeric orientation of the C14 side-chain attached to the glucopyranoside ring, have been prepared and the chiral selection properties of micelles derived from these compounds X-Ray analysis and high resolution 77Sesolid state NMR have been used as complementary probes in structural studies of a variety of organophosphorus selenide~.~~* 31P NMR data have been reported on a large number of thiophosphates.239An empirical approach, devised by the authors, allows more accurate calculation of 31Pchemical shifts of phosphates and thiophosphates than other methods. An analysis of calculated and experimental values of 'H chemical shifts and of 'H-31Pcoupling constants in a variety of phosphorylated alkenes has been carried out.240Methyl dichlorophosphate (259) acts as a new, chiral derivatizing agent for symmetrical d i 0 1 s . ~The ~ ~ resulting cyclic phosphate esters exhibit useful, diagnostic diastereomeric differences in their 31P NMR spectra.241 A number of chromatographic studies of phosphorus(V) acid derivatives,
Organophosphorus Chemistry
126
R
particularly ones involving chiral separation, have been reported. Examples include studies of the separation of enantiomers of various p h o ~ p h o n a t e s ~ ~ ~ and of a-hydroxybenzylphosphonates by chiral HPLC.243In the latter case absolute configurations are determined from CD measurements of a large number of substituted examples. Reverse-phase HPLC has been applied to a study of host-guest complexation of a variety of upper ring-substituted tetraalkylcalix[4]resorcinareneoctols,including phosphorylated examples, e.g. (260), with aromatic guest molecules.244A study of iodine-azide reagent for the detection of phosphorothioates in TLC and comparison with other detection methods has been reported.245An affinity enzymometric assay for the detection of organophosphorus compounds has been reported.246From a study of the abstract it appears that this method is only applicable to compounds which bind to cholinesterases.
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1998,128,102138). S . A. Bourne, T. A. Modro, L. R. Nassimbeni and H. Wan, J. Chem. SOC.,Perkin Truns. 2, 1998, 83. J-L. Li, B. Tian, C-Q. Zhao, Y-M. Wang, J-B. Meng and H-G. Wang, Chin J. Chem., 1997,15,450 (Chem. Abstr., 1998,128, 1 15074). S. M. K. Davidson and S. L. Regen, Chem. Revs., 1997,97, 1269. M. Shibakami, M. Inagaki and S. L. Regen, J. Am. Chem. SOC.,1997,119,12354. M. Inagaki, M. Shibakami and S. L. Regen, J. Am. Chem. SOC.,1997,119,7161. K. S. Brusik and J. S. Harwood, J, Am. Chem. Soc., 1997,119,6629. M. S. Spector, J. V. Selinger and J. M. Schnur, J. Am. Chem. SOC.,1997, 119, 8533. X. Song, C. Geiger, M. Farahat, J. Perlstein and D. G. Whitten, J. Am. Chem. Soc., 1997, 119, 12481. D. Tickle, A, George, K.Jennings, P. Camilleri and A. J. Kirby, J. Chem. Soc., Perkin Trans. 2, 1998,467. M. J. Potrzebowski, J. Blaszczyk, W. R. Majzner, M.W. Wieczorek, J. Braniak and W. J. Stec, Solid State Nucl. Magn. Reson., 1998, 11, 215 (Chem. Abstr., 1998,129, 136238). Y-j.Zhang, F-L. Yang, X-P. Liu and J. P. Liu, Gaodeng Xuexiao Huaxue Xuebao, 1997,18,2030 (Chem. Abstr., 1998,128,115005). T. A. Zyablikova, N. G. Khusainova and R. A. Cherkasov, Russ. J. Chem., 1997, 67, 1414 (Chem. Abstr., 1998, 129,67827). C . M. Garner, C. McWhorter and A. Goerke, Tetrahedron Lett., 1997,38,7717. G . Yang, M. Hudng, G. Li, A. Du, Q. Dai, R. Gao, R. Chen and Q. Wang, Sepu, 1998,16,427 (Chem. Abstr., 1999,130,46867 ). S . Caccamese, S. Failla, P. Finocchiaro and G. Principato, Chirality, 1998, 10, 100 (Chem. Abstr., 1998,128, 192704). J. Lipkowski, 0. I. Kalchenko, J. Slowikowska, V. 1. Kalchenko, 0. V. Lukin, L. N. Markovsky and R. Nowakowski, J. Phys. Org. Chem., 1998,11,426. A. Kotynski, W. Cielielski, Z. H. Kudzin, A. Okruszek, D. Krajewska and P. Lipka, J. Chromutogr., A, 1998,813, 135 (Chem. Abstr., 1998,129, 199927). A. Makower, A. Barmin, T. Morzunova, A. Eremenko, I. Kurochkin, F. Bier and F. Scheller, Anal. Chim. Acta, 1997, 357, 13 (Chem. Abstr., 1998, 128, 149067).
5 Nucleotides and Nucleic Acids BY JOSEPH S. VYLE
1
Introduction
Studies related to the therapeutic applications of nucleic acids continue to dominate work in this area. As oligonucleotide therapeutics enter late stage drug trials and the market, the need for large-scale synthesis has led to reports of chemistry with the potential for scale-up to the kilogram level using only limited reagent excesses. Interest in modified internucleoside linkages again forms the major area for new reports, which overwhelmingly relate to phosphorothioate, phosporamidate or PNA-derivatives. The problems associated with drug delivery of both mononucleotides and oligonucleotides has also received attention with some of the approaches relying on covalent attachment of molecules which give tissue-specific targeting. The minor groove-binding aromatic amino acid polyamides continue as strong therapeutic candidates with the introduction of a new aromatic residue that overcomes the A=T,T-A recognition degeneracy. Some of the most rapidly developingareas of research relate to the fabrication of devices based upon surface-immobilised DNA. Technology transfer from the microelectronics industry - including photolithography and robotic engineering - coupled with advances in sequence analysis algorithms and the expanding database of sequence information have led to reports of genome-wide expression profiling in yeast on DNA microarrays. Unprecedented miniaturisation of devices designed to integrate processes involved in DNA analysis has been reported with applications to diagnostics and also DNA computing. The use of DNA for the fabrication of functional nanoscale structures has been demonstrated. With advances in device design and preparation, expanding information on the human genome and the potential of such technology in functional genomics, the level of publications in this field looks set to expand rapidly. The reported use of combinatorial approaches to probing aspects of nucleic acid structure and function has increased dramatically leading to an increased activity in nucleoside triphosphate analogue preparation and also in nucleotide tagging that facilitate library deconvolution. In vitro selection has been applied to the generation of catalytic nucleic acids with putative prebiotic activities. Increased access to synchrotron radiation has led to a rapidly expanding database of structures and in particular, has facilitated studies on ribozyme folding and nucleic acid processing enzyme reaction pathways. Organophosphorus Chemistry, Volume 30 0The Royal Society of Chemistry, 2000 135
136
2
Organophosphorus Chemistry
Mononucleotides
2.1 Nucleoside Acyclic Phosphates 2.I . I Mononucleoside Phosphate Derivatives - Prodrugs of nucleoside monophosphates form the majority of such derivatives although less has been published again this year. Increased bioavailability of the monophosphate is observed using liphophilic phosphate ester derivatives which cross the cell membrane and are then hydrolysed to the corresponding monophosphates by chemical cleavage, e.g., of a labile P-N bond under the acidic conditions found within endosomes, or by cellular enzymes. In order to ameliorate side-effects of cytotoxic agents, phosphate esters of compounds which target specific tissues have been described. The decomposition pathways of aryl amino acid phosphodiester and phosphomonester amidates of AZT (1) or 3’-fluoro-3’-deoxythymidine (FLT) (2) in lymphocytes have been studied. An alternative decomposition pathway of the phosphomonoester amidates to that previously observed for related prodrugs was proposed. A series of stable, water soluble amino acid phosphomonoester amidate derivatives (3) of acyclovir (ACV) has been prepared.2 These were shown to act principally as prodrugs of the nucleoside rather than its monophosphate and metabolism studies revealed that incubation of cellfree extracts of Vero cells with the L-leucine phosphornonoester amidate of ACV (3c), resulted in a burst of acyclovir monophosphate production followed by the rapid generation of the nucleoside. The phosphodiester alaninate derivatives of 9-[24hydroxybuten- 1-yl]purines (4) and the Eadeninyl isomer (6) have been prepared via phosphorylation of the unprotected nucleoside analogue^.^ Hydrolysis of (4a) with either aqueous triethyl-
(1) R’ = N3, R2 = H, Me, Ph, R3 = Ph, 3-indolyl (2) R’ = F, R2 = H, Me, Ph, R3 = 3-indolyl
(4) R’ = Ph, R2 = Me (5) R’ = R2 = H
(3a) R = Ph (3b) R = 3-indolyl ( 3 ~ )R = Pr‘ (3d) R = Me
137
5: Nucleotides and Nucleic Acids
YGMe NH
I
O=P-OPh
I 0
amine or pig liver esterase gave the same product (5) and a phosphoramidase activity was postulated to account for the liberation of phosphate monoester. Only (4a) showed activity against HIV- 1. A bis-phosphorylated side product (7) was isolated from the preparation of (4b). An analogue (8) of the nucleoside antibiotic Agrocin has been prepared using phosphoramidite chemistry to sequentially introduce N6-phosphoramidate and 5’-(N-acylphosphoramidate) moieties to a d e n ~ s i n e . ~
0
H
HO OH
(9)i
X
Y
&7i-
H H CI H OMe H H OMe Me H H Me Me Me
A series of pronucleotides (9) that deliver d4TMP selectively via controlled chemical hydrolysis has been prepared. Diastereomeric mixtures were synthesised either by phosphitylation of the anti-HIV dideoxynucleoside d4T with the appropriate saligenylchlorophosphite followed by oxidation with t-butylhydroperoxide (in yields of 50-73%) or by reaction of the salicyl alcohol with the 5’-phosphodichloridate (<37%). All prodrugs exhibited considerable activity against HIV-1 and HIV-2. A 3-80-fold difference in antiviral activity between the separated diastereoisomers was observed. The S-acyl-2-thioethyl bearing 5’-monophosphate prodrug of p-L-FD4C (10) has been shown to be both more inhibitory against HBV and less cytotoxic than the parent nucleoside.6 Pronucleotides (11) have been synthesised in order to increase the
138
Organophosphorus Chemistry
bioavailability of the parent nucleotide which was released upon exposure to cellular glucosidases. 0
II P-om
Ro@-o RO OR
2
( l l a ) R=Ac (llb) R - H ( 1 1 ~ )R = A c , H
The unique liver receptor ASGP-R recognises terminal 9-D-galactoside moieties and the potential hepatophilicity of the cytotoxic 2'-deoxy-5-iodouridine (a known inhibitor of HBV) has been increased by conjugation with a trilactoside (12).* Conjugates of AZT and lipophilic esters of phosphonoformic acid (PFA) (13) have been ~ r e p a r e d Compounds .~ (13a-c) were shown to have antiviral activity against both Foscarnet- (the trisodium salt of PFA) and AZT-resistant strains of HIV-1.
The proposed use of purine nucleoside phosphorylase (PNP)inhibitors as immunosuppressive agents has led to interest in analogues of 9-(5,s-diflusro5'-phosphonopentyl)ganine which is a potent inhibitor of PNP. Conformationally constrained analogues of PNP (14), (1 5 ) have been prepared in both enantiomeric forms.lo The acyclicnucleoside phosphonates (16) were prepared as potential inhibitors of viral polymerases but were found to be inactive against HIV." A series of 3,4disubstituted tetrahydrofuran-derived nucleotides (17), (18) has been prepared from the corresponding 3-azido phosphonate diesters.l 2 Reduction of the azide and construction of either uridine or 6-chloropurine from the product amine was followed by conversion of the base to cytosine or adenine and deprotection.
5: Nucleotides and Nucleic Acids
139
HO-P-C (14) n = 1,2
(15) n = 1,2
0 0
0 II HO-P-0 I
II
(17a) B - T , X - O H (17b) B = C, X = 0- NH4+ ( 1 7 ~ )B = A , X = O H
(16) X = N , C H
b'
(I&) B - T , X = O H (18b) B = C, X = O-NH4+ (1&) B = A , X = O H
Chemoenzymatic syntheses of 5'-O-lysophosphatidyl-nucleosides ( 19) and nucleoside analogues have been reported and, unlike corresponding phosphatidyl nucleotide derivatives, these did not to undergo self-assembly. The novel nucleoside phosphotriester (20) has been prepared chemoenzymatically and found to generate a surfactant upon mild base treatment which spontaneously self-assembles and undergoes an autocatalytic self-reproduction process.I4
H b R1 (19) B = A, G, C, T; R1 = H; R2 = (CH2)14Me B = A, C; R' = H; R2 = (CH2)&Ie B = C; R1 = H; = (CH2)7CH=CH(CH2)7Me B = A ; R1 = OH; R2 = (CH2)14Me
-";j-ov exo " -
0 0
(20)
NC
HO OH
140
Organophosphorus Chemistry
The synthesis of nucleoside monophosphate and polyphosphate derivatives that act as substrates for glycosyl transferases has received some interest due to the stereo- and regio-specificity of enzymatic glycosidic bond formation. Cytidine monophospho-N-acetylneuraminic(CMP-NeuAc) acid (2 1a) is a substrate for sialyl transferases and several congeners of CMP-NeuAc have been prepared (21b-d).15 Phosphonate analogues of (21a) have also been prepared.I6 The L-isomers of d4C and d4A have been enzymatically phosphorylated by human deoxycytidine kinase. l7
(21a) R = NHAc (21b) R = O H ( 2 1 ~ )R = NHC(0)CHzOH (21d) R = NHCbZ
Buffer-independent rate constants have been obtained for the hydroxide ionand hydronium ion-catalysed transesterification reactions of a series of uridine 3'-alkyl phosphates (22a).'* The nucleoside phosphate diesters were prepared by H-phosphonate coupling and oxidation to the protected diester (22b). The rate constants for hydroxide ion-catalysed P-0 bond cleavage showed a strong correlation with the pK, of the esterified alcohols in contrast with the rate constants for the hydronium ion-catalysed isomerisation and cleavage reactions which were relatively insensitive to the pKa.
txo
R'o-w 0 I OR2
O=P-0I 0
(22a) R' (22b) R'
~
3
= R2 = H;
R3 = CHMQ, Et, (CH2)20Et,CH&H2CI, CH2CHCI2, CH2CC13 = DMT; R2 = Mthp; R3 = CHMe2, Et, (CH2)20Et, CH2CH2CI, CH2CHCI2, CH2CC13
There have been several reports on the use of biotin-labelled adenine nucleotides (23), (24) and 5'-amino-modified RN A for the attempted generation of RNA amide synthases by in vitro selection. Eaton and co-w~rkers'~ have employed a mixed anhydride-linked AMP-biotin conjugate (23) as substrate and a 5'-aminoalkylated randomised RNA. The substition of a 5-
5: Nucleotides and Nucleic A c i h
141
imidazole uridine triphosphate derivative for UTP in the transcription of amplified cDNA libraries was essential for activity. Zhang and Cech20applied an aminoacyl substrate (24a) and a disulfide linked 5'-amino modified terminus to select ribozymes that catalysed peptide bond formation; reductive cleavage of the disulfide selected against acyl transfer to internal sites. A very similar selection procedure adopted by Jenne and Famulok using (24b) without disulfide cleavage produced a ribozyme which acylated the 2'-hydroxyl of an internal cytosine residue.21
Sutherland and Whitfield22have proposed potentially prebiotic synthesis of RNA involving polymerisation of acyclic monomers (25) through aldol condensation, retro-Amadori rearrangement and ring closure. Monomers were prepared by oxidative cleavage of unsaturated cyclic phosphate intermediates (26) followed by ammonolysis or hydrolysis of the modified bases. Novel bisphosphitylating reagents (27) were employed in the synthesis of (26). In under 48 hours at room temperature at pH 9.5, polymerisation of (25; B = A, U), was observed although the polymeric products were not fully characterised. Initiator nucleotides consisting of an anthracene ring system coupled to the 5'-phosphate of guanosine monophosphate via polyethylene glycol (PEG) linkers (28) have been synthesised as mixtures containing PEG of varying lengths.23 These initiators were purified and the decaethylene glycol linker (n = 10) used in T7 polymerase catalysed transcription. Site-specific incorpora-
142
OrganophosphorusChemistry
(25)B = A, G, C, U
I NMe2 RO-P,
NMe2 (27)R = Bu‘, CH2CH2CN
B=
cAi
R = CH2CH2CN
I
tion of the nucleotide at 5’-termini of RNA gave fluorescently-labelled transcripts. Diels Alder reaction of the anthracene moiety with a maleimide linked to biotin was subsequently performed.
+ P
EtO,
d0
Etdp*0
The thymidine and 2’-deoxyadenosine-derivedally1 phosphites (29) have been used as substrates for a photochemical, single electron transfer (SET) induced rearrangement.24 The product diethyl phosphonates (30) were isomerised to the corresponding vinyl phosphonates. A series of 3’- and 2’-deoxyadenosine bisphosphate derivatives (31)-(33) has been prepared and the activity at P2Y1 receptors tested.25 The N6-Methyl derivative (31d) was found to be the most potent P2Y1 antagonist (IC50=330 nM) reported. 2.I . 2 Polynucleoside Monophosphates - Just and co-workers have reported some exciting results on the use of cyclic phosphoramidites (34)-(37) derived from a variety of chiral y-aminoalcohols for the stereoselective synthesis of phosphorothioates.26-27 Preparation of the phosphoramidites under thermodynamic conditions gave almost exclusively single isomers for (39, (36) and (37a) (as shown) which were rendered configurationally stable following removal of amine hydrochloride salts. Activation of the xylose-derived phosphoramidites (36) and (37) with 2-bromo-4,5-dicyanoimidazolein the presence of 3’-O-tBDMS-thymidine at sub-ambient temperatures gave phosphite tri-
5: Nucleotides and Nucleic Acids
143
@)--ONuc'
(34) ONuc'
ONuc'
NPh
H
o=<" NPh H
144
Organophosphorus Chemistry
esters, e.g., (38) from (37a), which were sulfurised to the corresponding phosphorothioate triester displaying isomer ratios of up to 68:l (in favour of the singly inverted product). The vicinal imidate in the phosphorothioate product derived from (37a) enabled deprotection of the phosphorus to be carried out under conditions compatible with standard DNA protocols. Diastereoselective formation of internucleoside phosphorothioate triesters and diesters has also been acheived using 3-(imidazol-1-ylmethyl)-4',4"-dimethoxytrityl-protected monomers (39).** Two groups have reported dinucleoside monophosphate analogues (40) and (4 1) in which neutral, sulfur-containing linkages replace the phosphodiester group.29-31
Hov
OMe
I
NH
sv *"V I
Et3NH+
OH
(39) Ar = phenyl, 2,6dichlorophenyl, 1maphthyl, 2-naphthyl
(40)
/I =
0, 1
OH
(411
4(S)-(6-Amino-9H-purin-9-yl)tetrahydro-2(S)-furanmethanol (isodideoxyadenosine) has been condensed with methyl dichlorophosphite to give the 5'-+ 5' dinucleoside monophosphate triester (42) and following deprotection, the d i e ~ t e r . ~ ~ An Aza-Claisen rearrangement has been employed to synthesise both diastereomers of an amino homothymidine from which a dinucleoside phosphoramidite (43) has been prepared.33 3'-Deoxy-3'- and S-deoxy-S-[(4-(purin9-yl/pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine have been prepared by
NHBz
NHBz
DMToY (43a) R' = H, R2 = Et (43b) R' = Et, R2 = H
5: Nucleotides and Nucleic Acids
145
a 1,3-dipolar cycloaddition of a 3'- or 5'-azidothymidine with the appropriate alk~ne.~~
2.2 Nucleoside Cyclic Phosphates - In order to stabilise the labile N - l glycosidic linkage in cyclic ADP-ribose, the synthesis of carbocyclic analogues and intermediates has received attention. The first total synthesis of a stable cyclic ADP-ribose related compound (44) has been reported. Previous synthetic schemes have used Aplysia californica derived ADP-ribosyl cyclase to form the adenine N1-ribose bond. However, Shuto et al.35 employed a chemical strategy in which cyclisation of a protected diphosphate (45a) was effected via EDC in 23% yield. In order for this reaction to be effective, 8bromoinosine was employed to give a syn conformation around the N-7glycosidic bond; the non-halogenated derivative (45b) could not be cyclised under these conditions. The halogen was removed by catalytic hydrogenation to yield the product (44). Gram quantities of an uncyclised precursor to another carbocyclic analogue of cADPR have been synthesised in the laboratory of Potter.36 cATPR is both more stable than cADPR and more potent in inducing Ca2+ release. 8-(6-Aminohexyl)amino-cATPR(46) has been prepared as an affinity probe for cADPR-binding proteins via the derivative (47).37
x
0 0 HO
OH
HO (44)
OH
(45a) R = H, POs2-; X = Br (45b) R = H, PO3*-; X = H
Conformationally rigid cyclouridylic acids (48) with intramolecular ethylene (n = 1) and propylene (n = 2) bridges between the uracil 5-position and the 5'phosphate group potentially mimic the proposed conformations of modified uridines in tRNA.38 Cyclisation was performed using either phosphotriester coupling via (49) or phosphoramidite chemistry using a bis-phosphitylating agent. Attempts at preparing the methylene (n = 0) bridged compound were unsuccessful. Molecular modelling of the cyclic trimeric d-oligonucleotide 3'isopropylphosphate (50) indicated that it mimicked the conformationally constrained central trinucleotide region of a thrombin-binding DNA aptamer. Compound (SO) was prepared by a combined phosphorylation/pyrophosphate
146
Organophosphorus Chemistry
0
phs-!o*xo0I
"
HO OH
(48) n = 1 , 2
O RO W OR
(49) R = Ac, P i
bond-forming reaction of the non-cyclised precursor (5 1) followed by deprot e ~ t i o nNo . ~ ~thrombin binding of (50) was observed. 0
Bis-(3 -+5)-cyclic bis( 1,4-anhydro-2-deoxy-D-erythro-pentitol-3-phosphate) (52) has been prepared as an abasic analogue of cyclic dinucleotides and
I47
5: Nucleotides and Nucleic A c i h
A
?
PriO-kO I OR’ (51) R’
= /&H&I,
R2 = DMT
shown to be one of the most potent inhibitors of HIV-1 integrase of this class of compounds.40
3
Nucleoside Polyphosphates
The term Nucleotide Analogue Interference Mapping (NAIM) has been coined to described the use of nucleoside a-phosphorothioate triesters bearing modified ribose or nucleobase moieties to probe the role of individual functional groups within a nucleic acid structure. RNA backbone cleavage at positions of phosphorothioate substitution is simple to perform and precise, thus making it an ideal chemical tag to mark sites of nucleotide analogue incorporation. NAIM involves generating libraries of RNA sequences with randomly incorporated, phosphorothioate-tagged nucleotide analogues by in vitro transcription. Selection of functional molecules and deconvolution of the library by phosphorothioate cleavage generates a footprint of sites at which either the phosphorothioate or the analogue have interfered with activity. A control library in which only the parent nucleotide phosphorothioates are used allows the contribution of analogues to be assessed. This technique has been applied to group I ribozymes using several novel nucleoside analogue aphosphorothioate triesters (53).41-43 Sergiev et al. 44 have randomly incorporated aminonucleosides into 5s
Organophosphorus Chemistry
148 0
0
0
AII
II II -0-P-0-P-0-P-0 0I 0t
Q B
(cj{CL ,
HO R
(53)
R = OH, B =
Y
; R = H, F, B = A
R2
I
rRNA by T7 transcription with the corresponding a-32Plabelled triphosphates (54). Approximately two photoreactive diazirines were incorporated per transcript by post-transcriptional labelling with the isothiocyanate or Nhydroxysuccinimide ester derivatives (55). Photoaffinity labelling using these diazirinyl derivatives in the presence of 23s rRNA produced cross-links which all involved the U89 of 5s rRNA; three sites on 23s rRNA were characterised. Base-substituted photoreactive analogues of CTP containing arylazido groups 0 0 0 II II II -O-P-O-P-O--P*-ONUC I l l 00- 0-
0
(55)R
S C N A
0
HO
40gp30T/ HO OH
I49
5: Nucleotides and Nucleic Acids
linked via the exocyclic amino group (56) have been prepared and used to affinity label viral RNA replicase proteins derived from f l a v i v i r u ~The . ~ ~ effects of 5-aminoallyl deoxyuridine triphosphates bearing different photoreactive moieties (57) on the efficiency and selectivity of DNA photoaffinity labelling of yeast Pol 111 transcription complexes have been i n ~ e s t i g a t e dNew . ~ ~ proteinDNA contacts were characterised using the diazirine derivative (57d). 0
HO
E
F
Several nucleoside triphosphates containing different isotopic labelling patterns have been prepared enzymatically from labelled glucose.47Incorporation of these nucleotides into a 30 nucleotide HIV TAR RNA considerably simplified 2-dimensional NMR spectra from this sequence. Such spectral editing should facilitate NMR structural studies of other large RNAs. 2'Thiocytosine triphosphate (58a) has been prepared via the o-nitrophenyl disulfide derivative (58b) and incorporated into the HDV ribozyme using a mutant T7 p ~ l y m e r a s e Transcripts .~~ were isolated using a thiol activated sepharose column and underwent self-cleavage to only a limited extent even in the presence of manganese. Stereospecific synthesis of methyl phosphotriesters has been accomplished using Pa-methyl deoxynucleoside triphosphates as substrates of a DNA polymerase in template-directed elongation of a primer.49 High sequence selectivity was observed for the replication of DNA using the thymidine triphosphate shape analogue (59). Combined with data from the use of this analogue in the template strand, the results suggest that hydrogen bonds may be less important in determining the fidelity of replication than nucleotide/template shape ~omplementarity.~~ However, this view has been ~hallenged.~~ The human genome consists of approximately three billion bases and one of the considerations in sequencing these is the choice of chain terminators. As a potentially cheaper alternative to dideoxy terminators, Martinez et al.52 have prepared acyclic nucleoside triphosphate analogues (60). Both were tested as dNTP surrogates using primer extension assays with a variety of DNA
150
Organophosphorus Chemistry F
F
HO SR (58a) R = H (58b) R =$-SQ
HO (59)
9
B
%
~
P
3 N\ 0 (ma) B = A (60b) B = T
~
4 N
polymerases and were tolerated as substrates by two derived from Taq, although in the presence of 0.5 pM dNTPs, even 1 mM (60b) gave only partial chain termination. Transcriptional sequencing provides several advantages compared with traditional Sanger methodology and has been successfully performed using a mutated RNA polymerase and the dye-labelled 3'-deoxynucleoside triphosphates (61) as chain terminator^.^^ 3'-dNTPs bearing shorter linker arms were also tested but did not give reproducible gel mobilities. New dye-labelled terminator sets based upon 4,7-dichlororhodamine, e.g., (62), have have been prepared and found to have improved properties for automated DNA ~ e q u e n c i n g . ~ ~ Alkylated imidazole 4-carboxamide-bearing nucleoside triphosphate analogues (63) have been prepared in order to study the effect of hydrophobicity on polymerase-mediated i n c o r p ~ r a t i o nBased , ~ ~ upon previous work on universal bases incorporated into hybridisation probes or primers, Brown and coworkers have prepared several universal deoxynucleoside 5'-triphosphates (65, X=N02), (65) and investigated their ability to act as template directed substrates for Klenow or Taq polymerase.56.57 However, incorporation of the nucleoside analogue triphosphates was limited to one base with limited or no further extension. In a related study, the same researchers showed that the 5nitroindole derivative (64)is a substrate for terminal deoxynucleotidyl transferase (TdT).S6*57 A new method for the detection of nucleic acid probes has been devised based upon the use of antibody detection of 5-nitroindole-labelled DNA. Triphosphates of deoxyribonucleosides derived from N6-methoxy-2,6diaminopurine (Ma) and N6-methoxyaminopurine (66b) have been prepared.58 Both analogue triphosphates produced transition mutations during PCR reactions with AT-+GC mutations predominating. The TDP-methylenehexopyranoside (67a) has been prepared and the anomeric mixture (alp=2/1) separated by HPLC.59 The a-anomer is a potential precursor to the 2-deoxy-3-uloside (67b) but although ozonolysis of (67a) at - 78 "C gave the desired product, this could not be isolated due to the rapid p-elimination of TDP. The UDP-5-thiogalactopyranoside (68) was prepared and used as a donor substrate for lactose synthase (a complex of a galactosyl transferase with lactalbumin) to prepare the potentially
151
5: Nucleotides and Nucleic Acids
(61), (62) B = Base, L = Link, Rh = Rhodamine Rh-L
G p=NH;! tI HH= Hf i
A
AT
E
\
Rhodamine (Rh) =
h
O
L
NAO
I
I
.MF
,R
R h 0 ' Y N H
-
Base B =
\
\
, '
y NHEt, H
2
i
A C
f
i
\
y
N
\
H
-
2
\
, a- '
m 2 -
'
x GO-L-
x CO-L-
Rha
Rhb
\
\
\
60-L-
GO-L-
RhC
Base(B) Link(L)
v
NAO
Rhd Rhodamine(Rh)
(61) A
Rha
T
Rhb RhC
R' X OH H
hydrolase-resistant disaccharide analogue (SSGalNAcp[ 1 44JGLCNAc) although at only 0.23% of the rate of formation of the natural disaccharide congener.60 Starting from 2',3',5'-tri-O-acetyl-2-iodoadenosine,2-(p-n-butylanilino)-2'arabino adenosine derivatives and the corresponding 5'-triphosphates (69) have been prepared. and found to inhibit calf thymus DNA polymerase abut not eukaryotic p- or E-polyrnerases.6' P-L-2',3'-Dideoxy-3'-fluoro nucleo-
152
Organophosphorus Chemistry
OH (63) R = Me, Pr
'%9
pa
R
P30
OH (65) X = N02, NH2, NHCHO
H
O
S
I:
: 0-P-0-Pg I
X
OH (66a) R=NH2 (66b) R = H
0
0p
0
T
0(67a) X=CH2 (67b) X = 0
OH
(68)
HO OH
side triphosphosphates (P-L-FNTPs) (70) have been prepared starting from L-uridine and L-thymidine and tested as inhibitors of HBV-DNA polymerases and HIV-RT. The p and y polymerases showed critical susceptibility to p-L-FNTPs although no activity against HIV-RT was observed.62 p-LAZT-triphosphate (71) has been prepared and found to inhibit HIV-RT in contrast with the parent n u c l e o ~ i d e .A~ ~series of 5-substituted deoxyuridine (72), (73) and thymidine (74) triphosphates has been prepared and evaluated as reverse transcriptase and DNA polymerase substrates.64 The C nucleoside
5: Nucleotides and Nucleic Acids
0
153
0
II II -0-P-CBq-P-0-P-0 I
0 II
0-
OH
(72)R = N3, NH2, NHCO(CH2)5NH2-Biotinyl, NHC(S)NH-Fluoresceinyl, NHCO-Rh,, Me 0
OH
(73)
R' = Me, R2 = (CHhN3, (CH2)2NH-2,4-Dinitrophenyl,(CH2)2NHCO(CH2)5NH-2,4-Dinitrophenyl; R' = CH2O(CH&N3, R2 = Ph, Me; R' = CH2O(CH2)gNH2, R2 = Ph
0
0
II II Me-P-CH2-P-0-P-0 I I
0 II
0-
(74) R = OH, N3
OH
triphosphates (75) have been synthesised as dTTP and dCTP analogues lacking the 2-keto Both were strongly inhibitory to Taq polymerase-catalysed PCR. Neither substituted for their natural congeners or were incorporated as chain terminators in primer extension assays. Arsenates are good phosphate mimics and as one of several non-hydrolysable terminal pyrophosphate linkages studied as inhibitors of glycerol kinase, the novel (76), was ATP analogue, y-arsono-~,a-methylene-adenosine-5'-diphosphate prepared.66
0 II
0
0
00
OH
(75) B = P H ,
(76)
Ho OH
154
Organophosphorus Chemistry HO OH
I
NH*
I
*O% HO OH (77a) X = H, Y = N3 (77b) X = N3, Y = H
-p309 N%
HO OH (79) R = OH, OMe, O(CH&Me, S(CH&Me, SMe, SH, N(Me).,, NHp,--NT\o,
u
NH(CH&,Me,
Excellent yields of y-methylated GTP (the U6 RNA 5'-terminus) have been reported by Sekine and c o - ~ o r k e r sA . ~series ~ of N6-derivatives of ATP has been prepared and used to engineer tyrosine kinases with unnatural nucleotide 69
8-Azidoadenosine diphosphate (hydroxymethy1)pyrrolidinediol (77a) and the 2-mido isomer (77b) have been prepared as photoaffinity labels for poly(ADP-ribose) glycohydr~lase.~~ ~ ~ ~ P - L a b e l(77a) l e d was used to photoderivatise the enzyme. Two analogues of Ap3A (78) have been synthesised and shown to be resistant to hydrolysis by the human fragile histidine triad protein (Fhit).71 A series of 4-substituted uridine 5'-triphosphates (79) has been synthesised as potential purinergic receptor agonists with greater stability than that of the natural congener (UTP).72 Caged NAD and NADP analogues (80)-(82) have been synthesised for use in time-resolved Laue crystallograph^.^^ Attempted preparations of (80a) and (80b) by pig brain NADasemediated direct exchange reactions of the caged nicotinamide with NAD(P) were not successful. The exchange reaction was therefore performed using nicotinate NHS ester and the products (80c,d) further derivatised. Lesiak et al. have described the use of 2-(4-nitrophenyl)ethyl methylenebis(phosphonate) (83a) as a versatile reagent for the preparation of nucleoside
5: Nucleotides and Nucleic Acids 0
R1O OH
H
NH2
0
'NH2
-
HO O OH M
5'-methylenebisphosphonates (83b).74 Treatment of (83a) with diisopropylcarbodiimide gave a bicyclic trisanhydride intermediate (84) which was reacted with a variety of protected ribo- and deoxyribo-nucleosides. Subsequent hydrolysis of the tetrakis-substituted Np4N (85) intermediates and deprotection yielded the products. Similar chemistry has been exploited by the same workers for the preparation of inosine monophosphate dehydrogenase (IMPDH) inhibitors.75*76 IMPDH inhibitors have previously been shown to induce differentiation in a variety of cancer cells. Dehydration of the 2'-deoxy-2'-fluoro-arabinoadenosine 5'-methylenebis(phosphonate) (83c) with dicyclohexylcarbodiimide(DCC) led to the formation of the corresponding bicyclic trisanhydride intermediate. Nucleophilic attack by 2',3'-O-isopropylidenethiazole-4-carboxamideor -ben-
156
Organophosphorus Chemistry 0 0 I1 II RO-P-CH2-P-OH I I OH OH (83a) R = O~N+CH~CH~-$ (83b) R = dT, dC, dA, dG, A, G y-42
OTHP
0
(84)
0
0
0
0
0 2 N e C H 2 C H 2 - O - P - O - P - O -I1P - O - PII- O - C HI I2 C H 2 I1
-
I I I ONuc 00(85)
I ONuc
zamide ribosides followed by hydrolysis and deprotection yielded non-hydrolysable analogues of adenine thiazole-4-carboxamide dinucleotide (TAD) (86a) and benzamide adenine dinucleotide (BAD) (87). The p-CF2-TAD analogue (86b) was prepared from the thiazole-4-carboxamide difluoromethylenebis(phosphonate) and found to induce differentiation of K562 erythroid leukemia cells. In contrast, the methylene phosphonate analogues did not induce differentiati~n.~~ The methylenebis(phosphonate) analogue of myco-
(Ma) CX2=CH2 (86b) CX2 = CF2
OH
OH
NH2
(87)
HO OH
157
5: Nucleotides and Nucleic Acids
phenolic adenine dinucleotide (MAD) (88) was found to be a potent inhibitor of an IMPDH isoform that is the domininant form in cancer cells and to reduce K562 cell proliferation. This analogue was not subject to metabolic deactivation via gluc~ronidation.~~ Isosteric analogues of NAD based upon thiophene-3-carboxamide adenine dinucleotide (89a) and furan-3-carboxamide adenine dinucleotide (89b) have been prepared by coupling adenosine-5’-phosphate with the appropriate imidazolate and evaluated as inhibitors of IMP dehydr~genases.~~
OH
6I-i
h’
y ‘
HO OH (89a) X = S . Y =CH (89b) X = 0, Y = CH
4
Oligo- and Poly-nucleotides
4.1 DNA Synthesis - Previously, the photolabile 3‘,5‘-dimethoxybenzoinyloxylcarbonyl (DMB) 5’-protecting group has been used in conjunction with photolithographic processing for the in situ synthesis of oligonucleotide arrays. In order to prevent removal of oligonucleotides from the surface during ammonolysis of the base protecting groups and avoid photoreaction of N4benzoylC, Pirrung and co-workers have described the preparation and use of 5’-DMB-protected phosphoramidites with more labile exocyclic amine protecting groups (90).78The use of p-eliminating base protecting groups such as 2-(nitrophenylethyl) (NPE) and 2-(nitrophenylethoxycarbonyl) (NPEOC) allows oligonucleotide deprotection without the use of ammonia and has been employed to prepare oligonucleotide arrays in which the oligomers were attached via an N-methylsuccinimide linkage. The quality of the oligomers was determined following ammonolytic cleavage and their use as primers.79Salo et aLgOhave given further details on the use of disulfide tethers (91), (92) as orthogonal linkers that permit oligonucleotide deprotection on the support. The resistance of these linkers to ammonia treatment is a function of the length of the carbon chain separating the disulfide from the support; p-
Organophosphorus Chemistry
158 OMe
Support (S) = Polystyrene: n = 1.4,9 Tantagel: n = 1,4,9 CPG: n-1
Support (S) = Polystyrene: n = 1,9 Tantagel: n = 1,9 CPG: n-1
elimination of mercaptopropionamide derivatives (n = 1) led to considerable loss of DMT loading. Furthermore, only a Tantagel-based support exhibited properties compatible with these conditions. The support derived from 11mercaptoundecananoic acid (n = 9) was used for the preparation of oligonucleotides with two N4-aminoalkyl cytosine residues which were both subsequently conjugated with photoluminescent europium chelates or dansyl groups. These conjugates were employed in a sandwich type assay to detect oligonucelotide hybridisation on a single microparticle.8* The demand for large-scale synthesis of therapeutic oligonucleotides has led to reports from several groups addressing this, although these reports have been concerned mostly with modified sequences. In particular, the use of solution-phase protocols with small excesses of reagents have been the focus of activity. Studies were undertaken on amidites of the form (93) in order to determine the most appropriate combination of dialkylamine and phosphorus protecting group und$r conditions in which the amine is scavenged using 13X molecular sieves (10A pore size).82 Using only 1.05 equivalents of amidite (R'= allyl and R2= ethyl (94), catalytic ( 5 mol %) p-nitrophenyltetrazole, and a bistrimethylsilylperoxide/trimethylsilyltriflateoxidation protocol, an average coupling yield of 92% was achieved for the solution-phase sythesis of an octamer on a multigram scale. Workers in the same laboratory have reported the electrochemical, Pd(0)-mediated removal of allyl phosphate- and allyloxycarbonyl sugar- and base-protecting groups.83Based upon the electrochemical regeneration of the Pd(0) catalyst, this methodology produced products that did not require further purification (an important consideration for large-scale preparations).
5: Nucleotides and Nucleic A c i h
I59
Reversed-phase HPLC purification of oligodeoxyribonucleotides is typically performed using the terminal hydrophobic 5’-dimethoxytrityl (DMT) group to give a large separation of the full-length sequence from the 5’-acetyl capped failure sequences. The acid-labile DMT group must be subsequently removed but yield is often lost prior to this due to detritylation during purification. The lipophilic phosphoramidite (95) has been employed as a capping agent and purification of the full-length oligomer was therefore carried out ‘trityl-~ff’.~~ Oligonucleotide synthesis has been carried out in a 5-3’ direction using NPE- and NPEOC-protected S-phosph~ramidites.~~ Oligonucleotide synthesis utilizing phthaloyl groups for protection of the heterocyclic amino functions within the phosphoramidite approach has been developed.86
160
Organophosphorus Chemistry
RNA Synthesis - Despite recent publications on the acid catalysed transphosphorylation of oligoribonucleotides at low pH, novel 5’-protecting groups that are compatible with 2’-THP protection have been explored. Phosphoramidite monomers (96) bearing a 1,1,3,3-tetraisopropyl-3-(2-( triphenyl-
4.2
P&N A
O
~
C
N
(96) B = U , R=OThp; B = T , R = H
methoxy)ethoxy)disiloxane-1-yl group have been employed in the solid-phase synthesis of UpT and TpTpT. Desilylation using fluoride was accompanied by concomitant p-elimination of the cyanoethyl moiety.87 2-(Levulinyloxymethy1)benzoyl (LMBz) and its 5-nitroderivative (LMNBz) have also been employed as orthogonal 5‘-protecting groups and phosphoramidite monomers (97) have been used for the manual synthesis of oligothymidylates and also an octaribonucleotide.88 The LMNBz protected monomers gave significantly better quality product using a two-step, twenty minute procedure to unmask the 5’-hydroxyl. 2’-O-tBDMS protected purine ribonucleosides present several synthetic problems due to the low regioselectivityof silylation, difficult purification of the 2’-and 3’-isomers and isomerisation during handling. Jones and coworkers have reported that silylation of a mixture of 2’- and 3’-H-phosphonate derivatives (98) of purine ribosides in the presence of DBU gives very high selectivity for the 2‘-hydr0xyl.*~The phosphoramidite monomers typically employed for RNA synthesis require extended coupling times using 1H-tetrazole (pK, 4.8) as a catalyst. However, this has been reported to lead to removal of minor amounts of the acid sensitive 5’-dimethoxytrityl protecting group during large- scale syntheses.The addition of 25 mol% N-methylimidazole as a buffer to an activator solution was shown to considerably improve the yield of full length RNA using only a two-fold excess of amidite per coupling.90This result led to the adoption of a new activator, 4,5-dicyanoimidazole(DCI) (99), which is less acidic (pK, 5.2), more soluble, and more nucleophilic than 1H-tetrazole. This reagent has been applied both to the synthesis of a phosphoramidite and also to the activation of phosphoramidites for the solid-phase synthesis of oligoribonucleotides. A thymidine phosphoramidite was prepared by reaction of the DMT-protected nucleoside with bis(N,N-diisopropyl)-2-cyanoethyl phosphoramidite in the presence of 0.6 equivalents of DCI. Using 1M DCI and only two equivalents of amidite per coupling, a 34-mer ribopurine-2’-fluoropyrimidine chimericsequencewas prepared in 54% yield following deprotection.
5: Nucleotides and Nucleic Acids
X
0 OTHP I P+2N p\O/\/CN (97) X = H, N G ; B = ABZ,GBujCBz,U
161
DMTov’G 0,o I
(98a) H,HPQ(98b) Tbdms, HPOz-
3’- 2’-HPQ2: 1 9 :1
The Synthesis of Modified Oligodeoxynucleotidesand Modified Oligoribonucleotides 4.3. I Oligonucleotides Containing ModiJied Phosphodiester Linkages - The literature has been dominated by phosphorothioate, phosphoramidate and peptide nucleic acid (PNA) analogues. A large number of base-labile phosphate, sugar and nucleobase modifications are currently difficult to access due to the typical methods of deprotection. Sekine and co-workers have reported the use of N-unprotected H-phosphonate monomers for oligonucleotide synthesis with considerable potential for diversifying the number of modifications available. Two publications from this group have detailed the overcoming of some of the practical problems associated with unprotected amino functions on the 92 In order to derivatise high cross-linked polystyrene (HCP) solid supports, N,O-bis-DMT-protected nucleosides were attached via a 3 ’ 4 oxalyl linker (which can be cleaved under mild conditions) and subsequently detritylated to give the desired support.92An initial survey of the reaction of phosphonylating reagents with O-protected deoxynucleosides revealed that the trivalent phosphorus reagents commonly used for preparation of H-phosphonates reacted with the unprotected exocyclic amino group. No such reaction was observed with reagents already containing the P-H function and O-selective phosphonylation of the 3’-hydroxyl was performed with diphenyl H-phosphonate which gave, after hydrolysis, yields of the corresponding nucleoside H-phosphonate - DBU salt in excess of 88%. An extensive survey of carbonium- and phosphonium-based condensing reagents was performed in order to determine that giving the most O-selective and rapid coupling. Despite having an unsubstituted benzotriazolyl group, the newly synthesised condensing reagent 2-(benzotriazol-1-yloxy)-1,3-dimethy1-2-pyrrolidin1-yl1,3,2-diazaphospholidiniumhexafluorophosphate (BOMP) ( 100) in the presence of pyridine gave complete coupling within 5 minutes and 99% average coupling efficiency by trityl assay for the synthesis of a tetranucleoside Hphosphonate on the oxalyl-HCP support. Anhydrous oxidation conditions using O,N-bistrimethylsilylacetamide and 2-(phenylsulfonyl)-3-(3-nitro4.3
162
Organophosphorus Chemistry
pheny1)oxaziridine (PNO) (101) gave the corresponding phosphate diesterlinked oligomer. Similar coupling yields were reported for the synthesis of a mixed sequence dodecanucleotide, but partial decomposition of the phosphonate backbone was observed (at the level of 1-2% per residue). A rationalisation for the 0-selectivity of the coupling reactions was proposed based upon ab initio molecular orbital calculations. Sekine and Wada93have filed a patent based upon this process in which novel antisense H-phosphonate oligonucleotides and their derivatives were prepared without PNO oxidation.
Reese and Songg4have described a versatile synthetic scheme with improvements to the H-phosphonate coupling protocol directed at eliminating side reactions of the activating agent for use in solution-phase coupling with small excesses of H-phosphonate monomer. Using 1.2 equivalents of H-phosphonate monomers activated with bis(o-chloropheny1)phosphochloridate in the presence of pyridine at -4O”C, very clean syntheses of dinucleoside H-phosphonates were effected. Sulfur transfer reagents (102), (103a) were then employed at this temperature to give the corresponding S-cyanoethyl or S-4chlorophenyl phosphorothioate triesters. The protected dinucleoside phosphorothiolates could be readily detritylated at - 50 “C under conditions which eliminated depurination and the synthetic strategy was demonstrated for a tetramer containing one central phosphorothioate. Reese et al.95 have also described solution-phase phosphotriester chemistry which has been used for the preparation of a protected phosphorothioatelinked octanucleotide on a gram scale. 3’-S-Cyanoethyl phosphorothioate diester monomer, dimer and tetramer blocks were prepared via the H-phosphonate and sulfurisation with (103b). These were coupled with 5’-hydroxyl moieties. Other solution-phase syntheses of phosphorothioates and phosphorodithioates using P o chemistry potentially scalable for large-scale have been i n ~ e s t i g a t e d .97~ ~Stec ~ and co-workers have described the preparation and diastereoisomeric purification of 5’-0-DMT-xylo-thymidine 3’-0-(2-thio4,4-spiro-pentamethylene-1,2,3-0xathiaphospholane) (1 Attempted chromatographic resolution of the diastereomers of the unsubstituted
5: Nucleotides and Nucleic A c i h
163
oxathiaphospholane (104b) was unsuccessful. Compound (1Ma) was applied to the stereocontrolled incorporation of xylothymidine 3'-O-phosphorothioates of predetermined P-chirality into oligonucleotides. Ab initio calculations performed on the base-catalysed methanolysis of an oxathiaphospholane have been employed to model the stereoselective coupling of such moieties with nucleoside 5'-hydroxyls to yield phosphorothioates? These calculations indicated that a trigonal bipyramidal pentacoordinate phosphorane intermediate is formed. Concomitant pseudorotation and collapse of this intermediate to the phosphorothioate yields an overall reaction which proceeds via substitution with retention of configuration (as observed in the synthesis of phosphorothioates).
Pr'*N,P,O-CN (105) B = I, GBuiCBL,U
The 3'-thio analogues of uridine, cytidine, inosine and guanosine have been prepared by Vorbruggen glycosylation of nucleobases with a peracylated 3'thioriboside and subsequently derivatised to give the phosphoramidites (105).loo Efficient incorporation of these phosphoramidites into oligoribonucleotides was accomplished by activation with p-nitrophenyltetrazole and manual delivery to the solid-supported oligomer. Characterisation of the oligomers included site-specific chemical cleavage of the P-S bond with several thiophilic agents. Phenylphosphonate and phenylphosphonothioate internucleotide linkages have been introduced into chimeric oligonucleotides using solid-phase synthesis with phenylphosphonamidite monomers (106) under prolonged reaction times. Only minor changes in the hybridisation of end-capped sequences to complementary DNA or RNA were observed with the sulfur-containing modification giving lower T, values. A new method for the rhenium(V)catalysed sulfurisation of a nucleoside phosphite triester with propylene sulfide has been reported.lO' Zhang et al. lo* have reported the use of a new sulfurising agent, bis(ethoxythiocarbony1)tetrasulfide (107) for the solid-phase preparation of oligonucleotide phosphorothioates. Three independent reports of boranophosphate linked oligothymidylates (108) have appeared, all of which use the same strategy for their construction. Either solution-103or solid-104,lo5 phase synthesis of the corresponding Hphosphonate-linked oligomer using standard chemistry was performed. Activation to the trimethylsilyl phosphite triester derivative with a neutral silylating reagent was followed by in situ conversion to the boranophosphate using borane-diispropylethylamine,-pyridine or -dimethylsulfide complexes. Higson
Organophosphorus Chemistry
164
DMToY
EtO-C-S-S-S-S-C-OEt II (107)
H+ov ?
O=P-BH3
S II
I
O
V
OH (108) n = 1, 13, 14
et a l l w reported that without protection of the lactam carbonyl of thymine,
the base is subject to reduction upon borane treatment. N3-Anisoyl-protected H-phosphonates were therefore employed and both Tms and RNase H activity were recorded from these oligomers. Beaton and co-workers have described a novel method for the automated synthesis of a 3'-hydroxymethylene phosphonate-linked heptameric thymidylate ( 1O9)lo6 using sequential 5'-+ 3' Arbusov coupling reactions of the DBU activated H-phosphonate (1 10) with the 3'-aldehyde on the growing oligomer (unmasked by acid treatment of the imidazoline). Coupling yields of 95-97% were reported and (109) was found to be completely resistant to snake venom phosphodiesterase but showed some susceptibility to calf spleen phosphodiesterase. A pyrrolidine methyl phosphonamidite (111) has been prepared on a multigram scale by an in situ method which obviates the need for purification, and has been incorporated into an 01igomer.'~~
0 It
DMTo-P Q
Peptide nucleic acids (PNA) and related analogues have received considerable attention due to their potential therapeutic and diagnostic applications and also in the recently reported potential prebiotic replication of information.107-109 Chiral ornithine-based nucleic acids (ONA) in which the backbone amide linkages are formed between the carboxyl and &amino groups and the
5: Nucleotides and Nucleic Acids
165
pendant nucleobase linked through the cc-amino group (1 12) have been studied.'lO- Although such analogues have the same number of bonds in the backbone as PNA, they have previously been reported to hybridise only poorly with RNA and not at all with DNA. Similar results were reported for the ribose derivative (1 13).l However, activated N"-acyl amino acids are known to be prone to racemisation and van der Laan et al. 110 report that initial construction of the backbone followed by acylation of the a-amine with thymin-1-ylacetic acid has been employed for the preparation of chirally pure D- and L-ONA homooligomers containing thymine. Both of these formed stable complexes with RNA. The same strategy has been applied to the liquid phase synthesis of PNAs. l2 Natural amino acid-based tetrapeptide derivatives with two adenine moieties (1 14) have been reported to form triplexes with poly dT and poly U.l13
k
O
0 (112) R
=
L
A
N'
H2N % ' J O& C & RH
HR
(1 14) R = H, CH20H, CH(OH)Me, CH2C6H40H
B (113) R = OH
In order to expand the sequence recognition repetoire of triplex-forming PNAs, Nielsen and co-workers have designed and synthesised the 3-oxo-2,3dihydropyridazine PNA monomer (1 15) which has been designed and incorporated into a Hoogsteen strand PNA-DNA chimera targeted against a polypurine tract interruputed by T bases.'l4 This PNA analogue was found to stabilise the complex when compared to either no-base or G recognition of the interrupting pyrimidine. The incorporation of other modified bases into PNA has been described in order to tune their hybridisation properties. These include N4-benzoylcytosine1l5 and diaminopurine (DAP).116 CBzwas found to
(115)
Organophosphorus Chemistry
166
inhibit PNA triplex formation but did not interfere with Watson-Crick hydrogen bonding and therefore has potential applications in PNA hybridisation arrays. Increased DNA binding and sequence discrimination was observed for PNA oligomers incorporating DAP via the monomer (1 16) and a homopurine decamer containing six DAP residues was found to form a strand displacement complex with a target within a 246bp double-stranded DNA fragment. L-a-amino acid dipeptide derivatives (1 17) have been employed for the preparation of a new PNA analogue designated a-PNA. A 20-mer peptide incorporating ten pyrimidines has been prepared on solid-phase and characterised by MALDI-TOF. Improved methods suitable for the large-scale preparation of MMT-protected PNA monomers and DMT-protected hydroxyethylglycine derivatives used as linker molecules for the generation of DNNPNA chimerae have been described. l 8 A tetrameric aromatic peptide nucleic acid (1 18) has been constructed and, although base stacking was proposed from the observed hyperchromism compared with the dimer, no duplex formation with & was observed.llg Distamycin nucleic acids (1 19) have been described by Leumann and Sauter120 in which the minor groove-binding drug distamycin is used as a neutral analogue of the ribose-phosphodiester backbone. Solid-phase oligomerisation of the monomeric building block was employed for the preparation of up to tetrameric structures with C-terminal lysine although progressively reduced yields were observed due to capping of the terminal amino group with DCCactivated dmf. No base pairing was observed with either DNA or RNA.
B = T, Cck, Ack, Gk LysHN H f 0,
RN
5: Nucleotides and Nucleic A c i h
I67
Isoxazole and isoxazoline-linked neutral di- and tri-nucleotide analogues have been prepared. Phosphonate PNA (pPNA) (1 20) is an isosteric analogue of PNA which has improved aqueous solubility compared to PNA. Previous reports were limited to oligopyrimidine pPNA. Dahl and co-workers have prepared protected N-(2hydroxyethy1)-N-(nucleobase-acety1)aminomethane phosphonic acids of all four DNA nucleobases (121). 122 Solid-phase synthesis of oligomers was performed on a ‘universal’ support (122) from which the oligomers were PixO,
cleaved with either pPNA phosphonate or DNA phosphate monoester termini. Decamers with up to ten substitutions of the natural nucleotides by pPNA were prepared. The phosphonate diester was found to be relatively unreactive and coupling was therefore performed using the strongly activating agent PyFNOP with NMI. Coupling efficiencies of ca. 95% for the first 3-4 bases were observed but subsequent monomers were incorporated with significantly diminished efficiencies (ca. 65%)’ improved only slightly by the use of lowloading polystyrene. Introduction of pPNA residues into DNA was found to destabilise duplexes with both complementary RNA and DNA. Two groups have described the preparation of mixed PNA-pPNA or PNA-analogue pPNA oligomers using dimer block strategies. 124 A phosphonate-linked dimer bearing a carboxylic acid group (123) was employed for the preparation of an alternating pPNA-PNA linked dodecamer on solid-phase using standard PNA 1239
T
T
(123)
(124) X = 0, NH
(125) RX = DMTO, MMTNH
6-
168
Organophosphorus Chemistry
chemistry.123 Efimov and co-workers have accessed a more diverse combination of PNA and pPNA or analogue pPNA linkages using dimers bearing a carboxylic acid group (124) or phosphonic acid monoester function (125).124 Both groups reported the formation of triplexes between pPNA (or analogue pPNA)-PNA copolymers and oligomeric dA. These sequences were also found to be resistant to endo- and exo-nuclease activity. Amide-linked dimer phosphoramidites derived from modified PKAs and 5'-modified nucleosides ( 126), (127) have been incorporated into oligonucleotides. T
The substitution of phosphodiester linkages in pentadecathymidyiate analogues with glycinamide (128) and carboxamidomethyl linkages (129) has been r e ~ 0 r t e d . lThese ~ ~ linkages were constructed on solid supports in either a 3'- 5' or 5'-3' direction (respectively) by coupling of the corresponding amino-protected monomer phosphonic acid (130) or carboxylic acid (131). The oligomers were characterised by MALDI-TOF MS. Both oligomers showed increased affinity to dA15 and rA15 compared with the natural congener. The glycinamide linkages were found to be susceptible to hydrolysis.
v
MMTHN
-
O I
B
MMTNH
n-
The effect on triplex stability of different linkers between the 5'-hydroxyl of DNA and the C-terminus of PNA chimerae has been investigated. Phosphonate analogues (132) were synthesised and compared with other DNA-PNA adaptors. Nucleobase-containing analogues including ( 132a) had a higher binding affinity for target RNA than native DNA. Their antisense activity was found to be mainly due to RNase H-mediated target cleavage.126By suitable protection of the nucleobase, sugar and C-terminal of a nucleoprotein con-
169
5: Nucleotides and Nucleic Acids
jugate, site-selective deprotection of these positions could be performed under mild conditions 12* This was applied to the synthesis of an acid- and base-labile nucleopeptide conjugate.
R
0 (132a) R=+
NH
O
I
0(133)
OH
(1 34) 6 = ABL,5*CBZ, T
0
(132b) R = . r o e
a-Oligodeoxyribonucleotide N3'+P5' phosphoramidates (1 33) have been prepared from the amines (134) using the oxidative phosphorylation procedure previously employed for the corresponding p-anomeric phosphoramidates.129 Oligomers up to eleven residues long were constructed in this manner with coupling yields of 93-97% for pyrimidine residues and 88-94% for the aadenosine derivatives. Both parallel- and antiparallel-oriented duplexes of pyrimidine a-oligomers with RNA and DNA complements were found to be less stable than those formed with the isosequential p-anomeric phosphoramidates. In contrast, the a- and P-decaadenylic N3'+P5' phosphoramidate formed duplexes with RNA and DNA of similar stability. Homoduplexes were not formed. The Boc protecting group has been employed as an alternative to MMT for masking the amine moiety in 5'-amino-2',5'-deoxynucleoside phosphoramidites ( 135).130The Boc group is more stable than MMT although its removal during oligonucleotide synthesis gives rise to depurination of terminal nucleotides. Internucleoside phosphoramidate linkages in which a non-bridging oxygen is substituted by NH2 are susceptible to acid and base degradation and have therefore previously been limited to short sequences. Workers in Imbach's laboratory have reported the preparation of longer sequences incorporating this modification in both the a- and p-anomer series.13'* 132 Both oxidative amination of the corresponding H-phosphonate oligomers' 31 and a dimer block strategy13*have been employed. In the latter case, a- and P-dinucleoside phosphoramidates incorporating a photolabile mask for the NH2 moiety were prepared by oxidative amination of either the internucleoside methylphosphite triester or the H-phosphonate. The a-dimer was further derivatised to give the phosphoramidite (1 36) which was incorporated into a-oligonucleotides and following phosphate and nucleobase deprotection, the P-NH2 moiety was liberated following UV irradiation. Diastereomeric dithymidine methanephosphonamidates ( 137a) were pre-
170
Organophosphorus Chemistry
pared and separated using silica ~hromatography.’~~ Both diastereomers of the fully deprotected dimers were resistant to the action of nucleases. Further elaboration of (137a) to the 3’-phosphoramidite derivatives (137b) and incorporation of the dimers using standard solid-phase methodology yielded chimeric dodecadeoxythymidylates containing alternating methanephosphonamidate and phosphodiester linkages. These oligomers were characterised by MALDI-TOF MS and destabilised duplex formation with dA12and A12. Triplex formation was observed with the introduction of four modifications. An efficient and versatile route to nucleoside N-alkyl H-phosphonamidates has been described. 34 Zwitterionic oligonucleotides containing alternating negatively charged N3‘-+ N5’ phosphoramidate monoester and positively charged phosphoramidate diester (138) groups have been prepared. 35 The oligomers were assembled on a solid support by coupling dimer blocks (139) using standard H-phosphonate coupling and performing a final oxidative amidation. An alternative strategy using oxidative phosphorylation of the 3‘-amino containing dimer block (140) gave only 6 0 4 5 % coupling yields. Several novel phosphoramidites (141) designed to incorporate aminoalkylated phosphotriester internucleotide linkages have been prepared. I 36 However, under the conditions of deprotection, cyclodeesterification proceeded cleanly to the phosphodiester. Support-bound oligonucleotides attached v i a photolabile linkers allow base-sensitive oligonucleotides to be prepared. More efficient photocleavage of a linker derived from coupling the o-nitrophenyl1,3-propanediol-based phosphoramidite (142) with LCAA-CPG was observed compared to other photolabile linkers, even with high 10ading.l~~ The utility of (142) was demonstrated by preparing a fully substituted methylphosphotriesterlinked dodecathymidylate. Guanidinium internucleoside linkages have been proposed as attractive targets for DNA therapeutics due to their positive charge and achirality but multiple incorporation has been problematic. Bruice and co-workers have reported the synthesis of a guanidinium-linked octathymidyl ( 143)13*on solid support. In situ activation of a trichloroethoxycarbonyl-protected thiourea (144) by addition of mercury(I1) chloride yielded the corresponding carbodii-
5: Nucleotides and Nucleic A c i h
171 H
DMTov I-V HN
I
0=P-O-
HN I O=P-Me I
OR (137a) R = Ac (137b) R = P[O(CH2)2CN]NPt$
?
o=P-x
OH
(138) 8 = A, T; X = 0-, NH(CH2)&e2
DMTov 0
I O=P-H I
0-E~&H (139) B =A&, T
mide which was coupled to the 3’-amino function of the growing oligomer. This procedure gave estimated average step-wise yields of 97%. A Job plot indicated that a triplex was formed with poly(rA) and the same group has performed a molecular dynamics simulation of the interaction of octameric guanidinium linked riboadenosine with (dTp).;rdT.139 The overall structure equilibrated to a B-DNA conformation with the cationic octamer adopting the general conforamtion of the DNA backbone. Previously, Imbach and co-workers have described the use of S-acyl-2thioethyl internucloside phosphate triesters as pro-oligonucleotides for enhanced bioavailibility of potential therapeutic agents; cellular esterases hydrolyse these to the corresponding phosphate or phosphorothioate diesters. However, the post-synthetic alkylation protocols employed for their synthesis were slow, low yielding and gave side-reactions. Therefore the phosphoramidites (145) have been employed for the solid-phase synthesis of prododecathymidylates (146). 140 A photolabile linker was employed due to the
172
Organophosphorus Chemistry
D"To-P 0 I P,0/\r(,NHCOCF3
,
Et2N (141) B = T , n = 1,3, 4; B=CBz, n = 3
(143)
NH2
Pri2N,
P-0
v&-.
Id
NC
(142)
HoJo-y-
(144)
HNFmoc
S
DMToY 1 0 I
P , ' 2 N ' s 0 ~ s
(145a) R = Me (145b) R = But
KR 0
4 R
(146a) R = M e , X = O , S (146b) R = Bu', X = 0,S
base-sensitivity of the phosphotriesters and the oligomers released following photolysis were found to be stable in the presence of phosphodiesterase enzymes, human sera, or human gastric juice. Incubation of the S-acetyl derivatives (146a) with pig liver esterase or CEM cell extracts liberated the anionic parent dodecathymidylate. Torrence and co-workers have reported that 2- SA-antisense chimeric oligonucleotides attached via a 3',3'-linker were significantly more resistant to degradation but still activated the target, complementary mRNA towards 142 RNase L-mediated cleavage. 1 4 1 3
4.3.2 Oligonucleotides Containing Modified Sugars - A new class of mechanism-based inhibitors with unprecedented binding affinity (&< 1pM) for the DNA base-excision repair enzyme MutY has been r e ~ 0 r t e d . IThe ~~ proposed transition state of such enzymes has an elongated glycoside bond
173
5: Nucleotides and Nucleic A c i h
and a developing positive charge in the ribose ether oxygen (147) and these features have been mimicked by using the pyrrolidine homonucleoside analogue (148) which is protonated at neutral pH. This analogue was introduced into an oligonucleotide via the phosphoramidite (149) and hybridised to a sequence containing 8-oxoG (OG) positioned opposite the analogue (OG/A is recognised by MutY and the A residue is cleaved). The phosphoramidite of 5’-iodo-5’-deoxythymidine ( 150) has been prepared and incorporated into oligonucleotides.’44The iodide was found to be stable to standard ammonolytic deprotection conditions but reacted with phosphorothioate monoesters and this chemistry has been used for template directed, site-specific chemical ligation of DNA. Several ligation protocols were followed to give a variety of DNA structural motifs.
I Enz
DNA’
0
DNA’
(148)
CI
0
A hammerhead ribozyme has been prepared in which the 2’-hydroxyl nucleophile was protected by the photolabile 2-nitrobenzyl group. 145 The ribozyme was prepared with 2‘-O-Fpmp protection and the 2’-0-(2-nitrobenzyl) protected phosphoramidite (15 1). Upon photolysis of the caged ribozyme, cleavage was initiated under native conditions. Fully modified oligonucleotide sequences derived from 2’-O-propargyl amidites (152) have been prepared and characterised by MALDI- or ES-mass spectrometry.146 This modification represents a compromise between increased stability and the adverse side effects (e.g. self-association) from the introduction of hydrophobic groups at the 2’-position. Hybridisation of the 2’-0propargyl oligonucleotides with complementary RNA and DNA showed an increase in T, from the corresponding RNARNA or RNADNA duplexes in both cases but most significantly with the DNA.
Organophosphorus Chemistry
174
P$2N’p\ONcN
(152) B = Ah, GDMF,CBz,Tm
A simple large-scale synthesis of L-ribose phosphoramidites (153) and (1 54), starting from D-glucose, has been reported and the 2’-protected monomers used to prepare an active enantiomeric hammerhead ribozyme and its enantiomeric ~ u b s t r a t e . ’A~ ~2’-5’-linked substrate was found to be resistant. Improved photolysis conditions for the removal of the 2’-protecting groups are described. The L-related isodeoxynucleoside phosphoramidites (isoA, isoT) (155) were incorporated into a self-complementary dodecamer sequence at the central AATT region.14* These analogues exhibit high exonuclease resistance and isoA-isoT base pairing was shown to contribute stability to the duplex.
(153) B = ABz, GBu:CBz,T, U
‘,
.aDMT Pr‘2N.
O+/CN
I
(155) B = Ah, T
Tricyclic nucleoside phosphoramidites (156) have been prepared and incorporated into homopurine or pyrimidine oligomers. The fully substituted oligonucleotides have constrained conformational flexibility and form stable duplexes with complementary DNA or RNA and are resistant to Snake Venom PDE.149, 150 3’-C-(3-BenzoyloxypropyI)-thymidine(157) and the bicyclic nucleoside monomers (158) and (1 59) have been incorporated into oligonucleotidesand shown to destabilise duplexes. 51 The acyclic 2’-deoxy-1’,2’-seco-D-ribosylnucleoside phosphoramidites ( 160) and corresponding secodeoxynucleoside-derivatised CPG support have been prepared and incorporated into oligomers using solid-phase chemistry.* 52 These did not form duplexes with either each other, DNA or homo DNA. An aptamer-based interaction is believed to be the basis for the anti-HIV-1 activity
DMTo-p-o g DMTP
5: Nucleotides and Nucleic Acids
175
DMTO
BzO
? 1
p
of the purine-rich hexadeoxyribonucleotide S'TGGGAG3' with pendant 5'aromatic groups such as 3,4dibenzyloxybenzyl (3,4-DBB) or trityl. Hotoda et al. 153 have reported that substitution of the 3'-terminal purines of this sequence by (9-or (R)-glycerylguanineusing the corresponding phosphoramidites (16 1) gave improved anti-HIV potency and greater stability towards nuclease digestion. The solid-supported synthesis of oligonucleotides typically involves a sugar-support attachment. Waldvogel and PfleidererlS4have investigated the application of several bifunctional amino-protecting groups as linkers for attaching the nucleobase to a support. Pentane-1,3,5-tricarboxylic acid 1,3anhydride was found to have the most appropriate properties and the corresponding imide derivatives of cytidine, adenosine, guanosine and the acylic analogue of adenosine (162) were prepared. Compound (162) was used to prepare the 2',5'-linked trimer (1 63).
0 I
P&N P , O N C N (160) B = A & , T
OR
n
2'-deoxy-D-mannitol nucleosides in the purine series have been prepared and incorporated into fully modified hexameric mannitol nucleic acid (MNA; dodecamer MNA could not be isolated) via their phosphoramidites ( 164).155 The lack of stability of MNAnRNA duplexes was investigated using molecular
176
Organophosphorus Chemistry
dynamics simulations which indicated frequent H-bonding contacts between the 3’-hydroxy and the &-oxygen thus giving a non-ideal sugar conformation.
(164) B = ABL,GBu’
(165)
Eschenmoser and co-workers have continued a series of papers on the chemistry of hexopyranosyl oligonucleotide systems as potential alternative information-carrying molecules in a prebiotic w ~ r l d . ’57~ Bolli ~ * ~ et al. 156 have summarised previous results and performed further exhaustive studies on the template-directed ligation of tetrameric pyranosyl-RNA terminated with 2’,3’cyclic phosphates (165). These were readily formed in solution from the unprotected 2’-phosphomonoester terminated sequence via carbodiimide coupling. These cyclic phosphates did not undergo ligation in the absence of template and are therefore potentially useful models for non-enzymatic informational replication. 5’-Amino- and 5’-mercapto-5’-deoxy-2’-O-methyl nucleoside phosphoramidites (166) and (167) have been prepared and used to introduce these modifications at the 5’-termini of hammerhead ribozymes; the 5’-amino modified ribozyme showed increased resistance towards digestion with a 5’exonuclease.15’ 2’-Amino-2’-deoxyarabinoadenosinehas been incorporated into oligodeoxynucleotides via its phosphoramidite (168) and covalently crosslinked with a complementary strand bearing a carboxylate function. 159 Adenine and thymine cyclopentylethyl nucleoside H-phosphonates (169) have been prepared from the corresponding phosphoramidites and used for the incorporation of a single modification into a tridecanucleotide.’60 Attempted coupling of the phosphoramidites was not successful. 3’-Deoxy(2’-5’)-oligonucleotides bind selectively to complementary RNA but not to DNA, and synthesis of the 3’-dG phosphoramidite has been reported.16‘
v ph3csv
MMTNH
5: Nucleotides and Nucleic Acids
177
4.3.3 Oligonucleotides Containing ModiJied Bases - An octadecaribonucleotide which incorporates the naturally occurring, base-labile N4-acetylcytidine has been prepared using allyl- and allyloxycarbonyl-protected RNA phosphoramidites (170) and a photolabile linker. Standard solid-phase RNA synthesis conditions were employed (coupling efficiencies of >93% were reported) to construct the oligopyrimidine. The fully protected oligomer was initially treated with a homogenous palladium(0) catalyst in the presenece of butylammonium hydrogen carbonate to remove the allyl and allyloxycarbonyl protecting groups, followed by photolysis, to liberate the oligomer and finally treated with TBAF. It is anticipated that the reported protocol should be general for base-labile modifications.162 0 JNH
N I KONPE
I
5-Aza-2’-deoxycytidine is not stable towards ammonia treatment and has been incorporated into oligodeoxynucleotides via the nitrophenylethoxycarbonyl-protected phosphoramidite (1 7 1). 163 A comprehensive survey of base protecting groups for the incorporation of 2’-deoxyisoguanosine and 2’-deoxy5-methylisocytidine into oligonucleotides using solid-phase phosphoramidite chemistry has been made by Battersby and co-workers.’@ The 5-hydroxypyrimidine phosphoramidites (1 72) and (173) have been prepared and introduced into oligodeoxyribonucleotidessite-specifically.16’- 67 Replication of an M13 viral genome incorporating these putative mutagens at a single site showed that 5-hydroxy-2’-deoxycytidinegave only low levels of mutation compared to 5-hydroxy-2’-deoxyuridinewhich predominantly gave C +T
0 0-DNA
178
Organophosphorus Chemistry
transition mutations, thus providing a model for the C+T oxidative mutagenesis. The convertible nucleoside (174) has been used to introduce 5-fluoro-2’deoxycytidine into oligonucleotides as a 19F NMR probe. 168 8-0~0-7,8-dihydroguanosinephosphoramidite and its 2’4-methyl derivative have been incorporated into oligoribonucleotide reverse transcriptase templates using phosphoramidite monomers (175). 69 Dihydropyrimidine lesions have been characterised as products of a variety of DNA-modifying agents. Dihydropyrimidine phosphoramidites, including (176), have been used to incorporate the corresponding nucleotide analogues into oligodeoxyribonucleotides.170 These analogues were found to inhibit Klenow fragment (ex0 -)-catalysed DNA polymerisation.
‘
Coleman and co-workers have described the incorporation of 6-thio-2’deoxyinosine into oligonucleotides using a 2-cyanoethyl-derivatised phosphoramidite (177). 171 Deprotection of the oligonucleotide was performed by treating with 1M DBU in acetonitrile followed by aqueous ammonia containing 50 mM NaSH. The oligonucleotide was then cleanly alkylated. Only monoprotection (N2) of the exocyclic amino functions of 2,6-diaminopurine 2’-deoxyriboside was found necessary for the successful incorporation of this analogue into oligomers using phosphoramidite chemistry. 72 2’-Deoxyguanosine analogues carrying various hydrophobic substituents in the N2 and C8 positions were synthesised and introduced via monomers (178), (179) into a pentadecanucleotide sequence which forms a chairlike structure consisting of two G-tetrads at the sites of tetrad formation.173 The allyl-modified nucleoside (180) self-alkylates and depurinates on treatment with iodine (Scheme 1) and therefore provides a new route for the sitespecific generation of abasic sites without significant disruption of cognate ba~e-pairing.’~~ Nucleoside analogue (180) was introduced into an oligonucleotide via the phosphoramidite (181) which was treated with neat allylamine to displace the iodide. Surprisingly, the iodine treatment also gave nonselective DNA cleavage at unmodified purine sites. N4-Ethyl-2’-deoxycytosine has been shown to hydridise specifically with dG to give a base pair which has similar stability to that of a natural A*T base pair.175This modified base should therefore have applications in DNA arrays.
’
5: Nucleotides and Nucleic Acids
179 0
DNA
I
I
0-DNA
I
6-DNA
Scheme 1
I
Several base-modified nucleosides including 8-azaadenosine, its 2'-deoxy derivative and 7-alkyl-7-deazapurines have been incorporated into oligonucleotides by Seela and co-workers using either phosphoramidite or Hphosphonate monomers (182)-( 184). 176-179 Enhanced RNA-binding affinities were found for oligodeoxynucleotides containining 7-iOdO-, 7-cyano- and 7propynyl-7-deaza-2-amino-2'-deoxyadenosines which were incorporated using the corresponding phosphoramidites. * *O The substitution of deoxycytidine 2,4-diazaphenoxazine-3-one(a tricyclic analogue) has previously been found to give significantly enhanced duplex
180
Organophosphorus Chemistry
NBU'
(182) R' = HPO-, R2 = OSiPr'3; R' = P(OCH2CH2CN)NPr'2, R2 = H
(183) R' = HPO-, OSiPr'3; R2 = -C=C(CH2)&le, -C=C(CH2)3NHCOCF3
HNL O M e
DMTO1-4Jc"
(184) R'
=
R'O OSiPri3 HP02-, P(OCH2CH2CN)NP$2
stability and incorporation was via an H-phosphonate monomer. A phosphoramidite synthon of this duplex stabilising analogue (185) has now been prepared.'*' Oligonucleotides incorporating fluorescent pteridine-derived bases have been prepared via the corresponding phosphoramidites (1 86) or support bound nucleosides and were found to substantially increase duplex
DMTov
5: Nucleotides and Nucleic Acids
181
stablility.182* 183 The carbocyclic nucleoside phosphoramidites (187) have been used to incorporate extended heterocyclic structures into triplex forming oligopyrimidines and showed preferential binding of pyrimidine over purine bases. 184 Bis-alkylation of guanosine with 1,2-dibromoethane was used to prepare 5,6,7,9-tetrahydro-9-oximidazo[ 1,2-a]purine (ethanoguanosine) which was incorporated into a template strand as its phosphoramidite (188) and its effects on misincorporation and blockage of DNA polymerase activity compared with other alkylated g u a n o ~ i n e s . 'The ~ ~ core trimer of 2-5A has been prepared with a variety of single site subsitutions by either the antiviral nucleoside ribavarin or the cytokine 6-benzylaminopurine riboside using solution-phase phosphotriester chemistry via the monomers (189).186
O=P--oI
{cg
ONPE
(189) B = A B Z ,
$3 N" I
,
I
An analogue of the 2-5A core trimer containing an 8-(4-aminobutyl)aminoadenosine residue has been synthesised (190)although only low binding to an RNase L was 0 b ~ e r v e d . lThe ~ ~ phosphoramidite (191) has been incorporated into an oligonucleotide template and its effect on DNA amplification evaluated. 188 The degeneracy of molecular recognition was compared with several other similarly shaped azole nucleobase analogues with multiple hydrogen bonding orientations. In order to study the metabolism of neutral oligonucleotide analogues with potential as antisense agents, the l4C-radio1abelledphosphoramidite (192) has been prepared and incorporated into a dode~athymidylate.'~~ 14C offers the highest specific activity and longest half-life of commonly employed isotopes
182
Organophosphorus Chemistry
(190) R = NH(CH2)dNHz
(191)
0 I ,P, -SBU' Pr'zN 0 (192) = 14C
for tracing radioactive metabolism. The positions of radiolabeling were chosen from the perspective of isolating metabolites which are more conveniently analysed than the 14C02that is produced from the C2 position. 5
Linkers
In vitro selection using oligonucleotides with pendant functionality has been
applied to the generation of libraries of catalytic nucleic acids with new activities. A library of RNA molecules with Diels-Alderase activity has been generated by ligating a 100-nucleotide long random region incorporating 5pyridyl-modified uridines (193) flanked by constant region primer-binding sites to a 5'-diene-PEG-modified decadeoxynucleotide ( 194). This construct was designed such that the diene had full access to the whole of the RNA and selection was performed by incubation with a maleimide dienophile (195) in the presence of transition metals. Of the cloned sequences from the library tested, the most active was found to have an absolute dependence on Cu+, to be inhibited by addition of a free cycloaddition product (between (195) and a model diene) and the product of the Diels-Alder reaction characterised by ESMS following RNase I digestion. One of the most exciting applications of nucleic acid conjugates has arisen from the use of the support-bound puramycin (P) (196) for the preparation of polypeptides fused with their coding RNA.I9' Puramycin mimics the aminoacyl end of tRNA and acts as a translation inhibitor by entering the A-site of the ribosome and accepts the Psite polypeptide arising from the peptidyl transferase activity of the ribosome. (196) was used to prepare d(Ap&pCpC)P under standard solid-phase methodology. This was ligated to T7-transcribed RNA sequences which
183
5: Nucleotides and Nucleic Acids
RNA-0
0 OH ANA
r
I
PEG+ (193)
DNA
I
I
(1 94)
lOON
I
I
0
NHCOCF3
contained mRNA open reading frames (ORFs) coding for up to 33 amino acids and included PCR primer-binding sites. Translation of the ORFs in reticulocyte lysate paused at the 3'-oligo dA tail and the terminal puramycin, which only binds slowly, then entered the A-site and accepted the C-terminus of the nascent polypeptide to produce the peptide-coding RNA fusion product ( 197). The dA-tail also facilitated capture of the oligonucleotide-protein fusion product by hybridisation to an oligo dT probe. The potential of such selfencoding combinatorial polypeptide libraries that can be evolved in the manner that has been applied to RNA and DNA was demonstrated by fusing a synthetic mRNA with its encoded myc epitope. Partially randomised ORFs coding for 33 amino acids were generated and used to dilute the 33-residue myc sequence 20-2000-fold. One round of selection involved a multi-stage
184
Organophosphorus Chemistry
procedure: i) dA tailed sequences were captured by binding to (dT)25 agarose; ii) properly initiated sequences containing methionine were cross-linked with thiopropyl Sepharose; and iii) immunoprecipitated with an anti-myc antibody. PCR amplification from a single selection round produced 20- to 40-fold enrichment of the correct coding sequence as determined by site-specific cleavage of a restriction site. Signal amplification is particularly important in emergent techniques which exploit oligonucleotide arrays. Several reports on the construction of branched nucleic acid structures that enhance signal have appeared. Dendritic (198) branching (in which branching occurs through the backbone) or comb-like (199) branching (in which secondary sequences are attached to the primary sequence through non-backbone linkages) motifs have both been applied in have described some exciting results using a this context. Shchepinov et novel phosphoramidite based upon a pentaerythritol structure (200) for the synthesis of oligonucleotide dendrimers with increased 5‘-hydroxyl loading. Using 500 CPG, (200) could only be coupled three times before coupling yields started to decrease. However, a 240-fold increase in 5’-hydroxyl loading of a model sequence (corresponding to addition of five branching monomers) was acheived by the use of 1000 CPG. Probe and PCR primer sequences with a nine-fold enhancement in hydroxyl loading were efficiently radiolabelled using polynucleotide kinase. The minimum length of spacer required for full exploitation of the enhanced 5’-hydroxyl loading following a double addition of the monomer was found to be a pentathymidylate. When used as probes, hybridisation of these multiply labelled structures to oligonucleotide arrays was found to be dependent on the orientation of the array sequences. Dendritic probes gave significantly enhanced sensitivity compared to singly labelled probes when hybridised to array sequences attached to a glass surface through the 3’-end (201).
A
A
(198)
’
(199)
Signal amplification using comb-like motifs arises by constructing multiple secondary hydridisation sites off a single probe sequence and generating signal from the recognition of these secondary sites by a sandwich-type assay. Horn
5: Nucleotides and Nucleic Acids
et al.
185
194 have reported investigations into optimising the divergent synthesis of branched DNA comb structures. Branches were introduced using monomers with either levulinyl(202a) or an anthraquinone-derivative (202b) protection of an N4-hydroxyalkyl cytosine. The secondary sequences were analysed and optimal branch length determined following periodate-mediated cleavage of monomers (203) and (204) introduced into the branch sequences. Compound (202a) was found to be the most successful branch point monomer and was used in conjunction with the nucleosidic cleavable monomer (204) to synthesise branched DNA combs with fifteen secondary sequences. These were further elaborated by enzymatic ligation to branched amplification multimers with an average of 36 repeated DNA oligomer sequences, each capable of hybridising to an alkaline phosphatase-labelled oligonucleotide. Such a system has detected as few as 50 molecules of DNA. 1937
The commercial availablity of 5'-phosphoramidites has allowed the facile construction of oligonucleotides in a S+3' sense and this has been exploited in Damha's laboratory as the basis for incorporating dendritic branching motifs into either DNA using a branching ribonucleoside monomer (205)195 or a
Organophosphorus Chemistry
186 HNBz
DNA-RNA chimera.196The branch point in this latter structure (found in many bacterial species) was constructed by the chemoselective desilylation of a single 2'-tBDMS-protected nucleotide embedded within a CPG-bound 2'Fpmp-protected RNA. Triethylamine-mediated decyanoethylation of the protected phosphate triesters prior to desilylation prevented migration of the RNA strand to the 2'-hydroxyl during its deprotection. The final structure was characterised by treatment with yeast debranching enzyme and DNaseI. In an extension of previous work, Grotli et al. 197 have synthesised branching monomers of all four ribonucleosides (206), the corresponding sarcosinelinked support-bound branch-point nucleosides and compatible 5'-phosphoramidites of both deoxyribo- and ribo-nucleosides (207), (208), from which branched oligonucleotides of different lengths and base composition attached to the 2'- or 3'-hydroxyl groups were prepared. The cyanoethylated phosphoramidites (209) were employed for the first coupling to the branching monomer. This linkage was converted to the phosphodiester (with DBU) prior to deprotection of the second hydroxyl of the branch point monomer in order to prevent isomerisation of the branch point. A sarcosine linker was used to attach the oligonucleotides to the solid support due to its stability during hydrazinolytic removal of the 2'-levulinyl protecting function.
R2dp-o-r!
P&N,
~
(207)R'
= H, R2 = Me (208) R1 = OFpmp, R2 = Me (209) R1 = H, OFpmp, R2 = OCH2CH2CN
(206)-(209)6 = A'", GDMF,CBz,TPOM(R'
= H), UPOM(R' = OFpmp)
Polymer-bound 3-chloro-4-hydroxyphenylacetic acid (210) has been employed for the synthesis of cyclic oligonucleotides.'98 Initial coupling of a cyanoethyl-protected phosphoramidite was followed by chain elongation with methylphosphoramidites. The 3'-terminal phosphate was deprotected selec-
187
5: Nucleotides and Nucleic Acids
tively and coupled with the 5'-terminal hydroxyl using P(V) chemistry. Only the 0-aryl triester that has reacted in this fashion was liberated from the support upon oximate treatment.
I
b"' P
"q
Oligonucleotides containing terminal 5'-amino and 3'-carboxy groups have been prepared using an alkylsulfonylethyl-derivatisedsolid support (211). Non-templated circularisation was performed by chemical ligation of the termini.199*2oo A novel catenane topology has been defined for a circular triplex-forming oligonucleotide by performing a ligase-mediated circularision of the linear triplex-forming oligomer in the presence of a circular doublestranded target.201 Improved post-synthetic conjugation procedures have been reported.2025'Aminoalkyl functionalisation of protected support-bound oligonucleotides using a variety of phosphonylation methods and subsequent coupling with isothiocyanates has been described. These workers also report that such aminoalkyl-functionalised oligomers give significant N-alkylation with acrylonitrile in 33% ammonia which may be the cause of lowered yields of conjugates derived from cyanoethyl-protected oligomers. High isolated yields of homogenously labelled oligonucleotide using an orthogonal, convergent strategy have been reported.203 Fully protected oligonucleotides bearing a 3'-alkyl m i n e were released from a support following irradiation of a photolabile linker (212). A redox condensation process which has been successful for amide bond formation under dilute conditions was employed on the crude photolysate with a variety of acids and gave 83-99% isolated yields. In an alternative strategy, a pyrene carboxylic acid ester was conjugated to a protected, support-bound oligonucleotide via a free amino group generated by palladium(0)-mediated removal of an allyloxycarbonyl protecting group.204 The 2'-aminoalkylated phosphoramidite (2 13a) and support (213b) were used to introduce the orthogonally protected amine. In order to facilitate tissue-specific targeting of oligonucleotides and cellular uptake via receptor-mediated endocytosis, conjugates of an octadecamer with folic acid, retinoic acid, arachidonic acid and methoxypoly(ethy1ene glycol)propionic acid have been s y n t h e s i ~ e d .The ~ ~ ~ amino-carboxylate coupling
Organophosphorus Chemistry
188
r l
R’O OR2 (213a) R’ = P(OCH2CH2CN)NPt2,R2 = (CH2)6NHCOCH2CH=CH2 (213b) R’ = (CH~)GNHCOCH~CH=CH~, R2 = CO(CH2)2CON H-CPG
reaction was performed on the solid support and, as exocyclic amino groups on the bases were protected with the labile pent-4-enoyl protecting groups, only mild ammonolysis was required to give the fully-deprotected oligomer. The compounds were characterised by MALDI-TOF MS. Low Density Lipoprotein (LDL) receptors are highly expressed in tumour cells and 3Hlabelled oligonucleotides with lipophilic 3’-termini have also been prepared and shown to associate with LDL.206Pamamycin is an antibiotic that forms lipophilic ion pairs but exhibits cytotoxicity. Alkaline hydrolysis of pamamycin liberates the anionophoric moeity (DMAD) which retains the ability to form lipid pairs but is considerably less cytotoxic than the parent compound. The support bound-DMAD (214) has been prepared and used to synthesise oligonucleotide conjugates with potentially enhanced cell penetration capabili t i e ~The . ~ CPG-oxalyl ~~ Isoargentatin-D (215) has been used for the synthesis of oligonucleotides with this cholesteryl-like natural product attached at either the 3’- or 5’-terminus of oligothymidylates.20* Covalent cross-linking of the SV40 large T-antigen nuclear localisation signal (NLS) to double-stranded DNA has been reported using an NLScyclopropapyrroloindole conjugate (216)209This reacts with double-stranded DNA to form an N3-adenine adduct (217). A polypeptide sequence derived from the growth control gene product Antennapedia has been shown to transport peptides and oligonucleotides into cells.210Chimeric molecules of this sequence and PNA have been prepared and are efficiently taken up by mammalian cells in culture. The anti-HIV- 1 activity of hexadeoxyribonucleotide STGGGAG3’ with 5’terminal modified aromatic groups such as 3,4-dibenzyloxybenzyl (3,4-DBB) or trityl has been tested with a variety of 3’-end-m0difications.~” These 3’termini were introduced via modified supports (218) prepared from the corresponding phosphoramidites or the 0-arylphosphate diesters. An increase in anti-HIV-1 activity was observed for the 5’-3,4-DBBcapped sequence with a 2-hydroxyethylphosphate, 2-hydroxyethylthiophosphate or methylphosphonate 3’-terminus. The 2-hydroxyethylphosphate derivative was found to be the most stable when incubated with human plasma.
189
5: Nucleotides and Nucleic Acids Me, ,Me Me-N,+
A series of labelled phosphoramidites (219) and CPG supports based upon cyclohexyl-4-amino-1,l -dimethanol has been synthesised.*'* These reagents have been used to label oligonucleotides with biotin and fluorescein at 5'-, 3'and internal positions. Using a universal support, thirteen different 3'-endlabelled oligonucleotides have been prepared from the corresponding phosphoramidites without the need to prepare a separate CPG for each one, although some of the primary hydroxyl containing amidites gave poor (< 55%) yields.21 Fluorescent conjugates have been the targets for several groups due to their application in detecting hybridisation. Tetramethylrhodamine-derivatisedsupports (220) and (221) were used to prepare double dye-labelled oligonucleotide probes incorporating fluorescein at the 5'-terminus and the rhodamine at the
Organophosphorus Chemistry
190
A
(218a) X = S, 0; R = OMe, Me, O(CH2CH20)6H,O(CH2CH20)dc (218b) X = 0;R = OPh, O(2-CI)Ph. 0(4-CI)Ph, O(CH2CH20)&
D M T o F h f X - R
0 I
Pr'2NA
0
~ C (219)
N
(220a1221a) X = -CH2CH2-
X
-
R biotinyl
-CO(CH2)5NH- N-(4-But-Bz)4iotinyl 4 0 f luorescenyl 4 0 (CH2)5NHCOCF3
(220b1221b) X = -CH20CH2-;
3'-termin~s.~'~* 21 The cleavage rate of the diglycolate ester (220b) proceeded rapidly and without degradation of the dyes. The probes were used in real-time monitoring of PCR reactions based upon exonuclease-mediated removal of the rhodamine (and consequent reduction in fluorescence quenching) following hybridisation and elongation. The pyrene phosphoramidite (222) has been prepared and used for multiple internal labelling of oligodeoxynucleotides. An octadecamer oligothymidylate in which the two central positions were substituted by pyrenyl residues exhibited enhanced excimer fluorescence upon
5: Nucleotides and Nucleic A c i h
191
hybridisation to dAl8.216 Pyrene phosphoramidites (223)-(225) have been prepared and used to fluorescently label oligon~cleotides.~~
Puri et al.218 have synthesised a series of planar hydroxyalkylated polyarenes with different steric and electronic characteristics. These were coupled with thymidine 5’-phosphoramidite derivatives to give polyarene tethered nucleotides (226 a-g) and (227) and further elaborated to give monomer synthons for the 5’-labelling of either nonamer or octadecamer oligodeoxy-pyrimidinenucleotides. These were tested as duplex- and triplex-stabilising moieties, respectively, and the nitrophenanthrene conjugate derived from (226c) found to perform best in both of these roles. Several conclusions about the effect of linker lengths, steric factors and electronic properties of the conjugates on duplex- or triplex-stabilisation were drawn. A pyrene phosphoramidite (228) was also reported. Direct attachment of a hydrophobic fluorescent probe to an aminosugar and its incorporation into oligonucleotides via its phosphoramidite (229) has been reported.*19The fluorescence emission spectrum of this probe overlapped with the absorption spectrum of fluorescein and did not appear to be involved with duplex intercalation. New pyranone derivatives having tri- or penta-methyleneamine linker functions have been covalently attached by post-synthetic redox condensation with a 5’-phosphate monoester to a heptamer and the effect of this on duplex stability with a complementary octamer tested.220The coumarin (a-pyrone) and chromone (ypyrone) derivatives strongly stabilised the duplex ( - 1.O to - 1.7 kcal mol- ’). Internal and terminal biotin-labelled oligonucleotides were prepared using 2’- and 3’-aminoalkylphosphoramidites(230); the 3’mbstituted compounds maintained a much larger proportion of N-type sugar conformation.221 Several reports of post-synthetic modifying protocols involving nucleophilic attack on a modified base have been made. Verdine and co-workers have prepared convertible ribonucleoside phosphoramidites (231) that were used to introduce functionalised tethers into RNA (232) in a site-specific fashion by reaction with the appropriate amine.222From the same laboraory, a report has
Organophosphorus Chemistry
I92
(226a-c) R =
do-\~ (2264) R = \
Me
”
/
’
(226a) X = H, n = 1,3 (226b) X = H, I/ = 1,3 (226~)X = NO*, n = 1
‘OBZ
’NM*
DMTov R’O OR2
(230) R’ = P(OCH2CH2CN)NPr‘z. (CH~)BNHCO(CH~)~X R2 = (CH2)eNHCO(CH2)4-X, CO(CH2)2CONH*CPG X = ~(bBu~-Bz)-biotinyt
193
5: Nucleotides and Nucleic Acids
appeared on the use of the deoxyanalogue of (231a) to generate the M. HaeIII DNA (cytosine-5)-methyltransferase recognition sequence with variable basepairing stability. Introduction of variable length disulfide cross-links between the duplex strands at a remote site gave structures with variable degrees of strain in the recognition sequence.223Using short, destabilising cross-links gave higher affinity of the substrate for the enzyme. The same convertible nucleoside was also applied as a mechanistic probe for the B-2 transition in DNA.224Diaz et al. 225 post-synthetically modified DNA containing the same 2-fluoro-2’-deoxyinosine derivatives with double-helix stabilising molecules such as spermine, spermidine and propylimidazole. The phosphoramidite of the convertible nucleoside (233) has been prepared.226The cyanomethyl ester is reported to give improved reaction of sequences with monoamines compared with other C-5 esters that have previously been reported. Compound (233) has been used to radiolabel a pentadecamer complementary to HIV rev with lZ51 via its tyramine conjugate.
DMToY! 0 OTWms
F
(231~) B=
tk0 I
.Iw.
Internal aldehyde functions were introduced into oligonucleotides using the modified alkenylthioadenosine phosphoramidite (234).227The alkene served as a masked aldehyde during synthesis and deprotection of the oligonucleotide. Treatment with osmium tetroxide followed by periodate-mediated cleavage of the resultant cis-diol yielded the corresponding aldehyde (235). Reaction of this moiety with an oxyamino-tethered dansyl group (236) yielded the corresponding oxime linkage in a rapid and highly selective fashion. Chemical affinity modification of nucleic acid processing enzymes has typically been performed with abasic sites or external 3’- or 5’-reactive functions. A new report has appeared detailing the generation of a reactive dialdehyde group within a DNA sequence from the 1-P-D-galactopyrano-
194
Organophosphorus Chemistry NHBz
O M T O Y
0
DNA-0
DMTov 9
-@
0-DNA
sylthymine (Tgal) phosphoramidite monomer (237).228The Tgal modification was incorporated into a pentadecanucleotide incorporating a central EcoRII (MvaI) recognition sequence both within this sequence and also in flanking positions. Some loss in duplex stability and endonuclease/methylase activity was observed. Removal of the isopropylidiene group and periodate oxidation of the exposed cis-diol gave the dialdehyde (238) which underwent specific cross-linking to the enzymes. 2'-O-Aminonucleosides were incorporated into a hammerhead ribozyme sequence using the corresponding phosphoramidites (239).229 Slightly improved catalytic rates were observed and this moiety should facilitate postsynthetic modication of RNA sequences via oxime formation at lower pHs. A neutral porphyrin phosphoramidite with only minimal length alkyl tethers (240) has been prepared and incorporated into an octamer and an octadePreviously, only end-linked porphyrins have been used. The thermal stability of duplexes involving the octadecanucleotide containing the embedded porphyrin depended on the sequence of the complementary strand. Juxtaposition of T and the porphyrin gave the highest melting duplex, single-stranded footprinting only giving positive results in the immediate region of the porphyrin and unprecedented hyperchromicity (1 80%) at 50 1 nm. NMR studies suggested that the porphyrin ring was only partially intercalated but that the interations of this neutral molecule were different from those found for the more typically studied cationic tetraarylporphyrins. The conductance of double-stranded DNA remains controversial. Typically, these studies have been performed with guanine as the electron donor and a variety of intercalators as acceptor. Fast fluoresence quenching (k > 10'O s-')
5: Nucleotides and Nucleic Acids
195
DNA-01
H
238)
&DNA
LCN
(239)B = ABufBr, U
was observed by Barton and co-workers for duplexes 10-14 base pairs in length, the 5'-termini of which were covalently modified with ethidium and an intercalating rhodium complex.231 The photoinduced electron transfer was found to be both distance- and stacking-dependent. Distance-dependent electron transfer was also observed for a series of synthetic DNA hairpins in which a stilbene dicarboxamide formed a bridge connecting two complementary oligonucleotides consisting of hexameric thymidine and adenine tracts interrupted at various positions by a G-C base pair (241).232Fluorescence quenching and the formation of the stilbene anion radical resulted from this electron transfer which proceeded faster (k > lo8 s-') than in proteins. However, Giese and co-workers have found rates of electron transfer in a cation radical modified sequence which more closely mimic that in prot e i n ~ .Models ~ ~ ~for * rapid ~ ~ ~conduction in DNA have been d e ~ e l o p e d . ~ ~ ~ . ~ ~ This issue has also been addressed by Schuster and co-workers who have reported the preparation of modified PNA monomers with intercalating anthraquinone moieties (242), (243).237The first evidence for long range
Organophosphorus Chemistry
196
5'
3
electron (hole) transport in PNA-DNA hybrids has been provided using PNA incorporating internal anthraquinones. The same group has also reported the shortest strand invasion complex derived from an N-terminal-anthraquinone bis-PNA conjugate targeting a duplex DNA with a d(A5) Irradiation of the strand invasion complex resulted in asymmetric cleavage of the displaced strand, with more efficient cleavage at the 3'-end of the loop. Intercalation of non-nucleobase anthraquinone moieties has been shown for PNA-DNA duplexes239and hairpin-forming P N A s ; prepared ~~~ using (242) and (244).
Amide dimers (245) have been incorporated into oligonucleotides but despite the presence of the potentially intercalating anthraquinone, duplexes formed with complementary RNA or D N A were destabilised compared with the unmodified congeners.240
5: Nucleotides and Nucleic Acids
197
Griffin et al. have mass-labelled allele-specific PNA hybridisation probes using 8-amino-3,6-dioxooctanoicacid and demonstrated the application of these probes to the analysis of multiple polymorphic sites using MALDI-TOF mass spectometry."' Preliminary results from Xu et al.242 have established the feasibility of high-speed multiplex electrophore mass tag dideoxy DNA sequencing. A new method for the mapping of inosines within RNA has been described; reaction of RNA with glyoxal and borate forms stable guanosine adducts (246) such that subsequent treatment with RNase TI cleaves only 3' to i n ~ s i n e .Camptothecin ~~~ and its analogues act as topisomerase poisons, trapping covalent tyrosine-phosphodiester linked enzyme-DNA intermediates derived from initial DNA cleavage by the enzyme and thus preventing religation. Such compounds exhibit significant antitumour activity and sequence-specifictrapping of the intermediate has been acheived by tethering a 10-carboxycamptothecin derivative (247) to the 3'-terminus of a triple helix forming oligonucleotide.244Photocross-linking of double-stranded DNA with 8-azido-3-amino-6-phenyl-5-ethylphenanthradinium (248) at levels as low as one covalently bound drug per 130 base pairs was found to enhance topoisomerase 11-mediated DNA strand cleavage.245 A strategy of linking an oligodeoxyribonucleotide targeted against a singlestranded RNA and a double-stranded targeting oligomer has been applied to the recognition of a modified version of the Rev response element.246The kinetics of this recognition process have been studied and a mechanism proposed in which rate-limiting duplex formation precedes triple-helix association.
0
(cu)~u~u~-o-P-o I
0(247) C = 5-methyldC, U = 5propynyldU,
OH
0
198
Organophosphorus Chemistry
Dervan and co-workers have prepared N-methylimidazole (Im) and Nmethylpyrrole (Py) amino acid-containing polyamide hairpins with an EDTAmFe(I1) moiety tethered at the C - t e ~ m i n i .248 ~ ~Such ~ . hairpins recognise DNA through minor groove interactions in a sequence-specific manner and a new upper limit for the binding site size of seven base pairs has been achieved using ten-ring hairpin^."^ The DNA-binding affinities of these ten-ring hairpins were found to be similar to those of eight-residue polyamide hairpins249 and displayed 18- or 300-fold selectivities for the cognate over single base pair mismatched sequences. Pyrrole-imidazole polyamides have been described which recognise eleven base pair248and sixteen base pair250sequences by dimer binding. Affinity cleavage experiments were used to study the binding orientation preferences of Py-Im polyamides. The pairing rules using only Py and Im give degenerate recognition of A-T and T.A by a Py-Py pair. The introduction of a new aromatic amino acid, 3-hydroxypyrrole (Hp) has been used to give unique recognition of A=T(by Py-Hp) and T-A (by Hp-Py) base pairs.251Sequencespecific DNA photocleavage has been reported for oligopyrroles (249) conjugated to a benzotriazole moiety.252 H
I (249) n = 1, 2.3
Miller and co-workers have reported the first example of the selection of DNA-binding compounds from a self-assembled, equilibrating combinatorial library of coordination complexes.253
6
Interactions and Reactions of Nucleic Acids with Metal Ions
The hydrolysis of polynucleotides continues to be of interest exemplified by the publication of a whole issue of ChemicaZ Reviews devoted to DNNRNA hydrolysis,254much of which involves metal ion catalysis. Catalytic cleavage of target RNA has been observed for an oligodeoxynucleotide internally labelled with a dysprosium-containing macrocycle introduced as its phosphoramidite (250).255 Internal modification was found to give considerably improved activity compared to a previously reported end-labelling strategy; under the same conditions the former gave 67% cleavage compared to 5% for the latter. A series of macrocyclic lanthanide complexes (25 1)-(253) have been tethered to an oligodeoxynucleotide.256Sequence-specific cleavage of a complementary RNA by these conjugates was found to be fastest for europium(II1) complexes and other structure-activity relationships were also described. The complex
5: Nucleotides and Nucleic Acids
I99
[Rh(Phen)~Phi]~'has been shown to interact with RNA triple helices in a structure-specific manner and the photoactivated cleavage patterns examined.257Preliminary results described by Coates et al. for [Rh(L)2(dppz)l2+ have demonstrated the potential of transient resonant Raman spectroscopy to probe the excited state intercalative interactions of metal complexes with DNA.258
b(251) A r =
(252) Ar = R'
(251a) (251b) (251c) (251d) (2519) (252a) (252b) (253)
vp
R' (253) Ar =jyN\+
k 1
N-N,
R'
Ln* = Eu, R' = R2 = H, R3 = <6H&lHC(S)Ln* = Eu, La, R' = --(CH2)2CO-, R2 = H, R3 = Ph Ln3+= Eu, R' = -(CH2)2CCb, R2 = R3 = H Ln* = Eu. R' = -N(Me)CH&O-, R2 = H, @ = Ph Ln* = Eu, R1 = - ( C H 2 ) S t F , R2 = Me, R3 = Ph R' Et, R2 = H, R3 = <6H4NHC(S)R1 = %H40Me, R2 = H, R3 = +H4NHC(S)R' = %H40Me, R2 = H, R3 = +H4NHC(S)-
Komiyama el al. have proposed a novel mechanism for RNA hydrolysis by several cobalt(II1) complexes involving general acid catalysis by Co"'-bound water.259Workers in the same group have also reported the use of dextrans that maintain DNA-hydrolysing mixtures of cerium(1V) and lanthanide(II1)
200
Organophosphorus Chemistry
ions as homogenous solutions at neutral pH.260Specific cleavage of the 5’-cap structure of mRNA as part of an RNA-DNA duplex was reported for a cyclen based europium complex.261Dinuclear copper(I1) complexes have been shown to exhibit highly selective cleavage of ribonucleoside 2’,3’-cyclic monophosphates.262y263 Oivanen and co-workers have performed detailed studies on the metal ion-promoted cleavage, isomerisation and desulfurisation of the RP and Spdiastereomers of 3 ’ , 5 ’ - U p ( ~ ) U . ~ ~ Several studies on the involvement of metal ions in catalysis by different ribozymes have been p e r f ~ r r n e d . ~ ~Two-metal ~ - ~ ~ ’ ion mechanisms have been proposed for hammerhead, Tetrahymena thermophila group I and Tetrahymenu thermophila L-21 Scal ribozymes. The rates of group I ligation265and hammerhead cleavage269of native and sulfur-substituted substrates in the presence or absence of thiophilic metal ions such as Mn2+have been shown to be consistent with two-metal ion involvement in the chemical steps of these reactions. Similar studies on spliceosomal precursor mRNA intron removal established the involvement of metal ions in the initial 5’-exon cleavage but not in the second reaction step.267 Addition of metal ions that compete for magnesium ion binding sites such as La3+ and Ca2+ has been used to study the individual roles of Mg2+. Pontius and colleagues have shown that two-metal ion binding sites on the hammerhead ribozyme regulate the cleavage reaction.270Upon displacement of the more strongly bound magnesium ion (&=3.5 mM) by La3+ rate enhancement was observed. In contrast, inhibition of catalysis was displayed upon displacement of the more weakly bound ion. The results are consistent with a two-metal model in which the ions are directly coordinated to the attacking 2’-oxygen and to the 5’-oxygen of the leaving nucleotide. Data from the inhibition of Tetrahymena thermophila L-21 Scar ribozyme by added Ca2+ has provided evidence for four functions for bound Mg2+ions in the catalytic cycle: one increases the rate of RNA substrate binding, one or more decrease the rate of dissociation of substrate and two are involved in the chemical step.268Li and Tuner have performed transient kinetic studies on the same system using 5’-pyrene-labelled oligonucleotides and identified at least three local co-operative transitions induced by magnesium ions.271The 2’-OH of the guanine nucleotide substrate was also suggested to be important for the proper substrate positioning. A core of five closely packed magnesium ions bound at a three helix junction region of the Tetrahymena group I ribozyme has been identified using X-ray crystallography and phosphorothioate interference studies as essential for cognate folding.272Based upon these studies, it has been suggested that a metal ion core in RNA is equivalent to a hydrophobic core in a protein. RNA cleavage by iron(I1) in the absence of EDTA or other chelators has been used as a method for visualising magnesium-ion-binding sites.273Terbium(II1) has been shown to compete with magnesium at binding sites in the hammerhead ribozyme and has been used to identify these sites by X-ray ~ r y s t a l l o g r a p h y .Feigon ~ ~ ~ and coworkers have employed the ammonium ion as an NMR probe for monovalent cation coordination sites in DNA.275A novel rhodium intercalator has
5: Nucleotides and Nucleic Acids
20 1
been used to recognise DNA base mismatches that involve thermodynamic disruption.276 The ability of DNA to reversibly self-assemble through a well-characterised and programmable hydrogen bonding network has led to its consideration as a potential molecular scaffold for nanoscale structures. One of the most exciting demonstrations of this has been the DNA-templated assembly of a conducting silver wire 12 pm long and 100 nm A multi-step procedure was employed in which bacteriophage L D N A was used to construct a bridge between two gold electrodes, followed by exchange of the Na+ ions associated with the anionic DNA backbone for Ag' and reduction to Ag(0). 7
Nucleic Acid Devices
Several prokaryote genome projects were completed within the period of this review bringing the total to thirteen and sequence data from eukaryote genomes has continued to increase. The availability of sequence information from open reading frames (ORFs) and expressed sequence tags (ESTs) facilitates the construction of devices that can exploit such information. Microarrays of DNA or oligonucleotides (often termed DNA chips) have received considerable attention due to the potential commercial rewards derived from their application in a variety of roles in functional genomics. Applications of microarrays that have been reported include sequencing by h y b r i d i ~ a t i o n parallel , ~ ~ ~ thermodynamic analysis of DNA duplexes,279polymorphism analysis,241mapping RNA accessible sites for antisense applications280and mRNA expression profiling.281-282 Several different methods for preparing such arrays have been employed and some of the highest oligomer densities have been obtained by in situ synthesis using phosphoramidites bearing photolabile protecting groups and photolithographic masking techniques to generate sites for reaction. Wodicka et al.281* 283 have described the application of this technology to the generation of four 1.28 x 1.28 cm arrays each bearing over 65,000 unique 25-mer sequences (more than lo7 copies of each, approximately 20 sequences for each ORF) complementary to the ORFs (6200) of the yeast Saccharomyces cerivisiae. An alternative method of microarray preparation involves robotic printing of cDNAs, typically 200-5000 nucleotides long, onto amino-functionalised surfaces. Brown and co-workers used PCR amplification of individual Saccharomyces cerivisiae ORFs to generate a library of DNAs which were printed onto glass microscope slides pretreated with poly-L-lysine.282v284 The arrays thus generated consisted of 6400 distinct DNA sequences and genome-wide expression monitoring was used to follow the changes accompanying the metabolic shift from fermentation to respiration. Both of the above studies employed fluorescence detection of hybridisation at particular loci. Other methods of hybridisation detection on arrays have been described including mass spectrometry,285-286 surface plasmon resonance,287ellipsometry288and refractometry .289
202
Organophosphorus Chemistry
Developments in miniaturising devices that can perform several, sometimes integrated, operations including cell lysis, PCR, gel electrophoresis and DNA sequencing have provoked considerable i n t e r e ~ t . ~ ~Typically, ’ - ~ ~ ~ a micrototal-analysis-system (pTAS - also termed ‘lab-on-a-chip’) consists of 2-3 cm2 of silicon, glass, quartz or plastic etched or moulded with reaction chambers connected by channels with cross-sections as small as 50 pm. Considerable advantages of speed of operation are derived from such miniaturisation. The interactions of oligonucleotides or PNA bound to the surface of a quartz-crystal microbalance with complementary DNA or a leucine zipper peptide have been r e p ~ r t e d . ~ ~ ~ - ~ ’ ~ A polypyrrole film (254) derived from the co-polymerisation of pyrrole-3acetic acid with its N-hydroxyphthalimide derivative has been reacted with 5’aminoalkylated oligonucleotides and used as an electrochemical probe for h y b r i d i ~ a t i o n .5’-Ferrocene ~~~ conjugated oligodeoxynucletotides have also been employed for a sandwich-type assay of hybridisation to a complementary sequence immobilised on gold using electrochemical detection methods.299 Aggregation of ferrocene moieties with pendant alkyl quaternary ammonium groups along the DNA backbone has been d e m o n ~ t r a t e d .The ~ ~ redox potential of the ferrocene shifted due to this aggregation.
li
OH
H N-DNA
Herne et d 3 0 1 have applied several .techniques to the characterisation of mercaptoalkyloligonucleotide probes immobilised on gold surfaces. It was found that using mixed monolayers of the thiol-derivatised probe and a spacer thiol facilitated control of the amount of surface coverage and also removed non-specifically adsorbed DNA. Niemeyer et al.302 have reported decreased and sequence-dependent rates of annealing and melting for surface-immobilised oligonucleotide probes. The DNA-templated assembly of gold nanoparticles (approximately 13 nm in diameter) has been exploited for the highly selective colorimetric detection of oligonucleotides. The gold was derivatised with mercaptoalkyloligonucleotide probes complementary to both termini of the target sequence, and the polymeric network of nanoparticles which resulted from probe-target hybridisation enabled 10 femtomoles of an oligonucleotide to be detected 304
5: Nucleotides and Nucleic A c i h
203
Since Adleman first demonstrated the potential of DNA to compute in 1994, there has been considerable interest in developing protocols to make this effective. DNA computation has principally been performed as simulations, e.g., a Turing machine equivalence for DNA-based computing has been modelled.305A DNA version of the self-assembly model of computing has also been proposed in which input signals are coded into unmethylated and methylated oligonucleotides with different equilibria of B- and 2-DNA and output is read using circular d i c h r o i ~ mA . ~series ~ of preliminary experiments based upon a word design strategy for DNA computing on surfaces has been performed.307
9
Nucleic Acid Structures
The increased application of synchrotron irradiation to the structural biology of nucleic acids has provided a large amount of data. The structural characteristics of the Tetrahymena group I ribozyme have come under intense scrutiny and several exciting results have been reported. One of the most interesting, with potentially wide-spread applications, is the use of synchroton radiation to generate hydroxyl radicals on a millisecond timescale coupled with stoppedflow methodology to follow the entire magnesium ion-mediated kinetic folding pathway of the r i b ~ z y m e . ~ ~ ~ Two groups have identified parallel folding pathways for this system; a small fraction rapidly folds to the active conformation and a slowly folding population is trapped in metastable misfolded structure^.^^^ 310 Although such kinetic traps have been characterised for proteins, this is the first example of its type identified in RNA folding. Pan et aZ.311have also demonstrated that the same general mechanism operates in the folding of an RNaseP sequence. Modified nucleotides have been shown to play a predominant role in canonical folding of human mitochondria1tRNA1yS.312 The structure of ribosomal RNA and the ribosomal translation machinery have also been actively ?tudied using hydroxyl radical probes,313*314 electron cryomicroscopy (at 18 A resolution),315and chemical Correll et al. have determined the structures of both a dodecamer model of the loop E region of 5s rRNA and also of a 62-nucleotide fragment (at lower resolution) using X-ray ~rystallography.~These structures show high levels of correlation with a solution structure of a 42 nucleotide fragment of 5s rRNA.318 The solution structure of the ternary complex of EF-Tu, PhetRNAPhe and GTP has been shown to be very similar to that in the crystalline The stucture of a 23-nucleotide stem-loop RNA containing the conserved residues of the GAAA tetraloop receptor has been solved by NMR.320 The stabilisation of RNA-binding protein structure by the binding process has been shown through several structural The first structure of a protein bound to RNA in a sequence-independent manner has been solved using X-ray ~ r y s t a l l o g r a p h y . ~ ~ ~
204
Organophosphorus Chemistry
A slow cleaving variant of the hammerhead ribozyme (in which a 5’-Cmethylated ribonucleotide was incorporated adjacent to the cleavage site) has facilitated the X-ray crystallographic characterisation of a conformation that is poised to form the transition state geometry.326The crystal structure, at 2.8 resolution, of an RNA aptamer bound to bacteriophage MS2 coat protein has been determined.327 Interdomain RNA cross-linking via disulfides has been used to investigate the tertiary structures and dynamics of several A model of the hairpin ribozyme was derived from the data.330The use of thionucleotides as intrinsic photoaffinity probes of nucleic acid structure and nucleic-acid interactions has been reviewed.33’ Zegers et al.332 have employed time-resolved crystallography to study the hydrolysis of exo (Sp) guanosine 2’,3’-cyclophosphorothioateby RNase T 1 to 3‘-GMP. Several crystal structures of DNA-transcription factor complexes with up to three different protein components have been solved and a new type of specific DNA contact c h a r a ~ t e r i s e dInsight . ~ ~ ~ into ~ ~ ~the ~ mechanism of site-specific DNA recombination has been gained from the crystal structures of several recombinases in complex with DNA including a covalent phosphotyrosine intermediate derived from a suicide substrate.337.338 The crystal structure of a 121 base pair region of a DNA sequence organised by the histone core particle has been solved at 2.8 resolution.339 A high resolution (1.4 crystal structure of the Dickerson dodecamer has been determined and the authors suggest that experimental error may account for some of the conformational heterogeneity previously reported to be intrinsic to DNA sequence.340A high resolution co-crystal structure of a viral DNA polymerase complexed with a primer-template and a nucleoside triphosphate in the active site has been reported.341The structures of a bacterial polymerase bound to DNA primer-templates during several rounds of nucleotide incorporation have also been solved.342Further evidence that steric matching may be the mechanism by which the fidelity of replication is maintained has been provided by a co-crystal structure of human DNA polymerase p in complex with a gapped DNA duplex and ddCTP.343 FokI is a member of an unusual class of bipartite restriction enzymes that recognise a specific DNA sequence and cleave DNA non-specifically a short distance away from that sequence: The crystal structure at 2.8 A resolution of the complete FokI enzyme bound to DNA has been determined.34 A novel conformation-specific restriction enzyme has been created by fusing the nuclease domain of FokI endonuclease with the Z-DNA-specific recognition region of an adenosine d e a m i n a ~ eA . ~high ~ ~ resolution X-ray crystal structure of a four-ring pyrroleimidazole polyamide specifically bound as a dimer to a core GGCC region of a decanucleotide has been reported. 346 The complexes of polyamide hairpins containing linkers of incremental length with an undecamer have been studied using NMR spectroscopy.347The solution structures of several triple helix motifs have been solved.348-352 The solution structure of an AMP-DNA aptamer complex has been solved
A
A)
A
5: Nucleotides and Nucleic Acids
205
using NMR.353 The first report has been made of the conformations of a deprotonated oligonucleotide in the g a s - p h a ~ e . ~ ~ ~ G (guanine-nucleotide-binding)proteins play a central role in many cellular signalling processes and several crystal structures of such proteins complexed with non-hydrolysable or transition-state analogues have been solved.355-358 New catalytic activities for DNA have been developed using in vitro selection including Cu+-dependent DNA cleavage,359histidine-dependent RNA cleavage360 and trinucleotide cofactor-dependent self-cleavage at a phosphoramidate linkage.361A selection protocol for ATP-binding DNA aptamers with a short (eighteen-nucleotidelong) random region has been described. This protocol does not include intervening amplification but relies on rare-DNA PCR amplification of the final sequences.362 Scanning force microscopy has been applied to measure the mechanical forces required to separate the strands of a 48.5 kilobase long hairpin hDNA.363 Much shorter sequences have been analysed using chemical force m i c r o s ~ o p y C60-N,N-dimethylpyrrolidinium .~~ iodide has been used to facilitate imaging of DNA nanoarchitectures by transmission electron microscopy (TEM) without the need of heavy metal c o m p l e x a t i ~ nA . ~self-complemen~~ tary tetradecanucleotide containing both iodine and platinum to facilitate visualisation by TEM has been immobilised on carbon n a n ~ t u b e sIt~ is ~~ anticipated that such adsorbates will have potential as models for biomoleculecarbon interactions in future biosensors. Cat ionic self-assembled monolayers have been found to immobilise DNA without altering its native s t u ~ t u r e . ~ ~ ~ c 6 0 was incorporated into these monolayers and shown to induce photocleavage of dG-containing DNA. DNA tertiary structure has been controlled by the redox state of Fe2+/Fe3+.368
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Organophosphorus Chemistry
T. Yokomatsu, M. Sato, H. Abe, K. Suemune, K. Matsumoto, T. Kihdra, S. Soeda, H. Shimeno and S. Shibuya, Tetrahedron, 1997,53, 11297. P. Franchetti, G. Abu Sheikha, P. Perlini, F. Farhat, M. Grifantini, G . Perra, C. Milia, M. Putzolu, P. LaColla and M. E. Marongiu, Nucleosides Nucleotides, 1997,16, 1921.
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6
Ylides and Related Species BY NEIL BRICKLEBANK
1
Introduction
June 1997 saw the centenary of the birth of George Wittig who, in 1982, won a Nobel prize for discovering the reaction which bears his name. Emsley' has written a fascinating article, providing an insight into the life and work of Wittig, which will be of interest to those who want to know more about the man behind the reaction. However, perhaps the greatest tribute to Wittig is the omnipresence of his reaction, and reagents, which continue to find application in the synthesis of a diverse range of compounds.
2
Phosphonium Ylides
2.1 Theoretical and Mechanistic Studies of Phosphonium Ylides and the Wittig Reaction - Puke and co-workers2have reported a combined chemical, computational and structural study of the controversial subject of the involvement of betaine-type intermediates in the Wittig olefination reaction. Their results provide evidence for both phosphetane and betaine intermediates depending on the reaction conditions and the electronic features of the ylidekarbonyl compound. A quantum mechanical study of the "Stevens rearrangement" (thermally induced rearrangement) of phosphorus and arsenic ylides has been reported. The calculations, carried out at the RMPZ level, show the mechanism to be strongly dependent upon the migrating group. Restrepo Cossio et aL4v5 have carried out two theoretical studies into the gas-phase reactions of ylides and aldehydes. A comparative study4 of the interaction of unstabilised ylides (H3P=CH2, H2MeP=CH2, HMe2P=CH2 and Me3P=CH2) with formaldehyde at various levels (Hartree-Fock, HF; density functional theory, B3LYP; MP2 and quadratic configurational interactions QCISD) showed an unusual dependence of the reaction path on the level of theory. At the HF level, the reactions of H3P=CH2 or H2MeP=CH2 with Organophosphorus Chemistry, Volume 30 0The Royal Society of Chemistry, 2000 219
220
Organophosphorus Chemistry
formaldehyde proceed via the formation of oxaphosphetane. However, at the B3LYP, MP2 and QCISD levels, the same ylides react by a nucleophilic attack of the ylidic carbon on the carbonyl group, concomitant with the proton abstraction from the phosphorus atom to form 2-phosphinoethanol. The reactions of HMe2P=CH2 or Me3P=CH2 and formaldehyde are predicted to proceed with the formation of oxaphosphetanes irrespective of the level of theory employed. These results have led this group to question the use of H3P=CH2 (the most popular ylide for modelling the Wittig reaction) as a model for realistic systems. In a second study,5 the reaction of an unstabilised ylide (Me3P=CHCH3), semistabilised ylide (Me3P=CHC = H) and a stabilised ylide (Me3P=CHCN) with acetaldehyde are compared at various levels of theory (ab initio, HF and MP2; MNDO-PM3). The reactions proceed via oxaphosphetane intermediates although, once again, the calculated energy barriers vary considerably with the level of theory employed. However, selfconsistent geometries of reactants, intermediates, transition states and products are obtained at all levels. Several electrochemical studies of phosphorus ylides have appeared. The rate of proton transfer between electrogenerated base and ylidic phosphonium ions in DMSO solution has been determined.6 The electrochemical properties of ylides and their complexes with chromium, molybdenum and tungsten carbonyls in acetonitrile solution have been in~estigated.~ Ab initio calculations of the insertion reactions of CH with PH3 (Scheme 1) show that the HC-PH3 addition complexes initially formed have ylide-like character.* An ab initio study has also been carried out into intermolecular C-H---C hydrogen bonding in y l i d e ~ The . ~ kinetics of protonation of a new group of phosphorus-containing dyes, 6-(triphenylphosphonio-3'-cyclopentadienyl)-2,3,5-trihalocyclohexa-2,5-diene174-diones(1), have been assessed.l o CH
+
PH3
[HC--PH3]*-
H2C-PH2
Scheme 1
2.2 Synthesis and Characterisation of Phosphonium Ylides - The structure of imino(tripheny1)phosphorane (2) has been determined using a combination of low-temperature X-ray and neutron diffraction studies. Breitsameter et al. l 2 have reported the synthesis and reactions of some ylide-substituted phosphines (3) and diphosphines (4). Addition of ylidyl-phosphines (3) to perthiophosphonic anhydrides produces zwitterionic 1-phosphonoalkyldithiophosphinates.l 3 A series of new phosphonium salts incorporating dimethylaminosubstituted naphthyl ligands ( 5 ) have been prepared. l4 NMR studies, together with a crystallographic investigation of compound ( 5 ) (R' = Ph, R2 = H), show that the pendant dimethylamino groups coordinate to the phosphorus centre creating steric hindrance. Phosphonium salts ( 5 ) react only slowly with benzaldehyde under Wittig conditions and this was attributed to the steric hindrance around the phosphorus. The halogenation and substitution reactions of bis(phosphonio)isophos-
22 1
6: Ylides and Related Species
Ph
0
(1) X = F,CI, Br, I
Ph3P=NH (2)
Ph3PA p O H I R (3) R = Me, Et, But, Ph R’
R
H
Ph3PA P , A Y P P h 3 I H R (4) R = Ph, 3-MeCsH4, Me3Si
(5) R1 = Ph, Me; R2 = H, CH2C02Et
phindolide salts (6) have been r e p ~ r t e d . ’One ~ of the substitution products, phosphonium salt (7), has been crystallographically characterised. The reactions of two ylidyl-dichlorophosphines(dichlorophosphinyl triphenylphosphonium ylides) (8) with tris(trimethylsily1)phosphine have been reported (Scheme 2).16 The primary products of these reactions are the diphosphenes (9) which readily dimerise in solution giving tetraphosphetane (10) or tetraphosphene (1 1). Recrystallisation of (1 1) from benzene/dichloromethane resulted in the formation of bicyclotetraphosphetane (12). The molecular structures of (10) and ( 12) were determined crystallographically.
/
\
222
Organophosphorus Chemistry
Although not strictly ylidic species, the chemistry of low coordination number organophosphorus derivatives involving P=C and P=N bonds continues to attract much attention (see Chapter 1). In this chapter we will restrict our discussion to those compounds which can be described as ylide-related species. Treatment of iminophosphene (Me3Si)3CP=NMes* (Mes* = 2,4,6-'BuC6H2-)with diiodine produces imino(methy1ene)phosphorane (1 3) (Scheme 3).17 Subsequent treatment of (13) with silver chloride produces the analogous chloro derivative (14) which can then be converted into the bromo derivative (15). The structures of this neat little family of phosphoranes, (13), (14) and ( 1 3 , have been determined crystallographically and feature planar phosphorus atoms. NMes' P(' C(SiMe3)3
Mes'
12 THF, 4 0 "C
= 2,4,6-But3C6H2
- 1-8
NMes* \\C(siMe3),
AgCl. CH2C12.25
(1 3)
NMes'
"C
* CI-P
//
\\C(SiMe&
1
(14) MqSiBr, THF, 25 "C
NMes'
Scheme 3
(15)
Oxidation of bis[bis(dialkylamino)phosphino]methanes with hexafluoroacetone in hexane did not yield the expected dioxaphospholane heterocycle but carbodiphosphoranes (16) (Scheme 4). l 8 The synthesis, stability and reactivity of a series of halogenated ylides (17) have been reported. l9 Chlorination of the alkoxypyrazole-substitutedphosphine (18) affords highly unstable chlorophos-
Scheme 4
phonium salts which undergo dealkylation producing chlorodiphenylphosphonium ylides.*O The synthetic utility of these ylides would appear to be limited since butyl lithium in tetrahydrofuran yields the corresponding ylide which is stabilised by abstraction of the CC13 group producing the triphenyl-p-tolylphosphonium cation (20) (Scheme 5).2' Dimethyl(fluorenylidene)(tributylphosphorany1idene)succinate(21) is a new, air and moisture stable, ylide which
6: Ylides and Related Species
223
X
EtO
Ph3P=C, C02R (17 ) X = F, CI, Br, 1; R = Me, Et
(18)
-
CMe 1 3 c 0 6 P h 3 B r BuLi, -78 THF "C
M e e b P h 3
has found utility as a dehydrating agent for synthesising acid anhydrides, esters and amides.22 In a series of publications, Aitken and c o - ~ o r k e r s have ~ ~ - described ~~ their studies of the flash vacuum pyrolysis of a large number of phosphorus ylides. For example, a-benzotriazolyl-P-oxophosphorus ylides (22) generally decompose producing triphenylphosphine oxide, dinitrogen and intractable products. Similarly, ylides with an arylsulfonyl substituent (23) undergo loss of triphenylphosphine oxide to give intractable products. However, ylides bearing an arylmethylsulfonyl substituent (24) lose triphenylphosphine and sulfur dioxide indicating that they decompose via the formation of sulfonyl carbene intermediates. The different thermal behaviour of these two groups of sulfonylstabilised ylide, (23) and (24), was attributed to the existence of significant P. - -0interaction in ylides of type (23) which is absent in those such as (24).25
a)
HR2
R'3P
(211
(23) R' = Me, Et, R2 = Ph, 4-MeCeH4
0
(22) R1 = Ph, But, R2 = Me, Et, Ph, But
(24) R'
=
Ph, 4-M&H4,2-M-H4,
2-MeSGH4
The use of activated magnesium to generate ylides under neutral conditions has been reported.26 This new method could be of use in the synthesis of alkenes from base sensitive substrates.
2.3 Ylides Coordinated to Metals - The coordination and organometallic chemistry of phosphorus- and arsenic-carbonyl-stabilisedylides has been reviewed.27Niecke et aL2* have isolated the first phosphonium ylidides (25) (Scheme 6). One of these complexes, (25) (E = Mes*), undergoes transmetallation reactions with mercury(I1) chloride producing mercury complexes (26)
Organophosphorus Chemistry
224 Ar-P=E
H2CSM4 SMez
Ar-y.
-
/FH2 E
Buli
THF, 0 “C
(THF)3Li \
y.
Ar -
1
E
(25) HgCh
and (27). As part of their investigations into the mechanism of the Wittig reaction, Neumann and Berger2’ have isolated betaine-lithium salt adduct (28) which they characterised by solution and solid state 31PNMR. The chelating effect of the pyridyl substituents helps stabilise the adduct. Metallation of imino(triphenylpheny1)phosphorane (2) with ethylmagnesium chloride in toluene, in the presence of HMPA, yields a dimeric N-magnesioiminophosphorane complex (29).30
A short paper describing the preparation and reactions of titanium-, zirconium- and hafnium-substituted ylides has a ~ p e a r e d . ~Several ’ niobium complexes of the a-keto ylide [(2-thiazolylcarbonyl)methyleneltriphenyl phosphorane (30) have been prepared and the structure of one, (31), determined crystallographically.32 Treatment of the molybdenum complexes [ M O ( S R ) ~ H ( P P ~ ~with M ~ )alkynes ] (HC=HR1, R 1= Ph, 4-MeC6H4-)results in the formation of ylide complexes (32).33Treatment of iron pentacarbonyl or chromium hexacarbonyl with (Me2N)3P=CH2 produces ionic complexes (33) and (34) re~pectively.~~ Whereas (34) is thermally stable, complex (33) decomposes at room temperature yielding [MeP(NMe2)3]2[Fe2(CO)8]. Both (33) and (34) are alkylated by treatment with MeS03CF3 producing the corresponding
6: Ylides and Related Species H
225
O RS. II SR
Ph2MeP + + y CRtH CR' /
(32)R = Me, Pr', R2 = Ph, tolyl
0 [MeP(NMe2)3][(CO)4Fe-C~P(NMe2)3] II
(33)
carbene complexes (35). The same workers34also treated (Me2N)3P=CH2with CS2 which leads to [MeP(NMe2)3]'[SC(S)CH=P(NMe&]-. Nickel ylide complexes feature prominently this year. The oxidative addition reactions between the unsaturated organophosphorus compound (36) and an assortment of nickel(0) complexes containing triphenylphosphine (together with other ancillary ligands) result, initially, in the formation of phosphavinylidene-phosphorane complex (37).35 Addition of a second equivalent of the nickel(0) reagent to (37) leads to the novel dinuclear complex (38). The
synthesis and applications of nickel ylide complexes are the subject of a recent paper by Braunstein and c o - ~ o r k e r sTreatment .~~ of bis( 1,S-cyc1ooctadiene)nickel(0) with ylide (39) in the presence of a tertiary phosphine yields nickelylide complexes (40) (Scheme 7).36 Similarly, treatment of bis( 1,5-cyclooctadiene)nickel(O)with ylide (41) in the presence of a tertiary phosphine produces complexes (42). However, if the reaction is carried out at temperatures above
(39)
(40)
R = Me, Cy, Ph; COD = 1,!j-cyclooctadiene Scheme 7
60 "C then the bis-ylide complex ~i{Ph2P(o-c6H4)}2]is the only isolable product. Addition of compound (43) to bis( 1,5-cyclooctadiene)nickel(0) in the presence of tris-p-tolylphosphine yields complex (44) (Scheme 8). The utility of
226
Organophosphorus Chemistry
complexes (40), (42) and (44) for the catalytic oligomerisation of ethylene into linear a-olefins was also investigated.36 The complexes showed widely varying activities [500-180,000 mol CZH4 (mol catalyst h- ')I and produced olefins with broad mass distributions. Complexes of type (40) displayed a tendency to oligomerise ethylene into olefins with higher molecular weights than complexes of type (42). However, complex (44) showed no activity for ethylene oligomerisation. The first mono-nuclear nickel(I1) complex containing an iminophosphorane ligand, (49, has been prepared by Crociani et aZ.37
(43)
Scheme 8
(44)
Matt and c o - w o r k e r ~have ~ ~ described the synthesis of the hybrid phosphine-P-keto-ylide ligand (46). The crystal structure of (46) revealed a 1:l mixture of two rotamers built around the CH2-C(O) axis, the C(=O)CH=PPh3 moiety of both conformers adopting a cisoid form. The coordination chemistry of this potentially tridentate ligand towards a variety of Group 10 metal species has been investigated (Scheme 9).3s Navarro and c o - ~ o r k e r continue s~~ to explore the coordination chemistry of stabilised ylides towards platinum and palladium. In their latest study they
0
(46)
\II X = Br, I
Reagents: i, [{Pd(q3C3H4Me-2))2](0.5 equiv.), CH2Cb; ii, [{PdCI)C6H4CH2NMe-o)H(0.5 equiv.), CH2C12; iii, AgBF4, CH&12; iv, [Ni(q3-C5Ph5)X(CO)](1 equiv.), CH2Cl2or THF
Scheme 9
227
6: YIides and Related Species
have prepared a series of complexes containing the keto-stabilised ylide, Ph3P=C(H)CONMe2, which coordinates through its carbon atom giving complexes such as (47). The oxidative addition reactions of unsaturated organophosphorus compound (36) with a number of palladium(0) complexes have been investigated.40 Phosphavinylphosphonium complex (48) was obtained when tetrakis(triphenylphosphine)palladium(O) was treated with (36). In the presence of KPF6, the chloride ligand in (48) can be substituted by acetonitrile or triphenylphosphine producing (49). In contrast, treatment of one or two equivalents of tetrakis(triethylphosphine)palladium(O) with (36) yields monomeric complex (50) or dimeric complex (5 1) respectively. Similarly, treatment of [Pd(dba)(dppe)] [dba = dibenzylideneacetone, dppe = bis(dipheny1phosphino)ethanel with (36) produces (52).
Steiner et aL41 have reported the synthesis and reactions of the first azincated phosphorus ylides such as (53). Several ylide complexes of p-block metals have also been reported including ylidic diphosphadigermetanes,42 2-stannaindane (54),"3 and the 2-spiro-stannaindane (55).43 Other tin-substituted ylides, (56), have been prepared and characterised spectroscopically, including Mossbauer spectroscopy.M Ferrocenyl bis(methy1ene)phosphorane (57) can be prepared from either ferrocenyl dichlorophosphine, [(q5-C5H5)Fe(q5-C5HqPC12)]or ferrocenyl dilithiophosphine [(q 5-C5H5)Fe( q 5-C5H4pLi2)].45 X-ray crystallographic and
Ph3P%Me
0
(56) R = Ph, Me
6 (57)
228
OrganophosphorusChemistry
NMR spectroscopic studies of (57) reveal considerable interaction between the ferrocenyl and phosphorane moiety. As a consequence of this interaction, the rotational barrier of the methylene bonds is extraordinary low. Therefore, in contrast to other bis(methylene)phosphoranes, the endo- and exo-SiMe3 groups are indistinguishable on the NMR time scale even at - 100 "C. 2.4
Reactions of Phosphonium Mides
2.4.I Reactions with Carbonyl Compounds - The methods of preparation, and applications, of ylides substituted at the ylidic carbon have been reviewed.46 Akiba and c o - ~ o r k e r s ~have ~ * ~reported * the Z-selective olefination reactions of spirophosphoranes, such as (58), which react with aldehydes to produce olefins bearing an alkoxycarbonyl group with Z:E of up to 99: 1. The effect of experimental conditions and the nature of the ylide on the outcome of stereospecific alkenylation reactions is discussed in a recent paper49 in which thirteen aldehydes were reacted with no less than eighteen different ylides.
(58) R = Et, But, PhCH2
The azulene-substituted phosphorane (59) has been prepared and utilised in A number of coumarin the synthesis of azuleneoazulenes (Scheme derivatives have been prepared from the Wittig reaction of o-hydroxyformylcoumarin (60) with several different ylides (Scheme 1l)? Coumarin derivatives, para-quinone-dimethanides,substituted phenols and phosphonium salts (6l), are amongst the products obtained when 2,3-dichloro-5,6-dicyano-benzoquin0
6: Ylides and Related Species
229
om
Me
BU'
BU'
Scheme 11
(61) R = OMe, OEt, Ph, H
one is treated with stabilised ylides, Ph3P=CHCOR (R = OMe, OEt, Ph, H).529s3 The reactions of ylides and carbonyl compounds continue to find use in the synthesis of new heterocycles. Treatment of hydrazines with phosphonium ylides produces pyridazinone and tetrahydrocinnolinone derivatives.s4 Similarly, treatment of 3,5-di-t-butyl-2-benzoquinone-N-phen ylmonohydrazone with ylides yields pyrazoles and pyridazine derivatives.ss (3-Alkoxycarbonyl-2-oxopropy1)phosphonium salts (62) are potentially useful synthons for the production of heterocycles; however, their utility is somewhat limited by their difficult synthesis. Moorhof16 has reported a new pathway for the preparation of salts of type (62) (Scheme 12), together with an investigation into the chemistry of their enolates. Treatment of trifluoroacetamido derivatives with Ph3P=CHC02Et in boiling toluene produces the corresponding enamines (Scheme 13), valuable p
R
0
i
X
T
C
0
O
R
ii
3,
R = OMe, OEt, OPri, SEt; X = Br R = OMe, OEt, NH2, NHPh, N Reagents: i, Br2, CH2C12; ii, PhsP, solvent, 24 h Scheme 12
X- P h $ T C O R
0 (62)
N Z O , X=CI
Organophosphorus Chemistry
230
precursors for trifluoromethylated indoles and q u i n ~ l o n e sWittig . ~ ~ reactions are key steps in the synthesis of cyclopenta[b]indol-3-ones(63) and both isomers of the enol lactone (Ma) and (64b).58 Oxazolones (65) (R'= H) and munchnones (65) (R1= Me), generated in situ, undergo highly regioselective cycloaddition reactions with phosphonium ylides producing the corresponding pyrroles (Scheme 14).59The high regioselectivitywas attributed to a favourable electrostatic interaction between the phosphonium salts and the carbonyl 0
R
-0 R24
1I R
2
R2
I
R2
R' R' (65) X = [Ph3PCHCHdBr; R1 = H, Me; R2 = Ph, 4-MeCsH4, 4-C%H4, MQCH; R3 = H X = [Ph3PC(Me)CHdBr, [Ph3PCHCHCaH]Br; R' = H, Me; R2 = Ph, 4-MeC6H4,4-ClGH4, W H ; R3 = Me, CQH Scheme 14
functionalities of (65). Treatment of nobornadiene derivatives with the tri-nbutylphosphine-carbon disulfide adduct (66) leads to the formation of extended dithiolanes.60 The annulation reactions of phosphoranes Ph3P=CHC(OEt)C02R (R=Et, Bur) with a variety of substrates leads to
(66)
(67) R' = CHCOPh; R2 = Phi R3 = Et R1 = CH(C02Et)*; R2 = Me, SEt, (CH2)2CQMer CH(0Ac)Me
6: Ylides and Related Species
23 1
substituted 1,3- and 1,4-~yclopentadieneswhich are converted into the corresponding cyclopentenones (67) by treatment with acid? Standard Wittig olefination procedures have been used to synthesise bromodienes6* and chiral vinyl halides.63 Jarosz and c o - w o r k e r ~have ~ ~ ~utilised ~ sugar-derived phosphoranes such as (68) and (69) for the synthesis of oxygenated decalins and higher monosaccharides. Polper-supported phos/CH=PPh3
co I
HC-0,
phonium salt (70) has been used for the production of resin-bound aminobutadienes (Scheme 15)." Treatment of the rhodium complex (71) with phenylpropargyl aldehyde provides a route to the enyl complex (72) (Scheme 16).67It has been reported6* that Wittig olefination of substituted aromatic aldehydes with ylides derived from phosphorinanium salts (in which the phosphorus is incorporated into a six-membered heterocycle) proceeds with trans-selectivity. Treatment of (2)-P-telluroacrolein with ethoxycarbonyl-
(70) R = 4-FCsH4, CButCgH4, Ph, ~ - I U ~ ~ O C & I ~ , ~ - N4-NCC& @ C ~ H ~3iUCC&l4,3pYridyl, , 2-fUV1, But, n-nonyl, cyclohexyl Reagents: i, piperazinedioxane, 70 "C, 16 h; ii, propargyl triphenylphosphoniumbromide, CH2CI2, RT, 3 h; iii, KOBU',THF, 0 "C, 5 min; iv, RCHO, reflux, 16 h; v, 3% TFA, CH2C12,10 min Scheme 15
I H ~
1 ,H
iF6-
i. Bu"Li. THF, -20''C
Scheme 16
232
Organophosphorus Chemistry
metheny1)triphenyl phosphorane yields ethyl 5-telluro-(2E,4Z)-pentadienoate (73) as the principal product.69 Use of the Wittig reaction in carbohydrate synthesis usually requires the prior protection of the alcohol groups. However, Abelt and c o - w ~ r k e r have s~~ applied the differing acid-base properties of phosphonium ylides and carbohydrates in DMSO solution to facilitate the Wittig olefination of an unprotected P-cyclodextrin; thus the Wittig reaction of 6-deoxy-6-formy-Pcyclodextrin and phosphonium salt (74) proceeds smoothly in DMSO solution, using potassium butoxide as the base, producing 6-deoxy-6-(9,1O-dicyanoanthracenyl-2-methylene)-~-cyclodextrin as the principal product. Phosphonium salts such as (75) have been used for the synthesis of 2,3a,4,5tetrahydrofuro[2,3-c]quinoline-2,4-dionesvia an intramolecular Wittig reacti~n.~' CN
CN
(73)
(75)R'
A'
= H, Me, Ph; R2 =
(74)
Bun, CH2Ph, Ph
2.4.2 Reactions of Aza- Wittig Reagents - Molina and c o - ~ o r k e r s have ~~-~~ utilised iminophosphoranes such as (76), and the aza-Wittig reactions thereof, for the synthesis of a variety of heterocycles including quinolines, quinazolines and benzodiazepins. Molina's group has also prepared [(P-ferrocenylviny1)iminolphosphorane (77) from ferrocene carbaldehyde by sequential treatment with ethyl diazoacetate and triphenylphosphine. Compound (77) has been used to prepare ferrocene-containing imidazole rings bearing one, two, or three
(77)
(78)R'
= Me, R2 = Et R' = Et, R2 = Pr R' = Ph, R2 = PhCH2 R' = Ph, R2 = 4-MeCsH4
233
6: Ylides and Related Species
ferrocene subunits, such as monoferrocene derivatve (78).75Aza-Wittig reactions have been used in the synthesis a variety of nitrogen-containing heterocycles including triazine and diazepine derivative^,^^-^^ and pyrimidothienopyridazines. Treatment of naphthoquinone diazide with triphenylphosphine produces phosphorane (79) (Scheme 17).81X-ray structural analysis of (79) shows an entirely planar molecule (except for the PPh3 moiety). Ylide (79) undergoes an aza-Wittig reaction with benzaldehyde and is hydrolysed by hydrochloric acid, producing the free 2-amino-1,2,3-triazole. Sugar-derived aza-Wittig reagents have been used for the synthesis of carbodiimide-tethered pseudooligosaccharides.82Ylide (80) has been utilised as a intermediate in the conversion of an a i d e to a diazo 79980
a'' WN3 NaN3
PPh3,MeOH,3 h,
__c
CI
\
N / N--N=PPh3
N3
0
0
0
/ ~ ~ 1~ MHHCI, ~AC l ~ ,
N-NH2
*
RT, 12 h
PhCHO, CH1Clp, A
N-N=CHPh N
0
0
Scheme 17
2.4.3 Miscellaneous Reactions - Tandem Michael and intramolecular Wittig reactions of ylide (81) and a$-unsaturated esters lead to cyclic enol-ether derivative^.^^ Taylor et al.85 have devised a new route to diastereomerically pure cyclopropanes which involves the treatment of substituted dioxines with stabilised ylides (Scheme 18). Cristau and Taillefer86 have examined the reactivity of diylides (82) towards carbonic acid derivatives. Treatment of
CHR
0TN=PPh3 Ph$'
R
(80) R = H. Me
Ph/ \Ph (81)
'LHR (82) R = H, Me, Et
unprotected aldoses with bromoacetate in the presence of tri-n-butylphosphine and zinc produces the corresponding Wittig adducts with good stereoselectivity (Scheme 19).87Similarly, zinc has been used to activate phosphonium ylides so that they can be acylated at their or-carbon (Scheme 20).88 Oxidation of
Organophosphorus Chemistry
234
H R'
-
R2
R'
=
H R'
< 75% Ph, Me, H; R2 = H, Me; R3 = CO&H2Ph, CO2Et, COMe, C02Me
Scheme 18
BrCH2C02Me,Bun3P,Zn
HO
*o, , HO
dioxane, A
OH
c
Scheme 19
Ph3P=CHC02Et + ACCl
PhMe, Zn
Scheme 20
/ CaMe
OH 72%
PhsP*Ac CQEt
terminal diols with Dess-Martin periodinane in the presence of stabilised phosphoranes, Ph3P=CHC02R (R = Me, Et), yields trans-die~ters.~~ Oxidation of allylic, propargylic and benzylic alcohols in situ with manganese dioxide, also in the presence of stabilised ylides, has been used to generate a,Punsaturated esters.90 Booth et aL9' have reported the synthesis of enamino(tripheny1)phosphonium salts (83) which react with an excess of borane to give novel azaboretidinium salts (84) (Scheme 21). Upon heating in aqueous alkali, compounds (84) are converted into the corresponding phosphine oxide.
Br
i.
=-N3,
-
I
I
R' = R2= (S)-(CH2),-CH(CQOH) R' = R2 = (3-CHMePh R1 = (3-CHMePh; R2 = H
Scheme 21
6: Ylides and Related Species
235
Annulation of allylidene triphenylphosphorane with 1,2-diacylethylenesand 1,2-diacylacetylenesprovides a convenient one-step synthesis of tri- and tetrasubstituted cyclopentadienes and f ~ l v a l e n e s .Yavari ~~ and c o - ~ o r k e r s ~ ~ . ~ ~ continue to develop the use of phosphonium ylides generated in situ from acetylenedicarboxylatesand triphenylphosphine to create a range of unusual heterocycles. Triphenylphosphonium ethylide has been used to deprotonate diphenylamine producing the first phosphonium amide, [Ph3PEt]+[NPhz]-.95 Phosphonium phosphide (85) was prepared in an identical manner by deprotonation of the secondary phosphine, [2,4,6-(CF3&H2]2PH, by triphenylphosphonium m e t h ~ l i d e . ~ ~
3
The Synthesis and Reactions of Phosphonate Anions
Asymmetric olefination using optically active Homer-Wadsworth-Emmons reagents, and other Wittig derivatives, is the subject of a recent review.97The mechanism of the Homer-Wadsworth-Emmons reaction has been evaluated using high level quantum calculation^.^^ The relationship between the chemiluminescence of phosphonoacetates and their reactivity in Homer-WadsworthEmmons reactions has been i n ~ e s t i g a t e d .Perhaps ~~ not surprisingly, both parameters were found to be dependent upon the nature of the phosphorussubstituents. The solution and solid state structures of lithiated cyclic phosphonates, belonging to the 1,3,2-dioxaphosphorinane2-oxide family (86) have been investigated using a combination of NMR spectroscopy and X-ray crystallography.loo Griffiths and co-workerslO1have reported the synthesis and reactions of ylidic phosphonates (87) (Scheme 22). Under acidic conditions, the ylidic phosphonates (87) decompose to give tetraalkyl phenylmethylene-1,l -bis(phosphonates). However, under neutral or basic conditions (87) decompose to give dimethyl benzylphosphonates and trialkyl phosphate. The same grouplo2 has also investigated the synthesis and reactions of aminobenzoyl phosphonates (88). Treatment of (88, R = H ) with trimethyl phosphite produces the cyclic ylidic phosphonate (89). Treatment of a,P-unsaturated monoterpenic ketones, for example (+)-2caren-4-one (90), with the sodium salt of diethyl phosphite, in diethyl phosphite media, results in the formation of the corresponding diethyl oxophosphonates (Scheme 23). lo3 Diphenyl cyanomethylphosphonate (9 1) has been prepared in a one-step process from acetonitrile, diphenyl chlorophos-
236
X
Organophosphorus Chemistry
= 2-halogen,
2CF30
(87)
:;>!p P N- Me
d
(88)R = Bu', H
(89)
HP(O)(OEt)*, Na
t
Me Me
(90)
Me
Scheme 23
Me
90%
phate and lithium diis~propylamide.'~~ The potassium salt of (91) is a useful precursor for the formation of a$-unsaturated nitriles. The synthesis and reactions of a number of fluorinated phosphonates, including (92)lo5and (93),lo6have been reported. Elimination of the phosphonate moiety from (93) afforded the corresponding perfluoroalkyl a-fluoro-a, punsaturated ester. Fluorinated vinylacetylenes have been prepared from the condensation of fluoropropargyl phosphonate esters and aromatic aldehydes.Io7 Horner-Wadsworth-Emmons reactions of or-fluoroaldehydes have also been used in the synthesis of 4-deoxy-4-fluoro-~-arabinopyranose. lo* 0 ( E t O ) 2 P pR F C02Et
N
(911
(92) R' = CN, COZEt, P(O)(OEt)2
(93)R = CF3, C2F5, C3F7
6: Ylides and Related Species
237
Similarly, methyl bis(2,4-difluorophenyl)phosphonoacetate reacts with aldehydes to give cis-unsaturated esters.log A range of bis(phosphory1)- (94) and phosphoryYphosphonium (95) disubstituted pyridines has been prepared.'1° One compound, (95) (R'= Ph, R2 = CHMe2), was characterised crystallographically. Horner-WadsworthEmmons proceedures have been utilised in the production of a number of nitrogen-containing heterocycles including pyrazo1es"l and functionalised triazoles. I l 2 Chromium tricarbonyl complexed allenylphosphonates (96) have been used in the synthesis of Cr(C0)3 complexed heterocyc1es.Il 3
(94) R = Et, CHMe2
(95) R'
=
Ph, Bu; R2 = Et, CHMe2
(96)
Shibasaki et aZ.Il4have discovered that treatment of enones with a phosphonate in the presence of a base and a catalytic quantity of aluminium lithium bis(binaphth0xide) leads exclusively to the corresponding 1,4-addition adducts with high enantiomeric excess (Scheme 24). Asymmetric Horner-WadsworthEmmons reactions have also been carried out under phase-transfer conditions
0 > 58% Yield > 98% ee n = 1,2; ALB = Aluminium lithium bis(binaphth0xide) Scheme 24
using quaternary ammonium salts as catalysts.' * Disubstituted Q-oxophosphonates (97) and (98) have been obtained in high enantiomeric excess from the asymmetric Michael addition of lithiated SAMP hydrazones to alkenylphosphonates followed by oxidative cleavage.' l 6 Horner-Wadsworth-Emmons procedures have been used to convert aldehyde-terminated dendrimers into a$-unsaturated groups, including amino acids.1 1 7 Cyclobutane-dehydroamino acids, e,g. (99), have been prepared using a similar methodology. The synthesis and reactions of lithiated (2-pyridy1)methylphosphonatehave been described. Treatment of various aldehydes with diethyl 3-(trimethylsily1)propenylphosphonateyields the corresponding alcohols albeit with poor diastereoselectivity. The alcohols so produced were then dehydrated, pradu-
238
/"il/c R2
R'
Organophosphorus Chemistry 0 !(OEt)2
Me,&,f,$OEt)2
I
Me
he (97) R' = 2-naphthyl, Ph, Et; R2 = Ph, Et, Pri
(98) R'
= 2-naphthy1,
Me R2 Ph, Et; R2 = Me, Et, PhCH2
RHN
o=d\
Me0
H
OMe (99) R = Ac, Bz, BOC
cing substituted dienes. Greater stereoselectivity was achieved by combining the two steps in a one-pot proceedure. 120 4
Structure and Reactivity of Lithiated Phosphine Oxide Anions
A short review on lithiated phosphine oxides has been published.121 The structure of the first lithiated phosphine oxide to contain Li-C bonds (100) has been reported. 122 The compound is tetrameric, assembling round a (LiO),, pseudo-cubane core.
Ph Ph2P=0 OCH2Ph
H Et
Li
Warren and c o - ~ o r k e r s ' continue ~ ~ - ~ ~ to ~ explore the Wittig-Homer chemistry of phosphine oxides, including compounds (101)123and (102),'24 with a particular emphasis on the stereochemical aspects of their reactions. As part of a study of heterocyclobutanes, Kawashima et uZ.'*~ have reported the synthesis, structures and thermolysis of three diastereoisomers of 2,2,6,6-tetrakis(4chloromethyl)-3,7-dimethyl-4-pheny11,5-dioxa-4h5-phosphaspiro[ 3,3Jheptane (103) (Scheme 25). Other compounds prepared using Wittig-Horner techniques include (2)-1chlorovinyl sulfoxides, obtained from the corresponding [(a-ch1oro)sulfinyl-
Ar-
P(
Et
i , BuLi,THF,-78"C
Et
ii, 2 equiv. 4,4'dichlorobenzophnone
*
Ph3P/CC14
EtN P&
Ar = 4-CICeH4
Scheme 25
1103)
239
6: Ylides and Related Species 0
0
II
II
h2pxS, H CI
(104) R = Me, cyclohexyl, Ph, 4-MeCsH4,4- CF3CBH4
methylldiphenylphosphine oxides (104), 127 (E)- and (2)-styrylphosphines together with their correspondingoxides and sulfides’28 and 8-substituted-a,Punsaturated esters.129 5
Selected Applications in Synthesis
Basic Wittig reactions, and their derivatives, continue to play important roles in the synthesis of ever more complex compounds. In this section we review some of the more significant andlor unusual compounds prepared using these reactions. 5.1 Compounds with Potential Biological Properties - A number of unusual ylides have been reported in the past year, including (105), which has been used in the preparation of nucleotides, (106), used to synthesisefumonisin B2,132and (107), used to assemble the F-M ring framework of cig~utoxin.’~~ A major fragment of ulapualide A is the tris-oxazole unit contained in phosphonium salt (108).134Seven different derivatives of this salt have been prepared in an attempt to determine the extent of translcis selectivity when this fragment is coupled with the C26-C42 fragment of ulapualide A. 1309131
OCH2Ph ButMe2Si0 Me
(107)
(108) R = Alkyl, Avl
240
Organophosphorus Chemistry
Wittig reactions have been used in the synthesis of macrodiolide (109) instead of the usual macrolactonisation methods. 35 Other lactone-containing molecules prepared using Wittig technology include "Yuzu lactone" (1 10) (a volatile ingredient of Yuzu fruit), 36 the marine natural products nalicolactone (1 11) (R = cis-CH=CH),and neohalicholactone (1 1 1) (R = CH2CH2),*37dihydroxerulin (1 12), which is a potent inhibitor of the biosynthesis of cholester01,'~~ the polyketide calystatin A (l13),13971mand (1 14), an intermediate in the synthesis of irinotecan and other camptochein analogue^.'^'
0U
O
(1 1 1)
R
=
cis-CH=CH or CH2CH2
Wittig coupling of phosphonium salt (1 15) and aldehyde (1 16) is the key step in the synthesis of 5-0x0-6(E),8(Z), 1 l(Z), 14(Z)-eicosatetraenoic acid (1 17).142Witig reactions were also prominent in the synthesis of (52,92)-14methylpentadeca-5,9-dienoic acid (1 18) (n = 1) and (52,9Z)- 14-methylpentacosa-5,9-dienoic acid (1 18) (n = 1 l).143Coupling of chiral aldehyde (1 19) and phosphonium salt (120) led to the enantiospecific total syntheis of the
24 1
6: Ylides and Related Species
arachidonic acid metabolite 3-hydroxyeicosatetraenoicacid (12 1). Similarly, a Wittig reaction was used to prepare the cis-skipped triene (122) (Scheme 26), this being a major sequence in the synthesis of methyl- 14-hydroxy-(all-cis)5,8,11-tetradecatrienoate, a useful intermediate in the preparation of arachidonic acid derivatives.145
BuLi, HMPA, -78"C, THF
OSi'BDP
OMe
( 122)
Scheme 26
Stereoselective Wittig olefination steps have been used in the total synthesis of epothilone derivatives, including 26-hydroxyepothilone B ( 123). Treatment of t-butyl( 1S,6R,7R)-3-bromomethyl- 1-oxo-7-(phenylacetamido)ceph-3em-4-carboxylate with triphenylphosphine gave phosphonium salt (124), an intermediate in the synthesis of P-lactamase indicators cefesone and nitrocejin. 48 Coniferin (125) has been prepared in a one-pot process, under phase-transfer 1469147
242
Organophosphorus Chemistry
conditions, using 1,3-dioxolan-2-ylmethyltriphenylphosphoniurnbromide (Scheme 27). 149 Galacto- and gluco-pyranose-6-phosphoranes(126) and ( 127), respectively, have been used in the preparation of disaccharides by condensation with sugar aldehydes. 50 Phosphoranes bearing sugar groups have also been used to make carbon-linked calixarene-carbohydrates. 51 D-myo-Inositol1,4,5-triphosphate (128), which acts as an intracellular signalling molecule, has been prepared by a new route which involves a Wittig olefination step.152
'
H
O
P
o +
" ' q AcO
+ P h 3 P d 2
1
Me0
Br
CH2CI2, aq. K2C03, tris[(2-methoxyethoxy)ethyl]amine
AcO OAc
(125) Scheme 27
Matsuda and co-workers' 53 have reported the one-pot conversion of a,Punstaturated alcohols into the corresponding carbon-elongated dienes using a combination of stabilised ylides with barium manganate (Scheme 28). This procedure has been used to prepare analogues of the nucleoside neplanocin. Wittig olefination has also been used to affect carbon-elongation in the preparation of 3'-deoxy analogues of 6'-halohomovinyladenosines, (129) and ( 130). 54 Other molecules with potentially useful biological properties prepared using Wittig reactions include the hexacyclopropane cholesteryl ester transfer
Scheme 28
R = C02Et, CN
6: Ylides and Related Species
243
X
OH
OH
(129) X = H, F, CI
(130) X = F, Br, I
H
(1%) (R = H, CN)
CH20Me
(136) R = H. CN,
R1 = W M e ; R = H, R' = a-OMe
protein inhibitor U- 106305 ( 13l), 55 natural (+)-tausin (132), 56all four isomers of the C18-sphingosines(133) (which have been synthesised independently by two groups using different routes, from ~ e r i n e and ' ~ ~ chloroben~ e n e *and ~ ~ the ) marine natural product (+)-A9(12)-caprellene(134).159 The unusual Wittig reaction between nitriles (135) and methoxymethylphosphorane, Ph3P=CHOMe, is a key stage in a new, simplified route to substituted antimalarial artemisinin analogues (136). Treatment of dialdehyde (137) with phosphonium salt (138) leads to tetramethoxy-substituted diolefin (139a) together with its two other isomers, (139b) and (139c) in equal quantities.16' Compound (139a) is a useful intermediate for the production of fjord region bis-dihydrodiol and bis-anti-diol epoxide metabolites of benzo[s]picene which are potent carcinogenic hydrocarbons. Compound (140) has been
244
QCHO (137)
Me0
CHO
i
($
OMe
OMe
(139a)
Organophosphorus Chemistry
OMe
(139b)
-+
(139c)
converted into a range of indolizidine alkaloids, (-)-205A (141), (-)-207A (142) and (-)-235B (143), by treatment with phosphoranes (Scheme 29).162 Wittig olefination has been used in the synthesis of y,&unsaturated Nformylenamines (Scheme 30),163 and ( f)-kainic acids (144).lM A Wittig reaction is used to convert compound (145) into the widely used progestin desogestrel (146). However, the 5a-isomer of (145) shows a dramatically reduced reaction rate compared with the 5 p-isomer. Computational studies suggest that this is due to the different energies of the intermediary 1,2oxaphosphetanes. 165 0
Scheme 29
B-
245
6: Ylides and Related Species
-PPh3
Scheme
0
30
I H (144) R = Me, Bu
Ph3P=CH2, DMSO, 80 "C
(146)
(145)
5.2 Solid Phase Synthesis - Nicolaou and co-workers'66 have developed a polymer-supported phosphonate (147) which they have used to create a library of macrocyclic lactones via an intramolecular keto-phosphonate reaction. Supported a,P-unsaturated ketones, which are valuable intermediates for the combinatorial assembly of nitrogen-containing heterocycles, e.g. pyrimidines, pyridines, pyrazines and dihydropyrimidinones, have been obtained from aldehydes by Wittig and Claisen-Schmidt reactions (Scheme 3 1). 167 Resinbound olefins, obtained from Wittig reagents and immobilised 4-hydroxybenz-
0
Reagents: i, H02CC6H4CH0,DIC, HOBt, DMA, Rt, 1 h; ii,
Scheme 31
0
PPh3
R
H
yc-<
,60 "C, 4 h
246
Organophosphorus Chemistry
aldehyde, have been utilised in the synthesis of supported tetrahydroquinolines. Wittig olefination has also been used to synthesise polymer-bound a,P-unsaturated amino acid derivatives.169
5.3 Tetrathiafulvalenes and Related Organic Materials - Wittig technology continues to play a routine role in this ever expanding field of research. Here we give some illustrative examples. New compounds reported include conjugated tetrathiafulvalenes which are covalently bound to [60]fullerene, e.g. (148),I7O new 1,3-dithio1-2-ylidene derivative^,'^^ and a blue light emitting fluorene/phenylenedivinylenecopolymer. 72
MR
R
sKs
(148) R = H, SMe, (SCH&
Cycloaddition reactions between the Bu3P+CS2- reagent, (66), and norbornadiene have been used to construct polycyclic dihydro-TTF structures ( 149).173Treatment of TTF-aldehyde (150) with phosphonium salt (15 1) leads to new naphthalene based donors ( 152).174
~)=0=(7JCH0+ S
6: Ylides and Related Species
247
Synthesis of Miscellaneous Compounds - Eickmeier and Frank175have used the reaction step outlined in Scheme 32 to prepare several novel hexavinylogous porphyrins with aromatic 30~-electronsystems (153). Treatment of 5,5’-carbonylbis(furan-2-carbaldehdye)( 154) with bisphosphonium salt (155) yields tetraepoxy-lH-[2l]annulen-l -one (1 56), which undergoes a
5.4
0
McMurray reaction to yield the corresponding fulvalene.176 Wittig reactions have been used in the synthesis of the polycyclic hydrocarbons, 3-hydroxybenz[c]phenanthrene (157) and 12-hydroxybenzochrysene (1 58).177The synthesis and strutural properties of a range of distellenes, which contain 2,6stelladiene (159) as a primary building unit have been reported. 17* Takayasu
(157)R’
= OH,
H; R2 = OH, H
(158) R’ = OH, H; R2 = OH, H
Organophosphorus Chemistry
248
OEt
ii
1
&PPh3 OEt
OEt
(161) Reagents: i, K2C03, DMF, Rt then 80 "C for 12 h; ii, BubK, DMSO, Rt
Scheme 33
and Nitta'79 have prepared novel 4,9-methanopentacycloundecenederivatives (160) and (16 1) from prop-2-enylidenetriphenylphosphoranesand 9-chloro1,6-methanol[1llannulen-%one (Scheme 33). &-Skipped polyenic hydrocarbons are main structural feature of polyunsaturated fatty acids. A range of these compounds (162a-c) has been obtained through classical Wittig reactions, or the oxidative dimerisation, of phosphoranes (1 63) and (164).180
(162a)
(162b)
(162C)
n
=
1,2,3
A range of 3-ally1 benofurans (165) has been prepared via a Wittig olefination and Claisen rearrangement sequence.1 8 ' In a comparative study, Barluenga et al. 182 have described three approaches to chiral 2-alkoxydienes and heterodienes, two of which involve Wittig reagents (Schemes 34 and 35).
6: Ylides and Related Species
249
R'
4
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Organophosphorus Chemistry
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Organophosphorus Chemistry
90 91
X. Wei and R.J.K. Taylor, Tetrahedron Lett., 1998, 39, 3815. B.L. Booth, N.J. Lawrence and H.S. Rashid, J. Chem. SOC.,Perkin Trans. I, 1997,3509. Y. Himeda, H. Yamataka, I. Ueda and M. Hatanaka, J. Org. Chem., 1997, 62, 6529. I . Yavari, R. Hekmat-Shoar and A. Zonouzi, Tetrahedron Lett., 1998,39, 2391. I. Yavari and M.R. Islami, J. Chem. Res. ( S ) , 1998, 166. M.G. Davidson and S. Lamb, Polyhedron, 1997,4393. M.G. Davidson, K.B. Dillon, J.A.K. Howard, S. Lamb and M.D. Roden, J. Organomet. Chem., 1998,550,481. K. Tanaka and K. Fuji, Yuki Gosei Kagaku Kyokaishi, 1998, 56, 521; Chem. Abstr., 129: 40688~. P. Brandt, P-0. Norrby, I. Martin and T. Rein, J. Org. Chem., 1998,63, 1280. J. Motoyoshiya, S. Tsuboi, K. Kokin, Y. Takaguchi, S. Hayashi and H. Aoyama, Heterocycle Commun., 1998,4,25. S.E. Denmark, K.A. Swiss, P.C. Miller and S.R. Wilson, Heteroat. Chem., 1998, 9, 209. D.V. Griffiths, K. Karim and J.E. Harris, J. Chem. SOC.,Perkin Trans. I , 1997, 2539. D.V. Griffiths, J.E. Harris and B.J. Whitehead, J. Chem. Soc., Perkin Trans. I , 1997,2545. V.D. Kolesnik, M.M. Shakirov and A.V. Tkachev, Mendeleev Commun., 1997, 141. T.Y. Zhang, J.C. O’Toole and J.M. Dunigan, Tetrahedron Lett., 1998,39, 1461. G.A. Artamkina, E.A. Tarasenko, N.V. Lukashev and I.P. Beletskaya, Tetrahedron Lett., 1998,39,901. Y. Shen and J. Ni, J. Org. Chem., 1997,62,7260. T.C. Sanders, J.A. Golen, P.G. Williard and G. Hammond, J. Fluorine Chem., 1997,85, 173. F.A. Davies, P.V.N. Kasu, G. Sundarababu and H. Qi, J. Org. Chem., 1997,62, 7546. K. Kokin, J. Motoyoshiya, S. Hayashi and H. Aoyama, Synth. Comrnun., 1997, 27, 2387. M. Haase, H. Goerls and E. Anders, Synthesis, 1998, 195. N. Almirante, A. Cerri, G. Fedrizzi, G. Marazzi and M. Santagostino, Tetrahedron Lett., 1998,39,3287. D. Sikora and T. Gajda, Tetrahedron, 1998,54,2243. T.J.J. Muller and M. Ansorge, Tetrahedron, 1998,54, 1457. T. Arai, H. Sasai, K. Yamaguchi and M. Shibasaki, J. Am. Chem. SOC.,1998, 120,441. S. Arai, S. Hamaguchi and T. Shioiri, Tetrahedron Lett., 1998,39,2997. D. Enders, H. Wahl and K. Papodopoulos, Tetrahedron, 1997,53, 12961. D. Prevote, S. Le Roy-Gourvennec, A.M. Caminade, S. Masson and J.P. Majoral, Synthesis, 1997, 1199. A.G. Moglioni, E. Garcia-Exposito, G.Y. Moltrasio and R.M. Ortuno, Tetrahedron Lett., 1998,39,3593. J. Carran, R. Waschbusch and P Savignac, Phosphorus, Sulfur, Silicon Related Elem., 1997, 123,209. F. Chevalier, H. Al-Badri and N. Collignon, Bull. SOC.Chim. Fr., 1997, 134, 801.
92 93 94 95 96 97 98 99 100 101 102 103 1 04 105
106 107 108 109 110 111 112 113 114 115 116 117
118 119 120
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P.A. Otten, H.M. Davies, J.H. van Steenis, S. Gorter and A. van der Gen, Tetrahedron, 1997,53, 10527. M. Taillefer and H.J. Christau, Tetrahedron Lett., 1998,39, 7857. 0. Piva and S. Comesse, Tetrahedron Lett., 1997,38, 7191. K. Butterfield and E.J. Thomas, J. Chem. SOC.,Perkin Trans. I , 1998, 737. B.J. Mellor and E.J. Thomas, J. Chem. Soc., Perkin Trans. I , 1998,747. Y. Shi, L.F. Peng and Y. Kishi, J. Org. Chem., 1997,62,5666. M. Inoue, M. Sasaki and K. Tachibana, Angew. Chem., Int. Ed. Engl., 1998, 37, 965.
C.A. Celatka, P. Liu and J.S. Panek, Tetrahedron Lett., 1997,38, 5449. S.J. Amigoni, L.J. Toupet, Y.J. Le Floch, J. Org. Chem., 1997,62, 6375. L. Rodefeld and W. Tochtermann, Tetrahedron, 1998,54, 5893. D.J. Critcher, S. Connolly and M. Wills, J. Org. Chem., 1997,62, 6638. K. Siege1 and R. Briickner, Chem. Eur. J., 1998,4, 11 16. N. Murakmi, W.Wang, M. Aoki, Y. Tsutsui, M. Sugimoto and M. Kobayashi, Tetrahedron Lett., 1998,39,2349. 140 N. Murakami, W. Wang, M. Aoki, Y. Tsutsui, K. Higuchi, S. Aoki and M. Kobayashi, Tetrahedron Lett., 1997,38, 5533. 141 K.E. Henegar, S.W. Ashford, T.A. Baughmann, J.C. Sih and R.L. Gu, J. Org. Chem., 1997,62,6588. 142 S. Khanapure, X-X.Shi, W.S. Powell and J. Rokach, J. Org. Chem., 1998, 63,
134 135 136 137 138 139
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1998,63,4489. S. Shuto, S. Niizmura and A. Matsuda, J. Org. Chem., 1998,63,4489.
M.J. Robins, V. Neschadimenko, B.O. Ro, C.S. Yuan, R.T. Borchardt and S.F. Wnuk, J. Org. Chem., 1998,63, 1205. A.G.M. Barrett, D. Hamprecht, A.J.P. White and D.J. Williams, J. Am. Chem. Soc., 1997, 119,8608.
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7
Phosphazenes BY J.C. VAN DE GRAMPEL
1
Introduction
This review covers phosphazene literature over the period June 1997 to June 1998 (Chemical Abstracts Vols. 127 and 128) and discusses linear phosphazenes including compounds derived thereof (Section 2), cyclophosphazenes (Section 3) and polyphosphazenes (Section 4). Structural data have been summarized in Section 5. 2
Linear Phosphazenes
Synthesis of new phosphoranimines (iminophosphoranes) via the Staudinger reaction still draws considerable attention. Phosphoranimines have been proven to be versatile reagents in synthetic chemistry, for instance in the azaWittig protocol. The Staudinger reaction of the P-ferrocenylvinylazide C ~ H S F ~ C ~ H & H = C ( C O ~and E ~ phenylphosphines )N~ Ph2P(CH2),PPh2 leads to compounds having the general formula C5H5FeC5H&H=C(C02Et)N=PPh2(CH&PPh2 (1). N=PPh2(CH2),,PPh2
+ Ph2P(CH2)"PPh2 (1) n = 1 4
Organophosphorus Chemistry, Volume 30 0The Royal Society of Chemistry, 2000 255
256
Organophosphorus Chemistry
Treatment of (1, n = 1) with Pd(C6H5CN)2C12 gives the Pd containing metallocycle (2). This compound appears to be active as a catalyst in aryl amination reactions. Staudinger reactions of C5H5FeC5H4CH=C(C02Et)N3 with 1,l (-bis (diphenylphosphino)ferrocene, 172-bis(diphenylphosphino)ethene, and tris(diphenylphosphinomethy1)ethane also lead to the corresponding monophosphoranimines. p(-Ferrocenylvinylphosphoranimine C5HsFeC5H4CH=C(CO2Et)-N=PPh3 reacts with isocyanates according to an aza-Wittig reaction to give carbodiimides, which are transformed into ferrocenylimidazoles on treatment with primary amines and subsequent cyclization.2 Reaction of phosphoranimines C6H5(CH2)30C(0)CHRN=PPh3(R = H, Me) with NOBF4 in presence of a tertiary amine shows conversion of the NPPh3 group into a diazo (N=N) group.3 The Staudinger reaction between phenyl azide and glycosyl phosphites or glycosyl phosphoramidites offers the corresponding pho~phorimidates~ or pho~phoramidimidates~. Both compounds appear to be useful glycosyl donors in glycosidation. Staudinger reaction of ( 1R)-2,3,4,6-tetra-O-acetyl1-azido-Dgalactopyranosyl cyanide with triphenylphosphine has shown to provide unexpectedly the phosphazide (-N=N-N=PPh3) intermediate in a high yield. The galactopyranosyl carboxamide analogue reacts straightforward with triphenylphosphine to the corresponding phosphoranimine.6 The aza-Wittig protocol involving glycosyl isothiocyanates and glycosyl phosphoranimine offers pseudosaccharides with N=C=N bridges between the glycosyl The synthesis of new ligands CH2(PPh2=S)(PPh2=N-aryl) (aryl =p-tolyl, panisyl) (3) has been described. Complexation with Pt2Cb(PEt3)2 offers platinum containing rings with four-membered cycles (4)as major products, and six-membered cycles (5) as minor products.
(4) R = ptolyl, Y = CI R = ptolyl, Y = BF4 R = ptolyl, Y = CFsCOO
R = panisyl. Y
=
L
-
BF4
Cyclic bis(phosph0ranimines) have been synthesized from Staudinger reactions of bis(azides) and bis(phosphines).1° Reaction of tripodal phosphanes RC(CH2PPh2)3 (R = H, Me) with trimethylsilylazide almost quantitatively gives silylated tris(phosph0ranimines) RC(CH2PPh2NSiMe& (R = H, Me). Both intramolecular and intermolecular aza-Wittig reactions offer a facile method for the preparation of a large variety of cyclic organic compounds. 12Polymorphism has been proven for Ph3NH at 20 K by X-ray and neutron diffraction methods.19 Metallation of Ph3PNH with EtMgCl in the presence of
7: Phosphazenes
257
hexamethylphosphoramide gives a complex with formula [Ph3PNMgCl.(Me2N)3P0]2,of which the central part consists of a NMgNMg square. The N-P bond length is shorter than that of the parent compound Ph3PNH.20 Synthesis, structure, and bonding of phosphoraniminato complexes of main group elements have been reviewed.21Recent advances in this area concern the use of the silylated phosphoranimine Me3SiNPMe3in reactions with Grignard reagents EtMgBr and MeMgI in diethyl ether to form [Me$iNPMe2CH2MgX], (n 2 2, X=Br, I). In addition complexes E(Me3SiNPMe3) (Et02)(MgBrl.2510.75)] and [(Me3SiNPMe3)2(MgI2)]have been isolated as side products.22 In the first complex magnesium is surrounded by two halogen atoms, an oxygen and a nitrogen atom, whereas in the second one coordination is effected by two halogen and two nitrogen atoms. Compound (6) can be isolated from the reaction mixture of Me3SiNPMe3and MeMgI after addition of THF. The formation of (6) probably arises from an MeCHO insertion into a Mg-CH2 bond of ( M ~ ~ S ~ N P M ~ Z C H ~ M ~ I ) ~ . ~ ~
Metathesis of the heterocubane (Me3SiNPZnBr)4 by PhMgBr or MesMgBr gives the analogous heterocubane (Me3PNMgBr)4.22Heterocubane derivatives of cadmium with formula [CdX(NPEt3)]4 can be obtained by the reaction of CdX2 (X=Cl, Br, I) with Me3SiNPEt3 in presence of NaF. Compound [Cd1(NPMe3)l4has been synthesized from Me3SiNPMe3 and CdI2. Formation of these complexes is governed by steric factors as well as by the Cd-X bond strength. Compound [CdBr(NPEt3)I4reacts almost quantitatively with MeLi or Me3SiC=CLi to give [CdMe(NPEt3)I4 and [Cd(Me3SiC=C)(NPEt3)]4, re~pectively.~~ Phosphoranimato complexes of boron can be obtained by reaction of BC13 with Me3SiNPR3, the degree of chlorine substitution by PR3 groups depending on the reaction temperature. The following compounds have been reported: [(Me3PN)(BBr2)]2, [(Pri3PN)2(BBr2)(BBr)]+Br-, [(Et3PN)2(BNPEt3)2]2+Br:-, and [(Ph3PN)2(BBr2)(BNPPh3)]+BBr4-.These compounds can be all characterized by an almost flat (BN)4 ring.24A novel BN six-membered cation [(BNMe2)4(NPEt3)2I2+(7) has been synthesized by the reaction of Me3SiNPEt3with BzC12(NMe2)2.24
258
Organophosphorus Chemistry
The boron compound B(NPPh3)3 has been described as reaction product of the diethyl ether complex of BF3 with Ph3PNLi.25 The phosphoranimine Me3SiNPPh2CH2SiMe3has been proven to be an interesting precursor for a number of cyclic CPNM (M = Li, K, Pb) complexes. Treatment of this compound with BunLi yields the two cyclic compounds (8) and (10) depending on the molar ratio of the reagents. An ortho-lithiated intermediate probably plays a role during formation of (10). The lithium atom in (8) can be replaced by potassium by treatment with KOBu‘ to yield compound (9). Reaction of (8) or (10) with PbC12 leads to (11) or (12) respectively.26 SiMg I +N\ PhzP, M C i I SiMe3 18) M = Li
is)
=
Me3Si
I
SiMe3
P,\ t
+N\ Ph2P, Pb ,PPh2 CH ‘CH
dimer in solid state with a central planar NLiNLi ring
Compound (8) and analogues with general formula LiCH(R?P(R2) =NSiMe3 react with PhCN to give compounds LiN(R’)C(Ph)C(H)P(R2)=NSiMe3 (13) via a 1,3 trimethylsilyl (R’=Me3Si) or hydrogen (R’=H) C+N shift. For R = Ph and R’ = SiMe3 the corresponding potassium complex can be synthesized via an exchange reaction with K O B U ‘ . ~ ~ I
SiMe3 I N PhCN R2P: :Li
YH
1
H C Ph R,P(--?C’ I n :I Me3SiN,Li,NR’
-
At
R = Me, R’ = SiMe3 R = Ph, R’ = SiMe3 R = Ph, R’ = H
(13)
A number of papers deal with synthesis and structure phosphoraniminato complexes of transition metals, Ti(NPPh3)4,28 ri3C18(NPMe3)3]C1.2Me3P0.2CH2C12,29[V2C14(NPPh3)3],29riC13(NPEt3)]2,30piC13(NPEt3)(THF)2],30 { TiC14[Me2Si(NPEt3)2]} ,30 [Zr2Cb(NPMe3)4-(HNPMe3)].MeCN,3 and of rare earth elements [M2(C5H5)3(NPPh3)3].3C7H8 (M = Y, Dy, Er).32The molecular structures of these compounds differ with respect to coordination of the metal centres. Four-(N, N, N,N)-coordination of titanium has been found in [Ti(NPPh3)4].28In the cation [Ti3C18(NPMe3)3]+ the titanium atoms are linked by two p3-N atoms of the NPMe3 group forming together a distorted trigonal bipyramid. pl-Bridges between titanium are formed by two chlorines and
259
7: Phosphazenes
nitrogen of the remaining NPMe3 Vanadium and p2-nitrogen form a four-membered ring in [V2C14(NPPh3)3].29 A similar metal-nitrogen core has been found in [TiC13(NPEt3)].30In [TiC13(NPEt,)(THF)z] titanium is surrounded almost octahedrally by three chlorines, one nitrogen, and two oxygens of two thf molecules.30 A planar TiN2Si four-membered ring is present in (TiC14[Me2Si(NPEt&]}, the Me2Si(NPEt3), group acting as a tridentate ligand.30 In [Zr2CL(NPMe3)4(HNPMe3)]the metal atoms are connected by three p2-N atoms (two NPMe3 groups and HNPMe3).3’ Compounds [M2(C5H5)3(NPPh3)3].C7H8 with M = Y, Dy and Er [(14).C7H8]are isomorphic [space group (Pbcu)]. The central part of the molecules is formed by an almost planar M2N2 ring.32
’\/M
Ph3P-N
ua
M ‘ ”P -ph3
(14) M = Y, Dy, Er
Reaction of HN(PPh2)2 with NaH in the presence of Me2N(CH&N(Me)(CH&NMe2 ( = PMDTA) in THF solution shows the formation of a sodium salt with formula PaN(PPh2),(PMDTA)]. The metal is coordinated by three nitogens of the triamine ligand, and by a nitrogen and a phosphorus of the N(PPh2)2 group. A comparable situation has been found for LiN(PPh&(thf)3, where also nitrogen and a phosphorus of the N(PPh2)2 form a part of the coordination sphere, together with three oxygens of the THF groups. A crown ether complex { [NaN(PPh2)2I2(12-crown-6)S) was formed when the reaction of HN(PPh& and NaH was carried out in presence of 12crown-6.33 The interesting oxidation-reduction reaction of LiN(PPh2)z with PbC12 offers the versatile PIr1--PVreagent PhzPN=P(Ph)2P(Ph+NPPh2 and a novel bicyclic Pb complex (15) in high yields.34 Ph2
,P
.
Both the Pb-Pb distance [304.1(1) pm] and the large 207Pb-207Pbcoupling constant in the 207Pb nmr spectrum of the 207Pb labelled (15) point to a covalent Pb+-Pb+ bond. The two five-membered rings are almost perpendi-
Organophosphorus Chemistry
260
cular. The reaction of hC13 and LiN(PPh2)2 leads to formation of [In(Ph2PNPPh2)3](16), which means that in this case no redox mechanism is operative.34 Compound Ph2PN=P(Ph)2P(Ph2)=NPPh2has been reported to react with [CpFe(CO)(p-C0)]2 to give a six-membered FeP3N2 ring (Cp)(CO)FeP(Ph2)NP(Ph2)2NP(Ph2)after elimination of a Ph2P group. In a side reaction cleavage of the P-P bond in Ph2PN=P(Ph2)P(Ph2)=NPPh2 Seven-memleads to a four-membered ring (CP)(CO)F~P(P~~)NP(P~~)~.~~ bered metallacycles (17) are formed by treatment of Ph2PN=P(Ph2)P(Ph2)=NPPh2 with [PtX(Y)(cod)] or [PdX(Y)(cod)] (X, Y = Cl, Br, I, Me; cod = cycloocta-l,5-diene). When treated with Ph2PN=P(Ph2)P(Ph+NPPh2 bridge cleavage occurs in compounds [{ Pd(pCl)(CgH12N, or C12H12N)}2] (CgH 12N = N,N-dimethylbenzylamino, C12H12N = N,N-dimethyl-1-naphthylamino),leading to { [Pd(Cl)-(C9HI2N)l2 [pPh,PN=P(Ph,)P(Ph,)=NPPh2]} (18) and { [Pd(Cl)-(C12H12N)]2[p-Ph2 PNPPh2PPh2NPPhz]},re~pectively.~~ I
-
i
//N P-P Ph2 Ph2 (1 7) M=Pt, X = Y = C I M=Pt, X = Y = B r M=Pt, X = Y = I M-Pt, X = Y = M e M=Pt, X-Me, Y = C I M-Pd, X = Y = C I M=Pd, X = Y = B r N\\
Reactions of Ph2PN=P(Ph2)P(Ph2)=NPPh2with M(PPh3)4 (M = Pt, Pd) yield complexes M(Ph2PNPPh2)2 (19), arising from P-P bond cleavage in the linear phosphazene. No P-P bond cleavage has been observed for the sulfur and selenium oxidized derivatives Ph2P(E)N=P(Ph2)P(Ph,)=NP( E)Ph2 (E = S, Se).36 The synthesis of (NH&P(S)N=P(NH2)3 has been reported. Dimer formation takes place by NH. .N hydrogen bridges in the solid state, giving rise to eight-membered rings.37 Linear phosphonitrilic chlorides have been used as catalysts for polycondensation and redistribution of organo-substituted p o l y s i l ~ x a n e s . ~The ~ - ~con~ densation of pentamethyldisiloxan 01 to decamethyltetrasiloxane in the presence of [C13PNPC13]+[SbC16]- obeys second-order kinetics. Similar kinetic
26 1
7: Phosphazenes
behaviour is observed for C13PNP(O)C12 as catalyst. Both systems can serve as a model for polycondensation of siloxanes in the presence of linear phosphonitrilic chlorides as described above. First-order kinetics has been found for the redistribution of decamethyltetrasiloxane in the presence of [C13PNPCl3]'[SbC16] - or C13PNP(0)C12.44 which starts at about Thermal decomposition of (Ph0)3Pn~(o)(OPh)~, 250°C, leads to a number of products, among which are hexaphenoxycyclotriphosphazene and octaphenoxycyclotetraphosphazene.Cyclization of linear phenoxy-substituted phosphazenes probably leads to the formation of cyclic products .45 The well-known Kirsanov compound Cl3PNS(02)Cl (20) has attracted renewed interest. Ab initio and charge density calculations show the N-P bond to be shorter than the N-S bond.46 X-ray studies support this c o n c l ~ s i o n . ~ ~ Compound (20) can be obtained in a high-temperature (monoclinic) and a low-temperature (orthorhombic) modification. In both modifications the molecules adopt an eclipsed configuration along the P..-S line.47 Reaction of (20) with (Me3Si)2NR ( R = H , Me) leads to linear compounds with formula Me3SiNRPCl2NS(O2)C1(21a, R = H), (21b, R = Me). By refluxing (21a) in acetonitrile addition of MeCN takes place, followed by ring closure to give the cyclic compound (22).48Reaction of (21a) and (21b) with BC13 yields the linear compound [ClS(02)NPC12NH]2BCl (23) and the cyclic compound NP(Cl2)N(Me)B(Cl2)0S(O)C1(24), re~pectively.~~ I
1
Me3SiNHPCI2NS(02)CI (21 a)
Me3SiNMePCI2NS(02)CI (21b)
[CIS(02)NPC12NH)2BCI
(23)
Linear PNSrV compounds [S(NPEt3)3]Cl and [S(NPEt3)2]C12 have been prepared by reaction of Me3SiNPEt3with S2C12 in MeCN?* Phosphazene bases have been applied as deprotonating agents in a broad range of application^.^*-^^ Preparations of phosphazenium salts have been reported as well as their use as catalysts for the polymerization of poly(a1k~1ene)oxides.~~ X-Ray structure determinations of some miscellaneous linear compounds containing a N=P entity57-64-'25,127 are summarized in Section 5 .
Organophosphorus Chemistry
262
3
Cyclophosphazenes
The number of reviews on ring systems with one or more NPV segments is limited. Synthesis, reactivity, and structure of 4n-electron heterocycles R1R2b=N-P(R3R4)=N, R1R2P=N-C(R3)=CR4, and R1R2P=N-C(R3)=N have been discussed along with the properties of other compounds with general formula R1R2P=XY=Z .65 Another review deals with synthetic and physical data of BNPV and PVNSV1heterocycles, and PNS polymers derived thereof by ring opening polymerization.66 Bonding, linear, and nonlinear properties of cyclic and polymeric phosphazenes have been summarized. It has been shown that changes in the charge distribution of the NP bond affect x3 values to a great extent.67 Ab initio calculations to estimate the aromaticity of (NPH2)3 lead to a dual answer. Whereas stabilization energy points to an aromatic n-electron system, magnetic data do not support this conclusion.68Application of the cyclophosphazene N3P3(0C6H4CF3-3)4(0C6H4F"4)2 as additive in polyperfluorinated polyether lubricants has initiated an interesting theoretical study on Lewis acid-base interactions of cyclophosphazene derivatives and AlF3. It turns out that ring nitrogen atoms, if sterically accessible, provide the preferred coordination sites to the aluminium compound. This interaction can explain the mitigating effect of the phosphazene additive on the degradation of polyperfluorinated ether lubricants by Lewis acids.69Ab initio calculations at the 6-31G level have been carried out to determine a scaled quantum mechanical force field for (NPC12)3. Geometry optimization based on this molecular description shows a satisfactory correlation between calculated and observed structural and spectroscopic data.70 The ab initio scaled force field approach has also been successfully applied in the case of two conformers (S4 skew tube and Cj chair) of (NPC12)4 and in the case of (NPC12)5.71Semi-empirical PM3 calculations for compounds NPC12(NPClPip)2, (NPClPip)3, and (NPCl&NPClPip (Pip = piperidyl) show a reasonable correspondence between calculated and experimental structural data.72p73By the same method of calculation, structural data have been predicted for the corresponding azido derivative [ N P ( N ~ ) & N P ( N ~ ) P Empirical ~ P . ~ ~ relations have been proposed for cyclotriphosphazenes to correlate 31PNMR data with ligand electronegativity and degree of s u b ~ t i t u t i o n . ~ ~ In the reaction of (NPC12)3 and the quadridentate amine ligand H2N(CH&NH(CH&NH(CH&NH2 product formation strongly depends on the molar ratio of the reactants m d the reaction procedure. At a molar ratio amine/phosphazene of 112, two cyclophosphazene molecules react with one amine to form a bis-spiro compound (NPC~~)~NPS~~I-O[NH(CH~)~N](CH,),spiro[N(CH2)3NH]PN(NPCl2)2. For a molar ratio amine/phosphazene of 2 a dispiro-ansa compound NPC12wPNH(CH2)3N(CH2)l2has been claimed as reaction product.75 The synthesis of bicyclic cyclotetraphosphazenes (NPC12)3NPC1NH(CH2)nNHNPCl(NPC12)3 (n= 6, 12) has been reported as well as hydrolysis experiments with these compound^.^^ The synthesis of I
1
1
I
263
7: Phosphazenes
cyclotriphosphazenes with silicon containing side groups has been described: e.g. {NP[NH(CH2)3Si(OEt)3]2}3 can be prepared by aminolysis of (NPC12)3 with NH2(CH2)3Si(OEt)3, and { NP[O(CH2)3SiMeC12](0CH2CF3)}3 can be prepared by treatment of (NPC12)3with NaOCH2CH=CH2 and CF3CH20Na followed by hydrosilylation with HSiMeC12.77Spiro derivatives (25) have been obtained from reactions of (NPC12)3 with N-alkylated dihydrazidophosphoric acid derivatives (S)P(OPh)(NRNHR’)2 (R + R’= cyclo-Pr; R = R’= Me; R = H, R‘ = Me).78
I I RN, ,NR N’BN II ClpP, SPCh N 25a R + R’ = CyclO-Pf 25b R = R’ = Me 25c R = H, R‘= Me
Syntheses of mononuclear and binuclear metal complexes MX2L (MX2 = CuC12, CuBr2, NiBr2, CoC12, NiC12, PdC12) and MX2LPdC12 (MX2=CuC12, CuBr2, NiBr2, CoC12), in which L represents the cyclophosphazene (26), have been reported. Based on IR data it has been suggested that coordination to the ligand L takes place in the mononuclear complexes via one endocyclic nitrogen and two exocyclic nitrogens, viz. a pyrazolyl and amino propane nitrogen. In the binuclear complexes the extra coordination to the Pd2+ ion is provided by two nitrogens each belonging to two geminal pyrazolyl groups.79 The participation of endocyclic nitrogen atoms in metal coordination has been proven by the X-ray structure of the analogous complex (27). The ansa loop N-N-Co-N-N in (27) induces a relatively short non-bonded P- - .P distance [2.699(2) A] between the dimethylpyrazolyl-substituted phosphorus atoms.80 A similar phenomenon has beenPbserved in compound (49), where the short P . - . P distance equals 2.675(1) A.Io2 Complexation of Cu2+ with [NP(OPh)2]2NP(Pma)2 (Pma = 2-pyridylmethylamino) takes place through an amino and two pyridyl nitrogens, and one oxygen (NO3-), forming together a regular plan:. Two other oxygens are in apical position (28) with Cu-0 distances about 0.4 A longer than the in plane Cu-0 distance8’ But I
But I
(PhO)pP, N~ P(OPh)2 (26)
Dmpz = 3,!jdimethyClpyrazolyl
264
Organophosphorus Chemistry
Thermal decomposition of [NP(OPri)(OC6H4NH2-4)]3follows a three-step process: first, partial elimination of aliphatic residues followed by formation of POP linkages between cyclophosphazene residues, secondly, ring opening with further breakdown of aliphatic structures and cross-linking, and finally formation of polyaromatics containing phosphorus-nitrogen oxide structures. In contrast, for compounds FJP(OCH2CMe3)(0C6H4NH2-4)]3and NP(OCH2CMe3)2[NP(OCH2CMe3)(OC6H4NH2-4)]2 only a two-step decomposition can be discerned, which leads to similar phosphorus-nitrogen oxides as found for the decomposition of [(NPOPri)(OC6H4NH2-4)]3.82 The formation of a smectic C phase has been observed for N3P3[OC6H4{ C&140(0ctn)-4’}-416. A smectic layer structure is not formed in case of the tetrameric analogue, presumably due to the random orientation of the l i g a n d ~ In .~~ addition, optically active derivatives N3P3 (OC6H4[C6H4(0CHMe(CH2)~Me)-41-4>6and N3P3 { OC6H4[C6H4(O(CH2)5CH( Me)CH2Me)-41-4}6 have been investigated with respect to their liquid crystalline b e h a v i o ~ r .Cyclotriphosphazenes ~~ (29)-(32) bearing linear and branched ethyleneoxy units have been prepared and applied as additives to improve the conductivity of the well-known system [NP(OCH2CH20CH2CH20Me)2].-lithium triflate [MEEP-LiS03CF3 (4:l)]. It has been observed for (29), (31) and (32) that conductivity increases with increasing amount of cyclophosphazenes, which has been ascribed to a decrease of ionic cross-linking within the MEEP polymer. Addition of compound (30) initially causes a decrease of the conductivity, possibly related to the crystalline nature of the MEEP/LiSO~CF3/cyclophosphazenemixture.85 Conductivity of the lithium triflate complexes with compounds (33)-(36) has been shown to decrease in the order (35) > (34)=(36) > (33), thus being dependent on the length and the number of oxyethylene arms.86
(29)n (30)n
1, R = OCH~CH~(OCH~CH~O)&~B OCH2CH2(0CH2CH20)&le ,0CH2CH20Me (31)R =OCH&H, CH20CH2CH20Me ,OCH&H20Me =
= 6, R =
/OCHZCH, CH20CH2CH20Me
(32)R = OCH2CH (33) (34)n (35)n (36)n
,0CH2CH20Me ‘cH20CH2C H, CH20CH2CH20Me
= 3, R = = 7.2, R = OC6H~[C(O)(OCH2CH~),OMeI2-3,5} = =
11.8, R = OC6H3([C(0)(OCH2~H2),QMe]23,5} 11.8, R = OC6H4{[C(O)(OCH2CHq)nOMe]2-4)
A new method has been reported for the preparation of [NP(OCH2CF3)2]3, [NP(OC6H4R-4)2]3,and [NP(OC&R-4)2], in acetone or THF, using Cs2CO3 as proton a b ~ t r a c t o rPreparation .~~ and characterization of cyclophosphazenes and polyphosphazenes bearing phenoxy groups with photosensitive substitu-
7: Phosphazenes
265
ents, such as t-butoxycarbonyloxy, on the para-position have been described.88 An interesting study comprises results of substitution reactions of (NPC12)3 and its 1,3-ansa-oxy(tetraethyleneoxy) derivative with bis-(P-naphthol). Whereas the reaction with (NPC12)3 in presence of NaH quantitatively leads to the spiro compound tetrachloro-spiro-(binaphthalenedioxy)cyclotriphosphazene, chlorine substitution in the ansa derivative offers two other ansa derivatives (37) and (38). Host-guest interaction between the macrocycle and Na+ has been put forward as the driving force for the formation of (37) and (38). 89390
Reactions of (NPX2)3 (X = F, C1) and (NPC12)4 with ferrocenol in a molar ratio 1:1 yield the corresponding monosubstituted derivatives (NPX2)2NPX(OC10H9Fe), and (NPC12)3NPCl(OCloHgFe).Ansa-derivatives NPXZNPX(1,l’-02CloHgFe)(39a, X = F), (39b, X = Cl) are formed when using the diol 1, l’-(H0)2C10HsFeas reagent. However, spiro compounds with general formula (NPF2)2(NP(1,1’-E2CloHgFe)with E = S (40), or Se (41) are obtained from reactions of (NPF2)3 with the corresponding 1,1’-dilithioferrocene dithiolate or ~elenolate.~’ N - t \ - O a
X2Pt
N
Fe
N’i-0(39a) X = F (39b) X = CI
,k N \ , N\\ I)?\ P-N E F2
E
Fe
a
e
(40) E = S (41) E = S e
Ring opening polymerization of the N-carboxyanhydride of y-benzyl-Lglutamate initiated by N3P3(OC6H&H2NH2-4)6 leads to a hexa-armed polyglutamate with a cyclophosphazene core. The polyglutamates have a righthanded a-helical structure. Preliminary results show that the introduction of oxyethylene chains allows this polymer, supported by Teflon, to act as an enantioselective membrane for Trp, Phe, and Tyr.92 Dendrimers with a cyclophosphazene core attract continuing attention.
Organophosphorus Chemistry
266
Complex formation of dendrimers (generation 1-5) (42)with diphenylphosphine end groups have been investigated using organometallic species such as Fe(C0)4, W(CO)S, RhCl(cod), and AuCl. No changes in reaction rates or yields have been observed, when going from generation 1 to 5.93
(42)
generation 1
It has been demonstrated that reactions can be carried out not only at the surface of dendrimers but also at internally situated sites. The latter reaction mode offers the possibility to synthesize polydendritic macromolecules.94 In the presence of a ten-fold excess of triethylamine reactions of (NPC12)3 in THF with pyrimidine-2-thiol, 4,6-dimethylpyrimidine-2-thiol, or 3-trifluoromethylpyrimidine-2-thiol only provide the geminal disubstituted derivatives. Molecular structures of (NPC12)2NP(2-S-pyrimidinyl)2 and (NPC12)2NP(2-S4,6-dimethylpyrimidinyl)2 reveal significant interactions between exocyclic nitrogens and the adjacent phosphorus atom with mean N- - .P distances of 2.98( 1) and 3.12(1) re~pectively.~~ Treatment of the cyclothionylphosphazene (NPC12)2NS(O)Cl with AlC13 in 1,2-dichloroethane yields the novel compound (NPC12)2NS(0)CH2CHC12.The S-substituted derivative (NPC12)2NS(O)OS(02)CF3 can be obtained by reaction of (NPCl&NS(O)Cl with Ag[OS(02)CF3]. In both cases, the cation (NPC12)2NSO+ has been suggested as reactive intermediate. This cation has also been proposed as initiator for the ring opening polymerization of (NPC12)2NS(O)Cl in presence of GaC13.96 Chlorine substitution in chlorocyclocarbophosphazenes (NCC1)2NPC12 and NCCl(NPC12)2 by HOCH2(CF&CH20H in presence of Et3N or Prn3N has been described. Apart from forming a spirocycle at phosphorus, chlorine linked to carbon is regiospecifically replaced by a dialkylamino group, generated by a tertiary amine. The phenomenon of C-N bond cleavage has also been observed for 1-methylpiperidhe and 4-methylmorpholine as HCl scavengers, now involving a N-Me bond. It has been observed that aminosubstituted cyclic monocarbodiphosphazenes are more thermally stable than the parent compound NCCl(NPC12)2.97 The reaction of the linear compound [(Me2N)2P(NH2)=NP(NH2)(NMe2)2]Cland C13VNSiMe3 in presence of acetonitrile has been reported to yield a P-amino substituted ring system [NP(NMe2)&NVCl2 (43)-Similar reactions using metal nitride halides C13MoN or C13WN offer [NP(NMe2)2I2NMo(C13) MeCN (44)and [NP(NMe2)2]2NW(C13)MeCN(45),re~pectively.~~ Organic backbone polymers with pendant cyclophosphazene groups are the subject of various investigations. In general, it can be stated that the thermal stability of the polymer concerned increases by the incorporation of the inorganic component, provided a sufficient phosphazene content. Free radical
A,
267
7: Phosphazenes
initiated grafting of the cyclophosphazene derivatized poly(methylmethacry1ate) (PMMA) { C(Me)[C(O)0C6H4OR-4]CH2}. with R = N3P3(OCbH4Et-4)5 (46) onto a poly(viny1 alcohol) surface shows the grafting yield to be dependent on the presence of ethyl groups.99 Me -+CH2*"
o=c
I 0
Et
(46)
Et
The vinyl acetate derivative (NPC12)2NP(Pri){ C[OC(0)Me]=CH2} copolymerizes with MMA and styrene. It has been argued that these polymerizations are governed by steric hindrance, in particular due to the phosphazenic component. This is in line with the inability of (NPC12)2NP(Pri){C[OC(O)Me]=CH2}to homopolymerize.loo,lol A similar behaviour in radical polymerizations has been found for (NPC12)2NP(Pri)[C(Me)=CH2] (48). lo2 Compound (48), one of the few compounds in which the unsaturated moiety is linked to the phosphazene ring by a P-C bond, can be prepared by an elimination reaction of the sulfonium substituted cyclophosphazene N3P3Pri[CMe20S(02)Me] (47) according to the scheme given below. Apart from (48) traces of an ansa compound (49) have been iso1ated.lo2 PI,'
Me .Me, ,C-OH
N"*N II I C12P, ,peg N
-
Pr',
CIS02Me
Me Me, ,COS02Me
N'BN II I C12P, /,Pa2 N (47)
dbu
N"N II I ci2p, N
(48)
+
II CgP,
I 11 +P, ,CMe N I O CI (49) traces
268
Organophosphorus Chemistry
Free radical copolymerization of (NPC12)2NPCI { OC&&6H4(CH=CH2)41-4) with MA, EA (ethyl acrylate) or MMA offers a broad range of copolymers with phosphazene contents to a maximum of 9O%.lo3 Solvent effects have been recognized for the radical polymerization of (NPR2)2NP(R)OC6H4(CH=CH2)-4 [R = O(CH2)2NMe2 (50a), NH(CH&NMe2 (50b)l in ethanol or thf solution. Whereas ethanol proves to be the more effective soivent for the polymerization of (49a), the opposite is true for (50b). Reactivity ratios for copolymerization of (50b) with MMA in ethanol and THF also point to a larger reactivity of (50a) in the latter solvent.lW A significant increase of the fluorescence intensity of Eu3+ has been observed when Eu3+ions are added to a methanol solution of (50b) or its corresponding polystyrene (PS) derivative.lo4 The compounds (50c-f) as well as polystyrenes derived from them show a strong selectivity for extracting Ag+ ions from aqueous solution into a CH2C12layer. Copolymers [(SOc)-co-MMA]exclusively extract Ag+ ions. Ion transport experiments confirm these findings. It has been argued that complex formation between Ag+ and phosphazene ring nitrogens underlies the extraction and transport phenomena. lo5
Q (50a) R = O(CH2)2NM* (50b) R = NH(CH2)sNMez
(50~) R = OEt
(50d) R = O(C2H40)Me (50e) R = O(C2H40)2Me (500 R = O(C2H40)3Me
Application of cyclophosphazenes N3P3(0C6H4F-4),(0C6H4CF3-3)6-x (code name X-1P) as additive in lubricants is the subject of a number of papers and patents.lo6-l1l The retarding effect of X-1P on the Lewis acid catalysed degradation of polyperfluorinated ethers has been mentioned earlier.69 Cyclophosphazenes play an important role as flame retardant additives. Hexaphenoxycyclotriphosphazene has been used for flame retarding polystyrene formulations' l 2 or for polyester resins.' l 3 Epoxy resins are treated with spirocyclic cyclotriphosphazenes or cyclotetraphosphazenes, possessing at least two epoxy curing functionalities.' l 4 Flame retardant polyesters (5 1) can be prepared by copolymerization of bis[spirobis(4-hydroxyphenoxy)]cyclotriphosphazene and bisphenols with terephthalic acid chloride in a two-phase solution. l 5 Fire retardant electrolyte compositions are prepared with fluoro-containing cyclophosphazenes N3P3F5[O(CH2)20Me] or N3P3F3[0(CH2)20Me]3.116 Reactive organo-substituted cyclophosphazenes can be applied as curable
7: Phosphazenes
269
m
cross-link agents.' l7l1l8 In addition cyclophosphazenes have been used as an additive for processing silver halide photographic material. 194 Addition of [NP(NHCH2CH=CH2)2]3lowers the melt flow index of blends of polypropylene and poly(ethylene-co-propylene-co-5-methylene-2-norbornene). l 9 Fluoroalkoxy-substituted cyclophosphazenes are used as one of the components of ink for ball pens. 120*121 Fluorine-releasing dental materials have been prepared by curing mixtures of N3P3F,[(OCH2CH20C(0)C(Me=CH2]6-.r (x = 1,2 or 3) and MMA, and subsequent blending with PMMLI.'~~ Cyclotriphosphazene derivatives can be used as multifunctional initiators for atom transfer radical polymerizations (ATRP). For example, N3P3{OC6H4[CH20C(O)CHBrMe]-4)6 has been used for the ATRP of MA and isobornyl acrylate (Bn'A). Multiarm star block copolymers of MA and Bn'A have been prepared in this way.'23 X-Ray structure determinations of some miscellaneous cyclic compounds containing a N=P entity have been summarized in Section 5.124-127 4
Polyphosphazenes
In this Section, polyphosphazenes and polythionylphosphazenes are discussed having a P-N or P-N-S backbone, respectively. Organic polymers with phosphazene entities as side groups have been discussed in Section 3. Polyphosphazenes and polythionylphosphazenes are reviewed together with other inorganic and organometallic polymers. 2 8 ~ 1 2 9An extended overview concerning the functionalization of polyphosphazenes has appeared with emphasis on chemical modification of polyphosphazenes bearing OCH2CF3 and OC6H4R-4 substituents ( R = H , Et, Bus, or OMe).13' In addition general applications of polyphosphazenes as solid electrolytes,13' biomaterials' 32 and carriers for protein delivery have been reviewed.133 Optical and hydrodynamic properties of fluorine containing high-molecular weight polyphosphazenes pP(OR)2], with R = CH2CF3, CH*(CF&H, and CH2(CF2)4H have been investigated. 34 The temperature and concentration dependent behaviour of the well-known polyelectrolyte (NP[OC6H4(Co2Na)-
'
270
Organophosphorus Chemistry
4I2Inin aqueous solution is governed by the partial hydrophobic character of the polymer chain. 35 Thin films of organo-substituted polyphosphazenes have been investigated by optical methods. Comparison with other polymers shows the molar refractivity of the [N=P] unit to be comparable with that of a conjugated [C=C] unit.136 An IR and Raman spectroscopy study has been carried out for [NP(OC,Hh,1)2ln (rn = 1-9) in the temperature range - 100 to + l o 0 "C. Temperature dependent changes have been interpreted in ~ * ' and ~ ~ X-ray terms of conformation changes of the alkoxy g r o ~ p s . ' ~DSC diffraction measurements have been used to study the effect of introducing O(CF2)6Me groups into [NP(OCH2CF3)2]non phase transitions in the resulting copolymers. 39 Poly(thiony1phosphazenes) [NS(0)X(NPC12)2]n(X = F, C1) have been investigated in the melt with respect to their chain flexibility by measuring the 31P spin-relaxation time.140{NS(O)Cl[NP(C,H&F3-3)2]2},, has been subjected to finite dilution inverse gas chromatography (FDIGC) experiments.I 4 l Blends of poly(alky1ene oxides) and a poly(fluoroa1koxy)phosphazene combined with a metal triflate as electrolyte form an important class of polymer electrolytes. Studies on cathodes consisting of V2O5, carbon black and blends of poly(ethy1ene oxide) (PEO), poly(propy1ene oxide) (PPO) and poly-(octafluoropentoxytrifluoroethoxyphosphazene(PPz) with LiCF3S03 as electrolyte reveal no coordination between the alkoxy oxygens and the lithium cations. 142 The use of PEO, PPO, PPz, and Mg(CF3S03)2in magnesium batteries has been described. It turns out that conductivity is enhanced in the presence of PPz, in particular for plasticized samples.143 Conductivity measurements have been carried out for a number of crown ether substituted polyphosphazenes {NP[O-(p-~rown-q)]2}~ (p = 12, q = 4; p = 15, q = 5; p = 18, q = 6) and mixed crown ether/2-(2-methoxyethoxy)ethoxy (ratio 1:3) substituted polyphosphazenes, all polymers being loaded with MC104 (M=Li, Na, Rb, or Cs). Comparison of conductivities provides strong evidence for a charge transport in which cations play a predominant role.144The method of electrochemical vapour deposition has been applied to prepare films of (MEEP), using (NPC12)3 and MeO(CH2CH20)2H as starting materials. Highly cross-linked films have been obtained, which were not suitable for rechargeable lithium batteries.14' As mentioned in Section 3, the conductivity of MEEP/Li systems can be increased by addition of cyclotriphosphazenes bearing linear and branched ethyleneoxy sub~tituents.~~ Charge cycling at the interface of { NP[(OCH2CH(OCH2CH20Me)(CH20CH2CH20Me)]2}n/Lihas been investigated. 146 The reaction of hydroxylated MEEP {NP[(OCH2CH20CH2CH2OMeIl.2[(OCH2CH20CH2CH20H]o.s}and (EtO)& in an acid medium leads to homogeneous, transparent polymeric films without any phase separation. When complexed with LiCF3S03, the conductivity of these films can be compared with that of the PEO/Li systems.147Nanoparticles of CdS have been prepared by reaction of [Cdlo(SCH2CH20H)16](N03)4 with Na2S in a matrix of hydroxylated MEEP, cross-linked by OCN(CH&qCH2)20(CH2)2NCO. Transparent, flexible films have been obFained, with the embedded CdS particles having a diameter of about 70 A.148 Complexation of LiClO4 to
27 1
7: Phosphazenes
[NP(NHPent")z], or [NP(NHH~x")~], creates new polymer electrolytes. The relation between ionic conductivities and temperature can be described by the Vogel-Tammann-Fulcher equation.149 Cationic polymerization of the phosphoranimine C13P=NSiMe3by PC15 as initiator has been proven to yield polyphosphazenes with controlled molecular weights and polydispersities. 50 Polymerization of C13P=NSiMe3by the macroinitiator K'(CH2CH2O)nCH2CH2N(H)[R2P=NPC13+][PCl6]-,with R' = NH[R2P=NPC13+][PC16-] and R = OCH2CF3 (52), yields the first triblock copolymer (53) with phosphazene blocks. Using MeO(CH2(R = OCH2CF3) as initiator a CH20),,CH2CH,N(H)[R2P=NPC13+][PC16]block copolymer (54) has been formed with M e 0 being one of the end groups. H R I &P613PN=+0
H I CH&H2N, NfCH2CH20j,,
R IP-N P613Pcl~ I
CI3P=N-SiMe3
Both block copolymers are soluble in dioxane, which enables substitution of the chlorine substituents (55).151 Deprotonation-substitution reactions of [NPMeR], (R = Bun, Hex") with Bu"Li take place exclusively at the methyl group giving rise to the reactive site - CH2-Li+.152 The polyphosphazene [NPMeC6H4(0CF=CF2)-4], has been obtained by thermolysis of the corresponding chlorophosphoranimine Me~SiN=PMe(Cl)C6H4(0CF=CF2)-4at 110 "C. Cross-linking of this trifluorovinyloxyphenyl substituted polyphosphazene at 160 (C results in the formation of a perfluorocyclobutane polyphosphazene thermoset (55). lS3 Silicon containing thermosets have been prepared in a similar way to polymers [NPMePhIn[NP(Ph)CH2SiMe2C6H4(0CF=CF2)-4],or [NPMePh],[NP(Ph)CH2SiMe2(CH2)2SiMe2C6H4(0CF=CF2)-4Im. * 53 Analogous to reactions with (NPC12)3,'54 phenoxy and spiro diphenoxy substituted polyphosphazenes have been prepared in a polar solvent by the reaction of [NPC12], and the corresponding phenols or biphenols in the presence of K2C03.155 Highmolecular weight homopolymers (56) and (57) have been synthesized with
272
Organophosphorus Chemistry
F
F
(55)
THF or 1,4-dioxane as solvent in the presence of K2CO3 or Cs2CO3 as proton abstractors. The use of racemic ( *)-,(+)-, or (-)-binaphthol leads to three forms of polymer (58). It is noteworthy that the specific rotations of the poly(dioxybinaphthy1phosphazenes) are larger than those of the free binaphthols. A similar phenomenon has been observed for the corresponding tris(spiro)cyclotriphosphazenes. 56 Following the same synthetic approach also polyphosphazenes with different dioxybiphenyl spiro groups, (59) and (60), have been synthesized.lS6In another approach, Et3N has been applied as proton acceptor for the preparation of polyphosphazenes bearing binaphthyl and alkoxy groups.156 Esterification of the carboxyl groups in [NP(OC6H&O2H-4)], by ROH [R = (CH2)20Me, (CH2)20(CH2)20Me, (CH&OCHzMe, (CH2)3Me] leads to polymers [NP(OC6H4C02R-4)],. 58 Polymers [NP(NHR),(OCH2CF3)2- Jn, [NP(OR),(OCH2CF3)2--x]n, and [NP(OCH2R),(OCH2CF3)2- .Jn with R = adamantyl have been synthesized in a two step substitution process starting with the adamantyl reagent. In each series of polymers, the glass transition temperature increases with increasing content of the adamantyl group, with the highest Tg ( = 180"C) for [NP(NHR)1. o ~ ( O C H ~ C F ~ ) O Ligand . ~ ~ ] , .exchange takes place for adamantyloxy and adamantylmethoxy derivatives in reaction with NaOCH2CF3.159 The synthesis of polyphosphazenes with 2-butenoxy or 4-allyloxyphenylphenoxy
273
7: Phosphazenes
substituents in combination with other organic substituents has been reported as well as the use of these polymers for the preparation of interpenetrating polymer networks with PS, PMMA, polyacrylonitrile, poly(acry1ic acid), and poly(dimethy1 siloxane).160 By mixing THF solutions of the commercially available polyphosphazene ~P(OPh)2]o.~7[NP(OPh)(OC6H4Et-4)]~.~~[NP(OPh)(OC6H4-Allyl-2)]o.05and PdC12(MeCN)2, complex formation takes place between the palladium salt and the polyphosphazene. Evidence has been presented that two ally1 groups of different polymer chains are involved in the coordination of palladium. 161 Reaction of the poly(thiony1phosphazene) [NS(O)C1(NPC12)2ln with two, three or four equivalents of NaOCH2CF3shows a regiospecific substitution of the chlorine atoms at phosphorus. Treatment with an excess of Bu"NH2 yields fully organo-subst ituted poly(t hiony lphosphazenes) with general formula ((NSONHBU~)[NP(OCH~CF~)~(NHBU~)~_,]~},, which are stable to weight loss to approximately 250 "C under nitrogen.162 0
II CH2-C-OEt
Grafting reactions involving polyphosphazenes have been performed by either grafting onto a polyphosphazene surface or by polyphosphazene transfer onto the surface of an organic polymer. In both cases, 4-alkylphenoxy or 4-benzylphenoxy substituted polyphosphazenes have been used as basic reagents. Radical-induced reaction of diethyl maleate with [NP(OC6H&t-4)2], in organic solvents leads to a partial conversion of the ethyl groups into CHMeCH(CH2C02Et)(C02Et) entities (61). The grafting yield increases with increasing molar content of maleate until a maximum value is reached. During grafting considerable scission of the polymer backbone takes place simultan e ~ u s l y . Degradation '~~ of the polymer chain does not take place when a lightinduced grafting process is applied, although the overall yield is lower in comparison to the radical-induced thermal method. Light-induced grafting reaction of maleic anhydride onto [NP(OC6H4Alk-4)2],,(Alk = Me, Et, Pr', Bun, Bus) followed by grafting of amino-terminated hindered amino light stabiliser (HALS) groups onto the resulting succinic anhydride (SA) moieties in {[NP (oc6H.&lk-4)2] .-g-SA} has been reported to lead to a photooxidative stabilization of the poly(organophosphazenes).165 It has been shown that grafting of { [NP(OCdH4Et-4)2ln-g-SA)onto poly(viny1 alcohol) reduces the hydrophilic character of the organic polymer surface. A lower yield is observed for grafting on poly(ethy1ene-co-vinylalcohol) compared to poly(viny1alcohol).166 Thermal stability of polymer blends has been discussed in a number of
274
Organophosphorus Chemistry
papers. As demonstrated by TGA analysis, the thermal stabilities of PS167and PMMA168 as well as the respective char yields increase slightly when the organic polymers are mixed with small amounts of [NP(OPrn)2], (ratio cyclic/ linear = 65 : 35). Based on a new kinetic model it has been argued that thermal degradation of PMMA occurs via zero- and first-order kinetics, whereas blends of PMMA and [NP(OPrn)2],are governed by first- and second-order kinetics due to a phosphazene initiated anhydride formation involving the ester groups of PMMA.169y170 Organo-substituted polyphosphazenes such as [NP(OCH2CF&], and [NP(OC6H5)2], have been widely used in membrane studies. Their sorption isotherms for their vapours obey Henry's law for a number of simple alcohols, ketones, and aromatic compounds. Both polymers show a reasonable permselectivity between the organic vapours and air, the fluorine containing polymer being more permeable. Within the series of polymers [NP(OPh)(OC6H4Alk)ln, with Alk=Me, Et, Pr' positioned on the meta or para position, solution-cast films of [NP(OPh)(OC6H4Me-3)Inand [NP(OPh)(OC6H4Me-4)], appear to be the most suitable for UV photo-crosslinking with benzophenone as photoinitiator, rendering these polymers very attractive as membranes.172 Films of sulfonated [NP(OC6H4Me-3)2], can be used as ion-exchange membranes, provided the molar ratio SOJpolyphosphazene is larger than 64%. 3C NMR data indicate that sulfonation occurs at the para-position. 173 Membranes of the polymer (62), obtained by solution-casting on microporous support, have been proven to be useful to remove colorants in ultrafiltration of sugar solutions. 74
Application of polyphosphazenes in medicine still receives attention with emphasis on biodegradable systems. Blends of two miscible polymers poly(1actide-co-glycolide, 1 : 1) and [NP(OC6H4Me-4)2-,(NHCH2C02Et),], (p = 1.5, 1.O, or 0.5) have been prepared. Near-zero-order degradation kinetics in aqueous solution has been observed for these systems of which the blend with the highest ethyl glycinato content degrades most rapidly.17s-176 It has been shown that in vitro degradation of polyphosphazenes bearing amino acid ethyl ester side groups depends on the reactivity of the amino acids. Rate of degradation can be increased by introducing small amounts of hydrolytically sensitive co-substituents (depsipeptide ester) or hydrolysis-catalysing cosubstituents (histidine ethyl ester). Blending of different poly(amino acid ester)phosphazenes forms another way of controlling the rate of degradaTubes of poly[bis(ethyl a1anato)phosphazenel have been used as tion. 1777178
275
7: Phosphazenes
conduits for in vivo nerve reconstruction.179 Polymers wP(OC6H4Me-4)(NHCH2C02Et)ln and [NP(OC6H4Me-4)1.6Imo.4In (Im = imidazolyl) loaded with colchicine have been used in in vitro drug release experiments. It was shown that release of colchicine depends on both diffusion and degradation.180 Films of polyphosphazene with ethyl phenylalanato and imidazolyl side groups (ratio 80 : 20) and loaded with the polypeptide hormone calcitonin form another example of a controlled release system.181 The same polyphosphazene has also been used for the preparation of biodegradable microspheres for entrapment of insulin182and naproxen. 183 The polyphosphazene with diethyl glutamato and ethyl glycinato side groups has been applied as matrix for in vivo release of naloxone or its HCl salt.184The biodistribution of nanoparticles of [NP{ NHCH(CH2C6H5)C02Et}0.8 { NHCH,CO,Et} I.& with their surface modified by absorption of [NP(NHCH2CO*Et)l.g{ NH(CH2CH2O),Me} o.I]n,has been studied in animal models. Systemic circulation and low liver uptake render these nanoparticles of interest for further biomedical studies, e.g. drug targeting. 85 The polyelectrolyte [NP(OC6H4C02H-4)& (PCPP) has been shown to possess a significant in vivo adjuvant activity on the immunogenicity for an influenza vaccine.186The preparation of PCPP microspheres by coacervation has been described. 87 Polyphosphazenes with dicarboxylic amino ester substituents can be applied as carriers for antitumour diamine Pt(I1) complexes. Bonding between platinum and the phosphazene backbone occurs via the dicarboxylato groups. Poly[(hydroxy)(l-glutamato-(trans-( k)-1,2-diaminocyclohexane)platinum(II)} phosphazene] (63), having no cross-resistance to the anticancer drug cisplatin, has been selected for preclinical studies for human phase I trials. 8g 889189
OH OH (63) Am = trans -(&)-1,2diaminocyclohexane
Miscellaneous applications of polyphosphazenes include flame retardancy 90- lg3 and processing silver halide photographic light-sensitive materia1.1g4It has been claimed that solutions of [NPC12], in THF can be stabilized by the addition of anhydrous d i g 1 ~ m e . l ~ ~ 5
Crystal Structures of Phosphazenes and Related Compounds
The following compounds have been examined by diffraction methods. Distances are given in picometres and angles in degrees. Standard deviations are given in parentheses.
Organophosphorus Chemistry
276
Compound
Comments
NP 162.8, no sd given (2) NP 155.6(4) (3).0.5C6H5Me,R =p-tOlyl NP 164.3(3) (4), R =p-tolyl, Y = BF4 mean NP 154.6(2) HC(CH2PPh2NSiMe3)3 mean NP 154.5(7) MeC(CH2PPh2NSiMe3)3 I P~~P=NC~H~-O-CH=CNHC(O)NHC(O) NP 159.2(1) NP 158.2(2) neutron dif. Ph3PNH NP 156.2(3) X-ray dif. [Ph3PNMg(C1)N(PPh3)MgCl.2(Me2N)3NP0 NP 155.5(1) NP 159.2(8) (Me3SiNPMe3)(EtO2)(MgBrl.25I0.75) NP 157.8(7) (Me3SiNPMe3)2(Mg12) mean NP 159.9(6) (6) 157.0(12k159.4( 12) (Me3PNMgBr)&Hs mean NP 1 5 8 313) [CdCl(NPEt3)]4.CH2C12 mean NP 159.1(12) [CdBr(NPEt3)]4.2C6H5Me mean NP 160.0(14) [CdI(NPEt3)I4.3C6H5Me mean NP 158.1(4) [Cd(C ECSiMe3)(NPEt3)]4 mean NP 159.3(5) [Cd414(NPEt3)3(0SiMe3)].MeCN NP 160.5(3) [(Me3PN)(BBr2)12 mean NP 164.1(6) [(Pr 3PN)2(BBr2)(BBr)] Br N(B)P 154.8(4), [(Et3PN)2(BNPEt3)2]2+Br: - .4CH2C12 NP 161.7(4) N(B)P 153.9(7), [(Ph3PN)2(BBr2)(BNPPh3)]+BBr4mean N(B2)P 159.9(4) NP 163.3(8) (7).3CH2C12 mean NP 154.8(2) B(NPPh3)3.0.5c6H~Me NP 162.8(2) (10) mean NP 156.9(3) 1) mean NP 158(1) { Klr\J(H)C(Ph)C(H)P(Ph2)=NSiMe3](tmen)} 2 tmen = Me2N(CH2)2NMe2 mean NP 155.1(3) [Ti(NPPh3)4].3c&I~Me mean NP 162.6(5) [Ti3Clg(NPMe3)3]C1.2Me3P0.2CH2C12 NP 158.9(4)-161.9(4) V2C14(NPPh3)3.3CH2C12 NP 165.3(4) [TiCh(NPEtdh NP 161.1(3) [TiC13(NPEt3)(THF)2] NP 161.2(5) TiC14[Me2Si(NPEt 3)2] NP 159-1 64 (estimated) [Zr2C14(NPMe3)4(HNPMe3)I.MeCN N(Y)P 154.7(8) ( 14).3C6H5Me,M = Y mean N(Y2)P 156.3(7) N(Dy)P 153.1(7) ( 14).3C6H5Me,M = Dy mean N(Dy2)P 155.6(10) N(Er)P 151.2(10) mean N(Er2)P 157.1(7) I
+
(!
i
Ref: 1 9 9 11 11 14 19 20 22 22 22 22 23 23 23 23 23 24 24 24 24 24 25 26 26 27 28 29 29 30 30 30 31 32 32 32
7: Phosphazenes
NP(..Na) 166.4(2), 167.6(2) LPNP 121.6(1) mean NP 160(1) mean LPNP 124.1(9) NP 158.7(6)-167.3(6) mean (PNP 111.4(2) (Cp)(CO)FeP(Ph2)NP(Ph2)2NP(Ph2).O. 5C6H6 NP 158.2(2)-162.5(2) L NPN 120.2(1) LPNP 124.3(1)-129.2(1) NP 156.1(8)-164.8(8) (17), M = P t X = Y =Me LPNP 126.9(5), 138.5(6) NP 155.2( l o t 165.2( 10) (17), M = P t X=Me, Y = I L PNP 130.4(6), 139.6(7) NP 157.6(2), 161.0(2) (NH2)2P(S)NP(NH2)3 L PNP 129.9(2) mean NP 155.3(2) (20), space group P2Jc mean NS 157.0(3) mean L PNS 130.2(3) NP 155.9(2) (20), space group Pbca NS 156.9(2) L PNS 1 3 0 31) NP 157.5(3), 159.7(3) (214 NS 157.2(3) LNPN 108.3(2) NP 156.7(3), 160.0(3) NS 156.3(3) LNPN 108.1(2) NP 157.4(2), 159.9(2) NS 158.3(2), 167.4(2) LNPN 115.1(1) mean NP 158.2(6) mean N(H)P 161.7(5) mean NS 156.4(13) L NPN 104.1(4), 107.6(4) NP 158.4(4), 160.0(5) NS 153.4(5) LNPN 113.1(2) mean NP 160.0(2) NS 159.3(3)-163.6(4) L PNS 119.7(2)-128.5(2) L NSN 103.6(2)-108.4(2) mean NP 164.6(5) mean NS 154.1(3) L PNS 125.2(3), 126.6(2)
[NaN(PPh2)2(PMDTA)]
277
33 34 34 35 36 36 37 47 47 48 48 48 49
49 50
50
278
Ph3PNS(02)0SiMe3 [Pa(NPbC13)4]+]+[Pc16]-
[Ph3PNPPh3]+[MoOBr41[Ph3PNPPh3]+[CpCrC13]
[Ph3PNC(NPh)Ph].HCl Mes*N=P(Cl)=C(SiMe& Mes*=C6H2But3-2,4,6 Mes*N=P(Br)=C(SiMe3)2 (64) fcP(S)(NCS)NMe2 fc = ferrocenyl (PriNH)2P(OC6H4Me-4)NC(C02Me)CHC02Me.HOC6H4Me-4 NPC12(NPClPip)2 Pip = CSHION
(NPClPip)
(25a)
Organophosphorus Chemistry L NSN 109.4(2) NP 159.1(8) NS 156.6(8) L PNS 127.2(5) N P 159.5(2)-161.1(4) NPb 151.5(4)-153.2(3) L NPaN 104.6(2)-111.7( 1) L P N P b 132.5(2)-142.9(3) NP 156.8(2)-160.0(2) NP 155.1(3)-159.1(3) mean NP 159.5(4) LPNP 133.5(3) mean NP 157.6(2) L PNP 147.3(3) mean NP 157.9(2) mean LPNP 141.3(5) NP 159.0(3) NP 152.7(4)
NP 151.8(3) NP 158.9(7) NP(C) 170.0(5) NP(N) 163.1(4) NP 157.1(5)
50 57
58 58 59 60 61 62 63
63 64 125 127
mean NP(C12) 156.7(4) 72 mean NP(C1Pip) 158.3(4) mean L NPN 118.8(2) mean L PNP 119.7(5) exocycl. mean NP 160.4(4) mean NP 158.1(1) 72 mean LNPN 118.9(2) mean L PNP 120.1(4) exocycl.: mean NP 163.0(2) in segment P(C12)NP(C12) 73 mean NP 158.2(5) in segment P(ClPip)NP(C12) mean NP(C12) 156.5(3) mean NP(C1Pip) 159.9(3) L NP(C1Pip)N 1 17.4(2) mean L NP(C12)N 119.2(1) mean LPNP 120.7(2) exocycl.: NP 162.0(3) in segment P(C12)NP(C12) 78 mean NP 156.9(8) in segment P(N2)NP(C12)
7: Phosphazenes
279
mean NP(C12) 154.8(4) mean NP(N2) 160.0(6) mean L NP(C12)N 119.5(2) in N3P3ring L NP(Nh)N 112.8(3) in N4P2 ring mean L NP(N)2)N 98.1(5) L P(ClZ)NP(C12) 119.1(4) mean L P(C12)NP(N2) 123.2(7) in N4P2 ring NP 161.7(6)-166.8(6) two indep. mol. in the unit cell 78 in segment P(C12)NP(C12) NP 154( 1)-159( 1) in segment P(N2)NP(C12) NP(Cl2) 153(1)-159(1) NP(N2) 158(1)-163( 1) mean L NP(C12)N 119.7(3) in N3P3 ring mean L NP(N)2)N 115.3(4); in N4P2 ring L NP(N)2)N 100.8(7)103.4(6) mean L P(C12)NP(C12) 120.3(5) mean L P(C12)NP(N2) 121.3(5) in N4P2 ring NP 159(2)-167( 1) in segment P(Dmpz2)NP(Dmpz2) 80 mean NP 161S(2) in segment P(Dmpz2)NP(NHBu')~ mean NP(Dmpz2) 154.7(1) NP(NHBut)2 161.5(2), 163.4(2) mean L NP(Dmpz2)N 1 18.4(4) L NP(NHBut)2N 1 10.9(1) LPNP 113.3(1)-125.7(1) exocycl. NP 161.8(2)170.1(2) in segment P(C12)NP(C12) 81
280
Pma = 2-pyridylmethylamino
(39a) (39b)
Organophosphorus Chemistry
mean N P 158.6(2) in segment P(C12)NP(Pma)2 mean NP(C12) 155.4(5) mean NP(Pma)2 162.0(3) mean L NP(C12)N 120.2(2) L NP(Pma)2N 1 12.6(1) LPNP 117.5(2)-124.1(2) exocycl. N P 160.9(3), 162.6(3) in segment P(OPh)2NP (OW2 81 mean N P 157(2) in segment P(OPh)2NP (Pma)2 mean NP(OPh)2 157.7(5) mean NP(Pma)2 161( 1) mean L NP(OPh)2N 1 18.1(9) L NP(Pma)2N 113.3(4) L PNP 120.6(4)-124.2(6) exocycl. mean NP 162.6(5) in segment P(0Ph)zNP (OPh)2 81 NP 154.7(9), 158.2(9) in segment P(0Ph)zNP (Pma)2 mean NP(OPh)2 157.2(9) mean NP(Pma)2 158.2(5) mean L NP(OPh)2N 1 17.0(5) L NP(Pma)2N 117.6(4) L PNP 120.8(4)-123.5(4) exocycl. N P 161.3(7), N(Cu)P 170.7(7) N P 154.9(3)-157.2(3) 91 L NPN 1 17.7(1)-119.7( 1) mean L PNP 121.0(2) in segment P(Cl)NP(Cl) 91 mean N P 157.7(2) in segment P(Cl)NP(C12) mean NP(C1) 158.9(2), mean NP(C12) 157.6(1) mean L NP(C1)N 117.8(2) L NP(C12)N 1 19.3(1) L P(Cl)NP(Cl) 122.3(1) mean L P(C1)NP(Cl2) 12141) in segment P(F2)NP(F2) 9 1
7: Phosphazenes
28 1
mean NP 156.3(2) in segment P(F2)NP(spiro) mean NP(F2) 154.5(2) mean NP(spiro) 160.2(2) L NP(spiro)N 115.8(l), mean L NP( F2)N 120.4(1) mean L P(Fz)NP(spiro) 121.1(1) L P(F2)NP(F2) 119.7(2) in segment P(C12)NP(C12) 95 mean NP(C12) 157.2(7) in segment P(C12)NP(S2) mean NP(C12) 158.0(4) mean NP(S2) 158.8(4) mean L NP(C12)N 119.6(3) L NP(S2)N 118.1(1) L P(C12)NP(C12) 120.4(3) mean L P(C12)NP(S2) 121.1(2) (NPC12)2NP(2-S-4,6-dimethylpyrimidiny1)2 in segment P(C12)NP(C12) 95 mean NP(C12) 157.0(3) in segment P(C12)NP(S2) mean NP(Cl2) 156.3(4) mean NP(S2) 159.1(3) mean L NP(C12)N 119.6(3) LNP(S2)N 116.1(2) L P(C12)NP(C12) 120.0(2) mean L P(C12)NP(S2) 122.4(1) in segment PNP 96 (NPC12)2NS(O)CH2CHC12 mean NP 156.9(2) in segment PNS mean NP 158.3(2) mean NS 156.5(2) L NPN 117.2(l), 117.9(1) L NSN 1 1 4 31) LPNP 121.2(2) L PNS 123.5(2), 124.4(2) in segment PNP 96 (NPCl&NS(O)OEt mean NP 156(1) in segment PNS mean NP 157.2(7) mean NS 156(1) mean L NPN 117.0(4) L NSN 114.5(5) L PNP 122.5(6)
282
(NCNEt2)2NP[OCH2(CF2)2CH20]
(NCNPrn2)2NP[OCH2(CF2)2CH20] NCNEt2 { NP[OCH2(CF2)2CH20])2
NCNPrn2(NPC12)2
(NCOPh)*NP[OCH2(CF2)2CH20] (NCSC6H4F-4)2NP[OCH2(CF2)2CH20] (NCNMe&NP[OCH2( CF2)2CH20] (NCNM~~)~NP[OCHZ(CF~)~CH~O]
(43)
Organophosphorus Chemistry
mean L PNS 124.4(5) mean NP 158.6(1) 97 L NPN 115.6( 1) mean NP 158.1(2) 97 LNPN 115.6(2) N(C)P 157.2(3), NP 158.4(2) 97 L NPN 118.8(l), L PNP 114.0(2) mean NP 159.8(2) 97 mean LNPN 118.8(2), LPNP 113.8(2) mean N(C)P 157.3(1) 97 mean NP 159.0(2) L NPN 1 1 8 3l), 119.3(1) LPNP 113.7(1) NP 158.4(2), N(H)P 165.5(2) 97 L NPN 106.6(1) mean NP 159.6(2) 97 L NPN 112.2(1) mean NP 161.0(1) 97 LNPN 111.7(1) NP 156.1(4)-160.9(4) 97 mean L NPN 1I6.9(3) LPNP 116.3(3) mean NP 158.8(3) 97 L NPN 114.2(2) mean NP 159.2(3) 97 L NPN 112.8(2) mean NP 157.5(4) 97 L NPN 115.0(2) mean NP 157.8(3) 97 L NPN 116.6(1) endocycl.: 98 mean NP 158.3(2) mean N(V)P 166.6(2) mean L NPN 111.4(3) L PNP 129.2(2) exocycl.: NP 162.7(3)-164.3(3) endocycl.: 98 mean NP 158.0(1) N(Mo)P 166.3(2), 168.1(2) L NPN 109.1(l), 109.6(1) LPNP 131.7(1)
283
7: Phosphazenes
(47)
fcP(S)N=C(NMe2)SC(NMe2)N fc = ferrocenyl fcP(S)N(Ph)P(S)(fc)S
exocycl.: NP 161.8(2)-163.4(2) two indep. mol. in the unit cell 102 in segment P(C12)NPC12 mean NP(C12) 158.6(3) in segment P(Clz)NP(org) mean NP(C12) 156.0(2) mean NP(org) 161.5(3) mean L NP(org)N 115.3(2) mean L NP(C12)N 119.9( 1) L P(CLJNP(C12) 119.7(3) L P(C12)NP( org) 122.4(2) in segment P(C12)NPC12 102 mean NP(C12) 157.9(2) in segment P(Clz)NP(org) mean NP(C12) 154.9(2) mean NP(org) 162.1(2) LNP(org)N 115.3(2) mean L NP(C12)N 120.0(1) L P(C12)NP(C12) 119.7(2) mean L P(Clz)NP(org) 122.0(3) NP 156.5(2)-162.7(2) 102 LNPN 114.0(1)-121.2(1) LPNP 113.8(1)-119.1(1) in segment P(C12)NP (Cl2) 124 mean NP 158.7(5) in segment P(C12)NP(spiro) NP 154.5(7)-163.6(9) mean L NP(C12)N 119.3(6) L NP(spiro)N 113.1( 1) mean L P(C12)NP(spiro) 123.8(9) L P(C12)NP(C12) 117.8(2) exocycl. NP 162.5(2) NP 164.8(6), 166.4(4) 125 LNPN 108.2(2) NP 170.4(5) 125 LPNP 104.5(4) NP 167.5(5) 125 L PNP 105.3(5) mean NP 161.1(5) 126 LPNP 111.3(2)
I
fcP(S)N(cycl-Hex)P(S)(fc)S
[Ph2PCH2CH2P(Ph2)N]+Br -
284
Organophosphorus Chemistry
(PriN)2PNC(0)C(cycl-HexNH)CC02Me
endocycl. NP 161.8(3) exocycl. mean NP
127
164.5(5)
References 1
2 3 4 5 6 7
8
9 10 11
12 13
14 15 16
17 18 19 20 21 22 23 24
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151 152 153 154 155
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8
Physical Methods BY R.N. SLINN AND M.C. SALT
While Section 1 contains theoretical studies of general interest, studies relating to specific physical methods will be found in the appropriate section as in Volume 29. Compounds in each subsection are usually dealt with in the order of increasing coordination number of phosphorus. In formulae, the letter R normally represents hydrogen, alkyl or aryl, while X represents an electronegative substituent, Ch represents a chalcogenide (usually oxygen or sulfur) and Y and 2 are used to represent groups of a more varied nature. 1
Theoretical and Molecular Modelling Studies
1.1 Studies Based on Semiempirical Methods - A number of semiempirical methods have been evaluated and compared in the structural analysis of some h3-heterobenzenes.’ The authors found that whilst MNDO gave the best geometry for benzene and pyridine, MIND0/3 gave the best geometry for phosphabenzene, and PM3 calculations gave the best geometries for arsa-, stiba-, and bisma-benzene. The semiempirical (PM3) charge densities have been approximated for eight new 2-phosphaindolizines (1, R’ = H, Me, R2=COBut, C02Me, COPh, CN, R 3 = H , Et), and shown to correlate approximately with their 31PNMR chemical shifts2 R’
(1)
k2
Semiempirical PM3 and AM1 methods have been applied in the structural analysis of a series of trialkyl phosphine oxide, sulfides, selenides and tellurides Alk3P=X (X=O, S, Se and Te).3 The results were found to be in reasonable agreement with X-ray crystallographic and gas phase electron diffraction data. The polarity of the P=X bonds was determined within the framework of the vectorial additive scheme, where experimental data was based on dipole moments of the compounds, and various basis sets of geometric parameters of Organophosphorus Chemistry, Volume 30 0The Royal Society of Chemistry, 2000
29 1
292
Organophosphorus Chemistry
the molecules. It was found that the P=X bond moment increases across the series (X = 0, S, Se and Te) owing to increasing length of the dipole. 1.2 Studies Based on Ab Znitio and Density Functional Methods - The structure of a diphosphaallene radical anion (2) (ArP=C=PAr)’- ,produced by the electrochemical reduction of 1,3-diphosphaallene, was investigated by a The structure of the parent combination of ESR and molecular rn~delling.~ neutral diphosphaallene, optimised by semiempirical AM 1 calculations, was found to be in close agreement with that determined by X-ray crystallography; however, when an electron is added to the allenic system, the molecule did not retain the geometry of the neutral molecule. A previous semiempirical (AMl) investigation, by the same authors, suggested that the radical cation, (HP=C=PH)’+ adopted a ‘trans’ and ‘cis’ like conformation, 0.3 kcal mol-’ in favour of the trans conformation; see Scheme 1 .596
Bu,‘
But
P=C=P,
“6.
+ 0.3 kcal mar'
‘Trans’ like
Scheme 1
‘Cis‘ like
Preliminary semiempirical (AM 1) analysis of the radical anion suggested that the rotation barrier about the P. - .P axis decreased from 33 kcal mol- in the neutral system to ca. 5 kcal mol-’ in the radical anion. However, due to limitations of the semiempirical model, DFT and ab initio methods were applied to the simplified model fragment (HP=C=PH)’-. A number of ab initio basis sets were also evaluated and their various merits discussed in some detail. The assignment of the conformational preference for the radical anion was based on comparison of the calculated coupling constants for the ‘trans’ and ‘cis’ like structures of the model fragment (HP=C=PH)’-, with those obtained experimentally. The authors conclude that the electrochemical reduction of the diphosphallene produces a slightly asymmetric ‘trans’ like radical cation, which rapidly interconverts between two equivalent structures. Ab initio (SCF, CAASCF, MP2, CI) and density functional (B3LYP) calculations with various basis sets have been applied in the structural analysis of the triplet ground state HCCP radical, all of which predict a linear ~ t r u c t u r eAb . ~ initio
8: Physical Methods
293
NMR calculations have recently been applied to the correlation of phosphorus shielding in a number of phosphine oxides, the results of which clearly suggest the absence of conventional multiple bonding in the phosphoryl bond.8 Atoms-in-molecule studies, yielding AIM-based localised MOs, indicate one highly polarised 0 bond plus strong backbonding of the oxygen n orbitals, a picture consistent with a number of prior investigations. It is suggested that whilst the high strength of the phosphoryl bond in phosphine oxides is highlighted well by the R3P:0 formula, the present study indicates that the electronic situation is better pictured as R3P+-O-. The structures, energies and natural atomic charges of three different conformations of 2-dimethylaminophenol N-oxide (3) and 2-dimethylphosphinylphenol(4),were computed at the ab initio MP2/6-31G* level.9 The authors suggested that the computed natural charges (approximately 0 on nitrogen and +2 on phosphorus) are quite different from that normally assumed in the usual representation of the formal charges in the compounds. In addition, the oxygen is considerably more electronegative in the phosphoryl group, than in the amine oxide. It was concluded that in the calculation of charges, electronegativity differences play a larger role than formal charges, and that, despite the more electronegative oxygen in the phosphine oxides, amine oxides are computed to be considerably more basic when participating in hydrogen bonding.
Ab initio methods have been applied to the analysis of hydrogen bonding in the complex between imidazole and 5,5-dimethyl-1,3,2-dioxaphosphorinane-2thiono-2-hydroxyacid (5).1° GIAO calculations at the HF/6-3 11+G(2d,p)// B3LYP/6-31G* level revealed correlations between I3C chemical shift differences and the N- - .H+ distance, which could be related to the strength of the H bonds and localisation of the proton within the various hydrogen bonded systems. Structural changes occurring during the interaction of PFS and pyridine have recently been modelled by ab initio methods.'" Results suggest that as pyridine enters the coordination sphere, the initial trigonal bipyramid of PFS isomerises to a square pyramid before forming an octahedron. The calculated reaction trajectory mimics that found for sulfur donors in cyclic pentaoxy phosphoranes where X-ray studies show a range of geometries with increasing octahedral character (from the square pyramid) as the P-S interaction increases. The authors suggest that inclusion of the donor atom as part of a cyclic system does not control the observed geometrical changes upon going from five- to six-coordinate phosphorus. The resistance of borophosphate nucleotides to digestion by nuclease enzymes has been investigated by a combination of X-ray crystallography and ab initio methods. ** The structures
Organophosphorus Chemistry
294
of dimethyl boranophosphate and its diisopropylammonium salt were established by single crystal X-ray diffraction, the results of which were compared with their ab initio structures, and the following conclusions drawn. Firstly, substitution of a BH3 group for oxygen in a phosphate or phosphite ester results in an increase in bond length for that group with minimal change in the remaining structure; bond polarisation towards the group is also significantly diminished. Constraints derived from ab initio calculations at the CISD(c)/ 6-31G** level, have been used in determining the gas phase electron diffraction structure of chloromethylphosphine. Two main conformers were observed in which the chlorine atom is either anti or gauche, relative to the phosphorus lone pair; see Scheme 2. Large differences in the PCCl angles for each of the conformers was rationalised by consideration of overlap between the nonbonding and antibonding orbitals.
Scheme 2
The structure of hexamethylphosphorustriamide has been reinvestigated by gas-phase electron diffraction utilising the results of ab initio MO calculations at the RHF/6-31G* 1 e ~ e l . The l ~ best structural fit involved a tetrahedral phosphorus in which two of the nitrogen lone pairs are orthogonal, whilst the remaining nitrogen lone pair is antiparallel to the phosphorus lone pair (6).
2
Nuclear Magnetic Resonance Spectroscopy
2.1 Biological and Analytical Applications - Recently authors have described the synthesis of a series of nitrobenzyl-based photosensitive phosphoramide mustards as potential prodrugs for cancer therapy.15 31P NMR and UV spectroscopy were used in order to study the liberation of the phosphoramide mustards upon irradiation with mercury arc lamps. The compounds (7, R' = H, R2= CO2Na; R1= CH2CH2CH20H, R2 = CH2NH3+ClA) derived from secondary benzyl alcohols were the most promising prodrug candidates. A new series of iron(111) complexes with phosphate-EDTA-polyglycol terpolymers have been prepared and evaluated as MRI imaging agents.16 The new compounds were shown by longitudinal relaxation measurements to perform better than Fe(II1)-EDTA. No obvious, acute toxicity was observed
295
8: Physical Methods
with one of the compounds tested. The Tl-weighted contrast imaging of rat liver showed clear MRI enhancement after injection of the new complex. The protonation behaviour of a new novel hexaaza macrocycle (8), with four methylene phosphonate pendant arms, has been followed by 31Pand ‘H NMR spectroscopy; it was found to behave rather like the corresponding macrocyclic amine.
0I
HO (9)
The conformational and stereochemical aspects of a conformationally restricted analogue of the second messenger inositol 1,4,5-trisphosphate (Ino( 1,4,5)P3) has been evaluated by 31PNMR, together with potentiometric techniques, over a pH range of 2-12. Within the physioliogical pH range the bicyclic phosphate (9) behaves as a diprotic acid.
2.2 Applications of 31PNMR Chemical Shifts and Shielding Effects - Positive chemical shifts, 631p, are downfield of the external reference 85% phosphoric acid, and are usually given without the appellation ppm. This year, a 37 reference review has been published on the 31P NMR chemical shifts of diphosphenes which have been shown to vary from 192 ppm for diphosphenes with an ylide substituent through to 816 ppm for disilyl diphosphines.l 8 2.2. I One-coordinate compounds - The reaction between [Ru&-H)(p-
NC5H4)(CO)lo]and chlorodiphenylphosphine followed by metathesis with bis(triphenylphosphorany1dene)ammonium chloride ([PPNICI), affords [PPN][RU8(C18-P)(C0)22],which gives 31P NMR signals at 600-800 ppm, consistent with the presence of at least two isomers of interstitial phosphorus within the cluster anion.l9 Single crystal X-ray crystallography of one isomer showed that the phosphorus occupies a square antiprismatic site defined by
296
Organophosphorus Chemistry
eight ruthenium atoms. The solid state 31PNMR resonance occurs at 596.1 ppm, and is assigned to the square antiprismatic interstitial phosphorus atom.
2.2.2 Two-coordinate compounds - A satisfactory method has been developed for estimating the phosphorus chemical shifts for a series of dicoordinated phosphenium cations.20 A simple relation is observed between the calculated atomic charges of the related atoms, the Wiberg bond orders, and bond angles for the immediately bonded substituents. The agreement of these calculated experimental results with the experimental data validated the use of this method for the prediction of phosphorus chemical shifts for dicoordinated phosphenium cations. Phosphaallene type compounds are mentioned for the second time this year, where the authors report the low field chemical shifts of 6p +159.7ppm and 6c +299.8 ppm, which are in accordance with the arsaphosphaallene structure 'H NMR has also been applied to investigate the rotational barrier about the aryl bond.
BuLi Low temp.
'But
2.2.3 Three-coordinate compounds - A review with 46 references covers the application of NOE and 2-D NMR spectroscopy to structural and dynamic problems encountered in chiral organometallic phosphine complexes.22The authors conclude that the method, which is based on correlation spectroscopy, is both versatile and potent. Recently, authors have investigated the effect of simple first row substituents ( Y = F , OH, NH2, CH3, BH2, BeH, Li and H) upon the 31P NMR chemical shifts of tricoordinate PX2Y molecules.23The chemical shifts were computed by ab initio methods (GIAO/6-3 11+G**// RMP2(fc)/6-31+G*) and evaluated by 31PNMR. The normal downfield correlation of 31P NMR chemical shift with increasing sum of substituent electronegativities (C EN) was substantiated for experimentally important molecules by the ab initio results. However, a reverse trend was observed where X = F, and was attributed to negative hyperconjugation. The reverse trend was also observed when X = OH and Y comprises electronegative substituents, however a normal trend was observed when Y was less electronegative. The best correlation between tip and E EN was found for monosubstituted
297
8: Physical Methods
phosphines PH2Y ( r = 0.955). The slopes of plots of 6p versus E EN, i.e. the sensitivity of tip to electronic effects for PX2Y molecules, ranges from 162 (X=BeH), 141 ( X = H ) and 98 (X=CH3 and BH2) to -105 (X=F). The authors also discuss some of the limitations of the relationship. A Si02 supported rhodium-phosphine complex catalyst for propene hydroformylation has been analysed by 31PNMR spectroscopy, before use, after 4 hours of use, then after 90 hours of use.24 Experimental results showed that, whilst the free complex in benzene [Rh(CO)H(PPh3)3] had a sharp signal at 41.1 ppm, the same complex supported on silica had a broader signal at 37.0 ppm, which was thought to originate largely from the interaction of the rhodium-phosphine complex with silica. After 4 hours of propene hydroformylation, the same analysis revealed that a rhodium-diphosphine complex was the dominant species at the surface, which implied that an intermediate containing two carbonyl or carbonyl/acyl ligands, was present. Peaks at 0.7 ppm were assigned to triphenylphoshine dissociated from the phosphine complex. After 90 hours of use, no rhodium-phosphine complex could be detected by 31PNMR, and the main phosphorus component in the spectra was phosphine oxide dissociated from the complex. The authors therefore concluded that dissociation and oxidation of the phosphine ligands from the rhodium complex was the main reason for deactivation of the catalyst. 31PNMR spectroscopy and X-ray crystallography have been applied in stereochemical analysis of the photoArbuzov rearrangements of benzylic p h o ~ p h i t e sIrradiation .~~ of the trans-(Rl R') phosphite (ll), in acetonitrile with UV light at 254 nm, resulted in rearrangement with predominant retention of configuration to give two diastereomers (80:20 ratio) of the cis phosphonate (12). The major isomer was isolated and shown by X-ray crystallography to be cis-(R,R'), whereas the minor product was identified (on the basis of 31P NMR) as the other diastereomer, cis-(R,27). The trans/cis ratios of the starting phosphite and product phosphonate are unchanged in the photorearrangement. The results are consistent with generation of an intermediate phosphinoyl radical that is configurationally stable at phosphorus. Ph
The production of phenyldichlorophosphine from the reaction between the AlC13-PC13 complex and benzene has been monitored by 31P NMR spectros c ~ p yThe . ~ ~authors observed three types of intermediate (within the NMR time scale), and based on the new evidence propose a new reaction mechanism. The weak ligand field affinities of a number phosphorus compounds have been approximated by 31PNMR spectro~copy.~~ The 31PNMR shifts arising from the interaction of triphenylphosphine, trimethyl phosphite and trimethyl
298
Organophosphorus Chemistry
phosphate with alkali metal fluorenone radical anions in THF solutions were determined and shown to depend significantly upon the cation for a given ligand, and the ligand for a given cation. The parameters were used to extend the corresponding 31Pcontact shifts, &(M), and are proposed as a measure of ligand affinity of a given phosphorus compound for a particular alkali metal. Trimethyl phosphate was shown to have the greater affinity for the lithium cation. The authors discuss the ionic/covalent nature between the cations and the radical anion. A combination of variable temperature 1-D 31PNMR spectroscopy, 31P-{lH}, and two dimensional [31P-31P] COSY and [31P-209Ag] HMQC NMR experiments has been applied to the structural analysis of a number of 1:2 silver nitrate adducts with bidentate 2-, 3- and 4-pyridyl phosphines.28The mode of bonding was shown to be solvent and temperature dependent. The complexes have potential significance in antitumour therapy. The mode of bonding of 2-(dipheny1phosphine)pyridine (dppy) in silver(1) complexes [Ag(dppy),]ClOs has been studied by variable temperature 'P NMR.29 The stepwise formation of the products (n= 1, 2, 3 and 4), was monitored by 31P NMR, and was effected by the addition of increasing amounts of dppy . The formation of a transition metal disubstituted diphosphene was monitored by 31P{1H}NMR spectroscopy which suggests formation of an intermediate (trans-l ,2-dihydro-l -dicarbonyl-$-pentamethylcyclopentadienylferrio)-2-(2,4,6-tri-tert-butylphenyl)-4-diisopropylamino1,2,3triphosphete) which, in solution, undergoes slow isomerism to the final product (13).30
The structures of 4'-diphenylphosphino and bromo derivatives of 10-phenyl1,4,7-trithia-lO-azacyclododecane (14) have been studied by X-ray methods, in which the nitrogen atom is nearly planar for both structures. In the case of the phosphine, a 31Psignal is observed at -7.3 ppm, which is considered to be indicative of a structure involving a planar nitrogen atom. 2.2.4 Four-coordinate compounds - A new phosphorus tin cage molecule (15), containing an extremely shielded 31Pnucleus, with chemical shift 8p - 554.65 ppm for the apical phosphorus atoms, has been ~ynthesised.~~ The authors
299
8: Physical Methods
discuss the 117’119Sn and 31Pchemical shifts and coupling constants in terms of the structure. Quantum mechanical ab initio calculations, for 31PNMR shielding parameters, at the MP2 level of theory have recently been performed on the neutral and singly charged 7-phosphabicyclo[2.2.l]-heptane,-heptene, and -heptadiene neutral, cationic and anionic molecules using a P:tz2p/C:tzp/H:dz locally dense basis set.32 In the anionic systems containing two lone pairs, drastically reduced HOMO-LUMO energy gaps and correspondingly large deshielding effects are observed. The absolute isotropic shielding of &-756.6 ppm (6 + 085.0 calculated) for the anionic diene is by far the largest downfield shielding predicted for phosphorus in a conventional organophosphorus compound. A recent investigation demonstrated a correlation between the ‘P NMR chemical shifts for a number of substituted phosphoric and thiophosphoric acid derivatives, using inductive (r* substituent constants, P=O bond orders, and charge densities on phosphorus and oxygen.33The authors also relate these parameters to infrared data of the phosphoryl bond. A similar investigation involved recording the 31P NMR spectra of around 80 thiophosphates, followed by the development of a semiempirical additivity equation for calculating the chemical shifts. The equation was based on a number of stereoelectronic and chemical shift parameters, and can be used to predict 6p more accurately.34 The dependence of chemical shift on electronegativity, bond angles and stereoeletronic effects was also discussed. The cage chirality of the bicyclic a- or p-P4S312 has been investigated by 31P NMR analysis. Diastereoisomers were obtained by their reaction with PhC*H(NH2)(Me), leading to products with one or two exocyclic amide substituents, or cage structures containing a bridging imide Four 31PNMR resonances were observed for each of the P atoms in the products. The authors suggest that comparison of the number of diastereoisomers observed by NMR with that predicted is a useful extra tool for the identification of non-separated new compounds. Solid state IR analysis of a series of phosphonium compounds revealed the presence of a mixture of both ionic and covalently bound cyanide.36 The 31P NMR spectra of a CDC13 solution showed that the structure comprises 90% covalently bound (16) and 10% ionically bound cyanide (17). The authors discuss the bonding and structure of these novel compounds with reference to some analogous structures, studied previously. XR\ R;Pt-CmN R
90%
(1 6)
-CN R\ R-,Pt-X R 10% (17)
Recently some new 2-(phosphonioaryl)imidazolidebetaines have been ~ynthesised.~~ Detailed ‘H, I3C and 31P NMR analysis of 2-(tributylphosphoniopheny1)benzimidazolidesrevealed significant differences in some of the spectroscopic parameters of the betaines compared with the phosphonium salts
300
Organophosphorus Chemistry
from which they are derived. The H transfer process for adducts (18) between tris(trimethoxypheny1)phosphine oxide and eight differently substituted phenols has been studied by solution and solid state 'H and 31P NMR spectro~copy.~~ The 'H NMR signal of the hydrogen bonded phenol proton underwent a downfield shift with increasing acidity of the corresponding phenol, as did the 31PNMR signal in the phosphine oxide. However, for highly acidic phenols such as picric acid, an upfield shift is then observed, which was attributed to increased shielding produced by the protonated phosphoryl oxygen atom. CPMAS 13C and 31PNMR experiments, which follow a similar pattern, suggest that the H transfer process might also occur in the solid state. Ph3P=O- -H-0-Ar (18)
Two new derivatising agents, N-[(S)-a-phenylethyl] substituted P-chloro1,3-diazaphospholidines derived from C2-symmetrical truns- 1,2-diaminocyclohexanes, have been applied to the determination of enantiomeric purities of chiral alcohols using 31PNMR spectro~copy.~~ The sequence distribution of a series of phosphorus containing polyesters [poly(ethylene terephthalate), poly(hydroquinone phenyl phosphonate), poly[bis(4-hydroxyphenyl)su1fone phenylphosphonate], and poly[bis(4-hydroxyphenyl)sulfone methylphosphonate] has been established by 31Pand 'H NMR s p e c t r o s ~ o p y31P, . ~ ~ 'H, I3C and 29SiNMR spectroscopy has been applied to the characterisation of a number of bis(organoamino)-diorganophosphonium bromides ( 19) and iminophosphinic acid amides (20), examples of which are shown below.41
Potentiometric methods and 31PNMR titrations have been compared in the evaluation of dissociation constants for a number of (a-hydroxyalky1)phosphonic acids amphiphiles (21, R=CH3(CH2),, n = 6 , 8, 10, 12).42 Both methods gave similar dissociation constants and the phosphinic acids were shown to be slightly stronger than the corresponding phosphonic acids. Six phosphorus triamides, in which the amide nitrogens have been incorporated into an increasing number of 1,3,2-diazaphospholidin-2-0nerings, were prepared and their 31PNMR spectra recorded.43 X-ray analysis shows that traversing the series of mono-, di-, and tri-cyclic systems (22)-(24) results in a decrease in the N-P-N bond angles, whilst the N-P bond length increases. The authors discuss the relationship of ijP with structure, degree of phosphorus hybridisation, and P-N bond order. 2.2.5 Five-coordinate compounds - The structures of a number of triorganophosphorus dichloride compounds were studied by 31P-{'H} NMR in CDC13
8: Physical Methods
30 1
solution, and shown to exist in the ionic form (25).44 Conversely, when the R groups contain pentafluorobenzene, the structures become trigonal bipyramidal, (26) and (27). The authors discuss these findings and the crystal structures of chloro(trispropy1)phosphonium chlorides, which comprise two crystalline entities. R, R-,P+-CI R
(25) R = mixed substituted aryl mixed aryl-alkyl or triaryl
CI F5c6 \ I F5C6' I c6F5 CI
'
(26)
CI Ph, I phflyTc6F5 CI
(27)
Distorted trigonal bipyramidal structure
A combination of 31P, 13C, 'H and *H/13CHECTOR NMR experiments have been applied to the analysis of the configuration of phosphorus in the single epimer produced in the stereoselective synthesis of a number of new tricyclophosphoranes from chiral auxiliaries (28).45 The assignment was confirmed by the X-ray diffraction analysis of the structure.
The room temperature reduction of Ph4P+Br- by LiAlD(H)4 has been monitored by 31PNMR spectroscopy, which initially shows conversion of the phosphonium salt to the monohydrophosphorane P h a H , followed by reduction to the dihydrophosphoranate anion [Ph4PH2]- , which finally decomposes to the dihydrophosphorane Ph3PH2.&31Pand 19FNMR has also been applied in the analysis of the reduction of phosphorus pentafluoride with phosphorodichloridic acid, where two products were 0bserved.4~The reaction of PFS with the silyl ester, Me3SiOPOC12, only occurs in the presence of small amounts of acetone to give [PF50POC12]-; see Scheme 3. 2.2.6 Six coordinate compounds - A new series of phosphonium salts, (29) and (30), with potential for hexacoordination, have been studied by NMR spectro-
302 PF5
+
Organophosphorus Chemistry
-
HP0&
[PF5OPOC12]-
PF5 + Me3SiOPOC12
trace of
acetone
+
[PF5OPC12OPF5]-
[PF5OPOC12]-
Scheme 3
Me
Me
/
\
scopy, and the magnitude of the 31PNMR chemical shift was shown to be related to the degree of coordination at p h o s p h o r ~ s . ~ ~ X-ray diffraction analysis has been used to assess the structures and degree of hexa- versus penta-coordination in a series of bicyclic tetraoxyphosp h ~ r a n e sThe . ~ ~ring constraints were also evaluated in order to give an order of conformational flexibility associated with the trigonal bipyramidal tetraoxyphosphoranes (34) > (33) (31) > (32) which paralleled the degree of shielding in the 31PN M R spectra, i.e. (34) > (33) (31) > (32). X-ray analysis also revealed that strucure (35) was hexacoordinate, via a P-S interaction. The barriers to rotation about the xylyl group were evaluated by variable temperature ‘H NMR.
-
-
Me
.Me
303
8: Physical Methods
A number of cyclic pentaoxyphosphoranes containing a sulfonyl group have been synthesised by the oxidative addition of a bis phenol to either P(OCH2CF3)3or P(OPh)3.50X-ray analysis showed that two of the parent compounds were octahedral, (36) and (37), whilst two, (38) and (39), were trigonal bipyramidal. 31PNMR analysis showed that in solution two of the solid state pentacoordinate compounds adopt hexacoordinate structures, an example of which is shown below, (38), (39). Variable temperature 'H NMR spectroscopy was applied in order to calculate an activation free energy of 17 kcal mol- I for this process.
(36) R = Me (37) R = Bu'
17 kcal mol-'
(solution)
(38)R = Me (39)R = Bu'
2.2.7 Other NucleilMultinuclearlGeneral N M R - It has been recently demonstrated that the 15NNMR chemical shifts, but not the ' J p N coupling constants, give a good indication as to the relative basicities of nitrogens in phosphoramidates, as demonstrated by the rates of acid-catalysed cleavage of the exoand endo-cyclic P-N bond in selected substrate^.^^
2.3 Studies of Equilibria, Configuration and Conformation - The conformational preferences of 2-aryl-2-oxo-4,6-dimethyl-and 4-methyl- l ,3,2h5-dioxaphosphorinane, have been investigated by a combination of IR, 'H, I3C and 31PNMR spectroscopy, in order to search for the existence of high energy boat or twist boat conformations in the equatorial e p i r n e r ~The . ~ ~difference in : ~ the axial and equatorial compounds, and infrared frequencies ( A V ) ~ between the magnitude of the Jpocc and anti J m C C H 3 values, as evaluated by 13C NMR, suggested the existence of these isomers. The lack of a large 3 J p H in the
304
Organophosphorus Chemistry
31PNMR spectra, for the equatorial isomer, was consistent with a predominantly chair conformation. X-ray analysis of a number of related compounds (e.g. 2-p-nitrophenoxy-2-oxo-cis-4,6-dimethyl1,3,2-dioxaphosphorinane) all showed predominantly chair conformations with various degrees of mild ring flattening being present in the OPO region. The authors discuss the application of solid state CPMAS 13C and 31PNMR analysis of some of the compounds. Recently, workers have recorded the I5N NMR spectra of both P(2) diastereoisomers of a trans fused bis(2-chloroethyl)aminooctahydro-1 ,3,2h5-benzoxaphosphinin-2-one (40, R = H ) and two further derivatives (40, R = M e or CH2Ph).53The coupling constants ' J 1 5 N 3 1 were found to be highly dependent on the configuration at phosphorus. The possibilities of utilising the exocyclic nitrogen and phosphorus couplings as a tool for determining the conformation of the hetero ring system, are also discussed.
In a separate publication, the same authors apply 'H, 13C 31Pand variable temperature NMR methods to the conformational analysis of cis- and transfused 2-[bis(2-chloroethyl)amino]-3,4,4a,5,6,7,8,8a-octahydro1,3,2-benzoxazaphosphorinane-2-oxidesand their 3-methyl and 3-benzyl derivative^.^^ For the trans fused isomers, an equilibrium between chair-chair and chair-twistboat conformations was found to be dependent on the P-2 configuration, whilst the chair-twist-boat conformation was increasingly favoured with substitution at N-3 in the order Me > benzyl > H. The reaction of pyridyl-2phosphonyl dichloride with 1 -phenyl-2,2-dimethylpropane1,3-diol gives two epimers which could be distinguished by their 31PNMR spectra.55X-ray and NMR analysis of one epimer of the parent compound and the N oxide, plus the thiophosphonate derivatives (NMR analysis only), all show an unusual conformation where the pyridyl group is axial to phosphorus with the nitrogen atom being directed between the two oxygen atoms of the six-membered ring, (41), (42). Conversely, NMR experiments suggest that the analogous N-Me pyridinium salt (43) and a borane adduct have structures where the nitrogen atom is not located between the two oxygen atoms. RHF geometry calculations were in accordance with the experimental observations and provided an insight into the underlying reasons for the unusual conformational behaviour.
305
8: Physical Methods
A recent study utilised X-ray crystallography and IR and NMR spectroscopy, to compare the solution and solid state hydrogen bonding and conformational preferences for five (2-hydroxyalky1)phosphoryl compounds (44, (a) R'=MeO, R2=Ph; (b) R 1 = R 2 = P h ; (c) R'=Ph, R2=But; (d) R' = Me, R2 = Ph; (e) R' = Me, R2= But).56The authors found that although there was conflicting X-ray and IR evidence concerning the equivalence of H-bonding in the dimeric structure of (44),the overall trend was. an equilibrium between monomers and dimers, which became extensively shifted towards intramolecular H-bonded monomers, when R' and R2 were bulky. The conformational preferences were dominated by steric factors and little influenced by changes in H-bonding or donation of electrons from the hydroxyl oxygen to vacant orbitals of the phosphorus atom. A distortion of 4-12' from the usually perfectly staggered geometry was noted for two of the compounds. A b initio (HF/6-31G*//HF/3-2 1G- *)) and molecular mechanic solvation studies were used to explain the NMR shift trends of the a-methylene protons and the phosphorus nucleus.
R
H?'
2.4 SpinSpin Couplings - The successive reaction of lithio-4,6-di-t-butylphenolates with ClP(NMe2)2 and ClSiMe3 gave a diastereoisomeric mixture of the diphosphine (45) as the main reaction product.57 Investigation by 3 1 P NMR revealed large through space couplings of 4Jpp= 152 and 237.5 Hz for the diastereoisomers.
The structure of the complex (CH~)~ASC(CF~)=AS(CH~)~W(CO)~I P(OC6H5)3 was investigated by variable temperature X-ray diffraction analysis, and was shown to be stereochemically non-rigid at 298 K.58Analysis of the 13C NMR chemical shifts and the 2J13C31p coupling constants provided important structural information for the assignment of the seven coordinate geometry. The NMR spectra were recorded for a series of eight phosphoric amides, and the mechanism of geminal 2 J 3 1 p13c couplings was i n ~ e s t i g a t e d . ~ ~ The findings suggested that, for the ring systems studied, the coupling constants were dominated by the two bond, rather that the three bond
Organophosphorus Chemistry
306
mechanism, and that the couplings were strongly influenced by the atom located between the coupled nuclei. Recently cyclotetraphosphine and a bis(ylidy1)bicyclotetraphosphine have been synthesised and their 31P NMR spectra recorded.60 Both structures allow a strong transannular interaction between the ylide substituted phosphorus atoms, resulting in large couplings of 2Jpp = 184 and 332 Hz respectively. Correlations between the atomic hybridisation, the net charges and the lJ13C13c and 1J13c31p coupling constants have been observed.6' The authors have extended this study to provide a tool for the prediction of coupling constants based on the parameters obtained from MNDO and EHMO calculations. The relationship between l J p t p and the Hammett substituent constants for a wide range of platinum complexes involving substituted aryl phosphine and phosphite ligands (46) has been evaluated. The ligands ranged from 'electron releasing' such as Me2N- to 'electron accepting' such as F3C- in platinum(I1) and platinum(0) In the platinum(I1) complexes, the magnitude of the coupling constants increased with increasingly electron-releasing substituents. However, in the case of platinum(0) complexes the reverse trend was observed, i.e. the magnitude of the coupling constants decreased with increasingly electronreleasing substituents. The authors rationalise these observations in terms of the CJ- and x-bonding components of the platinum-phosphorus bonds. CI,
,Cl R
R
31Pand 15N NMR spectroscopy have been applied to the analysis of P-N bonding in a series of closely related cyclic and non-cyclic phosphor amid ate^.^^ Correlations between the bond angles at nitrogen with the 'J31plSN coupling constants and ijIsN were observed. The latter chemical shift could be used to distinguish between the exo- and endo-cyclic nitrogen atoms, in a similar manner to work by other authors.53 A linear relationship between the 31P NMR chemical shift and coupling constants with the degree of substitution for a series of cyclotriphosphazenes (47) has recently been demonstrated.@
(48) Ar
=
C6H@ut3-2,4,6
8: Physical Methods
3
307
Electron Paramagnetic (Spin) Resonance Spectroscopy
The EPR spectra of phosphafulvene radical anions, formed by electrochemical reduction of (48), have been recorded between 110 K and room temperature and the g and 31P hyperfine tensors measured and compared to those previously obtained for a phosphaalkene radical anion.65 Ab initio studies on model phosphaalkene and phosphafulvene radical anions, in agreement with experimental results, indicate that the electronic structures of these two species are quite different. Whereas the unpaired electron is delocalised on the whole P:C(H)R moiety in the phosphaalkene anion, it is markedly localised on the P atom in the phosphafulvene anion. A single-crystal EPR study of the diphenyldibenzobarralene-phosphinyl radical (49), generated from radiolysis of the parent primary phosphine, illustrates hindered rotation of the P-H group around the C-P bond.66The spectrum of the radical, trapped in a single crystal of the parent, was studied at 77 K and room temperature. The directions of the 31Phyperfine eigenvectors were compared with the bond orientations of the undissociated compound as determined from its crystal structure. Densitymatrix analysis of the temperature dependence of the spectrum showed that interaction between the phosphinyl H atom and one of the adjacent the phenyl Ph rings bound to the C=C bond satisfactorily explains the potential energy profile, and density functional theory (DFT) calculations are consistent with experimental results.
Reactions of styrene and butadiene with the cationic complex [(PPh3)3Ni] BF,=OEt, have been followed by EPR.67 It was shown that the reactions with unsaturated hydrocarbons result in sequential substitution of the phosphino ligands and formation of cationic Ni(1) n-complexes of various composition, the EPR parameters of the latter being determined. It was established that the substitution of two phosphino ligands is followed by the oligomerisation of unsaturated hydrocarbons, during which nickel is retained in the paramagnetic state. The EPR parameters of the paramagnetic complex containing one phosphino ligand were found to be abnormally anisotropic, the origin explained by the fact that the oxidation state of nickel is +3. The role of Cp*TiR+ complexes in syndiospecific styrene polymerisation has been confirmed conclusively using EPR spectroscopy, and furthermore in the reaction of PMe3 with the '3C-enriched complex [CP*T~('~CH~)][RB(C~F~)~; Cp* = CSMe5, R = Me or C6F5] the PMe3 displaces the methylborate anion
308
Organophosphorus Chemistry
from the coordination sphere of the Cp*Til3CH3(pl3CH3)B(C6F5)3 ion pair producing the corresponding phosphine adduct.68 Spin-trapping with nitrones, coupled with the use of EPR spectroscopy, is one of the most effective techniques to observe reactive radical oxygen species (RROS), although the distinction between alkoxyl and alkylperoxyl radicals is not always easy. A major study with three nitrone spin-traps (and three watersoluble azo-radical initiators) concluded that only the corresponding alkoxyl radicals added to the nitrones, with no evidence being found for the alkylperoxyl radical-spin ad duct^.^^ The spin traps 5-(diethoxyphosphoryl)-5-methyl4,5-dihydro-3H-pyrrole N-oxide (50; DEPMPO), and methyl-N-durylnitrone (MDN), made a discriminative spin adduct assignment much easier compared N-oxide ( 5 1; DMPO), where LC-MS to 5,5-dimethyl-4,5-dihydro-3H-pyrrole was required to substantiate the EPR results.
0(50) DEPMPO
0(51) DMPO
Six novel b-phosphorylated nitrones, derived from a-phenyl-N-tert-butylnitrone (PBN), have been evaluated as spin-trapping agents, using them to trap various free radicals in organic or aqueous media and the EPR parameters of the different spin-adducts compared.70 Similarly, a new photochromic spintrap, belonging to the spiro[indoline-naphthoxazine]family (52), has been examined in its reactions with C-, 0-and S-centred radicals.71 Me. Me
HC II X (52) X = N(O)CM%P(O)(OEt)2
EPR and ENDOR (Electron Nuclear Double Resonance) studies of X-irradiated single crystals of deoxycytidine 5’-phosphate monohydrate (5’-dCMP) at 10 and 77 K have partly assigned the signals from distinct radical species.72 The EPR spectra at 10 K exhibit several distinct signals and analysis of the ENDOR spectra from two of the radicals present indicate that these arise from oxidation and reduction of the cytosine base. The fate of these radicals has been studied under controlled warming conditions, and attempts made to relate the fate of the low-temperature radicals with several radicals that have been detected previously at 77 K and at room temperature.
309
8: Physical Methods
4
Vibrational and Rotational Spectroscopy
4.1 Vibrational Spectroscopy - The use of IR spectroscopy (as a complementary technique) in the characterisation of organophosphorus compounds is abundant in the literature and some applications of this have been cited earlier. For example, in the synthesis of thirteen new a-[2-(2,4-dichlorophenoxy) propionyloxy]alkyl phosphonates, their structures have been confirmed using IR, 'H NMR and MS.73A new gas-phase process for the online production of phosphoryl halides POX3 (X = F, Br or I), starting from the chloride, has been devised and the products characterised by the FTIR spectra of their v a p ~ u r s . ~ ~ The low-resolution gas-phase spectra, reported for the first time, show strong bands centred at 1416.6, 1312.9, 1297.9, and 1285 cm-' when X = F, C1, Br, and I respectively. The bands are assigned to vl(al), the P=O stretching vibration. IR spectroscopy has been used to investigate intramolecular interactions in different P-substituted 2-phosphinoyl (axial)-l,3-dithianes (53).75 X-ray structure analysis of some of the compounds reveals unusually short PO-HC distances. Concurrently, in the IR spectra of the crystals of these compounds very intense C-H stretching bands and low wave-number P-O stretching bands have been detected in certain cases. It is concluded that while this does not prove the existence of a normal intramolecular H-bond it does indicate a special interaction between the groups.
R*
(53)R'
*R3
=
Ph, RO;
R2 = H, Me, But; R3 = H, Me
FTIR investigations into hydrogen bonding in sixteen systems comprising dimethylphosphinic acid and a N-base have been carried out. In-depth studies were performed on acetonitrile-chloroform (1:2) solutions and related to the basicity of the N - b a ~ e sThe . ~ ~complexes were measured in the middle- and farIR region of the spectrum at 20 and -40 "C, respectively. It was found that the largest proton polarisability occurred with the system that shows the most symmetrical proton potential, as indicated by the maximum bathochromic shift, in this case for the dimethylphosphinic acid-triallylamine complex. The most intense integrated absorbance of the IR continuum was also observed in this system. Characteristic intensity distribution at the symmetry point indicates medium-strong and relatively long OH - - N O--H+N hydrogen bonds. The proton transfer was studied considering the P-0 stretching bands; the simultaneous observation of the acid as well as acid anion P-0 bands reflect a proton-transfer equilibrium between the non-polar and polar structure, and for the first time it was possible to distinguish between these in the far-IR region.
*
310
Organophosphorus Chemistry
Correlation analysis of IR, 31PNMR and theoretical data for thirty-seven trisubstituted derivatives of the acids and K salts of disubstituted thiophosphoric acids has been performed and both the IR v(P=O) and NMR 831P data correlate significantly with o* substituent constants, P=O bond orders, and 0 and P charge densities.33A study of the bonding situation within the P4O& series (X = 0, S, and Se) has been examined by their geometrical structures and IR spectra.77Experimental data were obtained from pure P408 and P406Se2 crystals and theoretical geometrical structures determined from quantum mechanics. The disubstituted compounds behave in a very similar manner to the monosubstituted molecules in that shifts of the vibrational frequencies result mainly from the differences in the bond strengths of the P=X units and the different masses of the substituents, while the bonding situation within the P406frame remains nearly unchanged within this series. Use of IR and Raman spectroscopy normal coordinate analysis and molecular mechanics to study the conformations of the C12P(O)(CH2)2SCN molecule78and of IR and Raman spectroscopy to confirm the crystal structure of 1,5-bis[2-(diphenylphosphinomethyl)phenoxy]-3-oxapentanehas been described.79 A new type of phosphazene polymer [NP(02C12H& has been examined by IR and Raman spectroscopy.80The IR spectra are dominated by the vibrational modes of the main chain, whereas the Raman spectra are dominated by the vibrations of the peripheral groups. The full width at half maximum of the Raman band at 1609 cm-', corresponding to one of the C-C stretching modes of the biphenyl, decreases with increase in the degree of crystallinity of the polymer sample. Characteristics of 1:1 self-assembly (through hydrogen bonding) of cyclotriphosphazenes and formation of cylindrical structures has been followed using FTIR, X-ray, and elemental analysis.8l FT-Raman studies on new triphenylphosphinecopper(1) triazenido complexes confirm the coordination of deprotonated triazenido ligands to the CU(I)centres.82 4.2 Rotational Spectroscopy - The microwave spectrum of the CH2CP radical in its 2B1 ground state has been detected for the first time using a source-modulated microwave s p e c t r ~ m e t e rThe . ~ ~ radical was generated in the cell by a DC-glow discharge in a mixture of phosphine and ethyne. Fine structure of eight rotational transitions was observed in the 300-380 GHz region and 110 lines were measured for the K-structure, but no hyperfine structure relating to the P and H nuclei could be resolved. The rotational, centrifugal distortion, and spin-rotation coupling constants were obtained by a least-squares analysis of the measured frequencies.
5
Electronic Spectroscopy
5.1 Absorption Spectroscopy - UV spectroscopy has been used mainly as a complementary technique in structure elucidation, for example together with IR, H NMR, and MS in the synthesis of [(arylidenecyanoacetyl)imino]cyclo-
31 1
8: Physical Methods
diphosphazenes (54).84 In the photo-oxidation of bis[ 1,2-bis(diphenylphosphino)ferrocene]palladium(0) in CC14, the electronic spectrum of Pdo[(PPh2C5H4)2FeI1I2 in CC4 shows an absorption at Lax = 338 nm assigned to a charge transfer-to-solvent (CTTS) transition from the ferrocene to the cc14.8s The CTTS excitation gives Pd"[(PPh2C5H4)2Fe"]C1*.
(54)R'
= H, dmMe,
pOMe, 043,etc.; R2 = @Me, dpN@, etc.
5.2 Fluorescence and Chemiluminescence Spectroscopy - Fluorescent 1-peptidylaminoalkanephosphonatederivatives ( 5 9 , with emission maxima in the range 350-700 nm, have been synthesised and used-in detecting and studying the distribution of serine proteases in cells and biological systems.86 R Fluor-T-sp-AA3-AA2-NA
02
I
p/-OZ1 I1
H
O
(55) Fluor = 5fluoresceiny1, T = CS, sp = NH(CH2)&O,
AA2 = AA3 = Ala, R = Me, CH2CH2SMe, Z,Z1 = CsH4X; AA2 = Leu, AA3 = Phe, R = CH2Ph
Rare earth metal ions containing polymer-bond triphenyl-phosphine (PBDP), -arsine, -stibine, -bismuthine (and also thienoyltrifluoroacetone), as ligands, have been synthesised and their fluorescence studied.87The fluorescence lifetimes of the Eu3+-containingpolymer ternary complexes are between 0.350 and 0.469 ms. The organophosphonates MH(03PR)2 (M = Eu, Tb; R = Me, Ph) have also been prepared and interesting photophysical properties reported.88Whereas the Eu3+compounds exhibited a highly-red luminescence, ?LEM 614.5 nm ('Do-'~FJ) when excited at 378 nm, the Tb3+compounds gave a highly-green luminescence, EM 544 nm ( ' D 4 j 7 F ~transitions) when excited at 368 nm. A relationship between chemiluminescence and reactivity of Wittig type reactions of phosphonate carbanions has been reported.89 The chemiluminescence quantum yields (*OcL) of oxygenation of 10-methyl-9,lOdihydroacridine-9-phosphonatecarbanions depend on the nature of the phosphorus substituents. The acridinephosphonate with electronegative P substituents, such as a bis(2,2,2-trifluoroethyl)phosphono group, show higher quantum yields. This was established by comparing the reactivity of the
312
Organophosphorus Chemistry
phosphonoacetates in the Horner-Wadsworth-Emmons reactions involving the corresponding P substituents. 5.3 Photoelectron Spectroscopy - X-ray photoelectron spectroscopy (XPS) is a powerful tool for the investigation of bulk and surface electronic properties of materials. The material is illuminated with a beam of X-rays (1-2 keV) or energetic electrons (2-10 keV) and the energy distribution observed for the ejected photoelectron. XPS has been used in the surface characterisation (oxidation state) of vanadyl pyrophosphate (V0)2P207catalyst^.^' 6
X-ray Structural Studies
6.1 X-ray Diffraction (XRD) 6.1.1 Two-coordinate compounds - X-ray structural analysis of a novel 2-phosphaindolizine (1) is consistent with integration of the 1,3-azaphosphole ring in the 1On-aromatic system.2 6.1.2 Three-coordinate compounds - N, N, Nf,N'-tetramethyl-N'-(2,2,2-trichloro- 1-dimethylaminoethyl)phosphoric triamide (56), a product in a complex reaction mixture, has been characterised by XRD,91 and dimethylamino(imino)oxophosphorane is postulated as a three-coordinate P(V) byproduct. The structure of the 1,2-dihydro-1,2-diphosphete(57) has been determined by X-ray crystallography 92 and, in the reaction of the diphosphabicyclooctene (58) with 1 equivalent of Fe2(C0)9, metal complexation of one P centre occurs, the structure of the resulting ql-complex being confirmed by XRD.93
(56)
(57) R = 2,2,6,64etramethylpiperidino
The formation of the complexes o-carboranylmethylene-amineand -phosphine [(C2BlOHll)CH2PPh2] has been followed by a single crystal XRD study of the phosphine and related model [(H3B)(NMe*CH2CCH)I." Stable ruthenium complexes have been characterised by XRD, particularly (59),95 as has
(58) R = H, R',R2
=
Br
(59) Fe = C5H4Fe(q-CgH5)
8: Physical Methods
313
the green dinuclear Ru(I1)-bridged complex [{ RuC12(PPh3)}2 { C6H2-1,2,4,5(CH2PPh2)4>],96 in which the solid-state geometry reveals that the tetraphosphine is ortho-P,P'-chelated to each of the two [RuC12(PPh3)]units. 6.1.3 Four-coordinate compounds - The structure of the Mo(I1)-dicarbonyldppm complex [MoBr(CO), { K2(P,P)-dppm}2][PF6], where dppm = Ph2PCH2PPh2, has been determined by XRD revealing a capped octahedron geometry around the Mo atom.97 XRD analysis of a bis(phosphiren-1-y1)-iron complex shows that each P atom of the P,P-bridged bis(phosphireny1)ligand bonds to a Fe(C0)4 unit and that the two phosphirene rings have syn orientations to each other.98 X-ray structural confirmation of phosphazenes (see also Chapter 7) has continued including two related studies of interest concerning mono- and tetra-phosphazene systems. P,P-Dichloro-N-(dichlorophosphinoy1)-P-(diisopropy1amino)monophosphazene (60) has an acyclic mono-phosphazene skeleton and a bulky diisopropylamino side group, important in determining the molecular geometry.99The P-N bonds have neither single- nor doublebond character and are significantly shorter than the ideal P-N single bond length. The P-N-P bond angle of 134" is similar to that found in cyclotetraphosphazenes but wider than that in cyclotriphosphazenes. In a similar study, trans-2,6-bis(ethylamino)-2,4,4,6,8,8-hexamorpholino-2h5,4h5,6h5,8h5tetraphosphazatetraene (6 1) consists of a chair-shaped cyclic tetrameric phosphazene ring with six bulky morpholino and two ethylamino side groups, the latter in the trans position. loo The bulky substituents affect the eight-membered ring conformation, and the endocyclic N-P-N bond angles around the P atoms having different substituents are not the same as the P-N-P angles of the macrocyclic ring.
A thermally-unstable 1,3,5-triphosphinantriiumcation (62) has been characterised by XRD.lol In the case of the phosphonium amide, (Ph3PEt)+(NPh2)- , the X-ray crystal structure provides the first observation of an essentially ion-separated Ph2N- anion in the solid state, though weak association with Ph3PEt+cations occurs through C-H- - -N H bonding.'02
314
Organophosphorus Chemistry
A related study on the phosphonium phosphide (Ph3PMe)+ { C6H2(CF3)32,4,6]2P}- reveals that the cations and anions are weakly associated in the solid state via C-H. -P i n t e r a ~ t i 0 n s . lThe ~ ~ X-ray crystal structures of diphenylphosphinic acid amide, Ph2P(O)NH2, and its caesium salt, [Cs{Ph2P(O)NH>],show that whereas the acid amide forms dimeric molecules via N-He - -0hydrogen-bonds which are associated to form infinite double chains along the crystal axis, the caesium salt is associated via Cs-0 and Cs-N contacts along the crystal axis forming a tubular arrangement, with no hydrogen bonds. O4 XRD analysis of the bisthiourea condensation product (63) indicates that it has a meso configuration, a centre of symmetry between CH2-CH2, and normal bond distances and angles as expected.lo5The torsion angle, N-C-CN, of 180" indicates that the molecule takes on a layered conformational structure with respect to the two halves of the molecule. The strongest intermolecular interaction is between S and the methylene hydrogens of the ethyl phosphonate group of the nearest neighbour molecule.
The X-ray crystal structure of racemic dimethyl (?)-(1S*,2R*,3S*)-[3-phenyl1-(N-phenylcarbamoyloxy)-2,3-epoxypropyl]phosphonate has been determined.Io6The molecule comprises a tetrahedral P atom bonded to two methoxy groups, and an alkyl chain substituted at position 1 with a carbamate and an epoxide at positions 2 and 3 respectively, with the relative configuration of these substituents confirmed as anti (1S,2R,3S). The crystal structure contains an enantiomeric pair with two internal H bonds in a 14-memberedring, the bonds being formed between the P=O group of one enantiomer and the N-H group of the other. Selenophosphates have been studied including { Cu8(p8-Se)[Se2P(OPri)2]6},the first discrete cu18 cubane having an interstitial selenide (Se2-) ion and in which each face is bridged by a diselenophosphate ligand.lo7The oligomeric [PgSe18]6- anion in synthetic &jP8Sel8, which is the result of the fusion of three ethane-like [P2Se6] and two pyramidal [PSe3]fragments.'08 A novel polynuclear compound of europium with N-phosphonomethylglycine,Iw and new eight-membered Si-O-h5a4-P heterocycles (64)and (65)' l o have been analysed by XRD. Structural analysis shows phosphonate (64)to contain an eight-membered Si204P2 ring in the chair conformation. The Si-0 and P-0 bond-lengths within the ring are typical and the terminal P:O oxygen centres are in an axial position and oriented trans with respect to the central Si2O4 plane.
315
8: Physical Methods
6.1.4 Five- and six-coordinate compoundr - The structures of all three diastereomers of the five-coordinate phosphaspiro[3.3]heptane (66),' and that of the nickel(I1) phosphoramide complex (67)"* have been determined by XRD. The crystal structure of (67) shows the Ni atom geometry to be square planar with trans PMe3 groups, whereas the central P atom geometry is distorted trigonal bipyramidal with the Ni in an equatorial position. 0
0 (66) Ar = 4-CIC6H4
(67)
A cationic, macrocyclic six-coordinate phosphorus(V) compound, containing a mixed valence PrlI--Pv-PII1 linear chain (68) has been prepared, and X-ray crystal structure analysis has confirmed the octahedral environment around P(V) with facially-bound tridentate ligands. *
6.2 X-ray Absorption Near Edge Spectroscopy (XANES) - XANES has been used, together with DFT/SCI theoretical calculations to assign the experimental spectral data, in an investigation of the phosphorus oxide cage compounds, P406 and P406Ch (Ch = 0, S, Se).' l4 For an interpretation of the shape and energy positions of the resonances observed, the spectra were compared with those of the reference compounds, P(OPh)3 and XCh=P(OPh)3, which have a similar first coordination shell at the P atoms.
316
Organophosphorus Chemistry
6.3 Electron Diffraction - Electron diffraction has been used to characterise the molecular structure of an allylcyclophosphine, cyc1o-(Pri4P4),* and in an investigation of the reactions of trimethyl phosphite with clean and phosphorus pre-covered Fe (1 10) surfaces.
''
7
Electrochemical Methods
7.1 Dipole Moments - The dipole moments of iodine and ICN complexes with six phosphoryl compounds have been determined at 20 "C and compared with the values for the complexes between the corresponding phosphoryl compound and phenol. l 7 It was found that the vectorially calculated values for the iodine and ICN complexes are smaller than their corresponding experimental values.
7.2 Cyclic Voltammetry and Polarography - A cyclic voltammetry study of 1,l'-bis(dipheny1phosphino)ferrocene (dppf) derivatives in solution, particularly ( d ~ p f ) F e ( N O ~(dppf)Fe(C0)3, )~, and novel [(dppf)Co(NO)2][SbF,], has focused upon the interaction between the two metallic centres through the dppf ligand. l8 A series of tri~hloro[2,2':6',2''-terpyridine]ruthenium(III)phosphine complexes have also been characterised by cyclic voltammetry.' l8 The redox chemistry of Pd2+, Pt2+, and Rh3+-tris(m-sulfopheny1)phosphinetrisodium salt (TPPTS) water-soluble systems, and the influence of pH on lowvalent TPPTS complexes, has been investigated using a combination of 31P NMR, polarography and pH measurements. 12* 7.3 Potentiometric Methods - The K, values of fifteen a-substituted dimethylphosphinic acids, (RXCH&P02H, 121 and of some acid S-alkylphosphorus thio esters'22 have been determined by potentiometric titration in 50- 100% ethanol. The macrochelate, cis-Pt(NH&(dCMP), is a major product of the reaction of cis-[Pt(NH3)2(H20)2I2+ with 2'-deoxycytidine 5'-monophosphate (dCMP2-) at neutral pH, and by applying pD-dependent ('H, 31P) NMR spectroscopy and potentiometric pH titration 23 the Pt-coordinated phosphate group can be protonated (pKd1= 3.21 and 3.31). The NMR spectra also indicate deprotonation (pK,,2= 13.35) of the exocyclic amino group of the cytosine unit, and both techniques explain the acid-base properties of the macrochelate. Barium salts of 3,5-disulfophenylphosphonicacid, H4Y (Ba2Y, Bal.8H0.4Y, BaKHY, BaH2Y), have been characterised by a combination of XRD, IR, thermal analysis, a.c. conductance and emf measurements. '24 Emf measurements show K+ and H+ to be the main charge carriers in BaKHY and BaH2Y.
8
Thermochemistry and Thermal Methods
The equilibrium thermal dissociation of the tert-butylphosphine-trimethylaluminium complex has been studied in the 350-385 K range and the enthalpy
317
8: Physical Methods
of dissociation reported as 63.7 kJ molIrreversible thermal decomposition starts above 470 K and decomposition curves have a complex shape. The thermal stability of cyclotriphosphazene copolymers126and properties of some new polymeric phosphonitrilic acid esters127have been studied by DSC and TGA. Thermogravimetric studies of bromine-containing cage phosphates (69)128and poly(sebacoy1 hydrazine) phosphate (PSHP)129have aided their characterisation. Br
I
Br
Br
The thermal transformations of y-titanium phosphate, y-Ti(P04)(H2P04)-2H20, have been followed using TGA, DSC, XRD and temperatureresolved in situ powder diffraction. 130 9
Mass Spectroscopy
There are numerous publications using mass spectroscopy as a complementary analytical technique for structure elucidation, but the applications described below use MS as the sole or main technique. Electrospray ionisation (ESI) MS has been used both in the characterisation of a range of ferrocenyl-phosphines (e.g. FcCH2PR2) and of monosulfonated triphenylphosphines. In the former case in situ prepared hydroxymethylphosphonium salt derivatives, and both in the former and latter cases in situ prepared Ag(1) adducts were exarnined.I3l Sulfonated phosphines and their Na adducts were characterised by their negative-ion spectra. Aminoalkyl-ferrocenyl phosphines form strong [M + H]+ ions and ferrocenyl phosphines without amino functions give weaker [M + H]+ ions in their positive-ion spectra, and may also be complicated by the existence of [MI+ ions. In the latter case, less complex ions can be obtained following treatment with either AgN03 solution or a mixture of formaldehyde and hydrochloric acid. The FAB(+) mass spectrum of the purple Tc(1) complex [TcC12(NO)(HN:NC5H4N)(PPh3)2] displays the [M + H]+ parent ion at rnlz 570 and a [M - HCl]+ fragment ion at mlz 533, whereas the spectrum of the neutral Tc(1) complex [TcCI(NO)(N:NC~H~N~CF~)(PP~~)~] displays the [M + H]+ parent ion at rnlz 866 as well as the [M-N2H2C4H2N2CF3]+ fragment ion at mlz 688, in addition to the [M -PPh3]+ fragment ion at rnlz 604.132 Stable carbon phosphide anions have been prepared by the trapping and reaction of small carbon anions, C,- (n=3-9), with gaseous P4 in a FT-ICR mass ~pectrometer.'~~ This LA-FTICR study of the anions [C,P]-, [C,P2]-,
318
Organophosphorus Chemistry
[C,P4]- and [C,Ps]-, combined with DFT calculations, covers the full range (n = 3-9) for their composition and structure. The gas-phase reactivity of (Me0)2P+ phosphenium ions with 2,3-dimethylbuta-173-diene,in a quadrupole ion trap mass spectrometer, has investigated the occurrence of cycloaddition reactions.134 The mass spectrum showed that the generated (Me0)2P+ phosphenium ions reacted with the diene to give predominantly stable mlz 175 species, corresponding to a [4+2] cycloadduct, 3-phospholenium ion (70). These highly ionic species also undergo other ion-molecule reactions.
(70)
(71) R = 46sH4X
Seven new phosphorus heterocycles (71) have been studied by XPS and MS and the presence of isomers c ~ n f i r m e d .Doubly '~~ charged cations of bisphosphonium salts, e.g. Ph3P+(CH*),P+Ph3 (n=2, 4, 8), have been identified by FAB- and ESI-MS.136 Electrospray ionisation of some organophosphate esters has been examined in both an ion trap and a triple quadrupole mass ~pectrometer.'~~ The structures and fragmentations of the ions were studied by collision-induced dissociation (CID) experiments with up to MS4 being performed in the ion trap. There is a difference in the CID of the protonated methyl esters, which eliminate methanol, compared to the ethyl and isopropyl esters which eliminate alkenes. The use of partially deuterated dimethyl methylphosphonate has allowed the observation of the migration of a methyl group from the P to the 0 of a P-0 bond. CI- and EI-MS of eighteen methylphosphonothiolates,138 and nine phosphorothionates (72) * 39 have identified and confirmed their structures. OR'
0 (72)R' = M e B u , R2 = SPr, OMe
Matrix-assisted laser desorptiodionisation (MALDI) MS is being used increasingly in the characterisation of high mass species, usually of biochemical nature. In one study, metastable fragmentation of modified peptides during MALDI MS was investigated, the fragment ions generated by the metastable loss of modification-specific neutral fragments being detected in the reflector mode. 140 The suitability of phosphoramidite chemistry for the introduction of
319
8: Physical Methods
2'-0-propargyl modified nucleotides has been proven using MALDI or ESI MS of the final 01igomer.l~~ Fourteen ammonium salts have been evaluated as co-matrices for negative-ion MALDI analysis of several synthetic oligonucleotides in three different matrix systems,14*and 3-hydroxypicolinic acid/ ammonium fluoride found to be the best matrix system in terms of the analysis of high-mass nucleotides. Six cyclic nucleotide analogues, used as site-selective activators of CAMP-dependent protein kinases, have been studied by positiveion FAB- and CID mass-analysed ion kinetic energy (MIKE) spectrometry. 143 The mass spectral fragmentation pathways of pentacoordinate spirobicyclic imino(alky1)acetoxyphosphoranes (73) have been investigated by field desorption, EI-, and CI-MS, together with the BlE linked scan technique.lM
(73)R = H, s-alkyl, CH2Ph
10
Chromatography and Related Techniques
10.1 Gas Chromatography and Gas Chromatography-Mass Spectroscopy (GCMS) - Racemic acid amides, prepared using benzotriazol-1-yl-oxytris(dimethy1amino)phosphonium hexafluorophosphate, have been separated by gas chromatography.145 A novel calibration technique for headspace GC analysis of semi-volatile compounds, particularly tributyl phosphate (TBP) and dibutyl butylphosphonate (DBBP), has been developed.146 Acidic phosphate and phosphonate esters have been analysed by GC as their methyl esters, 47 and homologous series of 2-chloroethylphosphonic acid esters and benzylphosphonic acid esters have been studied on three silicone stationary phases. 48 GC-MS has been used for qualitative and quantitative analyses. Simultaneous GC-MS quantitation of TMS derivatives of phosphoric (and selected carboxylic) acids is based on both total ion count (TIC) and selective ion monitoring (SIM) using ion-trap detection (ITD). 149 Alkyl methylphosphonic acids have been detected and identified by GC-MS and extended techniques. 52 Alkyl methylphosphonofluoridates and alkyl methylphosphonic acids have been identified (screened) using GC-MS and GC-MS-MS techniques, in the case of the latter methylphosphonic acids as TMS derivatives. Such EI mass spectra display a base peak at mlz 153 and prominent fragment ion at mlz 169, but underivatised ethylphosphonofluoridates give a characteristic base peak at mlz 99. GC-MS-MS has been used in the detection of alkyl methylphosphonic acids in complex matrices (oil and soil extracts) by conversion to the TMS derivatives and then CID monitoring of ions mlz 153 to mlz 75, using EI or methane CI. In both cases,150*151 ammonia CI can be used for molecular mass confirmation. Some 0-alkyl methylphosphonic acids after
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derivatisation (diazomethane methylation, or BSTFA silylation) have been characterised by MS and IR in a GCIMSDIFTIR commercial system.1s2 10.2 Liquid Chromatography 10.2.1 High Performance Liquid Chromatography and LC-MS - Reversedphase LC-MS has been applied to studies of the host-guest complexation of tetraalkylcalix[4]resorcinarenes (74) (host) with some benzene derivatives (guest) present in the mobile phase. l S 3 Formation of the inclusion complexes results in changes in the retention of the aromatic guests, improving their separation. The stability constants of the complexes have been determined.
HPLC has been used for the separation of five phosphoamidothioate enantiomers using a series of silica and chiral columns.154The enantiomers of seventeen a-hydroxybenzylphosphonatediethyl esters have been separated on a chiral column, and absolute configurations of 4-methyl- and 2-methylsubstituted a-hydroxybenzylphosphonates obtained from circular dichroism (CD) measurement of the isolated e n a n t i o m e r ~ . 'The ~ ~ effects of the chiral selector, P-cyclodextrin, and bis(2-ethylhexyl)orthophosphoric acid, as modifier, on the retention and enantioselectivity have been studied.156HPLC and LC-MS have been used to monitor kinetics of the formation of the internucleotide bond in diguanylate synthesis in an aqueous solution at pH 8 in the presence and absence of poly(C). 157 Other biochemical applications of HPLC include confirmation of P-D-glucopyranosyl 1 -triphosphate as a reaction product,' 58 the separation of diastereoisomers of ribonucleoside 5 ' 4 ~ - P borano)triphosphates, 59 confirmation of a synthetic phosphopeptide, '60 and for the separation of sets of mono- and di-phosphorylated peptides. A novel method for separation and identification of organometallic compounds in complex mixtures utilises particle beam (PB) LC-MS, specifically used in the characterisation of diphosphine-substituted selenido Fe and Ru clusters.'62 Complex reaction mixtures are separated under adsorption chromatographic conditions and characterised online by positive- and negative-ion CI mass spectra of the eluates. PB LC-MS analysis gave spectra showing characteristic fragmentation patterns and detailed structural information.
8: Physical Methods
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10.2.2 Thin Layer Chromatography - A new sensitive and selective TLC method for the separation and detection of some fifteen organophosphorus pesticides involves a new spray reagent, 9-methylacridine (0.05% in ethanol), followed by uv366 examination, when the spots present different colours and intensities, with a detection limit of 0.1-10 p g / ~ p o t . ’Toxic ~ ~ metabolites of organophosphorus and other pesticides, etc., obtained by selective oxidation, have been separated and detected by TLC (PdC12 reagent/12), and their structures confirmed by EI-MS.lM 10.3 Capillary Electrophoresis (CE) and Micellar Electrokinetic Chromatography (MEKC) - The CE chiral separation of (I?,S-I, I’-binaphthyl-2,2’-diyl hydrogen phosphate has been carried out successfully using the monosaccharides glucose, mannose and derivatives as chiral selectors.165 Several CE/CE-MS methods use inorganic phosphates as buffer,166-168 and similarly for MEKC, 69-1 Anionic trace impurities, including phosphate, have been determined in excess glycerol at 1 ppm using capillary isotachophoresis with an enlarged sample load. 72 11
Kinetics
The Jones PLE active site model has been applied in order to explain the enantioselectivity encountered during the hydrolysis of racemic chiral methyl phosphonyl and phosphoryl acetates (75, R1/R2= PldMeO, PhO/EtO, EtZN/ MeO), in the presence of porcine liver e ~ t e r a s e . ’Under ~ ~ kinetic resolution conditions, the reactions gave the corresponding chiral phosphonyl and phosphoryl acetic acids in moderate to high enantomeric purity (up to 99% e.e.).
The kinetics and activation parameters have been evaluated for the alkylation of triphenylphosphine with three substituted benzyl halides, to give the corresponding phosphonium salts (76; (a) R’= H, R2 = GI, X = C1; (b) R1 = Me, R2 = H, X = GI; (c) R1= H, R2 = Me, X = Br).’74The reactions exhibit second order kinetics (SN2) with a large negative entropy of activation. The relative activities of the three solvents studied, chloroform, dichloromethane and benzene, are discussed with respect to the different benzyl halides. Recently, authors have investigated the media effect in the alkaline hydrolysis of 3-bromopropyltriphenylphosphoniumbromide (77). 75 In accordance with previous studies, the rate of hydrolysis is faster in aqueous dioxane compared with the equivalent methanol systems, since the rate of phosphonium salt hydrolysis is inversely proportional to the dielectric constant of
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(76)
R1
(77)
the medium. The authors attribute the enhanced rate of hydrolysis, compared with the tetraphenylphosphonium salt (78), to the inductive effect of the 3-bromopropyl group, increasing the positive charge on phosphorus. Rate constants, kinetic isotope effects and product ratio data have been obtained for the solvolysis of diphenyl- and bis(4-chlorophenyl)-phosphorochloridate, in a wide range of s01vents.l~~ The authors found no evidence suggesting a change in mechanism over the solvent systems studied, and also report a large MeOH/MeOD kinetic isotope effect. The reactions were found to be highly sensitive to solvent nucleophilicity, since large rate decreases were observed in trifluoroacetic acid 'rich' solvent systems. The experimental results were in accordance with the accepted SN2(P) mechanism, extended to incorporate two solvent molecules in the rate determining step. Conversely, the third order rate constants derived from product selectivities led to first order calculated rate constants that were not in agreement with the experimental values. The authors suggest that this may be due to initial state effects, reducing the third order rate constants as the alcohol was added to water. The reaction between tricoordinate phosphorus compounds and sulfenate esters has recently been evaluated by interpretation of product analysis data, kinetic data, Hammett data and solvent effects.177The authors suggest a two-step reaction mechanism, involving arylthiophosphoranes as intermediates. The kinetics and mechanism of the (isopropy1)diarylphosphinite catalysed dimerisation of acrylonitrile to a mixture of dicyanobutenes have recently been evaluated and the results discussed in some detail, including the factors which affect the product distribution. 178 The kinetics of the tetrazole catalysed alcoholysis of diisopropyl N,N-diisopropylphosphoramidite with tert-butyl alcohol have been evaluated by 31PNMR spectroscopy. The kinetics were interpreted in terms of the possible side reactions involved, i.e. via formation of the diisopropyl tetrazolylphosphite and its subsequent alcoholysis. 79 Variable temperature, quantitative, phase sensitive 31P{ 'H} EXSY NMR spectroscopy has been applied to studies of the kinetics, including full characterisation of the thermodynamics for the terminal ligand redistribution in Ni2(bis(diphenylphosphino)methane)2(C:CH2)X2, where X = SCN or C1.180 The kinetics and course of the reaction between a stabilised phosphonium ylide and phthalic anhydride have recently been evaluated by 31PNMR spectroscopy.
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31PNMR spectroscopy has been applied to the analysis of the kinetics of monoselenophosphate hydrolysis.’82 The hydrolysis was fastest at pH -7, and the presence of certain alcohols and amines, although phosphorylated, did not significantly affect the reaction rates. The authors also discuss a possible mechanism involving a monomeric metaphosphate-like transition state. Recent experiments show that, in the presence of lanthanum(II1) cations in aqueous 1,3-bis-[tris(hydroxymethyl)methylamino]propane] buffer at pH 9 .O, the hydrolysis of several phosphate diesters is catalysed, by up to lo3 times, compared with that observed in neutral solutions.183The role of different amine catalysts upon the kinetics of di(4-nitrophenyl) methylphosphonate hydrolysis (79), in an aqueous or a microemulsion system of n-hexane, water and propan-2-01, has been e ~ a 1 u a t e d .In l ~ the ~ case of hydrophilic amines, the rate constants increase in the microemulsion compared to that observed in an aqueous system, whereas the opposite is observed for hydrophobic amines.
Infrared spectroscopy has been applied in the evaluation of the kinetics of reaction between diethyl 1-amino- 1-methylethanephosphonate and phenyl isocyanate giving diethyl 1-methyl-1-(N-phenylcarbamoy1amino)ethanephosphonate. lS5 A mechanism was proposed for the reaction which was found to be second order. The authors also observed a reaction rate increase over the course of reaction, which was attributed to the autocatalytic effect of one of the reaction products. A new ‘flow tube reactor’ has been developed and applied in analysis of the hydrothermal reactions of adenosine and adenosine triphosphate.186 The authors report half-lives, as determined by this method, of 0.31 s at 473 K for adenosine triphosphate and 0.42 s at 573 K for adenosine. The new method allows real-time monitoring of model reactions of the chemical evolution of RNA in aqueous solutions at high temperature.
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Organophosphorus Chemistry
120 121
E. G . Kuntz and 0. M. Vittori, J. Mof. Cat. A : Chem., 1998,129, 159. A. A. Grigor'eva, M. I. Shermergorn, T. A. Mastryukova and M. I. Kabachnik, Russ. J. Gen. Chem., 1997,67, 1384. A. A. Grigor'eva, G. F. Litovchenko, N. N. Zalesova, L. S. Butorina, E. E. Nifant'ev, T. A. Mastryukova and M. I. Kabachnik, Russ. J. Gen. Chem., 1997, 67, 1389. G. Oswald, I. Rombeck, B. Song, H. Sigel and B. Lippert, J. Biof. Inorg. Chem., 1998,3,236. F. Adani, M. Casciola, D. J. Jones, L. Massinelli, E. Montoneri, J. Roziere and R. Vivani, J. Muter. Chem., 1998, 8, 961. S. V. Mitrofanov and V. A. Yablokov, Russ. J. Gen. Chem., 1997,67, 1864. H-S. Wu and D-Y. Ke, J. Pofym. Res., 1998,5, 95. X. Pang, Z. Xin and G. Dai, Gongneng Gaofenzi Xuebao, 1998, 11, 100, (Chem. Abstr., 1998,128, 322 042). Z. Peng and Y. Ou, Huaxue Tongbao, 1998,8,39 (Chem.Abstr.,1998,129,216 685). M. G . H. Zaidi, Orient. J. Chem., 1998, 14, 177. A. M. K. Andersen and P. Norby, Inorg. Chem., 1998,37,4313. W. Henderson and G. M. Olsen, Polyhedron, 1998, 17, 577. T. Nicholson, M. Hirsch-Kuchma, E. Freiberg, A. Davison, and A. G . Jones, Inorg. Chim. Acta, 1998,279,206. K. Fisher, I. Dance and G . Willet, Eur. Mass Spectrom., 1997,3,331. S. Gevrey, M-H. Taphanel and J-P. Morizur, J. Mass Spectrom., 1998,33,399. X. Li and F. Song, Guangpuxue Yu Guangpu Fenzi, 1998, 18, 261 (Chem. Abstr., 1998,129,20301 3). H. J. Cristau, C. Enjalbal, P. Mouchet and J-L. Aubagnac, Bull. Soc. Chinz. Befg., 1997, 106,407. A. J. Bell, D. Despeyroux, J. Watts and P. Murrell, Int. J. Mass Spectrom. Ion Processes, 1997, 16516, 533. V. Podborsky and V. Stein, NATO ASI Ser., Ser. I , 1997, 13, 109. Z-A. Li, S-B. Liu and L-J. Ci, Hecheng Huaxue, 1998,6,95 (Chem. Abstr., 1998, 129, 41 195). M. Schnolzer and Lehmann, W. D., Int. J. Mass Spectrom. fon Processes, 1997, 1691170,263. M. Grotli, M. Douglas, R. Eritja and B. S. Sproat, Tetrahedron, 1998,54, 5899. Li, Y. C. L., S-W. Cheng and T-W. D. Chan, Rapid Commun. Mass Spectrom., 1998, 12,993. T. J. Walton, M. A. Bayliss, M. L. Pereira, D. E. Games, H-G. Genieser, A. G. Brenton, F. M. Harris and R. P. Newton, Rapid Commun. Mass Spectrom., 1998, 12,449. H. Fu, Z. Li, Y. Zhao, D. Guo, H. Xiao, J. Wang and Y.Wu, Rapid Commun. Mass Spectrom., 1997, 11, 1825. H. Mattras, L. Galzigna and A. Previero, J. Chromatogr., A, 1998,803,307. A. B. Dindal, C.Y. Ma, J. T. Skeen and R. A. Jenkins, J. Chromatogr., A, 1998, 793, 397. N. Deng, S. Tian, Z. Liu, M. Li and H. Yu, Huanjing Kexue, 1997,18,68, (Chem. Abstr., 1998,129, 144 408). G. Ilia, R. Valceanu, P. Soimu and G. Dehelean, Rev. Roum. Chim., 1998, 43, 197. I. Molnar-Perl, A. Vasanits and K. Horvath, Chromatographia, 1998,48, 1 1 1 . D. K. Rohrbaugh and E. W. Sarver, NATO ASI Ser., Ser. I , 1997,13,313.
122 123 124 125 126 127 128 129 130 131 132
133 134 135 136 137 138 139
I40 141 142 143 144 145 146 147 148 149 150
8: Physical Methods
329
151 D. K. Rohrbaugh and E. W. Sarver, J. Chromatogr., A, 1998,809,141 152 M. Sokolowski, N A TO A S I Ser., Ser. I , 1997,13,99. 153 J. Lipkowski, 0. I. Kalchenko, J. Slowikowska, V. I. Kalchenko, 0. V. Lukin, L. N. Markovsky and R. Nowakowski, J. Phys. Org. Chem., 1998,11,426. 154 R-Y. Gao, H-Z. Yang, J-M. Huang and Q-S. Wang, Chin. J. Chem., 1998, 16, 145. 155 S. Caccamese, S. Failla, P. Finocchiaro and G. Principato, Chirality, 1998, 10, 100. 156 M.L. Bieganowska and A. Petruczynik, Chem. Anal. (Warsaw), 1998,43,583. 157 A. Kanavarioti, J. Org. Chem., 1998,63,6830. 158 H. Inoue, M. Watanabe, H. Nakayama and M. Tsuhako, Chem. Pharm. Bull., 1998,46,681. 159 K. He, A. Hasan, B. Krzyzanowska and B. R. Shaw, J. Org. Chem., 1998, 63, 5769. 160 J. W. Perich, Lett. Pept. Sci., 1998,5,49. 161 R. Hoffmann, M. Segal and L. Otvos, Jr., Anal. Chim. Acta, 1997,352, 327. 162 M. Careri, C. Graiff, A. Mangia, P. Manini and G. Predieri, Rapid Cornmun. Mass Spectrom., 1998, 12,225. 163 C. Marutoiu, V. Coman, M. Vlassa and R. Constantinescu, J. Liq. Chromatogr. Relat. Tech., 1998,21,2143. 164 B. Simonovska, J. A OA C International, 1997,80,688. 165 H. Nakamura, A. Sano and H. Sumi, Anal. Sci.,1998,14,375. 166 K. Sarmini and E. Kenndler, J. Chromatogr., A, 1998,818,209. 167 K. Sarmini and E. Kenndler, J. Chromatogr., A. 1998,811,201. 168 Y. Tanaka, Y. Kishimoto, K. Otsuka and S. Terabe, J. Chromatogr., A, 1998, 817,49. 169 T. H. Seals, J. M.Davis, M. R. Murphy, K. W. Smith and W. C. Stevens, Anal. Chem., 1998,70,4549. 170 H. Ozaki and S. Terabe, Chromatography, 1998, 19, 162. 171 S. A. Shamsi, C. Akbay and I. M. Warner, Anal. Chem., 1998,70,3078 172 T. Meissner, F. Eisenbeiss and B. Jastorff, J. Chromatogr., A, 1998,810,201. 173 P. Kielbasinski, P. Goralczyk, M. Mikolajczyk, M. W. Wieczorek and W. R. Majzner, Tetrahedron Asymmetry, 1998,9,2641. 174 R. Shieh, R. Lin, J. Hwang and J. Jwo, J. Chin. Chem. SOC.(Taipei), 1998, 45, 517. 175 F. Y. Khalil, M. T. Hanna and M. El-Batouti, C. R. Acad. Sci., Ser. IIb: Mec., Phys.,Chim., Astron., 1997,325, 546. 176 T. W. Bentley, D. Ebdon, G. Llewellyn, M. H. Abduljaber, B. Miller and D. N. Kevill, J. Chem. Soc., Dalton Trans., 1997, 3819. 177 C . D. Hall, B. R. Tweedy and N. Lowther, Phosphorus, Sulfur, Silicon, Relat. Elem., 1997,123, 341. 178 C. D. Hall, N. Lowther, B. R. Tweedy, A. C. Hall and G. Shaw, J. Chem. Soc., Perkin Trans. 2, 1998,2047. 179 E. J. Nurminen, J. K. Mattinen and H. Lonnberg, J. Chem. Soc., Perkin Trans. 2, 1998, 1621. 180 J. D. Heise, D. Raftery, B. K. Breedlove, J. Washington and C. P. Kubiak, Organometallics, 1998, 17,4461. 181 Z. Shi, M. Dong, Y. Yao and J. Liu, Bopuxue Zazhi; 1998,15,321. 182 R . Kaminski, R. S. Glass, T. B. Schroeder, J. Michalski and A. Skowronska, Bioorg. Chem. 1997,25, 247.
330 183
Organophosphorus Chemistry
P. Gomez-Tagle and A. K. Yatsimirsky, J. Chem. SOC., Dalton Trans., 1998, 2957.
184 185 186
V. E. Bel’skii, F. G. Valeeva and L. A. Kudryavtseva, Russ. Chem. Bull., 1998, 47, 1302. A. Alexiev, V. Lackova and G. Petrov, Phosphorus, Sulfur, Silicon, Relat. Elem., 1997,128, 191. K . Kawamura, Nippon Kagaku Kaishi, 1998,255.
Author Index
In this index the number in parenthesis is the Chapter number of the citation and this is followed by the reference number or numbers of the relevant citations within that Chapter. Abad, J.L. (5) 89 Abdelaziz, J. (8) 4,5 AbdelBaky, S.(5) 242 Abdou, W.M. (2) 13; (6) 52,53, 55
Abduljaber, M.H. (8) 176 Abe, H. (5) 10 Abe, K.(5) 153,211 Abon, M.(8) 90 Abraham, T.W.(5) 1,2 Abuelyaman, A S . (8) 86 Abushamaa, H. (5) 242 Abu Sheikha, G. (5) 11,77 Acevedo, O.L. (5) 180 Achiwa, I. (1) 114,115 Achiwa, K. (1) 73, 114, 115 Acosta, J.L. (7) 142, 143 Adam, D. (7) 73 Adam, W.(3) 9 Adamopoulos, S.G. (6) 5 1 Adamowicz, L. (4) 222 Adams, H. (1) 361; (8) 37 Adani, F. (8) 124 Adibi, M. (1) 388 Afarinkia, K.(4) 85 Afonin, A.V. (1) 286 Afonso, C.A.M. (1) 238 Ager, D.J. (1) 135 Aggarwal, S.K.(5) 205,212,344 Ahlemann, J.T. (1) 434 Ahlgren, M. (1) 19 Ahlmark, M.J. (4) 108 Ahmad, I.K. (1) 428; (8) 83 Ahmad, M. (1) 175 Ahmadian, M.R (5) 355 Ahrens, B.(1) 338,384 Aime, S.(4) 159 Airola, K.(1) 467; (6) 45
Aitken, R.A. (1) 190,383,458;
(6) 23-25,60, 173 Akabori, S.(4) 3 Akbay, C.(8) 171 Akiba, K.-Y. (6) 47,48 Aladzheva, I.M. (1) 352,353 Alajarin, M.(7) 10 Alam, S.(1) 300 Alazzouzi, E. (5) 198 Al-Badri, A. (1) 404; (8) 65 Al-Badri, H. (6) 120 Albert, J. (1) 267,268 Alberti, A. (8) 71 Albouy, D. (3) 17; (8) 42 Alder, M.J., (1) 249 Alder, RW. (1) 130, 131 Aldini, N.N. (7) 179, 180 Alexakis, A. (3) 5,6 Alexandrova, L.A. (5) 64 Alexiev, A. (8) 185 Alfonsov, V.A. (8) 78 Allaf, A.W. (8) 74 Allcock, H.R. (7) 85, 132, 136, 144, 148, 150, 151, 159, 160, 175, 176,180 Allen, D.W.(1) 361; (8) 6,37 Aller, E.(6) 74 Allerson, C.R. (5) 222 Allinger, N.L.(4) 220 Almasoudi, N.A. (5) 34 Almirante, N. (6) 111 A1 Obaidi, A.H.R. (5) 258 Alsarsur, I.A. (8) 67 Alsbeti, M.(5) 102 Al-Sulaim, A.M. (1) 2 15 Altmann, K.H. (5) 33 Alvarez, K.(5) 140 kvaret. R.M.S.(7) 46 33 I
Alvarez-Larena, A. (4) 6 Alvarez Sarandb, R. (6) 79,80; (7) 16
Amaral, L. (8) 118 Ambrosio, A.M.A. (7) 175, 176, 180
h e , J.C. ( 5 ) 70 Amigoni, S.J. (6) 135 Amit, B. (5) 297 Ammenn, J. (5) 33 Amosov, Y.I. (1) 68 Anderluzzi, D. (4) 155 Anders, E.(1) 358; (6) 110 Andersen, A.M.K. (8) 130 Anderson, P.P. (1) 69; (7) 40,43 Andersson, P.G. (4) 183 Ando, A. (1) 392 Ando, F. (6) 3 Ando, M.(1) 207 Andrews, P.C. (1) 127 Andrianov, A.K. (7) 133,186, 187, 195
Andrien, J. (1) 26 Andrus, A. (5) 87,214,215 Anelli, P.L. (1) 236 Anfang, S.(7) 32 Angelici, A.J. (6) 35, 40 Angelici, R.J. (1) 422 Angermund, K.(1) 510 Anisimov, V.M. (1) 5 13 Ansari, M.A. (5) 52 Anslyn, E.V. (5) 362 Ansorge, M. (6) 113 Antelmann, B. (1) 46 Anton, D.L. (4) 138 Antyspovich, S.I. (5) 159 Anzai, M. (7) 122 Aoki, M.(6) 139, 140
332 Aoki, S. (6) 140 Aoki, T. (5) 226 Aoyama, H. (6) 99, 109; (8) 89 Aparicio, D. (1) 315, 386 Apperley, D.C.(1) 306 Arai, S. (6) 115 Arai, T. (6) 114 Arakawa, K. (4) 13 Arancibia, V. (1) 355 Arbuzova, S.N.(1) 42, 105, 106, 286
Arca, M. (1) 308 Arduengo, A.J., 111 (2) 6 Arif, A. (3) 30; (8) 25 Arikawa, Y. (1) 12 Armitage, B. (5) 237-239 Armstrong, D.R. (6) 121 Armstrong, R W . (6) 168 Arnold, P.L. (1) 505 Amone, A. (1) 304; (4) 65 Arques, A. (1) 239; (7) 1 Arslan, T.(4) 215 Artamkina, G.A. (6) 105 Arterbum, J.B. (5) 101 Arthur, J.C. (5) 171 Artymiuk, P.J. (5) 338 Arumugam, S. (2) 27 Arva, P.(1) 50 Asai, T. (1) 119 Asakura, C.(1) 392 Asensio, J.L. (5) 35 1 Ashford, S.W. (6) 141 Ashton, M.R. (1) 167 Aspar, D.G. (4) 208 Asseline, U.(5) 175 Atoh, M.(1) 69 Aubagnac, J.-L. (1) 395; (8) 136 Aubertin, A.-M. (4) 216; (5) 63 Auer, F. (1) 170 Auffinger, P. (5) 266 Auffray, P. (5) 175 Augustin, S. (5) 123,207 Augustyns, P. (5) 160 Aumelas, A. (5) 112 Aust, N.C. (6) 2 Avamari, N. (1) 52 1,522 Avent, A.G. (1) 199 Avery, T.D.(6) 85 Avis, M.W. (1) 240; (7) 9 h m a , N . (8) 81 Baccolini, G.(1) 5 14 Baceiredo, A. (1) 250,25 1,424, 479,480
Bach, R.D. (1) 2 13 Bachrach, S.M. (1) 349,350,446 Badet, B.(4) 122,219
Organophosphorus Chemistry Badet-Demisot, M.-A. (4) 122, 219
Baek, H. (7) 189 Bahrrnann, H. (1) 169 Bahvalova, V.N. (5) 45 Baik, W. (3) 12 Baird, E.E. (5) 247-25 1, 346 Baker, B.F. (5) 261 Baker, T.J. (4) 67 Bakos, J. (1) 50, 5 1 Balakin, K.V. (5) 217 Balbi, A. (5) 220 Balcerzak, K.B. (4) 123 Baldwin, R.A. (1) 85,225 Balema, V.P. (1) 257 Balkhi, S.R (5) 359 Ballereau, S. (4) 23,24 Balow, G. (5) 180, 189 Baltork, I.M. (1) 370 Balueva, A.S. (1) 254 Balzarini, J. (4) 121; (5) 5 Bandoli, G. (6) 37; (7) 64 Bankaitis-Davis, D.(5) 106 Bansal, R.K. (4) 176; (8) 2 Bao, Y.J. (5) 280 Bar, N. (4) 92 Baraniak, J. (4) 224 Barascut, J.L. (5) 34 Barbas, C.F.,111(4) 212 Barberato, C. (5) 3 19 Barber Peoch, I. (5) 204 Barbetta, A. (7) 135 Barbour, L.J. (1) 111 Barco, I.L. (6) 39 Bardaji, M. (7) 93 Bardea, A. (5) 297 Barendse, N.C.M.E. (6) 148 Barg, L.A. (1) 30 Barluenga, J. (6) 182 Batmin, A. (4) 246 Barney, A.A. (1) 56 Barret, S.(7) 13 Barren, A.G.M. (6) 89,155 Barry, S.T. (1) 83 Bartels, B. (1) 328; (6) 125 Bartholomew, B. (5) 46 Bartkowska, B. (1) 37 Bartlett, P.A. (4) 161, 162 Bartley, J.P. (5) 352 Bartoli, G.(1) 330 Barton, D.H.R. (1) 22 1,253,3 13 Barton, J.K. (5) 23 1,257,276 Barton, R.J. (8) 58 Bartsch, R. (1) 22; (4) 95 Barz, M. (1) 43 Bashkin, J.K. (5) 254 Baskakova, P.E. (8) 14 Baskaran, D. (1) 393
Bass, B.L. (5) 243 Bass&, M.C. (5) 209 Bateman, J.E. (1) 247 Batey, R.A. (4) 2 Batsanov, A.S. (6) 30; (7) 20 Batteas, J.D. (8) 116 Battersby, T.R. (5) 164 Batz, H.G.(5) 237,238 Baudry, D. (1) 502 Bauer, I. (3) 28,33 Bauer, R (7) 52 Bauer, W. (7) 34,35 Baughman, T.A. (6) 141 Baulin, V.E. (8) 79 Baum, G. (1) 78,442 Baumann, W.(1) 4 Baumgartner, T.(1) 470; (6) 28 Baxter, A.D. (1) 167 Bayliss, M.A. (8) 143 Bayston, D.J. (1) 167 Beachley, O.T.(1) 84,224 Beaton, G.(5) 106 Beam, A. (1) 336 Beaucage, S.L. (5) 136 Becker, G. (1) 44 1 Beckett, I. (5) 95 Beckmann, E. (1) 417 Becquet, R. (7) 70,7 1 Bedair, A.H. (8) 84 Bedford, R.B. (1) 443 Beese, L.S.(5) 342 Begley, T.P. (4) 46 Beglieter, A. (5) 296 Beier, M.(5) 86 Beigelman, L. (5) 158, 178,229, 326
Bekarek, V. (1) 3 18 Bekiaris, G.(1) 109 Belaj, F. (7) 57, 58 Beletskaya, I.P. (6) 105 Belfield, K.D. (4) 91 Belfiore, L.A. (7) 161 Belhumeur, S. (1) 83 Belin, F. (8) 70 Bell, A.J. (8) 137 Bell, S.E.J.(5) 258 Bellan, J. (2) 11 Belluco, U. (6) 27 Bellus, D. (4) 84; (5) 33 Belogorlova, N.A. (1) 104-106, 286
Bel'skii, V.E. (8) 184 Belyakov, A.V. (8) 14 Ben-David, Y. (1) 266 Ben Dov, I. (5) 297 Benech, J. (4) 127 Benner, S.A. (5) 164 Bennett, D.W. (1) 334
Author Index Bennett, M.A. (1) 143 Bensch, W. (1) 376 Benson, M.T. (1) 453 Bentley, T.W. (8) 176 Bentrude, W.G. (3) 30; (5) 24; (8) 25
Benvenuti, F. (1) 166 Benvenutti, M.H.A. (1) 449 Ben Yoseph, G. (5) 277 Berclaz, T. (8) 66 Bere, K.E. (8) 90 Berens, C. (5) 273 Bergbreiter, D.E. (1) 168 Berger, S. (6) 29 Berges, D.A. (1) 204 Bergqvist, S. (5) 351 Bergstriisser, U.(1) 409,438-440, 444,448,473; (8) 93,98
Bergstrom, D.E. (5) 188 Berkman, C.E. (4) 166 Berlan, J. (1) 196 Berlin, K. (5) 230 Berlin, Y.A. (5) 217 Bernard, T.(1) 359 Bernardinelli, G. (8) 66 Bernatowicz, P. (8) 59,63 Bemers-Price, S.J. (1) 16; (8) 28 Berry, M.B. (4) 185 Bertani, R. (6) 27; (7) 130, 163, 165
Bertrand, G. (1) 250,251,401,
423,424,447,479,480; (7) 65, 127 Bertsch, C.F. (4) 143 Bessel, C.A. (8) 119 Bestennan, J.M. (5) 244 Bestmann, H.J. (1) 382 Bethell, D. (8) 27 Bettencourt, A.P. (6) 6 Betzemeier, B. (1) 2 Beuttenmueller, E.W. (1) 72 Beynek, H. (6) 68 Beyrich Graf, X.(5) 234 Beziat, Y. (4) 116 Bhan, A, (5) 161 Bhan, P.(5) 161 Bhanthumnavin, W. (3) 30; (8) 25 Bharatiya, N. (4) 176; (8) 2 Bhatt, R.K. (6) 144 Bhattacharyya, P. (1) 3 Bian, N.Y. (5) 242 Bianchi, D.A. (1) 201 Bianchini, C.(1) 157 Bickelhaupt, F. (1) 456,48 1 Bieganowska, M.L.(8) 156 Bieger, K.(7) 127 Bier, F.(4) 246 Biessen, E.A.L. (5) 206
Bijsterbosch, M.K. (5) 206 Bilgin, N. (5) 3 19 Bilkov, L.V.(8) 14 Binder, H. (8) 3 1 Binger, P.(1) 440 Birkett, P.R (1) 199 Bischofberger, N. (1) 229; (5) 173 Bisseret, P. (4) 125 Black, S.J. (1) 507 Blackbum, G.M.(4) 89; (5) 71 Blacque, 0. (1) 93 Blber, D. (1) 418,419 Blancafort, L.(3) 9 Blaszczyk, J. (4) 238 Bligh, A.S.W. (8) 17 Bockelmann, U.(5) 363 Boczkowska, M. (5) 133 Biicskei, 2.(1) 483,525 Boehlow, T. (8) 106 Boerers, C. (6) 23 Boemgter, H. (1) 284 Boese, R. (1) 418,419 Bogdan, F.M. (5) 162 Bogdanov, A, (5) 44 Bogoradovskii, E.T. (8) 14 Bohsako, A. (1) 392 Bojilova, A. (3) 16 Bolli, A. (5) 156 Bolte, J. (4) 40 Bolte, M.(1) 339 Bolton, P.D. (6)30; (7) 20 Bolubinskii, A.V. (8) 14 Bond, J.E. (1) 101 Bond, M.R (1) 82 Bongert, D. (8) 3 1 Bongibault, V. (4) 58 Bonne, F. (4) 2 14 Bonofacio, F. (1) 274 Bookham, J.L. (1) 107 Booth, B.L. (1) 387; (6) 91 Borcharat, R.T. (6) 154 Borge, J. (8) 97 Borgmeier, 0. (7) 32 Borner, A. (1) 133; (3) 21 Bornscheuer, U.T.(4) 49 Borzatta, V. (7) 165 Borzyk, 0. (6) 178 Boscarato, A. (6) 150 Bosch, B. (1) 92 Boschi, T. (2) 28 Bosco, M.(1) 330 Bose, S. (4) 57 Bosque, R. (1) 269 Bosscher, G. (7) 100-102 Botschwina, P. (8) 83 Botta, M. (4) 159 Bouchu, D. (4) 14 Boudou, V. (5) 63
333 Bouhadir, G. (7) 127 Bouix, C. (4) 125 Boulmaaz, S. (1) 154 Bourdon, C. (1) 93 Bourghida, M. (1) 28 BOU~SSOU, D. (1) 479,480 Bourne, S.A. (4) 229; (8) 43 Boutellier, J.-C. (8) 70 Bowen, J.P. (4) 220 Bowen, R.J. (1) 16; (8) 28 Bowler, W.B. (4) 207 Boyd, M.(5) 119 Boyer, J.L. (5) 25 Boyle, P.D. (8) 12 Boyode, B. (5) 189 Boys, D. (1) 355 Bracken, K. (4) 56 Brade, H. (4) 44 Bradley, B.P. (4) 153 Briiuchle, C. (1) 24 Braich, R.S. (5) 196 Brain, P.T. (8) 13 Braman, J.C. (5) 342 Branchaud, B.P. (5) 66 Brandi, A. (1) 227 Brandsma, L. (1) 42,106 Brandt, K. (7) 89,90 Brandt, P. (6) 98 Braniak, J. (4) 238 Branquet, E.(6) 63 Bras, J. (6) 163 Brassat, L. (1) 497,499,500 Brauer, D. (1) 62 Braun, A. (5) 286 Braun, E. (5) 277 Braun, N.A. (6) 62 Braunschweig, H. (1) 94 Braunstein, P.(6) 36; (7) 62 Breaker, R . R (5) 359,360 Bredikhin, A.A. (2) 17 Breedlove, B.K. (8) 180 Breipohl, G. (5) 118, 123 Breit, B. (1) 438,520 Breit, R. (1) 248 Breitsameter, F. (1) 126; (6) 12, 13
Breneman, C.M. (1) 98 Brenner, c. (5) 71 Brenowitz, M. (5) 308 Brenton, A.G. (8) 143 Breuer, E. (4) 193 Breunig, H.J. (1) 373 Brevnov, M.G. (5) 228 Bricklebank, N. (1) 306 Bridgman, A.J. (5) 192 Brimacombe, J.S. (4) 34 Brimacornbe, R. (5) 44,3 15 Bringer-Meyer, S.(4) 46
334
Organophosphorus Chemistry
Brintzinger, H.-H. (1) 9,362 Brisse, F. (1) 342 Broussier, R. (1) 93 Brown, D.M. (5) 56-58 Brown, E. (1) 230 Brown, J.M. (1) 117 Brown, J.W. (4) 134 Brown, P.O.(5) 282,284 Brown, R.S. (4) 59 Brown, T. (5) 35 1,352 Broxterman, R. (1) 228 Bruckmann, J. (1) 37,38 Briicher, R (6) 138 Brugger, J. (5) 180 Bruice, T.C. (5) 138, 139 Bruin, G.J.M. (5) 291 Brule, H. (5) 312 Brummel, H. (5) 104 Brun, A. (3) 17; (8) 42 Bruneau, C. (1) 27 Brunel, J.-M. (4) 168, 198 Brunelle, D.J. (1) 214 Brunner, H. (1) 7,35,99 Brusatin, G.(7) 147 Bruslk, K.S.(4) 234 Bryce, M.R. (6) 171 Brynda, M. (8) 66 Brzezinski, B. (7) 51,52 Buc, H. (5) 55 Buckingham, M.R (7) 114 Budker, V. (5) 209 Budzelaar, P.H.M. (1) 264 Biichner, M. (1) 53 Biirkle, U.(6) 62 Bugg, T.D.H. (4) 155 Buhling, A. (1) 141 Buijsman, R.C. (5) 39 Bujoli, B. (1) 293; (4) 98 Bujoli-Doeuff, M. (1) 293 Buono, G. (1) 75; (4) 78, 168, 198 Burczak, J.D. (5) 278 Burdette, S.C. (1) 397 Burger, K. (4) 135 Burger, W. (5) 302 Burgess, K. (5) 52 Burgin, A.B. (5) 178,229 Burilov, A.R. (2) 19 Burke, T.R., Jun.(4) 140 Burkus, F.S.,I1 (7) 42, 55 Burmeister, J. (5) 361 Bums, B. (4) 169 Burns, S.L.(1) 306 Burton, D.J. (4) 102 Burton, J. (3) 6 Buryakova, A.A.'(5) 125, 199, 200
Busalev, Yu.A. (4) 54; (8) 47 Busson, R. (5) 172
Butcher, S.E. (5) 320 Butler, 1.R (1) 14 Butler, RN. (4) 177 Butorina, L.S. (8) 122 Butterfield, K. (6) 130 Bykhovskaya, O.V. (1) 353 Byriel, K.A. (1) 340,34 1 Bym, R.W. (1) 30 Bystrom, C.E. (5) 66 Cababa, D. (4) 212 Caballeira, N.M. (6) 143 Cacwnese, S. (4) 243; (8) 155 Cadena, J.M. (1) 267 Cadet, J. (5) 165 Cadierno, V. (6) 67 Caesar, J.C. (4) 134 Cai, B . 2 . (4) 89 Cai, X.H.(5) 296 Cain, C.P. (4) 109 Caliceti, P.(7) 179, 180, 182, 183 Caliman, V. (1) 506,508,509 Camaioni, E.(5) 25 Camarasa, M.J. (4) 121 Camillen, P.(4) 237 Caminade, A.-M. (1) 160, 163; (4) 17-19; (6) 117; (7) 93,94 Camino, G. (7) 82 Campana, C.F. (1) 336 Campredon, M. (8) 71 Camuzat-Dedenis, B. (6) 160 Canac, Y.(1) 424,479,480 Canepa, C. (1) 213 Cano, H. (6) 5 Cantrill, A.A. (4) 167 Cao, P. (1) 66
Cao,R.(1) 17 Capitani, D.(7) 135 Cappellacci, L.(5) 77
Cardin, C.J. (1) 26 Careri, M. (8) 162 Carlini, C. (1) 166 Cannalt, C.J. (1) 405,460; (4) 164 Carmen, M. (6) 75 Carmi, N. (5) 359 Carmichael, E. (5) 6 Carmona, D.(1) 355 Caminci, P. (5) 53 Carr, M.D. (1) 30 Carran, J. (6) 119 Carrano, C.J. (1) 82 Carre, F.(6) 14; (8) 48 Carriedo, G.A. (7) 87, 156; (8) 80 Caniedo, U.(7) 154, 155 Carrho, J. (5) 290 Carson, S.(5) 242 Carter, J . ( 5 ) 90
Carter, K.W. (1) 332 Caruthers, M.H. (5) 104 Casciola, M.(8) 124 Case Green, S.C. (5) 288 Casey, C.P. (1) 72 Cassell, A.M. (5) 365 Castelhano, A.L. (4) 141 Castillon, S.(4) 6 Catalano, V.J. (1) 108,492 Cate, J.H. (5) 42,272 Catterick, D. (6) 171 Causoglu, N. (4) 104 Cavalier, J.F. (4) 78 Cavell, R.G. (1) 263; (2) 36; (8) 113
Cech, T.R. (5) 20,265,268,329 Celatka, C.A. (6) 134 Cella, J.A. (7) 42 Cenac, N. (1) 41 1,449 Cepanec, C. (5) 312 Cerri, A. (6) 111 Ceni, V. (8) 70 Chadha, R.K. (1) 23 1 Chae, H.K. (7) 95 Chaika, E.M.(7) 139 Chakhmakcheva, O.G. (5) 124, 125,199,200
Chalton, M.A. (6) 171 Chan, A.S.C. (1) 17 C h , G. (5) 323 Chan, T.-W.D. (8) 142 Chance, M.R. (5) 308 Chandrasekaran, A. (2) 3, 21,3035; (8) 49, 50
Chandrasekhar, V. (7) 103,131 Chane-Ching, K.(1) 3 16 Chang, C.A. (5) 193, 194 Chang, F.H. (7) 149 Chang, S.(7) 106 Chang, T.C. (8) 26 Chmg, Y.-T. (4) 20,27 Changenet, P.(1) 211 Chantegrel, B. (4) 181 Chao, Q.(5) 32 Chappell, M.D. (5) 15 Chapyshev, S.V.(1) 5 13 Chardon-Noblat, S.(1) 55 Charra, F. (1) 3 16 Charubala, R (5) 183 Chassagne, A. (4) 122 Chatal, J.-F. (4) 157 Chattopadhyaya, J. (5) 2 18 Chaudret, B.(7) 93 Chauhan, M. (6) 14; (8) 48 Chaulk, S.G.(5) 145 Chauvin, Y.(6) 36; (7) 62 Chen, C.€. (1) 17 Chen, C.H. (7) 145
Author Index Chen, D. (4) 97 Chen, E.C.M. (5) 235 Chen, E.S. (5) 235 Chen, F.E.(5) 334 Chen, G. (1) 336 Chen, H.-C. (8) 107 Chen, H.F. (5) 324 Chen, J. (4) 119, 206; (7) 187 Chen, L. (5) 223,333 Chen, L.-W. (7) 167, 168 Chen, M.J. (3) 24; (4) 2, 100; (7) 5 Chen, R. (4) 174,242 Chen, R.-Y. (4) 48,163 Chen, S.(4) 154 Chen, S.H.(5) 6 Chen, S.L.(5) 222 Chen, S.M. (5) 54 Chen, S.Y. (4) 75 Chen, W.Y. (8) 26 Chen, X.(2) 16; (6) 162 Chen, X.-F. (4) 184 Chen, Y.K. (5) 366; (7) 171 Chen, Y.Q. (5) 334 Chen, Z. (8) 24 Chenault, H.K. (5) 40 Cheng, C.-H. (1) 364 Cheng, J. (5) 290 Cheng, S.-W. (8) 142 Chentit, M.(1) 404,425,426; (8) 65
Chen-Yang, Y.W. (7) 149 Cheong, S.(7) 115 Cherkasov, R.A. (2) 10; (4) 240 Chernega, A.N. (1) 197,414; (6) 20
Chernyak, V. (5) 236 Cheruvallath, Z.S. (5) 97 Chesney, A. (6) 171 Chesnut, D.B.(8) 8,32 Chevalier, F.(6) 120 Chicote, M.-T. (1) 384 Chiesi-Villa, A. (1) 23; (3) 4 Chillemi, R.(5) 13 ChiMa, c. (4) 91 Chitsaz, S.(8) 104 Chiu, G. (4) 153 Chiu, W.-Y. (7) 167-170 Chiu, Y . 4 . (1) 296; (7) 168; (8) 26
Cho, H.D. (1) 202,313 Cho, H.N.(6) 172 Cho, R.J. (5) 283 Cho, S.Y. (1) 138; (8) 94 Cho, Y.H.(7) 189 Choi, N. (8) 17 Choi, S.-Y. (4) 71 Choi, Y.J. (4) 129
Chojnowski, J. (7) 44 Chondroudis, K. (8) 108 Choo, H. (1) 389 Choob, M.V. (5) 124, 199,200 Chow, C.S. (5) 162 Christau, H.J. (6) 128 Christensen, L. (5) 108, 115, 116 Chrisstoffels, L.A.J. (4) 96 Christoffers, J. (1) 74 Chrostowska, A. (1) 411 Chuang, 1.-S. (1) 165 Chuit, C. (6) 14; (8) 48 Chug, S.-K. (4) 20,27 Church, G. (5) 242 Churchuryukin,A.V. (1) 156 Ci, L.-J. (8) 139 Cicchi, S.(1) 227 Ciceron, L. (6) 160 Ciesielski, W.(4) 225,245; (8) 10 Cieslak, J. (5) 134 Cifbentes, M.P. (8) 19 Cindari, T.R. (1) 453 Cinta, S. (8) 82 Cipolla, L.(4) 117 Clade, J. (8) 114 . Clardy, J. (1) 320 Claridge, T.D.W. (4) 60 Clark, D.S.(4) 138 Clark, J.H. (4) 211 Clark, T. (1) 382,474 Claver, C. (4) 6 Clegg, W.(1) 97 CIBment, J.-C. (1) 121; (4) 180 Clemmer, D.E.(5) 354 Clerici, F.(1) 385; (6) 59 Clivio, P. (5) 33 1 Cloke, F.G.N. (1) 484,505 Close, D.M. (8) 72 Clyburne, J.A.C. (1) 405; (4) 164 Coates, C.G. (5) 258 Coates, R.M. (4) 9 Cobley, C.J. (1) 143; (8) 62 Cohen, B.E.(5) 73 Cohen, S.B.(5) 329 Coindet, M. (4) 127 Cole, D.L.(5) 97 Coleman, R.S.(5) 171 Collado, I. (6) 164 Collado, M.I.(1) 479,480 Collart, F.R (5) 77 Collignon, N. (6) 120 Collingwood, S.P.(1) 28 1 Colvin, M.(8) 12 Coman, V. (8) 163 Comesse, S.(6) 129 Comins, D.L.(6) 162 Condom, R.(5) 112 Condon, A.E. (5) 307
33 5 COMOIIY,S.(6) 137 Conrad, M. (5) 306 Conrad, 0. (8) 30 Constable, E.C. (1) 36 Constantieux, T. (4) 168,198 Constantinescu, R. (8) 163 Contreras, R (1) 355; (2) 20; (8) 45
Convery, M.A. (5) 327 Cook, P.D. (5) 204,221 Cook,R.A. (1) 101 Copley, R.C.B.(6) 30 Corain, B. (6) 37; (7) 64 Carey, D.R (5) 210 Corn, R.M. (5) 287,307 Cornils, B. (1) 169 Cornish, T.J. (5) 286 Correll, C.C. (5) 317 Corriu, R.J.P. (6) 14; (8) 48 Cosquer, A. (1) 359 Cosstick, R. (5) 3 1,265 Costa, E. (1) 102, 103 Costa, L.(7) 82 Costisella, B. (1) 282; (5) 62 Cotter, RJ. (5) 286 Couladouras, E.A. (1) 23 1 Coutre, S.(5) 173 Coward, J.K. (4) 154 Cowley, A.H. (1) 82,405,452, 460; (4) 164
Craig, D. (4) 185,186 Cravotto, G. (4) 114 Crawford, M.J. (1) 369 Cremer, S.E.(1) 334 Crescenzi, V. (7) 135 Crich, D. (4) 71 Crisci, G. (1) 379 Cristau, H.J. (1) 395; (4) 116; (6) 86; (8) 136
Critcher, D.J. (6) 137 Crociani, L. (6) 37; (7) 64 Crofts, S.(5) 255 Croom, D.K. (5) 72 Crossman, A., Jr. (4) 34 Croteau, R.B. (4) 9 Crowe, L.A. (2) 18 cuadrado, P.(1) 44 Culp, RD. (1) 82 Cumming, S.A. (4) 134 Cundy, V.A. (7) 193 Cunskis, S. (1) 48 Curiel, D. (6) 73; (7) 14 Cuth, E.H.(7) 46 CYPrYk M. (8) 10 C d o , W.(1) 378 Dagan, A. (5) 297
336 Dahan, F. (1) 250,251; (7) 127 Dahl, B.M. (3) 29 Dahl, 0. (3) 2, 29; (5) 96, 114, 116, 122
Dahlberg, A.E. (5) 316 Dahlenburg, L. (1) 100 Dai, G. (8) 127 Dai, L.-X. (4) 184 Dai, Q. (4) 242 Dai, X. (1) 142 Dal, H. (8) 99 Dalcanale, E.(4) 96 Dallas, A. (5) 3 18 Dalley, N.K. (1) 204 Dalpozzo, R.(1) 330 Damha, M.J. (5) 195, 196 Dance, I. (1) 276,277; (8) 133 Dancil, K.P.S. (5) 289 Dang, H . 4 . (1) 217 Dani, P.(1) 116; (8) 96 Darwish, A.D. (1) 199 Das, P. (7) 161 Daub, J. (6) 176 Dauban, P. (4) 126 Daubresse, N. (6) 149 David, M.-A. (1) 430 Davidescu, C.M. (1) 391 Davidson, M.G. (1) 367,368; (6)
11,30,95,96; (7) 19; (8) 102, 103 Davidson, S.M.K. (4) 23 1 Davie, K. (4) 197 Davies, D.B.(7) 89,90 Davies, F.A. (6) 108 Davies, H.M. (6) 127 Davies, J.E. (1) 333; (6) 122 Davies, M.C. (7) 185 Davies, R.P. (1) 333; (6) 121, 122 Davies, S.R. (4) 109 Davis, J.M. (8) 169 Davis, R.W. (5) 283,284 Davis, S.S.(7) 185 Davis, T.P.(1) 3 12 Davison, A. (8) 132 Davisson, V.J. (5) 188 Davleschina, G.R (2) 19 Day, R.O. (2) 3,21, 30-34; (8) 49, 50
Debart, F. (5) 132 Debelak, H. (5) 178 de Boer, E.J.M. (1) 504 De Bruyn, A. (5) 155 DeCian, A. (7) 62 Decken, A. (1) 82,405 de Claim, R.P.L. (5) 347 De Clerq, E. ( 5 ) 5 De Filippis, P.(7) 183 Deforth, T.(1) 178
Defrancq, E.(5) 227 Degoul, F. (5) 3 12 Dehelean, G. (8) 148 Dehnicke, K. (7) 11,21, 22,24,
25,28-32,50, 126; (8) 104
Dehollander, G. (5) 332 Deiters, J.A. (2) 29 De Jaeger, R. (7) 70,99, 147, 166; (8) 110 Dejardin, S.(7) 177, 178 de Kanter, F.J.J. (1) 456 De Kimpe, N. (4) 137 de Kort, M. (4) 25 De La Cruz, A. (8) 106 Delest, B. (1) 129 Delichere, P. (8) 90 Dell'Aquila, C. (5) 137, 140 Della VCdova, C.O. (7) 46 De Los Santos, J.M. (1) 386 Del Zotto, A. (8) 29 Demarcq, M.C. (1) 2 19 Dembeck, G. (1) 419 Dembkowski, L. (4) 80 De Mesrnaeker, A. (5) 240 de Monte, M.(4) 216 Deng, L. (5) 143 Deng, N. (8) 147 Deng, S. (4) 41 Denis, J.-M. (1) 287,408 Denker, M. (1) 373 Denmark, S.E.(6) 100 Denney, D.B. (2) 7 Denney, D.Z. (2) 7 Denq, B.-L. (7) 167-170 Dentini, M.(7) 135 De Parrodi, C.A. (8) 39 Depewv, W.T.(5) 8 DePinto, R.L. (8) 69 Depree, G.J. (1) 314 De Risi, J.L. (5) 282,284 Dernailly, G. (6) 87 Deronzier, A. (1) 55 Dervan, P.B. (5) 184, 247-251, 346,347
des Abbayes, H. (1) 121; (4) 180 Desamparados, V.M. (6) 75 Deschamps, B. (1) 50 1 Deshayes, C. (4) 181 Desmurs, P.(1) 502 Desper, J.M. (1) 294 Despeyroux, D. (8) 137 Devillanova, F.A. (1) 308 Devitt, P.G. (4) 109 de Vries, J.G. (1) 5 1 de Vroom, E. (6) 148 de Vrueh, R.L.A. (5) 206 de Wolf, W.H. (1) 456 Dez, I. (7) 99
Organophosphonis Chemistry Dhamelincourt, P. (7) 70, 71 Dhesi, J. (5) 35 1 Dhuru, S.P.(1) 208 Diaz, A.R. (5) 225 Diaz Perez, V.M. (6) 82; (7) 7,s Dickins, RS. (4) 159 DiCosirno, R.(4) 138 Dieckbreder, U.(2) 15 Dieckmann, T.(5) 320 Diederichsen, U. (5) 157 Diefenbach, U. (7) 78, 8 1 Dieleman, C.B. (1) 283 Diernert, K. (4) 178 Dieters, J.A. (8) 11 Diez-Barra, E. (6) 32 Digeser, M.H. (1) 81 Dillon, K.B. (1) 368; (6) 96; (8) 103
DiMare, M. (1) 432 Dinault, A.N. (4) 2, 100 Dindal, A.B. (8) 146 Dineva, M.A. (5) 49 Ding, H. (1) 171 Ding, M.W. (7) 18 Ding, Y.(1) 299 DiRenzo, A.B. (5) 158 Dirk, R. (1) 94 Diter, P. (1) 246 Diver, S.T. (4) 202 Dixneuf, P.H. (1) 27 Dmitriev, V.I. (1) 105 Dobbert, E. (8) 30 Dobrikov, M.I. (5) 45 Dobson, P.J. (5) 288 Dodd, R.H. (4) 126 Doetz, K.H. (1) 427 Dogadina, A.V. (1) 360 Doherty, S.(1) 97 Dohno, R. (4) 72 Doi, T.(1) 363 Dokudovskaya, S.(5) 44 Dolinnaya, N.G. (5) 159 Dornbrowski, A. (1) 8 Donde, Y.(1) 150 Dondoni, A. (6) 150, 151, 157 Dong, H.L. (5) 281 Dong, L. (1) 298 Dong, M. (8) 181 Donnadieu, B. (1) 146, 188, 258, 411; (4) 18, 19
Donoghue, N. (2) 4; (8) 46 Dontsova, 0.(5) 44 D o e , P.H. (4) 153 Doriguzzi, F.(7) 163 Donnond, A. (1) 502 Dorner, L.F.(5) 344 Doublie, S.(5) 341 Doucet,H. (1) 117
Author Index
Doudna, J.A. (5) 272 Dougherty, B.J. (7) 116 Dougherty, J.P.(5)173 Dougherty, R.W.(5) 72 Douglas, M. (5) 146;(8) 141 Dougulis, 0.(4)202 Dovgopoly, S.I.(1) 51 1; (4)99 Downing, J.H. (1) 134 Downs, A.J. (8) 13 Doxsee, K.M. (1) 259,260 Doyle, R.J. (1) 57 Doyle, T.W.(5)6 Drabowicz, J. (3) 7;(4)149 Drago, RS.(1) 256 Drake, G . R (1) 186 Dransfeld, A. (1) 78;(8) 23 Driess, A. (1) 47,63,64,90 Driess, M. (1) 433 Drmanac, R.(5) 278 Drmanac, S.(5)278 Drobyshev, A.L. (5) 279 Dros, A.C. (8) 55 Druckenbrodt, C. (1) 179, 180;(6) 42 Drysdale, M.J. (6)25 D'Sa, B.A. (2)26 Du, A. (4)242 Durn, J.-P. (1) 364 Dubovik, 1.1. (7) 139 Duesler, E.N. (1) 292,462 Duflos, M.(4) 157 Dujardin, G.(1) 230 Dullweber, U.(1) 58 du Mont, W.-W. (1) 179-181, 191;(6)42 Dunbar, L.(1) 333;(6) 121, 122 Dunigan, J.M.(6)104 Dunina, V.V.(1) 270 Dunn, C.J. (4)208 Dunn, S.(7) 185 Duppmann, M. (8) 41 Dupret, D.(5) 175 Duralski, A.A.(4)47 Durand, P. (6)63 Dutel, J. (1) 441 Dybowski, P. (4)86
Eagling,R D . (1) 247 Earnshaw, D.J. (5) 330 Easson, M.A.M. (4)158 East, M.B.(1) 135 Eaton, B.E. (5) 19, 190 Ebara, Y.(5) 294 Ebdon, D.(8) 176 Ebel, C.(5)319 Ebels, J. (1) 8 Ebert, K.H.(1) 373
Eccleston, J.F. (5) 357,358 Echarri, R.(4)6 Eckerle, A. (1) 5 10 Eckstein, F. (5) 330 Edlin, C.D. (4)94 Edwards,M.(7)96 Effenhauser, C.S. (5) 291 Efimov, V.A.(5) 124, 125, 199, 200 Efimtseva, E.V.(5) 228 Eguchi, S.(6)76-78;(7) 12, 15, 17 Eguchi, T. (4)13 E h t , M. (5) 291 Ehrenberg, M. (5) 3 19 Ehsan, M.Q. (1) 244 Eichen, Y.(5) 277 Eickmeier, C.(6) 175 Eilers, B.(1) 252 Eisenbeiss, F. (8) 172 Eisenstadt, A. (1) 135 Eisfeld, W.(1) 472 El-Amin, S.(7) 175, 176, 180 Elass, A. (7)70,71 El Bachir, K. (1) 148 El-Batouti, M. (1) 380;(8) 175 Eldred, C.(4) 175 Eldrup, A.B. (5) 114 El Essawi, M.M. (1) 374 Elgersma, J.W.(1) 141 Elghanian, R (5) 303,304 El Hallaoui, A. (4) 147 Elharli, A. (7) 174 Elias, A.J. (7)97 Eliel, E.L. (4)223;(8) 52 El-Kateb, A.A. (2)12 El Khatib, F. (2) 11 Ellenberger, T.(5) 341 Ellennann, J. (7)33-35 Ellinger, Y.(1) 425,426 Ellington, A.D. (5) 130,327,354, 361 Ellis, D.D. (1) 131 El Manouni, D. (4) 127 El-Masw, F.M. (8) 84 Elmore, C.S. (4)9 El-Nahhal, I.M. (1) 165 Elsevier, C.J. (1) 51,240;(7)9 Eltoukhy, A.H. (7) 109 . Emam, H.A. (8) 84 Emge, T.J. (4)57 Emsley, J. (6)1 Enders, D. (4) 13 1; (6) 116 Endler, K.(4)77 Endo, S.(1) 372 Enev, V.(1) 136 Engelhardt, U.(7)78 Engels, B.(8) 77
337 Engemann, C. (8) I14 Englert, U.(1) 94 Enjalbal, C. (1) 395; (8)136 Eremenko, A. (4)246 Erian, A.W.(6)54 Eriksson, S.(5) 17 Eritja, R.(5) 146, 163, 197,225; (8) 141 Erker, G. (1) 92;(6)2 Erlanson, D.A. (5) 223,224 Ermolaeva, L.V.(2) 19 Ermolinsky, B.S.(5) 228 Escaja, N.(5) 198 Eschenmoser, A. (5) 156, 157 Escher, J.H. (3) 8 Escudie, J.(1) 429;(8) 21 Essevaz-Roulet, B.(5)363 Essigmann, J.M. (5) 166, 167 Etemd-Moghadam, G.(1) 196; (3) 17;(8)42 Eustache, J. (4) 125 Evans, D.A. (4) 189 Evans, M. (4)85 Evans, S.A., Jun. (4) 148 Evans, T.A.(5) 51 Evilia, C. (5) 168 Ewers, C.L.J. (1) 136 Exarhos, G.J. (7)67 Eymery, F. (4) 101, 107 Ezquerra, J. (6) 164 Fabbn, D. (1) 137 Facchin, G.(6)27;(7) 130, 147, 163 Fader, L.D. (5) 119 Fager, S.K.(4) 138 Failla, S.(4)243;(8) 105, 155 Fairhurst, I. (6) 24 Fairhurst, S.A. (6)33 Falck, J.R (4)28,36;(6) 144 Falkiewicz, B. (1) 226 Fallon, L. (5) 78 Falvello, L.R. (6)39 Famulok, M. (5) 21 Fang, W . (8) 7 Fantin, G.(7)88 Fanwick, P.E. (1) 56,334 Farahat, M. (4)236;(5) 1 1 Faraj, A. (4)216;(5) 63 Farese, A.(5) 112 Farkens, M.(4)228 Farnetti, E. (1) 157 Farquhar, D.(4) 15 Faulhaber, M.(1) 64 Faure, B.(1) 75 Favero, G.(7) 164 Favre, A.(5) 33 1
338
Fa!, R.(8) 112 Fawcett, J. (1) 18, 132 Faza,N. (7) 11,24,28,30,31 Fedriui, G. (6) 111 Feher, R (1) 503 Fehrentz, J.-A. (6) 169 Feierbach, B. (5) 283 Feigelson, G.B. (6) 83; (7) 3 Feigon, J. (5) 275,320,348-350 Felber, R (4) 144 Felder, E.R (6) 167 Felix, I.R. (5) 56 Fell, T.S.(5) 288 Feng, H.-Y. (8) 87 Feng, J. (8) 16 Feng, M. (5) 6 Fenske, D. (1) 78 Ferguson, G.(6) 25 Ferguson, M.A.J. (4) 34 Feringa, B.L. (1) 172-174 Ferla, B.L. (4) 117 Fernandes, J.R. (5) 296 Fernandez, E.J. (1) 351,354 Fernandez, G.(7) 154 F e h d e z , S.(6) 39 Fernandez-Baeza, I. (6) 32 Ferretti, R (1) 274 Fcms, J.P.(1) 98 Ferris, K.F. (7) 67 Fems, L. (4) 182 Fessner, W.-D. (4) 118 Fetisova, E.N. (4) 103 Fettes, K.J. (5) 29,30 Fettinger, J.C. (7) 60 Fickert, C. (8) 82 Fiedler, W. (1) 447,45 1 Filippov, D. (5) 4 Fini, M.(7)179,180 Fink, S.P.(5) 185 Finlay, F.RV. (6) 146 Finocchiaro, P.(4) 243; (8) 105, 155
Fiorini, C. (1) 316 Firouzabadi, H.(1) 388 Fischer, A.K. (1) 29; (4) 228 Fischer, C. (1) 29; (4) 146 Fischer, J. (1) 120; (7) 62 Fisher, K. (8) 133 Fitcva, N.A.(4) 156 Flann, C.J. (4) 70, 172 Fleischhauer, J. (4) 170 Flesher, RJ. (1) 155 Flessner, T.(1) 13 Florenw C.(5) 3 12 Floriani, C. (1) 23; (3) 4 Flower, K . R (1) 249 Fluck, E. (1) 523,524; (8) 101 Fluharty, S.J. (5) 280
Fogagnolo, M. (7) 88 Fmt-Bardia, M.(1) 269 Foos, E.E. (1) 85 Foote, R.S.(5) 293 Ford, A. (6) 24 Foreman, M.RSt. J (1) 468; (4) 173; (7) 125
Fornies, J. (1) 26 Fonter, N.H. (7) 107, 108 Forsyth, C.J. (4) 130 Fortkamp, J. (4) 5 1 Fom, S.M.(5) 36 Fortunik, W.(7) 44 Fotiadu, F. (4) 78 Fotin, A.V. (5) 279 Fournier, D. (4) 58 Fourrey, J.L. (5) 33 1 Fraanje, J. (1) 141 Francesch, C.(6) 149 Franchetti, P.(5) 11,77 Francis, M.D. (1) 443 Frank, B. (6) 175 Frank, W. (1) 382 F d r , R (4) 74 Fraser, J.L. (1) 167 Fraser, S.A. (4) 205 Fraser, W.(5) 157 Frkhou, C. (6) 87 Fredoueil, F. (1) 293 Freeborn, B. (5) 3 17 Freiberg, E.(8) 132 Freitas, A.M. (6) 6 Frey, H.(1) 164 Frick, A. (1) 53 Frick, F.(8) 114 Friedrichs, S.(1) 18 Friend, C.M. (8) 116 Friot, C.(1) 408 Fritsch, V.(5) 240 Fritz, G. (1) 402,403 Fritzsche, G. (6) 178 Frtihlich, C.J.(4) 205 Frtihlich, R (1) 92; (6) 2 Friihlichovd, L. (7) 48 Frommen, C. (7) 29 Fromont Racine, k.(5) 283 Frqen, P. (1) 390 Frutos, A.G. (5) 287,307 Frydenlund, H.(5) 237-239 Fu, G.C. (1) 432,498 Fu, H.(8) 144 Fu, H.N.(5) 9 Fu, H.-X. (1) 337 Fu, J.-M. (4) 141 Fuchs, A. (1) 410; (8) 92 Fuentes, J. (6) 82; (7) 7, 8 Fuji, K. (6) 97. Fuji, M.(4) 52
Organopho,sphorusChemistty Fujii, M. (4) 69 Fujii, Y.(1) 398; (4) 52 Fujimoto, T.(1) 290; (6) 84 Fukunaga, K. (4) 62 Fukushima, K.(7) 45 Fukuwatari, N. (7) 194 Fulop, F. (4) 226,227; (8) 53.54 FWI, H.-K. (1) 335 Furegati, S.(4) 76 Furukawa, H. (5) 153,211 Furusawa, H. (5) 294 Fuselli, N. (5) 12 Fylaktakidou, K.C. (6) 5 1 Gabold, S.(5) 127 Gafhey, B.L. (5) 89 m e y , P.RJ. (4) 31 Gailbreath, B.D.(1) 349,350 Gait, M.J.(5) 330 Gajda, T.(6) 112 Galdecka, E.(8) 109 Galdecki, 2.(8) 109 Galimov, R.D.(2) 19 Galinet, L.A. (4) 208 Gallagher, J.A. (4) 207 Gallagher, M.J.(2) 4; (8) 46 Gallett, A.M.R (1) 166 Gallinella, B. (1) 274 Galliot, C. (7) 94 Galzigna, L. (8) 145 Gamasa, M.P. (6)67; (8) 97 Gamble, M. (4) 169 Gamblin, S.J. (5) 357,358 Games,D.E. (8) 143
Gan,X.(1) 292 Gancarz, R.(4) 132 Ganci, W.(4) 76
Ganoub, M.A. (2) 13 Ganter, B. (1) 497,499,500 Ganter, C. (1) 130,497,499,500 Gao, L. (7) 146
Gao,R (4) 242 Gao,R-Y. (8) 154
Garau,A. (1) 308 Garbuova, LA. (7) 137, 138 Garcia, A. (1) 239; (7) 1, 154, 155 Garcia, J. (1) 3 15 Garcia, R G . (5) 163,225 Garcia Alonso, F.J. (7) 87, 156; (8) 80 Garcia-Alvarez, J.L.(7) 156 Garcia-Exposito, E. (6) 118 Garcia Ferndndez, J.M. (6) 82; (7) 7, 8 Garcia-Gmda, S. (8) 97 Garcia-Montalvo, V.(7) 34 Garcia, X.(1) 279
339 Gopaul, D.N. (5) 337 Gielen, R (1) 62 Gardiner, M.G.(1) 223 Goralczyk, P. (8) 173 Gierasch, L.M. (5) 322 Garegg, P.J. (4)32 Gorbunova, M.G. (3) 13 Gierling, K.(1) 155 Gareis, B.(7) 190 Gorbunova, Y.E.(8)79 Giese, B.(5) 233,234 Gamer, A.C. (1) 16 Gorbunowa, E. (1) 524;(8)101 Giese, R.W. (5) 242 Gamer, C.M. (4)241 Gordillo, B.(4)223;(8) 52 Gigmes, D. (1) 424 Garnett, M.C. (7)185 Gorin, B.(4)217 Gil, J.M. (4)87 Gamier, F.(5) 298 Gomitzka, H.(1) 251,401,429; Gilardi, R.(4)210 Garrett, S.W. (4)22 (7)127;(8) 21 Gilbertson, S.R (1) 336 Ganyszewska, P. (8) 109 Gorter, S.(6)127 Gill, M.S. (4)59 G-c, M.-B. (4) 116 Gosner, C. (4) 14 Gilman, A.G. (5) 356 Gasparutto, D. (5) 165 Gossage, R.A. (1) 33, 116;(8)96 Gilmore, 1.J. (1) 504 Gates, D.P. (7)66,96,140,162 Gosselin, G. (4)216;(5) 7, 17,63 Gaumont, A.-C. (1) 287,359,408 Gimeno, J. (6)67;(8)97 Gotfiedsen, C . H (5) 348 Gimeno, M.C. (1) 351,354 Gautheron, B.(1) 93 Goti, A. (1) 227 Giovenzana, G.B. (4)114 Gavagan, J.E. (4)138 Gottlieb, M.(5) 183 Giunchedi, P. (7)183 Gavrilov, K.N. (2) 23 Gottlieb, P.A. (5) 48 Giusti, G. (8)71 Gavrilovic, D.M. (2)7 Goubitz, K.(1) 141 Gladiali, S.(1) 137 Gawdzik, B.(1) 33 1 Gracqk, P. (1) 348;(8) 75 Glass, RS.(8) 182 Gay, F. (6)160 Graham, J.C.H. (4)85 Glazer, A.N. (5) 292 Gaytan, P. (5) 208 Graiff,C.(8) 162 Gleiter, R (1) 130, 131;(6) 178 Gee, V. (1) 134 Gramlich, V.(1) 54 Glendenning, L. (1) 157 Gefflant, T.(4)40 Gleria, M. (7)88,130,147,163- Gramstad, T. (8) 117 Geierstanger, B.H. (5) 347 Grandas, A. (5) 198 165 Geiger, C. (4)236 Grandi, T.(5) 220 Glick, G.D. (5) 328 Gellman, S.H (1) 294 Granell, J. (1) 267,268 Glinsboeckel, C. (1) 500 Gelmi, M.L. (1) 385;(6)59 Grant, D.H. (5) 296 Gliide, J. (1) 282;(2)9;(4)179 Gendin, D.V. (1) 104 Gras, J.L.(6) 180 Glover, J.N.M. (5) 224,333 Genet, J.-P. (1) 148;(4)79 Grassi, A. (8)68 Glueck, D.S.(1) 430 Gengembre, L.(7)166 Graves, D.E. (5)245 Glukhovtsev, M.N. (1) 213 Genieser, H . G . (8) 143 Graves, R.(7) 172 Gnudi, S. (7)180 Genov, D.G. (1) 346;(8)56 Gray, D.E. (5) 288 Goad, M.E.P. (7)180 Gentile, C. (5) 284 Gray, G.M.(1) 454 Goddard, R (1) 158 GeofEoy, M. (1) 404,425,426; Godfrey, S.M. (1) 192-194,307; Graziani, M.(1) 157 (8)65966 Grech, E.(7)51 George, A. (4)237 (8)3644 Green, M.L.H. (5) 366 Godillot, P. (5) 298 George, J. (5) 74 Greenberg, M.M. (5) 170,203 Galler, A. (1) 382,448,474 Geraldes, C.F.G.C. (8) 17 Greenberg, W.A. (5) 184 Gerasimov, M.V.(7) 139 Giirg, M.(2)14, 15 Greenbiatt, J. (5) 321 Gerbase, A.E. (8) 118 Goerke, A. (4)241 Greene, T.M. (8) 13 Gefin, T.(1) 54 Goerlich, J.R. (1) 288 Greenfield, S.R.(5) 232 Geribo, J.R (7) 186 Goerls, H.(1) 358;(6)1 10 Gref, A. (1) 246 Germe, L.O.(5) 290 Goesmann, H.(7)126 Gregan, F.(8)33 Gershon, P.D. (5) 325 Goeta, A.E. (6) 11; (7)19 Grifantini, M. (5) 11,77 Gerus, 1.1. (3) 13 Goldstein, B.M.(5) 75,76 Griffin, L.C. (5) 173 Gescheidt, G. (6)176 Goldstein, S.W.(4) 153 Griffin, S. (1) 123 Gestin, J.-F. (4)157 Golen, J.A. (6)107 G r i m T.J.(5) 241 Gev-rey, S.(8) 134 Goller, R (1) 415 Grifliths, D.V. (4)128,134;(6) Geze, A. (4) 116 Gomez, E. (7) 154, 155 101,102 Ghadiri, M.R (5) 289 Gomez-Tagle, P. (8) 183 Griffon, J.F.(5) 63 Ghassemi, H.(1) 295 Gontarev, S.V. (5) 217 Grigor'eva, A.A. (8) 121,122 Ghorai, M.K. (1) 243 Gonzalez, C.A. (5) 229;(6) 4,5 Grimme, S.(8) 114 Ghosh, A.K. (4) 15 G o d e z , G.(7) 155 Ghosh, G. (5) 334 Gonzilez, P.A. (7)87, 156;(8) 80 Grishin, Yu.K. (1) 270 Grishkun, E.V.(4) 124 Giardino, R.(7) 179, 180 G o d l e z , S.(6)174 Gritsenko, O.M. (5) 228 Giavaresi, G. (7)180 Godez-Nogal, A.M. (1) 44 Grobe, J. (8)30 Gibbs, R A . (4)7;(5) 52 Goodson, F.E. (1) 365 Groebke, J. (5) 157 Gibson, H.W. (1) 303 Goodwin, N.J. (1) 132,247 Groeger, H.(1) 288;(4) 150 Giege, R.(5) 312 Goosen, M. (1) 240;(7)9
Author Index
OrganophosphonisChemistry
340
Grolle, S.(4) 46 Gromova, E.S. (5) 228 Grotli, M. (5) 146, 197; (8) 141 Grove, S.J.A. (4) 39 Gruber, H. (1) 377 Griitzmacher, H. (1) 90,91, 154; (6) 41; (8) 110
Grund, E.M.(7) 186 Gryamov, S.M.(5) 129, 135 Gu, R.L. (6) 141 Guan, M.X. (5) 186 Gudat, D. (1) 162,410,431,459,
470,477; (6) 15, 152; (8) 92
Gudmunsen, D. (1) 3 Guedj, R. (5) 1 12 Guengrich, F.P. (5) 185 Guerret, 0.(1) 423 Guglielmi, M. (7) 147 Guijarro, D. (4) 183 Guillaneux, D. (1) 246 Guillemette, G. (4) 23 Guillemin, J.-C. (1) 98, 125 Gulyh, H. (1) 50 Gumas, F. (4) 75 Gunther, K.(1) 440 Guo, D. (8) 144 Guo, F. (5) 337 Guo, M.J. (5) 65 Guo, Q. (7) 173 Guo, Z.J. (5) 366 Gupta, G. (4) 176 Gupta, N. (4) 176; (8) 2 Gupta, V. (5) 174 Gurevich, I.E. (1) 360 Gurudutt, V.V. (5) 77 G ~ S U O VN.K. ~ , (1) 42,104-106, 286
Gustavo, T. (8) 4,5 Gutell, RR. (5) 41 Guzaev, A, (5) 80,189 Guzei, I.A. (1) 79
Haaima, G. (5) 116 Haaland, A. (1) 71; (8) 14, 115 Haase, M.(1) 358; (6) 110 Habicher, W.D. (3) 28,33 Habimana, J. (7) 44 Habus, I. (5) 205 Hachiken, H. (6) 58 Hackenbracht, G. (4) 176 Haeberli, P. (5) 158 Haenel, M.W. (1) 37,38 Hafez, A.M. (6) 70 Hafkemeyer, P. (5) 62 Haher, M. (6) 176 Hagel, M. (1) 52 Hagiwara, H. (1) 207
Hagstrom, J.E. (5) 209 Hah, J.H. (4) 87 Hahn, I. (1) 199 Haiduc, I. (8) 82 Haigh, D.(4) 182 Haikal, A.F. (5) 332 Hajra, S. (1) 243 Hakala, H. (5) 81 Halcomb, R.L. (5) 15 Hall, A.C. (8) 178 Hall, C.D.(1) 381; (2) 8; (6) 10; (8) 177, 178 Hall, J. (5) 256 Hallenga, K. (5) 323,324 Hamada,Y.(1) 122 Hamaguchi, S. (6) 115 Hamann, B.C. (1) 20 Hambley, T.W.(5) 366 Hamilton, A.D. (5) 262,263 Hamilton, A.L. (5) 56,57 Hamilton, R (4) 145 Hammerschmidt, F. (4) 151 Hammond, G. (6) 107 Hammond, M.H. (5) 253 Hammond, P.J. (2) 7 Hammond, S.M.(4) 155 Hamprecht, D.(6) 89,155 Hamzaoui, M. (6) 160 Han, L.(1) 289; (6) 145 Han, L.-B. (1) 216 Hanawalt, E.M. (1) 259,260 Haner, R. (5) 84,256 Hanna, M.T. (1) 380; (8) 175 Hanna, R.L. (5) 272 Hannour, S. (4) 147 Hansen, C.B. (1) 481 Hansen, H.F. (5) 115,116 Hansen, M.M. (4) 143 Hanson, B.E. (1) 171 Hanson, P.R. (4) 190 Harada, K. (1) 363 Hardcastle, K.I. (8) 105 Harden, T.K. (5) 25 Harger, M.J.P. (4) 191, 192, 194196
Hargittai, I. (1) 345 Hargittai, M. (1) 345 Hargreaves, D. (5) 338 Harkness, A.R. (4) 143 Harmat, V. (1) 483 Harmata, M.(1) 332 Harms, K. (1) 520; (7) 23,29,32, 50
Harre, M. (1) 136 Harriman, A. (1) 11, 120; (6) 38 Hams, C.J. (1) 130, 131 Harris,D.L. (4) 223; (8) 52 Hams, F.M.(8) 143
Hams, J.E. (4) 128; (6) 101, 102 Hams, K.D.M. (1) 344 Hams, R K . (2) 18; (8) 38 Harrison, S.C.(5) 333 Harrod, J.F.(1) 87 Hartle, T.J. (7) 15 1 Hamann, M. (1) 77 Hartwell, J.G. (5) 161 Haavig, J.F. (1) 20 Harvey, P.J. (8) 28 Harvey, R.G. (6) 161 Harvey, T.C. (4) 120 Hanvood, J.S. (4) 234 Hasan, A. (5) 103; (8) 159 Haselgrove, T.D. (6) 85 Hashimoto, H. (5) 60 Hashimoto, Y.(1) 67, 153,206; (5) 113
Hashizume, H. (4) 52 Hashmi, A.S.K.(1) 339 Hassler, K.(1) 62 Hatanaka, M. (6) 61,92 Hatano, K. (1) 122 Hatger, M.J.P. (1) 469 Hattori, T. (1) 140 Haubs, M. (1) 169 Hauser, B. (5) 278 Hauske, J.R. (1) 234 Havenaar, P. (5) 126 Hawkins, M.(5) 183 Hawkins, P.T. (4) 39 Hawkrigg, J. (1) 361; (8) 37 Hawley, A. (7) 185 Hay, A S . (1) 299 Hayakawa, Y. (3) 23;(5) 82,83 Hayase, T. (4) 171 Hayashi, H. (5) 219 Hayashi, M.(1) 67,153 Hayashi, S.(6) 99, 109; (8) 89 Hayashi, T. (1) 118 Hayashizaka, N . (1) 140 Hayashizaki, Y.(5) 53 Hayes, C.J. (4) 2 18 Haynes, R.K. (1) 285 He, G.-X. (1) 229; (5) 173 He, H.W. (8) 73 He, K. (8) 159 He, L. (4) 174 He, L.-N. (4) 163 He, M. (1) 144, 145,394; (8) 57 He, 2.-J. (4) 12 Healy, P.C. (8) 28 Heath, G.A. (8) 19 Heath, L. (1) 123 Hecht, S.M. (4) 215 Heckmann, G. (1) 523,524; (8) 31, 101
Hegedus, L. (1) 323
Author Index Heilz, A. (6) 169 Hein, S. (5) 207 Heinemann, F.W. (1) 96; (7) 3335 Heiner, C.R. (5) 54 Heinicke, J. (1) 29, 65, 144, 145; (8) 2357 Heinze, K.(1) 29 1 Heise, J.D. (8) 180 Hekmat-Shoar, R (1) 183; (6) 93 Helena, S. (8) 4,5 Heller, D. (1) 29; (3) 10 Heller, M.J. (5) 290 Helm, M. (5) 312 Helsberg, M. (5) 207 Henderson, E.E. (5) 186 Henderson, W. (1) 132,247,278; (8) 131 Henegar, K.E.(6) 141 Hennaway, I.T. (2) 12 Henning, L. (4) 77 Hemiksen, U.(5) 122 Henry, J.-C. (4) 79 Herberhold, M. (7) 91 Herbert, A. (5) 345 Herbst-Irmer, R (1) 434 Herdewijn, P.(5) 155, 160, 172, 228 Herdtweck, E. (1) 60 Herker, M. (1) 25 Herman, B.T. (4) 194 Hermann, T.(5) 266 Hermanto, P.(5) 323,324 Heme, T.M.(5) 301 Heropoulos, G.A. (8) 27 Heroux, A. (1) 342 Herpin, T.F. (4) 105 Herrmann, B.G.(5) 335 Herrmann, D.B.J. (4) 75 Herschlag, D. (5) 268 Heslot, F. (5) 363 Hessler, A. (1) 76 Heydari, A. (3) 14 Heydt, H. (1) 474 Hey-Hawkins, E. (1) 88,89,257 fibbs, D.E. (1) 306,361,507; (8) 37 Hidai, M. (1) 12,152 Higashi, N. (5) 367 Higashiyama, M. (1) 392 Higgins, S.J. (1) 177 Higson, A.P. (5) 104 Higuchi, K. (6) 140 Hildbrand, S. (5) 65 Hill, A.F. (1) 421,443; (8) 95 Hill, F. (5) 56-58 Hill, H.A.O. (5) 366 Hill, L. (1) 190,383; (6) 60, 173
Hillebrand, S.(1) 37 Hillen, W. (5) 273 Hillisch, A. (6) 165 Himeda, Y. (6) 61,92 Hingst, M. (1) 41 Hirai, T. (5) 61 Hirao, I. (5) 87,327 Hirao, T.(5) 300 Hiratake, J. (4) 152 Hird, N.W.(6) 66 Hirotsu, K. (1) 406 Hirsch, J.A. (5) 344 Hirsch-Kuchma, M. (8) 132 Hirschmann, H.(4) 201 Hiscox, S.M. (7) 42 Hitchcock, P.B.(1) 484,506,508, 509; (7) 26,27 Ho, M.H. (5) 281 Ho, S.P.(5) 280 Hoaglund, C.S.(5) 354 Hodel, A.E. (5) 325 Homauer, W.(1) 410; (8) 92 Hoffmann, A. (1) 437 Hof€mann, J. (1) 474 Hoffmann, R (8) 161 Hofinger, A. (4) 44 Hofinann, A. (7) 91 Hofinann, M. (8) 13 Hogan, P.G.(5) 333 Hogen-Esch, T.E. (1) 393 Hoheisel, J.D. (5) 79 Hoic, D.A. (1) 432,498 Hoke, G.D. (5) 161 Hokelek, T.(8) 99, 100 Holbert, A.W. (8) 116 Holderberg, A.W. (1) 43 1; (6) 15 Hole, E.O. (8) 72 Holloway, J.H (1) 18 Holmes, A.B. (4) 39 Holmes, H.M. (4) 166 Holmes, RR. (2) 3,21,29-35; (8) 11,49,50 Holmgren, S.K.(1) 294 Holmlin, R.E. (5) 23 1 Holz, J. (1) 133; (3) 21 Holzner, A. (5) 157 Honda, F. (5) 91 Honeyman, C.H. (7) 150 Hong, F. (4) 42; (7) 4 Hoag, J.-I. (1) 389; (4) 200 Hong, M.K. (5) 161 Hooper, D.L. (6) 19 Hoops, G.C. (5) 188 Hoover, L.R. (1) 3 1 Hope, E.G. (1) 3, 18 Hope, H. (1) 259,260 Horan, C.J. (1) 454 Hone, T. (6) 22
34 1 Horikawa, K. (1) 114 Hormes, J. (8) 114 Horn, T. (5) 193, 194 Homer, J.H. (4) 71 Homer, M. (8) 118 Homung, L. (5) 207 Hornyak, M.J. (4) 212 Horrocks, B.R (1) 247 Horstmann, S. (7) 37 Horton, A.D. (1) 504 Horvath, I.T. (1) 101 Horvath, K. (8) 149 Horvath, S.E.(5) 186 Hosoito, N. (1) 372 Hossain, M.A. (1) 244 Hossain, N. (5) 155 Hostetler, K.Y. (5) 9 Hotoda, H. (5) 153,211 Houalla, D. (2) 21,22 Houlton, A. (1) 247 Housecroft, C.E. (1) 36 Housseini, S. (1) 381; (6) 10 Howard, J.A.K. (1) 368; (6) 11, 30,96, 171; (7) 19; (8) 103 Howard, S.T.(6) 9 Howarth, N.M.(5) 117 Hsiue, G.-H. (1) 296 Hu, G.G. (5) 340 Hu, H. (8) 16 Hu, Y.-S. (7) 168 Hua, R (1) 289; (4) 93 Huang, C. (2) 7 Huang, C.-C. (1) 364 Huang, D.B. (5) 334 Huang, J. (6) 31 Huang, J.-M. (8) 154 Huang, K. (4) 8 Huang, L. (5) 106 Huang, L.J. (7) 106 Huang, M. (4) 242 Huang, M.-B. (6) 8 Huang, Q.T.(4) 8; (5) 89 Huang, T. (4) 110, 133; (5) 244 Huang, X. (4) 71, 197 Huang, X.-Y. (1) 337 Huang, Y.-Z. (6) 69 Hubeman, E. (5) 77 Hubscher, U. (5) 62 Huck, W.T.S. (1) 161 Hud, N.V. (5) 275 Hudig, D. (4) 205 Hudlicky, T. (6) 158 Hudson, H. (8) 9 1 Hudson, R.H.E. (5) 195 Hue, X.-L. (4) 184 Huff, B.E. (4) 143, 187 Huffman, J.C. (1) 30,3 1 Hughes, D.L. (6) 33
342 Hughes, J.M.(4)134 Hui, Y.(4)41 Hume, S.C.(I) 325 Humphrey, M.G. (8) 19 Hung, J.-T. (1) 454 Hung, W.F. (7)18 Hung, Y.(7)106 Humble, P.(1) 484 Hunziker, J. (5) 157 Hurman, B.T. (1) 469 Hursthouse, M.B. (1) 306,361, 383,507;(6)60;(7)89,90; (8) 37 Husken, D. (5) 256 Hutchison, D.R. (4)143 Huttner, G. (1) 46-49,53,291 Huy, N.H.T.(1) 400,455,457, 491 Hwang, J. (8) 174 Hwang, J.J. (7)149 Hwang, S.Y.( 5 ) 284
him,S.E.M. (7)175, 176, 180 Ibrahim, A.R (1) 335
Ichikawi, Y.(I) 416 Igau, A. (1) 34, 129, 146, 188, 258,411 Ihara, T. (5) 299 Iida, A. (1) 320 Ikai, K. (1) 320 Ikeda, I. (1) 139 Ikeda, T.(1) 356 Ikematsu, H. (7)84 Ilia, G.(8) 148 Il'in, E.G.(4)54;(8) 47 Il'ina, M.N.(7)139 Illum, L. (7)185 Imada, Y.(4)69 Imai, T.(5) 260 Imai, Y.(1) 139 Imamoto, T. (1) 6 Imanishi, T.(4)188 Imbach, J.-L.(4)216; (5) 7,17, 34,63,131,137,140 Inagaki, M. (4)232,233
Lnaki,Y.(5) 1 1 1 Inamati, G. (5) 221 Indra, E.M. (7)161 Indzhikyan, M.G. (1) 189 Inoue, H.(1) 218;(8) 158 Inoue, K.(7)86,92,104, 105;(8) 81 Inoue, M.(4)3; (6)133 Inoue, T. (5) 367;(7) 191, 192 Inubushi, Y.(1) 400 Invidiata, F.P.(3) 15 Ionin, B.I. (1) 360
Iorga, B.(4)101,107 Ipaktschi, J. (3) 14 Iranpoor, N.(1) 15 Irie, K.(6)66 Irie, T. (4)152 Imgartinger, H.(6)178 Ishaq, K.(4)75 Ishido, Y.(5) 87,88 Ishmaeva, E.A. (1) 445;(8) 3 Islam, T.S.A.(1) 244 Islami, M.R. (1) 184;(6)94 Issberner, K. (1) 427 Issleib, K.(1) 59 Itabashi, A. (7)120 Itabashi, H. (4)3 Itaya, T. (7)86,92,104,105;(8) 81 Ito, S.(1) 235,412,413 Ito, Y.(1) 119 Itoh, K.(3) 3 1 Ivanov, I.G.( 5 ) 49 Ivanova, I.S. (8)79 Ivy, P.L. (6)70 Iwama, T.(1) 200 Iwao, Y.(6)84 Iwasaki, F.(1) 218 Iyer, N.(4)75 Iyer, R.P.(5) 205 Iyer, R.S. (5) 212 Iyer, V.R. (5) 282 Iyer, V.V. (5) 2 Izawa, M. ( 5 ) 53 Izod, K. (1) 97 Jackson, B.A. (5) 276 Jackson, D.S.(4)205 Jackson, S.L. (1) 307 Jacob, M.(1) 221 Jacobi, A. (1) 48,49 Jacobson, K.A. (5) 25 Jacobson, M.K.(5) 70 Jacobson, S.C. (5) 293 Jacopoui, P.(4)96 Jaquet, L. (5) 258 Jaeger, R. (7)140 Jaekle, F. (1) 60 Jaf€kes, P.A. (4)90,92 Jahnke, T.S.(5) 32 Jain, C.B. (8)2 Jain, R.K. (5) 230 James, K.D. (5) 130 James, M.K. (5)72 Jang, D.O.(1) 202,313 Janoschek, R. (1) 63,433,524;(8) 101 Jansen, M.(8) 77, I14 Janssen, R.C. (5) 19
Organophosphorus Chemistty
Janu~a,M.(1) 7,279 Janzen, A.F., (4) 197 Jarosq S. (6)64,65 Jaschke, A. (5) 23 Jasko. M.V. (5) 64 Jastorf€, B. (8) 172 Javier, F. (2)20 Jayanthi, S.(1) 212 J a y a m , H.N. (5) 77 Jayasuriya, N.(4)57 Jekel, A.P. (7) 100,101 Jemmis, E.D. (7)68 Jenkins, D.J.(4)29 Jenkins, I.D. (1) 16 Jenkins, R A . (8) 146 Jenkins, S.A. (7)186 JeMe, A. ( 5 ) 21 Jennings, K.(4)237 Jeon, G.S. ( 5 ) 24 Jerome, F.(1) 27 Jeske, J. (1) 179, 181,475,478 Jetzfellner, R.(1) 59 Ji, J. (7)153 Ji, Q.(1) 303 Jim, S.-H. (8)87 Jiang, M. (5) 296 Jiang, Q.(1) 66 Jiang, Y.(1) 66 Jimenez-Bueno, G.(4)85 Jin, H.(5) 12 Jin, Y.(5) 26 Jockusch, S.(1) 311 Joerg, S. (1) 256 Johnson,C.W. (1) 237 Johnson, D.A. (4)205 Johnson, J.S.(4) 189 Johnson, W.T. (5) 188 Jones, A.G. (8) 132 Jones, A.N. (5) 72 Jones, B.C.N.M.(5) 265 Jones, C.(1) 421,443,507;(8) 95 Jones, D.J. (8) 124 Jones, E. (1) 523 Jones, H.L. (1) 177 Jones, P.G. (1) 22,29,124,144, 179-181,191,283,288,317, 338,351,354,384,463,475-
478;(2)18;(4)95,228;(6) 42;(7)61;(8) 2,57 Jones, P.S. (4) 185, 186 Jones, R.A. (1) 82;(5) 89 Jones, V.A. (1) 461 Joo, Y.H.(1) 202 Jordan, C.E.(5) 287 Joseph, J.C.(1) 98 Joseph, S.( 5 ) 3 13 Jouanno, C. (5) 240 Jouati, A. (1) 404,425,426;(8)
Author Index 65 Juaristi, E. (1) 347; (8) 39 Juge, S.(1) 148 Jui, K. (6) 172 J u g , 0.-S. (7) 95,189 Jung, Y.G. (4) 200 Jungmann, 0. (5) 183 Jungmann, V. (5) 128 Junker, H.-D. (4) 118 Jurcqk, S.C. (5) 164 Just, G. (3) 26; (5) 26,27 Jux, U.(1) 145 Jwo, J. (8) 174 Kabachnik, M.I.(1) 352,353; (8) 121,122 Kabbaj, Y.(5) 34 Kabsch, W. (5) 355 Kaczmarek, R. (4) 224 Kadokura, M. (5) 67 Kadyrov, A.A.(2) 15 Kadyrov, R.(1) 29, 144, 145; (3) 10; (8) 57 K a b , S. (6) 71 Kagan, H.B. (1) 13,246 Kagechika, H. (5) 113 Kagoshima, H.(1) 206 Kahlil, F.Y.(1) 380 Kahn, M.(4) 139 Kai, Y. (1) 372 K a i q s. (1) 4 Kairies, s. (7) 77 Kajimura, A. (5) 260 Kajita, R (1) 195 Kajiwara, M.(7) 83,84 KajtBr-Peredy, M. (1) 241; (7) 6 Kajzar, F. (1) 3 16 Kakehi, A. (1) 290; (6) 76,78,84; (7) 15, 17 Kakinuma, K.(4) 13 Kakinuma, T.(5) 88 Kalchenko, 0.1. (4) 244; (8) 153 Kalchenko, V.I. (4) 244, (8) 153 Kalindjian, (7)13 Kalinichenko, E.N.(5) 187 Winkina, A.L. (5) 124,199,200 Kalnin'sh, K.K.(6) 7 Kalra, K.L. (5) 212 h, C.-M.(4) 205 Kamaike, K. (5) 88 Kamalov, RM.(8) 78 Kamei,H. (1) 118 Kamer, P.C.J. (1) 141, 149 Kaminicek, J. (1) 3 18 Kaminski, R (8) 182 Kanatzidis, M.G. (8) 108 Kanavarioti, A. (8) 157
Kanazawa, A. (1) 356
Kanazawa, H. (7) 111
Kandpal, L.D. (1) 300 Kanehisa, N.(1) 372 Kaneko, M.(5) 153,211 h g , D.-H. (1) 242 Kang, H . 4 . (7) 50 Kang, J. (1) 171 Kang, S.O. (8) 94 Kansui, H.(4) 62 Kant, M. (1) 40 Kanyo, J. (5) 168 Kao, J. (1) 336 Kaptein, B. (1) 228 Kamcar, A. (1) 22; (4) 95 Karaghiosoff, K. (1) 78; (4) 176 Kari, L.(5) 305 Karim, K.(6) 101 Karimian, A.(3) 14 Kariuki, B.M. (1) 344 b o p , M. (1) 179, 181 Karolctak, W.(4) 115 Karpati,T. (1) 125 Karpeisky, A. (5) 229,326 Karsch, H.H.(1) 25 Kaschke, M.(1) 178 h h a e v a , E.A. (1) 445 Kashiwagi, K. (1) 363 Kaska, W.C. (1) 155 Kasparek, F. (1) 318 Kasu, P.V.N. (6) 108 Kataev, A.V. (8) 3 Kataev, V.E. (8) 3 Katalenic, D.(3) 27 Kataoka, M.(3) 23; ( 5 ) 82 Kataoka, T.(1) 200 Kates, S. (5) 324 Kato, H. (4) 152 Kato,K. (1) 118 Kato, Y. (1) 320 Katoh, M. (4) 152 Katsyuba, S.A. (8) 78 Katti,K.V. (1) 110,111 Katzenbeisse, U. (i) 62 k h a n , T.S.(1) 201 KaufmaM,B. (1) 59 Kaukorat, T. (1) 3 17; (4) 228 b P P , M. (1) 90 Kawaguchi, K. (6) 48 K a w c h i , T. (5) 61 Kawahara, S. (5) 91 Kawai, R ( 5 ) 83 Kawamura, K.(8) 186 Kawamura, Y.(1) 235; (6) 22 Kawasaki, Y. (1) 195 Kawase, M.(5) 294 Ka~ashima,T. (6) 126; (8) 111 Kayser, M.M. (6) 19
343 Kayyem, J.F. (5) 364 Kazakova, E.I. (1) 270 Kazakova, E.Kh. (2) 19 Kazakova, M.Yu. (1) 270 Kazrnaier, U.(1) 187 Kazmierski, S.(4) 225; (5) 133; (8) 10 (8) 126 Ke, D.-Y. Kee, T.P. (1) 461; (4) 109 Keglevich, G. (1) 321-324, 483, 525 Kehler, J. (4) 193; (5) 96, 122 Keitel, I. (2) 9; (4) 179 Kelley, S.O. (5) 23 1 Kellogg, R.M.(8) 55 Kelly, J.D. (4) 134 Kelly, J.M. (5) 258 Kelve, N. (5) 187 Kernmitt, R.D.W. (1) 3 Keng, T.€. (8) 107 Kennard, C.H.L.(1) 340,341 Kenndler, E. (8) 166, 167 Kenney, P.(5) 214 Kent, M.A. (5) 213 Ken, A. (4) 80 Kerschl, S. (1) 61 Kerth, J. (1) 261 Kevill, D.N. (8) 176 Khalil, F.Y. (8) 175 Khalil, M.I. (6) 44 Khalili, H. ( 5 ) 261 Khan, S.H. (5) 54 Khandurina, J. (5) 293 Khanpure, S. (6) 142 Khamesh, B. (1) 370 Khau, V.V. (4) 143,187 Kheradmandan, S.(1) 79 Khidre, M.D. (1) 255 Khlebnikova, T.B.(1) 68 Khoury, R.G.(2) 28 Khusainova, N.G. (2) 10; (4) 240 Kickelbick, G. (7) 123 Kida, T.(1) 139 Kiefer, J.R (5) 342 Kiefer, W.(8) 82 Kielbasinski, P. (8) 173 Kielkopf, C.L.(5) 346 Kierkels, H. (1) 228 Kihara, T.(5) 10 Kilic, E.(8) 100 Kilic, 2.(8) 99, 100 Kim, B.H. (5) 121 Kim, C.Y. (6) 172 Kim, D.Y.(4) 129, 136,203; (6) 172 Kim, I.C. (1) 301 Kim,1.0. (1) 39 Kim, J.Y. (4) 203
Organophosphorus Chernishy
344
Kim, K.-C. (4) 27 Kim, K.-M. (1) 217; (7) 95 Kim, K.S. (7) 184 Kim, M . 4 . (4) 27 Kim, P.S.(5) 345 Kim, S.(4) 38; (8) 94 Kim, S.H. (1) 203 k m , S.J. (5) 121 Kim, S.K.(5) 169 Kim, Y.B. (7) 160 Kim, Y.G. (5) 345 Kim, Y.S. (7) 189 Kim, Y.T. (7) 95 Kimura, S. (5) 153,211 Kindermann, M.K. (1) 29 King, I.(5) 6 King, N.P. (4) 169 King, S.J. (1) 127 Kingston, J.V. (4) 5 Kiran, B. (7) 68 Kirby, A.J. (4) 237 Kirchhhoff, R. (1) 418 Kirchmeier, R.L. (7) 97 Kireev, V. (7) 157 Kireeva, I.K. (8) 79 Kirsche, K. (4) 81 Kirschning, A. (1) 37 1 Kiselev, V.D. (1) 445 Kiselyov, A.S. (6) 168 Kishi, Y. (6) 132 Kishimoto, S. (7) 113 Kishimoto, Y. (8) 168 Kishore, K. (1) 212 Kiss, G. (1) 101 Kita, D. (5) 278 . Kiyono, S. (7) 56 Klaebe, A. (4) 58 Kliisek, A. (6) 71 KlapZjtke, T.M. (1) 369; (7) 72,73 Kleban, M. (6) 15 1 Klein, I. (6) 62 Klekota, B. (5) 253 Klika, K.D. (4) 227; (8) 53 Klinowski, J. (8) 10 Knebl, R. (1) 44 1 Knerr, L. (4) 50 Knizek, J. (1) 81; (6) 43 Knobel, A.K.H. (3) 8 Knobler, C.B. (1) 259 Knochel, P.(1) 2,21,32 Knoke, S.(8) 17 Knovalov, A.I. (1) 445 KO,J. (8) 94 KO, Y.-H. (7) 115 Kobayashi, H. (7) 122 Kobayashi, K. (7) 111 Kobayashi, M. (6) 139, 140 Kobayashi, N. (5) 28
Koch, D. (1) 4 Koch, K.A.(7) 152 Koch, M.H.J. (5) 319 Koch, T. (5) 115,237-239 Kockritz, A. (1) 40,205; (4) 179 Kodama, Y, (1) 290; (6) 84 Kodra, J.T. (5) 164 Kohler, F.H.(1) 503 Koenig, B. (1) 252 Koenig, M. (1) 196; (2) 11 Koga, N. (6) 3 Koga, R (5) 21 1 Koga, T. (5) 106 Koh, D.W.(5) 70 Kohama, M. (1) 372 Kohlpainter, C.W. (1) 171 Kohring, G. (8) 114 Koidan, G.N. (1) 414 Koizurni, M. (5) 87, 153,211 Kojima, S.(6) 47,48 Kojima, T. (1) 495 Koketsu, J. (6) 3 Kokin, K. (6) 99, 109; (8) 89 Kolb, H.C.(4) 84 Kolbe, A. (1) 348; (8) 75 Kolbina, G.F. (7) 134 Koldziejczyk, A.S. (1) 226 Kolesnik, V.D. (6) 103 Kollegger, G.M. (1) 62 Kolmschot, S. (1) 116; (8) 96 Kolodiazhnyi, 0.1. (1) 147; (4)
Kosaka, T. (5) 153.2 1 1 Koshland, D.E.(5) 73 Kosky, P.G.(7) 42 Koslov, E.S.(4) 99 Koslowski, A. (4) 170 Kosma, P.(4) 44 Kosonen, M.(5) 18 Koster, H. (5) 286 Kostyuk, A.N. (1) 197,511; (4)
Kolomeitsev, A.A. (2) 14 Kolshorn, H. (1) 393 Komarova, L.I.(7) 137, 138 Komatsu, K. (5) 113 Kornen, C.M.D. (1) 456 Komiyama, M.(5) 259,260 Komuro, Y. (1) 140 Konovalov, A.I. (2) 19; (4) 156 Konovalova, I.A. (2) 17 Konovets, A.I. (1) 197; (6) 20 Konradsson, P.(4) 32 Konze, W.V. (1) 422; (6) 35,40 Kooijman, H. (1) 172,240; (7) 9;
Krause, H.W. (4) 146 Krause, W.E. (7) 159 Kraut, J. (5) 343 Krautscheid, H. (1) 403 Krawczyk, S.H. (5) 173 Krayevsky, A.A. (5) 64 Krebs, B. (8) 30 Kreher, T. (1) 205 Kreitmeier, P.(6) 176 Kresinski, R.A. (1) 346; (8) 56 Kretschmann, M. (7) 81 Kreutzer, D.A. (5) 166, 167 Krief, A. (1) 119 Krieger, M.(7) 22,23 Krill, S.(1) 454 Krivjansky, S. (5) 90 Kropp, E. (5) 90 Kroto, H.W. (1) 199 Krotz, A.H. (5) 97 Kroutchinina, N. (5) 293 Kriiger, C. (1) 37, 38,62,510 Krug, J. (1) 436 Krysiak, J.A. (4) 83 Krzyzanowska, B. (8) 159 Ksebati, M.B.(4) 7 Kuang, S.-M. (1) 45
124; (6) 46
(8) 55
Kool, E.T. (5) 50, 144, 174,201 Koolpe, G. (7) 116 Koppel, LA. (7) 53 Koppitz, M. (5) 107 Koptyug, I.V. (1) 3 11 Koreeda, M. (1) 232 Korkin, A.A. (1) 414 Komdorffer, F.M. (1) 504 Komer, S. (3) 33 Kornuta, P.P.(1) 198 KOIY~-YOUSSOU~~, H. ( 5 ) 298 Korshun, V.A. (5) 217'
99; (6) 20
Kotila, S.(1) 8 Kotoris, C.C. (4) 100 Kotynski, A. (4) 245 Kouno, M.(7) 56 Koutsantonis, G.A. (8) 28 Kova'cs, J. (1) 241,403; (6) 82; (7) 6-8
Kowall, B. (1) 65 Koyama, T. (7) 110 Kozamernik, T. (1) 245 Kozikowski, A.P. (4) 4,33 Koziol, A.E. (4) 225; (8) 10 Kozlov, E.S.(1) 5 11 Krabbenhoft, H.O. (1) 2 14 Kraemer, R (1) 163 Krafczyk, R (1) 124; (2) 6 Kraikivskii, P.B. (8) 67 Krajewska, D.(4) 245 Kramer, L. (4) 45 Kramkowski, P.(1) 442 Kraszewski, A. (4) 80; (5) 133, 202
Author Index Kubiak, C.P. (1) 56;(8) 180 Kubicki, K.M. (1) 93 Kubicki, M.M. (6)32 Kuboto, Y. (4)69 Kucera, L.S. (4)75 Kuchen, W.(4)178;(8) 41 Kucken, S.(1) 76 Kuda, S.O. (1) 119 Kudryavtseva, L.A. (8) 184 Kudzin, Z.H. (4)245 Kuhnigk, J. (1) 38 Kukhar, V.P.(3) 13 Kulak, T.I. (5) 186 Kulkarni, M.G. (6) 181 Kumar, G. (7) 112 Kumar, K.P. (4)53 Kumar, K.R. (1) 243 Kumar, S.(5) 56;(6) 177 Kunieda, T.(4)62 Kunkel, F. (7)50, 126 Kunkely, H. (8)85 Kuntz, E.G.(8) 120 Kupka, T. (7)89 Kurachi, Y. (7) 194 Kurakata, S.4. (4)43 Kurasawa, 0.(5) 38 Kurchavov, N.A. (5) 181 Kurochkin, I. (4)246 Kurth, V.(1) 100 Kurunczi, L. (1) 5 16 Kurz, S.(1) 88 Kusch, D.(5) 233 Kutney, L.(5) 242 Kutsuna, T. (1) 206 Kuwano, R.(1) 119 Kuyl-Yeheskiely, E.(5) 39,110, 126 Kuz'mina, L.G. (1) 270 Kvasyuk, E.I. (5) 186 Kwiatkowski, J. (1) 341 Kwon, J.H. (1) 203 Kwon, M.S.(7) 175, 176 Kwon, Y.-U. (4)20,27 Laali, K.K. (1) 451 Labarre, J.-F. (7)75, 124 Labarre, M.-C. (7) 124 Labat, I. (5) 278 Labeots, L.A. (5) 323,324 Lack c. (1) 164 Lackova, V.(8) 185 LaCOlla, P. (5) 11 Lagier, C.M. (8) 38 Laguna,A. (1) 35 1,354 Lagunas,M.-C. (1) 384 Lahoz, F.J. (1) 355 Laitinen, R.H. (1) 19
345 Lebuis, A.-M. (1) 87 Lake, C.H.(1) 262 Le Camus, C. (4) 122,219 Lam, V.Q.(4)166 Lechkin, D.V. (2)23 Lam, W.W.-L. (1) 285 Lee, C.-H. (8)94 Lamata, M.P. (1) 355 Lamb, S.(1) 367,368;(6)95,96; Lee, C.O. (7) 189 Lee, C.-Y. (7) 167 (8)102,103 Lee, D.H.(4)27 Lambert, C. (1) 24 Lee, E.J. (4)27 Lambert, J.B. (1) 319 Lee, G.H. (1) 17 Lammettsma, K. (1) 262,454, Lee, H. (7)95 456 Lee, I.Y.(4)38 Lampronti, I. (3) 15 Lee, J.Y. (5) 121 La Munyon, D.H.(6)162 Lee, K.-J. (1) 203 Lan, C.-W.(1) 296 Lee, L.G. (5) 54 Landry, D.W.(4)166,213;(7)5 Lee, M.-R. (1) 17 Lane, A.N. (5) 35 1,352 Lee, S.(1) 39 Lane, J.W. (1) 237 Lee, S.B.(1) 389 Lane, T.M. (1) 334 Lee, S.G. (1) 301 Laneman, S.A. (1) 135 Lee, Y.-A. (7) 189 Lang, H.(1) 27 1 Lee, Y.-H. (8) 94 Lange, H.(1) 130, 131 Lefebvre, I.M. (4) 148 Langer, F. (1) 32 Le Floch, P. (1) 518,519,521, Langley, J.G. (1) 199 522 Langner, R. (8) 76 Le Floch,Y.J. (6)135 Langouet, S.(5) 185 Le Gendra, P. (1) 27 Lao, K.Q. (5) 292 Legendziewicz, J. (8) 109 Lapina, N.N.(7)137,138 Leger, I. (6)49 Laporte, F. (1) 496 Le Goffe, F.(6)63 Lappert, M.F. (7) 26,27 LeGolvan, M.(7)195 Lara-Sanchez, A. (6)32 Legrain, P.(5) 283 La Rosa,G. (8) 105 Legrand, 0.(4)168,198 Larre, C. (4)19;(7) 94 Lehbauer, J. (5) 183 Lartigue, M.-L. (1) 160;(4)18; Lehmann, C.W. (6)11; (7) 19 (7)93 Lehmann, T.E. (5) 184 Laschi, F. (8)68 Lehmann, W.D.(8) 140 Lash,RP.(7)158 Lei, Z.-Q. (8) 87 Lashford, A.G. (5) 57 Leigh, K.M.(1) 237 Lashkari, D.A. (5) 284 Leininger, S.(1) 409,437-440, Latham, E.J. (6)57 444,448;(8) 93 La Torre, F.(1) 274 Leising, R.A. (8) 119 Lattman, M.(2)25 Leissring, E.(1) 59 Lattuada,L. (1) 236 Leitner, W. (1) 4 Laubender, M.(1) 10 Leito, I. (7) 53 Laue, E.(5)357 Lemaire, M.(4)40,204 Laugaa, P. (5) 331 Le Mignot, V.(6)87 Laukien, F.(5) 242 Lemmouchi, Y. (7)177,178 Launay, N. (4)18 Laurencin, C.T.(7)175,176, 180 Lengsfield, B. (7)69 Leost, F.(4) 181 Laurent, A. (5) 132 Lequan, M. (1) 316 Lauricella, R.(8) 70,71 Lequan, R.-M. (1) 3 16 Lautwein, A. (5) 355 Lerner, H.-W. (1) 78 Lavergne, D.(4)79 Leroux, J.P. (5) 3 12 Law, V.S.(5) 173 Lawrence, N.J. (1) 387;(6)68,91 Leroux, Y. (4)127 Le Roy-Gourvennec, S.(4)204; Lazrek, H.B. (5) 34 (6) 117 Lea,R.H. (7) 193 Le Serre, S. (1) 125 le Baut, G. (4)157 Lesher, T.(5) 280 Le Bec, C. (5) 55 h i & , K. (5) 74-76 Lebedev, A.V.(5) 220 '
346
Lesnik, E. (5) 180 Lesueur, W. (1) 23 Le Toumeau, M.E. (4) 143,187 Letsinger, R.L. (5) 232,303,304 Leumann, C.J. (5) 65, 120, 149, 150, 157
Leung, P.-H. (1) 271,485,486, 488-490
Levalois-Mitjaville, J. (8) 110 Levchik, S.V.(7) 82 Levis, R.J. (5) 285 Levy, J.B. (1) 345; (8) 9 Lewis, F.D. (5) 232 Leyser, N. (1) 9,362 Lhomme, J. (5) 227 Li, G. (4) 242 Li, G.Y. (5) 141, 142 Li, H. (3) 24; (4) 42; (7) 4 Li, J. (1) 5 17 Li, J.-L. (4) 230 Li, J.S. (7) 28 Li, L. (8) 16 Li, M. (8) 147 Li, P. (4) 88 Li, T.(6) 146 Li, W. (4) 30 Li, X.(8) 135 Li, X.Y. (5) 6 Li, Y. (5) 271 Li, Y.C.L. (8) 142 Li, 2.(6)3 1; (8) 144 Li, 2.-A. (8) 139 Liable-Sands, L.M. (1) 79,430; (7) 96
Liao, F.-L. (1) 364 Liao, W.P. (7) 4 1 Liberles, D.A. (5) 184 Licea-Claverie, A. (1) 305 Licoccia, S. (2) 28 Lidaks, M.Y. (5) 187 Lieber, C.M. (5) 364 Liesum, L. (1) 154 LiCvre, C. (6) 87 Lightfiit, P.(6) 173 Ligtenbarg, A.G.J. (1) 173 Lim, A.C. (5) 257 Lim, C.W. (1) 39 Lin, C.H. (5) 353 Lin, C.-L. (7) 171 Lin, C.4. (1) 5 17 Lin, G.(8) 24 Lin, K.-F. (7) 169 Lin, K.Y. (5) 244 Lin, R.(8) 174 Lin, V.S.Y. (5) 289 Lin, W.-H. (4) 1 Lindsay, A.J. (7) 82, 114 Linkletter, B.A. (5) 138
Liou, S.-Y. (1) 265 Lipka, P.(4) 245 Lipkowski, J. (4) 244; (8) 153 Lippert, B.(8) 123 Lippmann, T. (4) 96 Lippolis, V. (1) 308 Lis, T. (4) 225 Litinas, E.E. (6) 5 1 Litovchenko, G.F.(8) 122 Little, D.P. (5) 286 Liu, A.M. (1) 271,485 Liu, C. (4) 21.22 Liu, C.-W. (1) 517; (8) 107 Liu, H.4. (4) 68 Liu, J. (8) 181 Liu, J.P. (4) 239 Liu, K. (4) 209,210 Liu, P. (6) 134 Liu, Q.H.(5) 307 Liu, S.-B.(8) 139 Liu, S.H. (5) 262,263 Liu, X.(1) 3 19; (8) 34 Liu, X.H.(5) 71 Liu, X.-P.(4) 239 Liu, Y.(5) 68,69 Liu, Y.L. (1) 296 Liu, Y.-S. (1) 168; (5) 354 Liu, Z. (8) 34, 147 Liu, Z.J. (8) 73 Livak, K. (5) 214 Livinghouse, T.(1) 275 Livotto, P.(7) 127 Llewellyn, G. (8) 176 Llopis, J. (4) 30 Lloyd, R.G. (5) 338 Loake~,D. (5) 56-58 Lochner, U.(5) 179 Lockhart, D.J. (5) 281,283 Lodmell, J.S. (5) 316 Loebelenz, W.E. (7) 186 Loew, R.(1) 441 Loh, S.-K. (1) 489,490 Lohmer, G.(1) 159,366 Lohse, P.A. (4) 144 Lokhov, S.G. (5) 220 Lokshin, B.V. (7) 137, 138 Lomeli, V. (1) 460; (4) 164 Long, A.M. (5) 341 Longeau, A. (1) 32 hnnberg, H.(3) 22; (5) 18, 80,
OrganophosphorusChemistty Lorenz, K.(1) 164 Lorenzo, A. (6) 74 Lorey, M. (5) 5 Loris,
R.(5) 332
Lork, E. (1) 109,373; (2) 14 Losonczi, J. (1) 19 Lott, W.B. (5) 270 Lough, A.J. (6) 25 Loussouam, A. (4) 157 Lowther, N. (2) 8; (8) 177, 178 Lu, G.(8) 16 Lu, P.(5) 168 Lu, R.(4) 165 Lu, S.-J.(1) 337 Luca, C. (1) 391 Luccioni-Houze, B. (8) 71 Luda, M.P. (7) 82 Ludanyi, K.(1) 321,323,324 Ludtke, J.J. (5) 209 Ludwig, K.N.(7) 119 Lueken, H.(7) 32 Luger, K.(5) 339 Luisi, P.L. (5) 14 Lukashev, N.V. (6) 105 Lukhtanov, E.A. (5) 209 Lukin, O.V.(4) 244; (8) 153 Lunetta, J.F. (5) 119 Luo, H.(1) 263; (2) 36; (8) 113 Luo, J. (5) 139 Luo, Z.Y. (5) 262 Lustig, C. (6) 30 Lutz, B. (I) 343 Lutz, M. (I) 456 Luu, B. (4) 50 Luyten, I. (5) 172 Ly, D. (5) 237 Lynch, D.E.(1) 340,341 Lyzwa, P. (3) 7; (4) 149
Ma, C.Y. (8) 146 Ma, D. (4) 142 Ma, L.Y. (5) 280 Maas, G.(1) 26 1 Maat, L. (6) 163 McAuliffe, C.A. (1) 192-194,307; (8) 36944
Lopezde Luzuriaga, J.M. (1) 351,
McBurnett, B.G.(1) 460; (4) 164 McCart, M.K. (1) 177 McCarthy, W.J. (4) 222 McCary, J.L. (5) 171 Macciantelli, D. (8) 71 McConnell, T.S.(5) 268 McCusker, J.H. (5) 284 Macdonald, D.D. (7) 146 McDonald, R. (1) 263; (2) 36; (8)
Lon, S.(7) 179,180,182, 183
McFail Isom, L.(5) 340
81,264; (8) 179 33 Lopez, C. (1) 269 Lopez, J.A. (1) 355 Lbpez, L.A. (6) 182
Loos, D. (8)
354
113
A irrhor Index McFarlane, W.(1) 107,271 McGall, G. (5) 78 McGany, P.F.(1) 3 1 1 McGarvey, J.J. (5) 258 McGrath, J.E. (1) 295,298,302 Mach, M. (6)65 Machado, V.G. (4)61 Maciagiewicz, I. (4)86 Maciel, G.E. (1) 165 Mclntee, E.J. (5) 1,2 Mclntyre, G.M. (6)11; (7)19 Mack, A. (1) 438 Mack, H.-G. (7)46 McKee, V.(1) 18 McKenna, E.C. (4)177 Mackewitz, T.W. (1) 407,409, 444 McLaughlin, L.W. (5) 65 McLeod, D.(2) 27 McManus, D.(4)97 MacMillan, A.M. (5) 145 McMinn, D.L. (5) 203 McPartlin, M.J. (8) 17,91 Mcwhorter, C. (4)241 McWilliams, A. (7)162 Mader, A.W. (5) 339 Madison, S.A. (8)69 Maeda, H.(4)43 Maeda, M.(5) 299 Maeda, Y.(5)3 Maerkl, G. (6)176 Magda, A. (5) 255 Maghsoodlou, M.T.(1) 182 Magiera, D.(5) 242 Maglott, E.J. (5) 328 Magull, J. (7)22 Mah, T.F.(5) 321 Mahan, M.F.(4)26 Mahieu, A. (1) 258 Mahmood, A.J. (1) 244 Mahnke, J. (1) 179 Mahran, A.M. (6)54 Maichle-Miissmer, C. (1) 155;(7) 23;(8) 118 Main, L. (1) 314 Maitra, K.(1) 108,487,492 Maitra, RK.(5) 141 Maizel, M.(4)54; (8)47 Majima, T.(4)72 Majoral, J.-P. (1) 34, 129, 146, 160, 163, 188,258,411;(4) 17-19;(6)117;(7)93,94 Majumdar, A. (5) 75,76 Majzner, W.R (4)83,224,238; (8) 173 Mak, T.C.W. (1) 45 Makarova, N.A.(2)19 Maki, E. (5) 81
Makita, K.(6)3 Makower, A. (4)246 Malaika, S.A. (3) 33 Malakhov, A.D.(5) 217 Malarski, Z.(7)5 1 Malhotra, R.(5) 280 Malik, K.M.A.(1) 306,383,507; (6)60 Maloney, J.P. (1) 84,224 Maloney, L.(5) 158,326 Maltarello, M.C. (7) 179 Malysheva, S.F.(1) 104-106,286 Mamaev, S.V.(4)215 Mamaeva, N.V.(4)215 Manasova, E.V. (5) 217 Manassero, M. (1) 137 Mandes, RF.(5) 40 Manf'erdini, M. (3) 15 Mangeney, P.(3) 5,6 Manger, M.(1) 10 Mangia, A. (8)162 Manini, P.(8) 162 M~M, G.(4)96 Manners, I. (7)66,96,128, 140, 150, 151,162 Manning, U.(4)214 Manocha, S.K. (8)58 Manoharan, M. (5) 189,204,221 Mansour, T.S. (5) 12 Mantoulidis, A.(6)147 Manq B.(1) 261 Mao, C.(5)342 Mao, S.S.H. (1) 482 Mamngoni, M. (5) 160 Marazzi, G.(6)111 Marcantoni, E. (1) 330 Marcellin, M. (I) 11; (6)38 Marchenko, A.P. (1) 414 Marchionna, M. (1) 166 Marek, J. (1) 3 18;(7)49 Mari, F.(6)4,5 Majani, K.(6)33 Markovsky, L.N.(1) 434;(4)244; (8) 153 Marnett, L.J.(5) 185 Marongiu, M.E. (5) 1 1 Marque, S.(8) 70 Marqueq V.E.(5) 163 Mana, A. (6)151 Marsault, E. (3) 26;(5) 27 Marsel, H.E.(1) 61 Marshall, W.J. (2)6 Marsilio, F. (7)183 Martell, A.E. (4)97 Martens, J. (1) 288;(4)150 Martens, R.(1) 179 Marti, B. (5) 198 Martin, C.G.(1) 328;(6) 125
347 Martin, D.L.( 5 ) 57 Martin, 1. (6)98 Martin, M.M. (1) 21 1 Martin, N.(1) 345;(6) 170,174 Martin, S.(1) 90 Martin, T.J.(5) 16 Martinelli, M.J.(4)143, 187 Martinez, C.L.(5) 52 Martinez, F.N.(4)71 Martinez, J. (4)147;(6)169 Martinez, M.(2)20 Martinez, R.(5) 208 Martinez-Martinez, F.J.(8)45 Martihi, L. (7)179 Marlynov, B.I. (4) 103 Marutoiu, C. (8) 163 Marx, G. (5) 245 Marzinzik, A.L. (6) 167 Mas, A. (7)174 ~ a s a m b aw. , (1) 45% Masamichi, M. (5) 299 Masci, G.(7)135 Masquida, B.(5) 330 M a s 4 W.(7) 11,23,24,28-31, 50
Massil, T.(1) 383;(6)60 Massinelli, L.(8) 124 Masson, S. (4)204; (6) 117 Mastryukova, T.A.(1) 352,353; (3) 20;(8) 121, 122 Masuda, H.(1) 6 Masuda, S.(4) 1 Masui, M.(1) 392 Mateo, A.I.(6)164 Matem, E. (1) 402,403 Matheu, M.I. (4)6 Mathey, F.(1) 151,400,455,457, 491,493,494,496,501,518, 519,521,522 Mathies, R.A.(5) 292 Matorell, G.H. (1) 279 Matray, T.J.(5) 170,203 Matrosov, E.I. (1) 352,353 Matsuda, A. (5) 35;(6)153 Matsuda, Y.(1) 495 Matsukawa, S.(1) 6 Matsumoto, K.(5) 10 Matsumoto, Y.(5) 259 Matsumuq N. (1) 218 Matsuo, s.(7) 110 Matsuoka, H.(7) 191,192 Matsuoka, K.'(l)195 Matsuu~a,F.(1) 122 Matsuuta, S.(5) 53 Matt, D.(1) 55, 120,283;(6)38 Mattamam, S.P. (7)60 Matter, B.A.(1) 72 Matteucci, M.D. (5) 105,244
Organophosphorus Chemistry
348
Matthes, E. (5) 62 Mattinen, J.K. (3) 22; (8) 179 Mattras, H. (8) 145 Matulic-Adamic, J. (5) 158 Maturano, M.D. (4) 58 Matveeva, E.D. (1) 209 Maty@zewski, K. (7) 55, 123 Maupin, C.L. (4) 159 Maurinsh, J. (5) 183 Maury, G. (5) 17 Mamommatis, C.N. (8) 91 Mayer, H.A. (1) 170 Mayfield, L.D. (5) 2 10 Maynard-Faure, P. (4) 14 Mayrargue, J. (6) 160 Mazzah, A. (8) 110 Mazzei, M. (5) 220 Mbianda, X.Y.(4) 64, 1 16; (8) 43 Meade, T.J. (5) 364 Medici, A. (7) 88 Medvedeva, L.Y.(7) 76 Meerholz, K. ( I ) 24 Meester, B. (7) 145 Meetsma, A. (1) 172, 173; (7) 101,102
Meffie, P. (6) 63 Meggers, E. (5) 233 Mehmandoust, Y. (7) 109 Mehrotra, M. (5) 244 Meier, C.(4) 216; (5) 5 Meier, H. (1) 58 Meissner, T. (8) 172 Melenewski, A. (5) 177 Melguizo, M. (5) 183 Mellor, B.J. (6) 13 1 Mellors, J. (5) 9 Menchen, S.M. (5) 54 Menendez, J.R. (8) 80 Meng, J.-B. (4) 230 Meng, S.(8) 64 Meng, S . 4 . (7) 74 Mercier, F.(1) 15 1,493,494,496 Merkulov, A S . (1) 512; (3) 19 Merle, J. (7) 23 Men, K.(1) 90 Meshram, H.M. (6) 88 Meunier, P. (1) 146, 188 Meuzelaar, G.J. (6) 163 Meyer, C.(1) 9 1 Meyer, G. (1) 379 Meyer, H.H. (4) 49 Meyer, J.H. (4) 161 Meyer, Y .H. (1) 2 11 Meyers, A.I. (4) 170 Mezailles, N. (1) 522
Mhamdi, F. (6) 149 Mican, A.N. (5) 185 Michalik, M. (4) 146
Michalska, M. (4) 225; (8) 10 Michalski, J . (8) 182 Michel, G. (8) 4,5 Michelin, R.A. (6) 27 Micklefield, J. (5) 29,30 Micura, R (5) 156 Midura, W.H. (4) 83 Miekisch, T. (7) 29 Mignet, N. (5) 135 Miguel, Y. (1) 188 Mihichuk, L.M. (8) 58 Mikhailopulo, LA. (5) 186, 187 Mikhailov, S.N. (5) 228 Mikhailov, Y.N. (8) 79 Mikhaleva, A.I. (1) 5 11; (4) 99 Mikhel, I.S. (2) 23 Miki, Y. (6) 58 Mikdajczyk, M. (1) 348; (3) 7; (4) 83, 149; (8) 75, 173
Mil, M. (1) 130 Milia, C. (5) 11 Milius, W. (7) 91 Miller, B. (5) 253; (8) 176 Miller, D.J. (4) 155 Miller, J.R. (4) 128 Miller, P.C. (6) 100 Miller, P.J. (7) 123 Milne, P.E.Y. (6) 24 Milstein, D. (1) 265,266 Minasyan, G.G. (I) 189 Minguez, J. (1) 268 Minto, F. (7) 88, 130, 163-165 Miquel, Y. (1) 34,258 Mirkin, C.A. (5) 303,304 Mironov, V.F. (2) 17 Mirzabekov, A.D. (5) 279 Mishra, S.P.(1) 310 Misiura, K. (5) 98 Misner, J.W. (4) 143 Mitchell, M.C. (4) 109 Mitrofanov, S.V.(8) 125 Mitsui, T. (5) 219 Mitsurnoto, H. (4) 37 Mitsuya, H. (5) 3 Mittelbach, C. (5) 176 Mittmann, M.(5) 281 Miura, T.(1) 392 Miyabayashi, K. (5) 111 Miyahara, A. (7) 92 Miyarnoto, H. (7) 86 Miyano, S. (1) 140 Miyata, M. (5) 111 Mizuno, K. (1) 218,320 Mizuno, M. (4) 63 Mizusaki, H. (7) 83 Mizutani, K. (7) 56 Mlodnosky, K.L. (4) 166 Mo, X . 3 . (6) 69
Mochizuki, A. (5) 92 Modro, A.M. (8) 51,59,63 Modro, T.A. (4) 64,229; (8) 43, 51, 59,63
MGhlen, M. (7) 24, 25 Moglioni, A.G. (6) 118 Mogridge, J. (5) 32 1 Moharned, N.R (6) 54 Mohanram, A. (5) 25 Mohr, J.T.(1) 136 Mok, K.F.(1) 27 1,485 Mokler, V.R. (5) 158 Mokry, L.M. (1) 82 Molina, P. (1) 239; (6) 72-75; (7) 1,2, 10, 14
Molins, E. (6) 67 Molko, D. (5) 165 Moll, C. (1) 382 Moll, M. (7) 33-35 Molnar-Perl, I. (8) 149 Moltrasio, G.Y. (6) 118 Momota, K. (5) 211 Monastyrskaya, V.I.(6) 7 Moncoeur, E. (5) 42 Monfardini, C. (7) 180 Monkiewicz, J. (1) 5 10 Montenegro, I.M. (6) 6 Montestruc, A.N. (7) 193 Montgomery, C.D. (8) 112 Montoneri, E. (8) 124 Moody, C.J. (4) 182 Moon, B.J. (5) 169 Moore, J.P.G. (4) 207 Moore, P.B. (5) 317,3 18 Moore, R.B. (7) 119 Moore, W. (4) 201 Moorhoff, C.M. (1) 357; (6) 56 Morales, E. (7) 142, 143 Morales, M.S. (1) 305 M o m , S. (5) 50 Moreno, G.E. (8) 39 Moreno, M.G.(1) 305 Moreto, J.M.(6) 67 Mori, T. (5) 28 Moriarty, R.M. (4) 209,210 Moriguchi, Y. (4) 188 Morii, T. (5) 295 Morimoto, H. (4) 9 Morimoto, T. (1) 73 Morita, H. (7) 45 Moriuchi, T.(5) 300 Moriya, K. (7) 83,84 Morimr, J.-P. (8) 134 Morningstar, M.L. (5) 167 Morohashi, K.(1) 207; (5) 88 Morozova, O.V. (5) 45 Mom, M. (4) 51 Morris-Natschke, S.L. (4) 75
Author Itidex Morrison, J.J. (6) 23 Momssey, C.T. (7) 150 Morrow, J.R (5) 261 Morse, D.P. (5) 243 Morvan, F. (5) 140 Morzunova, T.(4) 246 Moses, A.C. (5) 246 Moses, E. (1) 167 Moskowitz, H. (6) 160 MOSS,R A . (4) 55-57 Mostafa, C. (8) 4,5 Motekaitis, R.J. (4) 97 Motesharei, K. (5) 289 Motherwell, W.B. (4) 105 Motoyoshiya, J. (6) 99, 109; (8) 89
Mouchet, P. (1) 395; (8) 136 Moureau, L.(2) 22 Moutsas, V.I.( I ) 23 1 Mowat, M. (5) 296 Mozeleski, E.J. (1) 101 Mozzon, M. (6) 27 Mracec, M. (1) 516; (8) 1 Mrksich, M.(5) 347 Mucic, R.C. (5) 303, 304 Mliller, A. (7) 22 Mueller, A.H.E. (1) 393 Mueller, C. (1) 445; (7) 24 Muhle, S.A. (5) 185 Mukamel, S. (5) 236 Mullah, B. (5) 214,215 Muller, B. (5) 16 Muller, C.W. (5) 335 Muller, G. (1) 268 Muller, J.F.K. (4) 10 Muller, M. (5) 185 Muller, 0. (1) 434 Muller, S.N. (5) 234,330 Muller, T. (1) 169; (5) 59 Muller, T.J.J. (6) 113 Muller, U. (1) 377,378 Mulzer, J. (6) 147 Munoz, A. (3) 17; (8) 42 Munoz, P.(1) 355 Munster, I. (5) 179 Munukah M.(1) 372 Murahashi, S.4. (4) 69 Murakami, F.(1) 1 Murakami, N. (6) 139, 140 Muramatsu, M.(5) 53 Murano, M.(8) 40 Mumhov, D.A. (7) 76 Murata, M.(5) 299 Murphy, F. (6) 166 Murphy, M.R. (8) 169 Mumy, C.L.(7) 13 Murray, J.B. (5) 326,327 Murrell, P.(8) 137
349
Murugaiah, V. (5) 242 Murugavel, R. (1) 434 Musiani, M. (7) 147 Musin, R.Z. (1) 254 Musina, E.I. (1) 254 Mustafha, A.R (2) 19 Mustain, S. (5) 207 Muthini, S. (5) 213 Myagmarsuren, G. (8) 67
Nepomnyashchikh, K.V. (1) 105 Neschadimenko, V. (6) 154 Nettekoven, U. (1) 149 Neuburger, M. (1) 36 Neumann, B.(1) 417,420,471,
Nachbauer, A. (1) 439; (8) 93 Nachtigal, C.(1) 375 Nada, A.A. (6) 54 Nadler, G. (6) 49 Nagai, K. (6) 66 Nagase, Y. (1) 356 Nair, H.K. (4) 74 Nair, J.S. (1) 185 Nair, V. (1) 185; (5) 32, 148 Nalcagawa, S. (5) 324; (7) 84 Nakahara, H. (7) 105 Nakajima, Y. (7) 122 Nakamura, H. (8) 165 Nakamura, M.(4) 72 Nakamura, T. (4) 37 Nakamuta, Y. (7) 45 Nakano, H. (5) 2 16,2 19 Nakano, K. (5) 299 Nakatani, Y. (4) 13 Nakatsuji, Y. (1) 139 Nakayama, H (8) 158 Nakayama, M. (7) 111 Nalepa, C.J. (7) 112 Namath, A.F. (5) 284 Nampalli, S.(5) 56 Natang, S.C.(7) 116 Narayanaswami, G. (5) 285 Narayan-Sarathy, S.(7) 153 Nardin, G. (1) 157 Nasim, M.(7) 79 Nassar, E.J. (8) 88 Nassimbeni, L.R.(4) 229; (8) 43 Natt, F.(5) 84 Naumann, F.(1) 3?9 Navarro, R (6) 39 Nawot, B. (5) 133 Nayyar, N.K. (4) 187 Neda, I. (1) 317; (2) 18; (4) 228 Neilson, RH. (7) 153 Nelson, A. (1) 327-329; (6) 124,
Neverov, A.A. (4) 59 Nevins, N. (4) 220 Newcomb, M.(4) 71 Newton, R.P. (8) 143 Nguyen, H.K. (5) 175 Nguyen, T. (4) 170 Ni, J. (4) 88; (6) 106 Ni, L.-M. (4) 205 Ni, Y. (7) 140 Nicholas, K.M. (1) 5 Nichols, A. (5) 102 Nichols, J.B. (1) 232 Nicholson, B.K. (1) 132, 3 14 Nicholson, T. (8) 132 Nicjisch, K.(1) 136 Nicolaides, D.N. (6) 5 1 Nicolaou, K.C. (6) 146, 166 Nicotra, F. (4) 117 Niecke, E. (1) 8,410,427,465-
125
Nelson, J.H. (1) 108,487,492 Nelson, J.M. (7) 151 Nelson, P.S.(5) 213 Nelson, S.L.(4) 2 18 Nelson, W.H. (8) 72 Nemeh, S. (1) 155
523
Neumann, C. (1) 463 Neumann, 0.(1) 96 Neumann, R.A. (6) 29 Neumiiller, B. (7) 22,24,25,29; (8) 104
467,470,484; (6) 17, 28,45; (7) 63; (8) 92 Nief, F. (1) 502,503 Nieger, M. (1) 8,410,427,431, 466,467,470; (6) 15, 17,28, 45; (7)63; (8) 92 Nielsen, F. (5) 151 Nielsen, M.F. (6) 6 Nielsen, P.E.(5) 107-109, 114116,296 Niemeyer, C.M. (5) 302 Nieuwenhuyzen, M. (1) 18 Nifant'ev, E.E. (8) 122 Nigam, S. (6) 144 Niikura, K. (5) 294,295 Niizmura, S.(6) 153 Nikanorov, V.A. (6) 2 1 Nikitin, M.V. (1) 104 Nikolaeva, I.L. (2) 19 Nikolova, R (3) 16 Nikonov, G.N. (1) 254 Nils, I. (4) 54; (8) 47 Nimura, K. (7) 110 Ninkovic, S. (6) 146 Ninomiya, Y. (6) 3 Ninoreille, C. ( I ) 93 Ninoreille, S. (1) 93 Nishibayashi, Y. (1) 12, 152
350 Nishigaki, T. ( 5 ) 153,21 1 Nishijima, M. (4)43 Nishimura, K.4. (1) 372 Nishiyama, M. (7) 122 Nissen, P. (5) 3 19 Nitta, M. (6)50, 179 Niu, D.Q. (3) 24 Niwa, M. ( 5 ) 367 Nixon, J.F. (1) 449,484,505,506, 508,509 Nobori, T.(7)56 Noeth, H.(1) 59,81,399;(6) 16, 176;(8) 60 Nolan, D.H. (1) 30 Noller, H.F. (5) 313,3 14 Noltemeyer, M. (1) 434;(7)98 Nome, F. (4)61 Nomoto, A. ( 5 ) 300 Norby, P. (8) 130 Norcross, R D . (4)84 Nomby, P.-0. (6)98 Novak, B.M. (1) 365 Novak, T.(1) 323,324 Novikova, V.G. (2)17 Novo, B.(1) 304;(4)65 Novotny, D. (7)49 Nowakowski, R. (4)244;(8) 153 Noy, A. (5) 364 Noyori, R.(5) 83 Nuding, W.(7) 117, 118 Nugent, R.A. (4)208 Nugent, T.C.(6)158 Nunes, J. (1) 227 Nunzi, J.-M. (1) 3 16 Nurmahomed, K. ( 5 ) 357 Nurminen, E.J. (3) 22;(8) 179 Nyborg, J. (5) 319 Nye, S.A. (7)38,39,41 Nyulaszi, L.(1) 125,484,508 Oae, S.(1) 195
Obara, R.(1) 331 Oblonkova, E.S.(7)139 OBrien, P. (1) 233 Ochs, H.( 5 ) 62 O'Connell, J.P.(5) 290 OConnor, S.J.M. (7)85, 144, 173 Oda,J. (4) 152 Odobel, F. (4)98 Odonnell, M.J. (5) 286 Ohler, E.(6) 147 Oehme, G. (4)146 Oesen, H.(1) 88 Oeser, T.(6) 178 Oevers, S.(1) 38 Offermann, W.(1) 109 Ogasawara, M. (1) 118
Ogawva, A. ( 5 ) 300 Oguro, D. (1) 206 Oh,D.Y.(4)87 Ohba, M.(1) 495 Ohe, K.(1) 12 Ohff, M.(3) 21 Ohkubo, M.(6)89 Ohmine, T.(5) 153,211 Ohno, A. (3) 3 1,32 Ohno, M. (5) 260 Ohtake, F. ( 5 ) 294 Ohtani, M. (4)52 Ohtsuki, C.( 5 ) 61 Ohya, Y.( 5 ) 255 Oivanen, M. ( 5 ) 264 Ojwang, J.O. (5) 200,207 Okabe, E.(7)120, 121 Okada, A. ( 5 ) 236 Okada, K.(1) 406 Okahata, Y.(5) 294,295 okamoto, Y.(7) 12 Okamum, M. (3) 32 Okawa, T.(6)76-78;(7)12,15, 17 Okazaki, R. (6) 126;(8) 1 I 1 Okazaki, Y.( 5 ) 53 Okeeffe, T.( 5 ) 242 Okruszek, A. (4)245 Oku, M. (1) 122 Okuno, T.(4)52 Olivera, A. (4)4 Olivieri, A.C. (8) 38 Olmeijer, D.L. (7) 144 Olmos, E.(1) 354 O'Loughlin, J. (1) 199 Olsen, G.M. (1) 278;(8) 13 1 Olshavsky, M.A. (7)136, 148 Olthoff, S.(1) 450 O'Neil, I.A. (7) 13 Ono, K.(1) 495 Ono, S. (7)45 Onysko, P.P. (3) 18 Ooshita, Y.(7)105 Oosting, R.S.(5) 126 Om, M.( 5 ) 264 Ordonez, M. (1) 347 Oretskaya, T.S.(5) 159 Orgel, L.E. (5) 107-109 Oritani, T.(1) 210 Oro, L.A. (1) 355 Orpen, A.G. (1) 130, 131 Orsini, F. (4) 1 1 1 Ortega-Blake, I. (4)222 Ortiz Mellet, C.(6)82;(7)7,8 Ortoleva-Donnelly, L. (5) 41,42 Oituno, R.M. (6) 118 OIUI, H.( 5 ) 237-239 Osakada, N.(6)76;(7)17
Organophosphorus Chemistry
Osanai, S.(4) 171 Osawska-Pacewicka, K.(4)66 Osbom, H.M.I. (4)167 Oscanon,S.(4)32 OShaughnessy, P. (1) 97 Osheroff, N.(5) 245 Oshikawa, T.(1) 320 Oshovskii, G.V. (1) 5 12 Ostrowski, A. (1) 463,475 Oswald, G. (8) 123 Otero, A. (6)32 OToole, J.C. (6)104 Otsalyuk,V.M. (4) 124 Otsuka, K. (8) 168 Otten, P.A. (6) 127 Otvos, L.(5) 207;(8) 161 Ou, Y.(8) 128 Ouazzani, F.(4) 147 Oulih, T.(5) 34 Ourisson, G. (4)13 Ouryupin, A.B. (3) 20 Ovakimyan, MZh. (1) 189 Owen, D.(5) 357 Ozaki, H.(8) 170 Ozawa, K.( 5 ) 53 Ozegowski, S.(1) 282;(4)179 Ozeki, H.(1) 428;(8) 83 Ozsoz, M. ( 5 ) 296
Paciorek, K.J.L. (4)1 Padiya, K.J. (1) 208 Page, P.C.B. (4) 207 Pagel, M.(5) 354 Pagliarin, R.(4) 114 Pai, N. (5) 9 Paige, D.R (1) 3 Paine, R.T.(1) 292,462 Painter, G.F. (4)39 Pairot, S.( 5 ) 112 Palacios, F. (1) 315,386 Palmisano, G. (4) 114 Palou, J. (1) 381;(6) 10 Pan, J. ( 5 ) 3 10 Pan, S.(4)42;(7)4 Pan,T.(5)311 Pancansky, J. (7)69 Pandey, G. (1) 243 Pandoifa, L. (6)27 Panek, J.S. (6) 134 Pang, S.S.(7)193 Pang, X.(8) 127 Pankiewicz, K.W.( 5 ) 74-76 Pannecoucke, X.(4)50 Pantelouris, A. (8) 114 Panza,L. (4)1 17 Paolesse, R. (2)28 Papadopoulos, K.(4) 13 1; (6)116
Author Index Papkov, V.S. (7) 137, 139 Paquette, L.A. (6) 156 Pardigon, 0. (1) 75 Paris, M. (6) 169 Parishi, E.(1) 434 Park, C.E. (4) 200 Park, I.Y.(1) 301 Park, J. (8) 94 Park, J.A. (7) 184 Park, K. (8) 94 Park, K.Y.(4) 87 Park, M.(5) 242 Park, Y.(1) 302 Park, Y.R (1) 301,302 Parkanayi, L. (1) 320 Parker, D.(4) 94,158-160 Parvulescu, V. (1) 39 1 Pascal, P. (1) 2 11 Pasechnik, M.P. (1) 352,353 Pastor, A. (6) 75; (7) 2 Pastor, S.D. (3) 11 Patel, D.J.(5) 353 Patino, N. (5) 112 Patrini, R.(1) 166 Patsanovskii, 1.1. (1) 445; (8) 3 Paul, N. (5) 188 Paulsen, E.L. (1) 72 Paulus, A. (5) 291 Paun, G. (5) 305 Pavia, G. (5) 63 Pavlova, N.A. (4) 103 Pawelke, B. (3) 33 Payne, L.G. (7) 133, 186 Payne, M.S.(4) 138 Peabody, D.S. (5) 327 Pearce, E.J.(1) 214 Pechet, S. (5) 55 Pedrini, P. (7) 88 Pedroso, E.(5) 198 Peinador, C. (6) 79, 80; (7) 16 Pelicano, H.(5) 17 Pelletier, H:(5) 343 Peltomaki, M.(5) 264 Pemberton, L. (7) 166 Pendergast, W. (5) 72 Peng, J. (4) 35 Peng, L . (5) 152, 157 Peng, L.F. (6) 132 Peng, S.-M. (1) 17 Pen& 2.(8) 128 Penicaud, V. (1) 293; (4) 98 Peplies, J. (5) 302 Pereira, M.L. (8) 143 Perera, M.P.S. (8) 19 Perera, S.D.(1) 15, 175,176 Perez, I. (6) 170 Perez, W.J. (8) 119 Perez-Perez, M.J.(4) 121
Perez-Pla, F.F.(1) 381; (6) 10 Perich, J.W. (3) 25; (8) 160 Perigaud, C.(4) 216; ( 5 ) 7 Pejessy, A. (8) 33 Perlini, P. (5) 1I Perlstein, J. (4) 236 Perov, A.N. (5) 279 Perm, G. (5) 11 Perrone, D. (6) 157 Perry, M.C. (5) 101 Perry, RJ. (7) 40 Persinger, J. (5) 46 P e d n i , M.(1) 157 Peters, C.(1) 409 Peters, K. (1) 450 Peters, W.(8) 41 Peterson, A.C. (1) 334; (4) 74 Peterson, B.C. (4) 143, 187 Peterson, K.(5) 90 Petkov, D.D. ( 5 ) 49 Petrov, G. (8) 185 Petrovich, L.M. (1) 72 Petrucqnik, A. (8) 156 Pettigrew, D.W. (5) 66 Petz, W.(6) 34 Peyerimhoff, S.D. (8) 77,114 Peyman, A. (5) 118,123,207 Peyrottes, S. (5) 131 P6dt.q A. (3) 8 Pfister-Guillouzo, G. (1) 4 11 Pfleiderer, W. (5) 34, 85,86, 154, 182, 183
Pfhdheller, H.M.( 5 ) 15 1 Phillips, B.W. (4) 201 Phillips, S.E.V. (5) 327 Philp, D.(1) 344 Phipps, A.K. (5) 349,350 Pianka, M.(8) 91 Piccirilli, J.A. (5) 100,267 Piccolo, 0. (1) 274 Pichereau, V. (1) 359 Pieken, W. (5) 90 Pierra, C.(5) 17,63 Pietsch, J. (6) 36; (7) 62 Pietschnig, R.(1) 8,467; (6) 45 Pihlaja, K.(4) 22% 227; (8) 53,54 Pikies, J. (1) 402,403 Pilard, J.-F. (1) 408 Pillai, S. (5) 242 Pinchuk, A.M. (1) 197; (3) 19; (6) 20
Pinchuk, V.A. (4) 228 Piniella, J.F. (4) 6 Pinkhassik, E.M. (4) 156 Pintauro, P.N. (7) 172, 173 Pintchouk, V. (1) 90 Pint&, I. (1) 241; (6) 82; (7) 6-8 Piquet, V. (1) 250,25 1
35 1
Pirio, N. (1) 188 Pinung, M.C. (5) 78 Pisch, S. (4) 49 Pitsch, S. (5) 147, 156 Pitts, A.E. (5) 210 Piva, 0. (6) 129 Plass, M. (1) 348; (8) 75 Platts, J.A. (6) 9 Player, M.R(5) 141 Plumeier, C. (1) 371 Plushkowski, J. (4) 225 Podborsky, V. (8) 138 Podkopaeva, T.L. (5) 187 Podrugina, T.A. (1) 209 Pohlmeyer, T. (8) 30 Pohlschmidt, A. (1) 382 Poirier, S.N.(4) 23 Poli, R.(7) 60 Poljansek, I. (1) 245 Poll, W. (4) 178 Pollini, G.P. (3) 15 Polywka, M.E.C. (1) 167 Pongracz, K.(5) 129 Ponomarenko, G.P. (4) 103 Pontius, B.W. (5) 270 Ponzo, V.L. (1) 201 Poon, C.C. (5) 252 Poortmans, F. (5) 332 Popa, A. (1) 391 Popova, E.V. (1) 445 Porinchu, M.(6) 159 Ponvolik-Czomperlik, I. (7) 89, 90
Posolda, M.(1) 3 18 Postar, J. (6) 166 Potapov, V.K. (5) 18 1 Pothion, C. (6) 169 Potnebowski, M.J. (4) 225,238; (8) 10 Potter, A.J. (7) 13 Potter, B.L.V. (4) 21,.22,26,29; (5) 36; (6) 152 Poujaud, N. (6) 32 Pounds, T.J. (1) 177 Powell, D.R. (1) 72,294; (4) 202 Powell, J. (5) 76 Powell, W.S. (6) 142 Powers, J.C. (4) 205; (8) 86 Powis, G.(4) 33 Prakash, 0. (4) 210 Prakasha, T.K.(2) 3,32,34; (8) 49
Prasad, R (5) 343 Prathap, S. (6) 159 Predieri, G. (8) 162 Preet.q w. (1) 375; (7) 59 Pregnolato, M.(1) 304; (4) 65 Pregosin, P.S. (8) 22
3 52 Prestwich, G.D. (4) 35, 119 Previero, A. (8) 145 Prevote, D. (6) 117 Price, R.D. (6) 11,30; (7) 19,20 Priemer, S.(1) 475,477 Prihoda, J. (7) 49 Primrose, A.P. (7) 151 Principato, G. (4) 243; (8) 155 Prindle, J.C.(7) 112 Pring, B. (4) 217 Pringle, P.G. (1) 102, 103, 134; (8) 62 Pritchard, R.G. (1) 192-194,249, 307; (8) 36,44 Pritzkow, H. (1) 63,64, 90,9 1, 178,433; (6) 41 Proevote, D. (4) 17 Proft, B.R (1) 72 Prokhorenko, LA. (5) 217 Pronayova, N. (8) 33 Protasiewicz, J.D. (1) 397 Proudnikov, D.Y. (5) 279 Provot, 0. (6) 160 Pryror, T. (1) 3 1 Przibille, G. (4) 76 Pudovik, A.N. (2) 24 Pudovik, M.A. (2) 19,24 Puke, C. (6) 2 Pulacchini, S.(1) 137 Purches, G. (1) 157 Pun, N. (5) 218 Pursianen, J. (1) 19 Puschl, A. (5) 96 Pushechnikova, A.O. (1) 5 11; (4) 99 Putzolu, M. (5) 11 Pye, P.J. (1) 113, 273 Pyshnyi, D.S.(5) 220
Qabar, M.N. (4) 139 Qi, H. (6) 108 Qian, C. (4) 110,133 Qian, Y.(6) 3 1 Qiao, L. (4) 4, 33 Qiao, S.(1) 498 Qiu, W. (4) 102 QuasdorfF, €3. (1) 420 Quayle, S.C. (1) 14 Quek, G.H. (1) 27 1 Qui, M. (6) 26 Quintela, J.M. (6) 79,80; (7) 16 Quintero, L. (8) 39 Quiocho, F.A. (5) 325 Quirmbach, M. (1) 133; (3) 21 Rabai, J. (1) 101
Rabe, G.W.(1) 79,86 Radek, J.T. (5) 323,324 M e r t y , J.B. (5) 338 Rafik, M. (7) 174 Raftery, D. (8) 180 Ragunathan, K.G. (4) 5 5 , 5 7 Rahon, J. (1) 309
Wines, K.(5) 48 Raith, T. (7) 117, 118 Raithby, P . R (1) 333; (6) 121, 122 Rakhov, LA. (3) 20 Ramakrishnan, G. (8) 66 Ramalingam, K. (1) 335 h a s w a r n y , M. (5) 103 Ramdane, H.(1) 429; (8) 2 1 Ramirez de Arellano, M.C. (1) 239; (6) 73,75; (7) 1,2, 14 h e y , J.M. (5) 293 Ramsinghani, S. (5) 70 Ramzaeva, N. (5) 176 Ranaivonjatovo, H. (1) 429; (8) 21 Rando, R.F. (5) 199,200,207 Rankin, D.W.H. (8) 13 Rankin, S.E. (4) 47 Rao, A. (5) 333 Rao, M.V. (5) 95 Rashid, H.S. (1) 387; (6) 9 1 Rasne, R.M. (6) 181 W o n , C.L. (1) 127,223 Rath, N.P. (1) 185; (8) 106 Rathbone, T.J. (6) 85 Ravikiran, R. (7) 85 Ravikumar, V.T. (5) 97 Ravily, v. (5) 112 Ravindran, K.(7) 5 Raper, B. (5) 131,132, 137,140 Razdan, R K . (6) 145 Razzano, J.S.(7) 40 Read, D. (1) 131 Reamer, R A . (1) 113 Rbu, R (1) 401; (7) 127 Rebrov, A.I. (2) 23 Reddy, G.S.(6) 88 Reddy, K.K. (4) 28,36 Reddy, K.M. (4) 28 Reddy, M.M.(6) 88 Reddy, V.S.(1) 110 Redon, M. (1) 119 Rees, D.C. (5) 346 Rees, M.T.L. (1) 312 Rees, N.H. (1) 271 Reese, C.B.(4) 31; (5) 94,95 Reetz, M.T. (1) 158,159,366 Refosco, F.(6) 37; (7) 64 Regen, S.L. (4) 231-233 Reginato, G. (1) 233
OrganophosphonisChemisiry Regitz, M.(1) 401,407,409,415, 437-439,444,447,448,45 1, 472-474; 496; (8) 93,98 Rehahn, M.(7) 129 Reider, P.J. (1) 113 Reimer, A. (1) 99 Rein, T. (6) 98 Reinhard, R. (8) I5 Reinhoudt, D.N. (1) 161,284; (4) 96 Reisacher, H.-U. (1) 462 Rell, S.(1) 63,433 Rernington, S.J.(5) 66 Remmel, R.P. (5) 1 Rcn, J. (1) 220 Ren, R.X.F. (5) 50 Renard, A. (5) 227 Rengakuji, S. (7) 45 Repyk, A.V. (5) 228 Reshetkova, G.R (2) 10 Resnati, G.(1) 304; (4) 65 Restrepo-Cossio, A.A. (6) 4,5 Rettig, S.J.(8) 112 Rettig, W. (1) 21 1 Revesz, L. (4) 214 Reye, C. (6) 14; (8) 48 Reyes, E.D. (6) 143 Reznik, V.S.(2) 19 Rhee, J.U. (3) 12 Rheingold, A.L. (1) 79, 85, 86, 430; (7) 96 Rheinhardt, R. (4) 16 Rhie, D.Y. (4) 136 Riant, 0. (1) 13 Ricard, L. (1) 15 1,400,455,457, 491,493,496,501,503,518, 519,521,522 Ricart, S. (6) 67 Riccio, D.A. (7) 38,39 Rice, D.W. (5) 338 Rich, A. (5) 345 Richards, R.L. (6) 33 Richardson, C.C. (5) 341 Riche, C. (4) 147 Richert, C. (5) 230 Richeson, D.S. (1) 83 Richman, D.D. (5) 9 Richmond, R.K. (5) 339 Richmond, T.J. (5) 336,339 Rideout, J.L. (5) 72 Ridges, M.D. (1) 204 Rieck, J.A. (4) 143 Riehl, J.P. (4) 159 Rifqui, M. (1) 196 Riley, A.M. (4) 22,26; (6) 152 Ring, S.(6) 165 Rinke Appel, J. (5) 3 15 Rittinger, K. (5) 357,358
Author Index Rivero, I.A. (1) 305 Rizo, J. (4) 36 Rizzi, C.(8) 70 Rizzoli, C.(1) 23; (3) 4 Ro, B.O.(6) 154 Roberti, M. (3) 15 Roberts, B.A. (1) 127 Roberts, B.E. (7) 186 Roberts, B.P.(1) 217; (4) 105 Roberts, RW. (5) 191 Robertson, B.E. (8) 58 Robertson, H.E. (8) 13 Robidoux, S. (5) 195 Robin, F.(1) 151,493 Robins, M.J.(6) 154 Robinson, J.M.A. (1) 344 Rocca, M. (7) 179, 180 Rocheblave, L.(6) 169 Rodefeld, L. (6) 136 Roden, M.D. (1) 368; (6) 96; (8) 103
Rodima, T. (7) 53 Rodios, N.A. (3) 16 Rodnina, M.V.(5) 315 Rodriguez, E. (1) 386 Roe, D. (8) 12 Rijschenthaler, G.-V. (1) 109; (2) 14, 15 Roesky, H.W. (1) 434; (7) 98 Rogers, R.D. (1) 84 Rohde, U.(1) 475 Rohrbaugh, D.K. (8) 150, 151 Roig, A. (6) 67 Rokach, J. (6) 142 Roland, S. (4) 105 Rolando, C.(6) 149 Romanenko, V.D. (1) 414,464 Romanova, E.A. (5) 44,159 Rombeck, I. (8) 123 Romieu, A. (5) 165 Rominger, F. (6) 178 Rondanin, R. (3) 15 Rook, M.S. (5) 309 Rosa, I.L.V. (8) 88 Rosa, P.(1) 518 Rosales-Hoz, M.de J. (2) 20; (8) 45 Rose, K. (7) 77 Rose, L. (1) 371 Rosemeyer, H. (5) 179,187 Rosenblum, B.B. (5) 54 Rosler, A. (5) 71, 182, 183 Rosowsky, A. (5) 9 Rospenk, M. (7) 51 Rossen, K. (1) 113,273 Rossignol, S. (1) 230 Rossmayer, S. (1) 503 Roth, A. (5) 360
Roth, H.J. (5) 152 Rothwell, I.P. (1) 128 Rottlander, M. (1) 32 Rouche, F.(6) 169 Roumestant, M.-L. (4) 147 Roux, P.(5) 55 Rowlands, G.J. (4) 185, 186 Rowsell, S. (5) 327 Royan, B.W.(1) 504 Rozanov, LA. (7) 76 Rozenberg, G. (5) 305 Rozenski, J. (5) 155, 160, 172 Roziere, J. (8) 124 Rozzell, J.D.(5) 164 Ruban, A. (1) 465,466; (6) 17; (7) 63
Rubinsztajn, S.(7) 42,43,55 Rubio, A. (6) 164 Rubira, M.R. (4) 121 Ruby, F. (1) 244 Ruda, K.(4) 32 Rueckert, T. (1) 35 Rueedi, P.(4) 76 Ruf, R (1) 44 1 Rufael, T.S.(8) 116 Ruhe, S. (4) 5 1 Ruisch, B.J. (1) 504 Rump, E.T.(5) 206 Russell, D.R (1) 18,132 Russell, D.W. (6) 24 Russell, G.A. (3) 12 Russell, G.T. (1) 3 12 Russell, M.G. (1) 328,333; (6) 122,125
Russo, D. (5) 13 Ruthe, F. (1) 180, 191,463,476, 477; (6) 42
R&?iEka, A. (7)47,48 Ryan, K. (5) 201 Ryder, S.P.(5) 42 R ~ uZ.-H. , (1) 242
Saa,J.M. (1) 279
Saanna, M. (5) 181 Sabes, S.F.(4) 130 Saccheo, S.(8) 68 Sada,T. (4) 113 Sadheghi, M.M. (1) 370 Sadler, P.J. (5) 366 Saeki, K. (1) 495 Safionov, I.V. (5) 45 Sagi, J. (5) 207 Sagstuen, E.(8) 72 Sahm, H.(4) 46
Saida, Y.(4) 150
Saigo, K.(1) 3467, 153,206
Sailor, M.J. (5) 289
Saint-Martin, H.(4) 222 Saintome, C.(5) 33 1 Sainz, D. (1) 268,269 Saito, A. (1) 2 10 Saito, K.(1) 210 Saito, S. (1) 428; (8) 83 Saitoh, A. (1) 73 Sakai,H. (1) 207 Sakai,R.R. (5) 280 Sakai, T. (1) 232 Sakamoto, K. (5) 38 Sakarya, N. (1) 508 Salam, M.A.(1) 244 Salanski, P. (6) 65 Salem, G. (1) 57 Salem, M.A.I. (6) 52,53 Sales, J. (1) 256 Salo, H.(5) 80 Salomaa, A. (5) 305 Salunkhe, M.M. (1) 208 Samani, H.R. (7) 109 Sambri, L.(1) 330 Samuel, E.(1) 87 Samuel, 0. (1) 13 Samuels, W.D.(7) 67 Sanchez, L. (6) 170 Sanchez, M.(1) 40 1,464 Shchez-Andrada, P.(7) 10 Sanders, T.C. (6) 107 Sandri, J. (6) 180 Sandt, F. (4) 178 Saneyoshi, M.(5) 61 Sanganee, M.J. (8) 17 Sanner, A.M.W. (5) 307 Sano, A. (8) 165 Sansom, P.(5) 255 Sansoni, M. (1) 137
Santagostino, M. (6) 111 Santelli, M. (1) 326 Santelli-Rouvier, C.(1) 326 Sarabia, F. (6) 146 Saraev, V.V.(8) 67 Sarfo, J.K.(1) 132 Sargent, D.F. (5) 339 Sargent, J.R (7) 195 Sarmini, K.(8) 166, 167 Sawer, E.W. (8) 150, 151 Sasai, H.(4) 150; (6) 114 Sasaki,M.(6) 133 Sasaki,N. (5) 53 Sasaki, (1) 1,398 Sasaki,Y.(7) 104 Satge, 1. (1) 429; (8) 21 Sato, M.(5) 10 Sato, Y.(5) 91,92; (6) 22 Sato-Kiyotaki, K.(5) 6 1 Saunden, G.C. (1) 18 Saunders, J.M. (5) 161
s.
3 53
3 54
Sauter, G. (5) 120 Savage, P.B. (1) 294 Savignac, P.(4) 101, 107; (6) 119 Sawada, M. (5) 295 Sawai, H. (5) 226 Sawamura, M. (1) 119 Sawaya, M.R.(5) 343 Sayers, 2.(5) 3 19 Sbmna, G. (1) 166 Schacht, E. (7) 177, 178, 185 Schafer, K.J. (4) 91 Scharer, O.D. (5) 143 Schaub, C.(5) 16 Scheer, M. (1) 436,442; (7) 61 Scheffer, M.H.(1) 4 17,47 1 Scheffzek, K. (5) 355 Scheller, F. (4) 246 Schenk, W.A. (1) 52 Schepartz, A. (5) 246 Scherba, O.N. (8) 78 Schermolovich, Yu.J. (1) 434 Scheuer Larsen, C.(3) 29 Schier, A. (1) 126,222; (6) 12 Schiesher, M.W. (1) 237 Schifier, H.M. (1) 8 Schilder, H.(7) 32 Schildkraut, I. (5) 344 Schilf, W. (8) 51,59,63 Schinazi, R.F. (5) 1,2,63 Schinkels, B.(1) 470; (6) 28 Schipperijn, J.W.J. (5) 39 Schlachter, S.T.(4) 208 Schladetzky, K.D.(1) 294 Schlager, J.J. (4) 211,212 Schlecht, S. (7) 11; (8) 104 Schlewer, G. (4) 23,24, 104; (6) 152
Schleyer, P.von R. (1) 78; (8) 13, 23
Schlienger, N. (5) 7 Schmilzlin, E.(1) 24 Schmid, R.D. (4) 49 Schmidbaur, H. (1) 222 Schmidpeter, A. (1) 126,399, 515; (6) 12, 13, 16,43; (8) 18, 60
Schmidt, B.F. (4) 16 Schmidt, C. (5) 278 Schmidt, F.K. (8) 67 Schmidt, H.G. (1) 70,434 Schmidt, J.G. (5) 108,109 Schmidt, K.(1) 9,362 Schmidt, M.(1) 59; (6) 176 Schmidt, 0.(1) 410; (8) 92 Schmidt, R.R (5) 16,59 Schmidt, U. (4) 146 Schmidt-Amelunxen, M. (1) 399; (6) 16; (8) 60
Schmitt, B.F.(8) 15 Schmitt, L. (4) 104 Schmitz, F.(5) 355 Schmitz, M. (1) 415,448 Schmock, F.(6) 34 Schmutzler, R (1) 22, 124,288,
3 17,445; (2) 5,6, 18; (3) 13; (4) 95,228 Schneider, A.G. (1) 36 Schneider, B.P. (5) 77 Schneider, H.-M. (7) 190 schnick, w . (7) 37 Schnolzer, M. (8) 140 Schnur, J.M. (4) 235 Schoeller, W.W. (1) 399,410, 424; (6) 16; (8) 60,92 Schenberg, H.(1) 154 Schoerken, U.(4) 46 Schofield, C.J. (4) 60 Scholz, P.(8) 82 Schoon, L. (1) 504 Schoonman, J. (7) 145 Schopper, N. (1) 169 Schoth, R.M.(2) 15 Schder, T. (4) 11,82, 199 Schreiber, K.-A. (1) 25 Schroedel, H.P. (1) 399; (6) 13, 16,43; (8) 18,60 Schroeder, G. (7) 5 1 Schrtider, M. (1) 496 Schroeder, R (5) 273 Schroeder, T.B. (8) 182 Schue, F.(7) 174 Schueler, J. (1) 44 1 Schiitz, M. (7) 33,35 Schultz, C.(4) 30 Schultze, P. (5) 275,348-350 Schulz, A. (1) 369; (7) 73 Schumann, I. (1) 471 Schur, M.(1) 376 Schuricht, U. (4) 77 Schuster, G.B. (5) 237-239 Schwabacher, A.W. (1) 237 Schwarz, S. (6) 165 Schwarz, W.S. (1) 77 Schweiger, A. (1) 154 Schwesinger, R (7) 53 Schwickardi, R. (1) 159,366 Schwink, L.(1) 2 1 Sciuto, S.(5) 13 Sclavi, B. (5) 308 Scott, A.I. (4) 8 Scott,W.G.(5) 266,274,326 Screttas, C.G. (1) 26; (8) 27 Scrivens, W.A. (5) 365 Scudder, M. (1) 276,277 Seals, T.H. (8) 169 Sebenik, A. (1) 245
Organophosphorus Chernisiry Sebestyen, M.G. (5) 209 Seddon, K.R. (5) 5 1 Sedelnikova, S.E.(5) 338 Sediek, A.A. (6) 52,53 Seela, F. (5) 176-179, 187 Seelig, B. (5) 23 Segal, M.(8) 161 Segawa, K. (1) 12 Segerer, U.(1) 89 Segre, A.L. (7) 135 Segstro, E.P. (4) 197 Segura, J.L. (6) 174 Seidman, M.(5) 75,76 Seio, K.(5) 38 Seip, J.E. (4) 138 Sekine, M.(5) 28,38,67,91-93 Sekljic, H. (4) 44 Selim, M.R. (8) 84 Selinger, J.V. (4) 235 Selke, R.(1) 29; (3) 10 Selvakumar, S.(1) 335 Selvaraj, 1.1. (7) 103 Selvaratnam, S. (1) 486 Semenova, M.G. (3) 19 Senanayake, K.(4) 160 Seneci, P. (6) 49 Seno, M.(5) 61 Seoane, C. (6) 170,174 Sergiev, P.(5) 44 Sergueev, D. (5) 103 Serra, O.A. (8) 88 Sessler, J.L. (5) 255 Setta, T. (1) 200 Settle, A. (5) 90 Seymour, L. (7) 178 Shabarova, Z.A. (5) 159 Shaddy, A.A. (2) 13 Shah, K. (5) 68,69 shah, s. (1) 397 Shaikudinova, S.I.(1) 105 Shakirov, M.M. (6) 103 Shamsi, S.A.(8) 171 Shang, X.(4) 68 Shao, G. (8) 7 Shaver, S.R (5) 72 Shaw, B.L.(1) 15,175, 176 Shaw, B.R (5) 103; (8) 12, 159 Shaw, G. (8) 178 Shaw, R.A. (7) 89,90 Shaw, R.W. (1) 504 Shawkataly, O.B. (1) 335 Shay, B.J. (8) 69 Shay, J.W. (5) 210 Shchepinov, M.S. (5) 192 Shea, RG. (5) 173 Shefield, J.M. (1) 192-194; (8) 36,44
Sheldon, E.L. (5) 290
Author hidex Sheldon, R.A. (6) 163
Sheldrick, W.S. (1) 76 Shen, G.S.(1) 259,260 Shen, L.X.(5) 205 Shen, Y.(4) 88; (6) 26, 106 Shenton, D.J.( I ) 176 Sherlock, D.J.(2) 3,30,34; (8) 49 Shermergorn, M.I.(8) 121 Shennolovich,Yu.G. (1) 198 Shetty, K.(5) 43 Shevchenko, I.V.(2) 25; (6) 18 Shi, X.-X.(6) 142 Shi,Y. (6) 132 Shi,Z. (8) 181 Shibakami, M.(4) 232,233 Shibamoto, Y.(1) 372 Shibasaki, M. (1) 138; (4) 150; (6) 114
Shibata, T. (4) 171 Shibuya, S. (4) 112, 113; (5) 10 Shieh, R. (8) 174 Shields, S.K. (4) 208 Shiiba, T.(5) 259 Shimada, K.(5) 153,211 Shimasaki, C. (7) 45 Shirneno, H.(5) 10 Shimura,H.(4) 3 Shimura,K.(1) 406 Shin, B . 4 . (4) 27 Shinohara, G.(5) 60 Shinomka, K. (5) 226 Shioiri, T.(1) 122,392; (4) 63; (6) 1I5 Shiozaki, M.(4) 43 Shirahase, K.(4) 52 shirai, s. (7) 110 Shirato, M.(5) 35 Shokat, K.M. (5) 68,69 Shreeve, J.M. (7)97 Shtennikova, LN. (7) 134 Shudo, K.(5) 113 Shui, X.Q. (5) 340 Shull, B.K.(1) 232 Shum, S.P. (3) 11 Shunner, B. (8) 112 Shuto, S. (5) 35; (6) 153 Siah, S.-Y. (1) 488 Siddiqi, S.M. (5) 72 Sidky, M.M. (2) 12 Sidorenkova, H.(1) 425,426 Siebert, W. (1) 178 Siegel, K.(6) 138 Sieler, J. (1) 88 Siemhala, A. (5) 104 Sigel, H.(8) 123 Sigl, M.(1) 222 Sigurdsson, S.T.(5) 330 S h , C.J. (5) 37
Sih,J.C. (6) 141 Sikora, D.(6) 112 Silverman, R.H.(5) 141 Simeon, F.(4) 90
Simiand, C. (4) 120 Simmonds, A.C. (5) 56,57 Simmons, C.G. (5) 2 10 Simon, A. ( I ) 287 Simon, J. (1) 473; (8) 98 Simon, M.D. (5) 230 Simon, Z. (8) 1 Simoni, D. (3) 15 Simonovska, B. (8) 164 Simpkins, N.S.(1) 325; (7) 54 singh, s. (1) 5 Singh, V. (6) 159 Singler, RE.(7) 158 Sint, T. (5) 77 Sisti, M.(4) 114 Sivan, U.(5) 277 Siwy, M.(7) 89,90 Skaptsova,N.V.(5) 181 Skeen, J.T. (8) 146 Skelton, B.W.(8) 19 Skoblov, A.Y. (5) 64 Skorobogatyi, M.V.(5) 217 Skowronska, A. (I) 34,129, 146; (4) 86; (8) 182 Slama, J.T. (5) 70 Slany, M. (7) 93 Slawin, A.M.Z. (1) 468; (4) 173;
(7) 36, 125 Slawomir, L. (4) 225 Sliedregt, L.(5) 206 Slowikowska, J. (4) 244; (8) 153 Sluggett, G.W. (1) 311 Slyusarenko, E.I. (1) 198 Smedley, S. (7) 116 Smeets, W.J.J. (1) 51, 173, 174 Smerdon, S.J.(5) 357,358 Smith, A.B., III (4) 201 Smith, C.J.(1) 110, 111 Smith, C.L. (5) 56,57 Smith, D. (5) 242 Smith, D.M.A. (4) 222 Smith, D.W., Jr. (7) 153 Smith, G. (1) 340,34 1 Smith, J. (5) 362 Smith, J.R.L. (1) 233 Smith, K.M.(2) 28 Smith, K.W.(8) 169 Smith, L.M.(5) 241,287,307; (6) 168 Smith, M.B.(1) 102; (7) 36 Smith, M.M.(4) 212 Smith, P.H. (1) 292 Smith, T.H.(5) 213 Smith, W.W. (4) 162
355
Smithies, D.M.(1) 107 Snaith, R.(1) 333; (6) 121, 122 Snellink-Rueel, B.(1) 161 Soai, K. (4) 171 Sobczyk,L.(7) 5 1 Soberon, X. (5) 208 Sobkowska, A. (5) 134 Sobkowski, M. (5) 134,202 Sochacki, M.(5) 98, 133 Soeda, S. (5) 10 Sohn, Y.S.(7) 95, 188, 189 Soimu, P. (8) 148 Sokolov, V.I.(1) 71; (8) 115 Sokolowski, M.(8) 152 Solans, X. (1) 269
Solari, E.(1) 23 Soltek, R. (1) 47 Sommadossi, J.-P. (4) 2 16; (5) 63 Somoza, V.P. (1) 257 So+ L.(I) 241; (7) 6 Sone, J. (5) 153 Song, B.(8) 123 Song, C.E.(1) 39 Song, F. (8) 135 Song, Q.L.(5) 94,95 Song, S.-C. (7)188 Song, X.(4) 236 Sonnenschein, H.(1) 205 Sonobe, Y. (7) 56 Sontheimer, E.J. (5) 267
Sood, P.(2) 3,32,33,35
Ssrensen, H.O.(1) 69 Sosnick, T.R(5) 3 11 Sotiropoulos,J.-M. (1) 41 1 Soto, T. (6) 180 Sottof’attori, E. (5) 220 Souchet, M. (6) 49 Soufli, LC.(1) 23 1 Soulier, E. (1) 121; (4) 180 Soulivong, D.(1) 11; (6) 38 Sournies, F.(7) 75, 124 Southern, E M .(5) 192,288 Spagnol, M.(1) 151 Spector, M.S. (4) 235 Spk,A.L. (1) 51, 116, 172-174, 240,456; (7) 9; (8) 55,96
Spengler, J. (4) 135 Spera, S. (4) 96 Spichty, M.(5) 233 Spiegel, S. (4) 4 Spiegler, M. (1) 43 Spiess, B.(4) 23,24, 104; (6) 152 Spilling, C.D. (8) 106 Spingler, B. (4) 10 Spitmer, D. (6) 62 Spooner, P.J.R.(4) 47 Sprang, S.R (5) 356 Sprenger, G.A. (4) 46
356 Sprengler, P.A. (4)201 Springs, S.L.(5) 255 Sproat, B.S.(5) 146, 197;(8) 141 Spurgeon, S.L.(5) 54 Squires, RR (1) 220 Sreedharan-Menon, R. (4) 191 Sreerama, N.(4)170 Srinivasachar, K.(5) 136 Srivastavq P.(5) 298 Stadler, C.(6)176 Stahl, M.M.(7)28,30,31 Staite, N.D. (4)208 Stalke, D.(1) 10 Stammler, H.G. (1) 417,420,471 Stanforth, S.P. (6)57 Starikova, Z.A. (1) 254,352,353 Stark, H.(5) 3 15 Stawinski, J. (4)80;(5) 202 Steams, T. (5) 283 Stec, W.J. (4)221,224,238;(5) 98.99, 133 Stecker, K.(5) 22 1 Steckhan, E. (4)45 Steele, B.R.(1) 26;(8) 27 Steenwinkel, P. (1) 116;(8)96 Stefaniak, L. (8)5 1,59,63 Steffens, R (5) 149,150 Stein, E. (8) 1 1 8 Stein, V.(8) 138 Steinborn, D. (1) 96 Steiner, M. (6)41 Steiner, T. (1) 343 Steinicke, A. (1) 71;(8) 115 Steinmuller, F.(1) 5 15 Steitz, T.A. (5) 317 Stelzer, 0.(1) 41,76 Stemp, E.D.A. (5) 23 1 Stepanov, G.(8)78 Stephan, M.(1) 148 Stephens, L.R.(4)39 Sternbach, D.D. (5) 244 Stetsenko, D.A. (5) 181 Stevens, C.(4) 137 Stevens, P.A. (1) 101 Stevens, W.C.(8) 169 Stevenson, D.E. (7)82, 114 Stewart, E.L.(4)220 Stewa& F.F.(7) 158 Steyaert, J. (5) 332 Stibor, I. (4) 156 Stobart, S.R (1) 33 Stock, H.(1) 178 Stockley, P.G.(5) 327 Stoddard, B.L.(5) 73 Stoessel, P. (1) 170 Stoianova, D.(4) 170, 190 Stolmar, M.(3)4 Stolnik, S.(7) 185
Stonehouse, N.J. (5) 327 Storhoff, B.N.(1) 30,3 1 Storhoff, J.J. (5) 303,304 Storozhev, T.V. (6)2I Straub, M.(5) 198 Streicher, B. (5) 273 Streubel, R.(1) 463,475-478 Strobel, S.A. (5) 41-43 Strohm, M.(5) 70 Strojek, S.(8)77 Strornberg, R.(5) 18 Strornburg, B.(7)78 Struess, S. (7)59 Strunin, B.N. (6)7 Stuart, A.M. (1) 3 Stubbe, M. (1) 52 Stubblefield, M.A. (7)193 Studley, 1.R (4) 169 Stiidemann, T. (1) 32 Stulz,E.(5) 120 Su, L.L.(5) 323,324 su, s.(5) 212 Suarez-Sobrino, A. (6)182 Sudheendra Rao, M.N. (4)5 Sudo, A. (1) 39 Sue, R.E. (1) 16 Suernune, K. (4)112, 113; (5) 10 Suenaga, Y.(1) 372 Sugirnori, T. (6)78;(7)12, 15 Sugirnoto, M. (6)139 Sugirnoto, T. (1) 372 Sugirnoto, Y.(6)58 Suginose, R.(1) 363 Sugiura, Y.(5) 295 Suh, S.Y. (7) 184 Suhadolnik,R.J. (5) 186 Sule, S.S.(7) 195 Sulkowska, A. (7) 157 Sulkowski, W.(7) 157 Sullivan,K.A. (4) 143 Sullivan, M.(5) 308 Sulu, M.(1) 54 Sumaoka, J. (5) 259,260 Sumi, H.(8) 165 Surnita, Y.(5) 35 Summers, J.S.(8) 12 Sun, D.(6)81 Sun, J. (4) 110 Sun, S.G. (5) 100,267 Sun, Y.-M. (7) 171 Sunahara, RK.(5) 356 Sund, C.(5) 218 Sundarababu, G. (6)108 Sung, D.-D. (1) 242 Sumna, A. (4) 176 Sutherland, J.D. (5) 22 Suzuki, K.(1) 320 Suzuki, T. (1) 207;(7)56,83
OrganophosphorusChemistry
Sverdlov, E.D. (5) 181 Svergun, D.I. (5) 319 Swalley, S.E. (5) 249 Swaminathan, S. (5) 173 Swamy, K.C.K. (4)53 Swang, 0.(8)14 Swann, E.(4)182 Swavey, S.(1) 397 Sweeney, J. (4) 167 Swetman, S.P. (4) 134 Swiss, K.A. (6) 100 Sykara, G.D.(7)89 Symons,M.C.R.(1) 310 Szarek, W.A. (5) 8 Szczepura, L.F.(8) 119 Szewczak, A.A. (5)4 1 Szewczyk, J.W. (5) 25 1 Szollosy, A. (1) 323 Szostak, J.W. (5) 191
Tabor, S. (5) 341 Tachibana, K. (6) 133 Tada, T. (1) 372 Taehtinen, P. (4)226;(8)54 Taguchi, K.(4) 13 Tagyu,Y. (1) 218 Taillefer, M. (6)86, 128 Taira, K.(4)221;(5) 99,269 Takada, K.(1) 218 Takada, T. (4) 188 Takagi, A. (1) 200 Takagi, R.(6)47 Takaguchi, Y.(6)99;(8) 89 Takahashi, H.(1) 140,406;(5) 259 Takahashi, K. (5) 88 Takaki, U.(7)56 Takaku, H.(5) 169 Takaoki, K.(1) 153 Takayasu, T. (6)50,179 Takei, I. (1) 152 Takei, M.(5) 216 Takeuchi, K.J. (8) 119 Takezaki, H.(1) 67 Tallenbach, A. (8)77 Tan, B.(1) 298 Tan, S.(5)336 Tan,Z. (7)141 Tanaka, A. (1) 210 Tanaka, H.(1) 218 Tanaka, K.(6)97 Tanaka, M. (1) 216, 289;(4)93 Tanaka,T. (5) 53 Tanaka,Y.(6)61;(8) 168 Tang, C.-C. (4) 12 Tang, H.(7) 173 Tang, J.X. (5) 102
Author Index Tang, J.Y. (5) 102
Tang, W. (5) 24 1 Tanigaki, T. (7) 104 Taniguchi, T. (4) 62 Tanner, D. (4) 183 Tao, A. (4) 209,210 Taourirte, M.(5) 34 Taphanel, M.-H. (8) 134 Taran, F. (1) 253 Tarasenko, E.A. (6) 105 Tarasow, S.L. (5) 190 Tarasow, T.M. (5) 190 Tarkoy, M. (5) 349,350 Tarlov, M.J. (5) 301 TBnaga, A. (6) 73; (7) 14 Tashlitsky, V.N. (5) 159 Tate, J.J. (5) 46 Tatematsu, T. (1) 392 Tatsuta, T.(4) 43 Tattershall, B.W. (8) 35 Taudien, S. (1) 13 Tautz, H. (1) 515 Taylor, B.F. (1) 361; (8) 37 Taylor, C.M. (4) 201 Taylor, D.K.(6) 85 Taylor, P.N.(1) 130, 13 1 Taylor, R (1) 199 Taylor, RG. (7) 44 Taylor, RJ. (1) 281; (4) 109; (6) 90
Taylor, S.D. (4) 2, 100 Taylor, S.V. (4) 46 Tchatchoua, C.N. (1) 298,302 Tebby, J.C. (1) 297,346, 360; (8) 6, 56
Tehranfar, D. (1) 288 Tei, Y. (7) 110 Teichert, M.(1) 10 Tejeda, J. (6) 32 Tepper, M.(1) 41 Terabe, S. (8) 168,170 Terent'eva, S.A. (2) 24 Terhorst, T. (5) 105, 173 Terreni, M. (1) 304; (4) 65 Tenon, G. (1) 425,426 Teny, M. (1) 95 Terwey, D.P. (5) 326 Teshirogi, T. (4) 52 Tesmer, J.J.G. (5) 356 Tesser, G.I. (5) 110 Teunissen, H.T. (1) 48 1 Thanh, H.T.T. (1) 324 Tharmaraj, P. (7) 79 Thatcher, G. (4) 217 Thelen, V. (1) 484 Thiel, A.J. (5) 287, 307 Thiel, F. (1) 205 Thiel, W.R(1) 43
Thiele, K.H.(1) 71; (8) 115 Thirumalai, D.(5) 3 10 Thomas, E.J. (6) 130, 131 Thomas, K.RJ. (7) 80 Thomiis, M.(6) 182 Thomas, R.C.(1) 507 Thompson, D.P. (7) 43 Thompson, G.M.(1) 192; (8) 44 Th6nnessen, H. (1) 22, 124,288; (2) 18; (4) 95
Thornton-Pett, M.(1) 15, 107, 175, 176,461
Thuong, N.T. (5) 175 Thurner, C.L.(1) 43 Tian, B. (4) 230 Tian, H. (4) 142 Tian, S. (8) 147 Tickle, D. (4) 237 Tiekink, E.R.T. (6) 85 Tilley, T.D. (1) 482 Timmers, C.M.(5) 4 Timoshenko, V.M. (1) 198 Timosheva, N.V. (2) 30 Tisato, F. (6) 37; (7) 64 Tivel, K.L.(5) 189,221 Tkach, V.S. (8) 67 Tkachev, A.V. (6) 103 Tlahuextl, M.(2) 20; (8) 45 Tochtermann, W.(6) 136 Tiike, L.(1) 321-324,483,525 Tohnai, N. (5) 111 Tok, O.L.(6) 21 Tokutake, N.(4) 152 Tolbert, T.J. (5) 47 Tolmachev, A.A. (1) 197,5 11, 512; (3) 19; (4) 99; (6) 20
Tolstikov, A.G. (1) 68 Tolstikova, O.V. (1) 68 Tomikawa, A. (5) 61 Tondello, E. (7) 130, 163 Topin, A. (5) 44 Tordo, P. (8) 70 Torrence, P.F.(5) 141, 142 Torwiehe, B. (1) 4 18 Tosquellas, G. (5)#140 Toth, I. (1) 51 Touami, S.M.(5) 252 Toupet, L. (1) 11,55,326; (6) 38, 135
Tour, J.M. (5) 365 Tourwe, D.(1) 228 Tovar, F. (6) 72 Toyota, K.(1) 406,412,413,416 Toyota, N. (1) 372 Trauger, J.W. (5) 250 Treiber, D.K. (5) 309 Trevisiol, E. ( 5 ) 227 Trimarco, P.(1) 385; (6) 59
357
Trivedi, H.K.(7) 107, 108 Trofimov, B.A. (1) 42, 104-106, 286,511; (4) 99
Trost, B.M. (1) 186 Tsai, H.-J. (4) 106 Tsalieva, A.G. (6) 7 Tsang, S.C.(5) 366 Tsantrizos, Y.S.(5) 119 Tseng, K.S.(2) 7 Tsien, R.Y.(4) 30 Tsivadze, A.Y. (8) 79 Tsou, N.N. (1) 113 Tsuboi, S. (6) 99; (8) 89 Tsuhako, M. (8) 158 Tsuji, K.(1) 398 Tsujimoto, M.(3) 3 1, 32 Tsukayama, M.(6) 22 Tsunoda, T. (1) 235 Tsurubo, M.(1) 114 Tsuruta, H. (1) 6 Tsuruta, 0. (5) 60 Tsutsui, Y. (6) 139, 140 Tsutsumi, 0. (1) 356 Tsutsumi, S. (5) 153 Tsuzuki, H.(5) 259 Tu, H.Y. (7) 18 Tuccio, B. (8) 70 Tuckmantel, W. (4) 33 Tungler, A. (1) 323 Tw, D.R.(7) 134, 137-139 Turner, D.H. (5) 27 1 Turner, J.M. (5) 247,25 1 Two, N.J. (1) 31 1 Turturici, E. (6) 157 Tweedy, B.R (2) 8; (8) 177, 178 Tye, H. (4) 169, 175 Uchida, Y.(1) 195 Uchimaru, T. (4) 221; (5) 99 Uchimura, M. (1) 320 Uchino, M.(7) 120 Uchiyama, M. (5) 83 Udalova, I.A. (5) 192 Udat, D.(6) 28 Ueda, E.(7) 194 Ueda, I. (6) 61,92 Ueda, K. (1) 372; (7) 111 Uemoto, K.(1) 235 Uemura, S. (1) 12 Ueno, Y.(5) 35 Uggeri, F. (1) 236 Uhlenbeck, O.C. (5) 274 Uhlmann, E. (5) 118, 123, 126, 207
Ujszaszy,K.(1) 321, 322,324, 525
Ullrich, D.(1) 444
Organophosphortrs Chemistry
358
Umeda, A. (5) 226 Umemiya, H. (5) 113 Uozumi, Y.(1) 118
Urashima, C.(5) 67 Urbach, F.L.(1) 397 Urban, J. (4) 139 Urbanek, R.A. (4) 130 Urdea, M.S. (5) 193, 194 Uribe, A. (5) 290 Urriolabeitia, E.P. (6) 39 Usman, N.(5) 158, 178,326 Uthmann, S. (1) 418 Utley, J.H.P. (6) 6 Uziel, J. (1) 148
Vaime, V. (4) 14 Vaino, A.R. (5) 8 Valceanu, R. (1) 391; (8) 148 Valderrama, M. (1) 355 Valeeva, F.G. (8) 184 Valentijn, A.R.P.M. (4) 25; (8) 77 Valentin, M.-L. (4) 40 Valerga, P. (1) 268 Van, D. (8) 30 Van Aerschot, A. (5) 155, 160, 172,228
van Amsterdam, 1. (5) 110 van Berkel, T.J.C. (5) 206 Van Betsbrugge, J. (1) 228 van Boeckel, C.A.A. (5) 39 van Boom, J.H. (4) 25; (5) 4,39, 110, 126
Vancso, G.J. (7) 140, 141 van de Grampel, J.C. (7) 100-102 van den Beuken, E.K. (1) 172-174 van der Boom,M.E. (1) 265,266 van der Gen, A. (6) 127 van der Klein, P.A.M. (6) 148 van der Laan, A.C. (5) 110, 126 van der Linden, A. (1) 504 van der Maas, J. (1) 343 van der Marel, G.A. (4) 25; (5) 4, 39
Van der Put, P.J.J.M. (7)145 Vanderveen, K.(5) 75,76 Vandorpe, J. (7) 178, 185 van Duijnen, P.Th. (8) 55 Van Duyne, G.D. (5) 337 van Eis, M.J. (1) 456 van Heel, M. (5) 315 van Koten, G. (1) 116; (8) 96 van Leeuwen, P.W.N.M. (1) 141, 149
van Rooyen, P.H. (4) 64 van Steenis, J.H. (6) 127 van Veggel, F.C.J.M. (1) 161 van Vliet, M.C.A. (6) 163
van Zoest, W.J. (6) 148 Vargeese, C.(5) 90 Varma, I.K. (1) 300 Vasanits, A. (8) 149 Vasquez, A. (8) 118
Vass, M.(1) 391
Vasseur, J.J. (5) 131, 140 Vastra, J. (3) 5,6 Vaugeois, Y.(8) 110 Vedejs, E. (1) 150; (4) 202 Veiga, M.C. (6) 79; (7) 16 Veits, Yu.A. (1) 156,270 Vejbjerg, H. (5) 122 Velasco, M.D. (7) 2 Veldman, N. (1) 116, 173,240; (7) 9; (8) 96
Venanzi, L.M. (1) 54; (6) 37; (7) 64 Venkataramani, P.S. (7) 79 Venter, M.(8) 82 Ventura, S.C. (7) 116 Vepsalainen, J.J. (4) 108 Verani, G. (1) 308 Verbeke, A. (4) 137 Verboom, W. (1) 284 Vercruysse, K.(7) 124 Verdine, G.L.(5) 143,222-224 Verger, R (4) 78 Vergoten, G. (7) 70,71 Verkade, J.G.(2) 26,27 Veronese, A. (5) 14 Veronese, F.M. (7)179, 180, 182, 183
Verweij, J. (6) 148 Vessey, J.D. (1) 15 Veszpremi, T.(1) 125 Vezenov, D.V. (5) 364 Viala, J. (6) 180 Viallefont, P. (4) 147 Vicente, J.V. (1) 384 Vichi, E.J.S. (8) 118 Victorova, L.S.(5) 64 Vidal, A. (6) 72; (7) 10 Vidal, C. (2) 22 Vidal, V.R (4) 79 Viguri, F.(1) 355 Vij, A. (7) 97 Vilijulatha, M.(4) 53 Vilaplana, M.J. (6) 75; (7) i Viljanen, T. (4) 226,227; (8) 53, 54
Villemin, D. (4) 90,92 Vinader, M.V. (7) 10 Vinod, A.U. (1) 185 Virgil, S.C. (1) 142 Virgilio, A. (6) 168 Visscher, K. (7)160 Vittal, J.J. (1) 489,490; (4) 53
Vittori, O.M. (8) 120 Vivano, R. (8) 124 Vlasov, V.M. (7) 53 Vlassa, M.(8) 163 VlCkovi, M.(7) 48 Vogler, A. (8) 85 Vo Huyhn, M.H. (8) 119 Volante, R.P. (1) 113 Volden, H.V. (1) 71; (8) 115 Volkert, W.A. (1) 111 Volkov, E.M. (5) 159 Volkov, V. (5) 3 19 Vollbrecht, A. (2) 18 von Hippel, P.H. (5) 270 von Janta-Lipinski, M. (5) 62 von Kiedrowski, G. (5) 130,36 1 von Matt, P. (4) 84 von Schnering, H.G. (1) 450 Vorontsov, E.V. (6) 21 Vu, L.D. (4) 46 Vurens, G.H. (7) 109 Vysotskii, V.I. (1) 112 Wada, C.K. (5) 184 Wada, T. (5) 28,38,67,91-93, 111
Wada, Y. (1) 6 Wagner, C.R (5) 1,2 Wagner, J.-P. (1) 96 Wagner, K. (5) 123 Wagner, M. (1) 60 Wagner, R.(5) 244 Wagner, T.(5) 85 Wah, D.A. (5) 344 Wahl,H.(4) 131;(6) 116 Wahl, R.U.R. (8) 69 Wakabayashi, S. (5) 83 Wakelin, L.P.G. (5) 117 Walden, G.L. (4) 218 Waldmann, H. (5) 127,128 Waldvogel, S.R. (1) 158; (5) 154 Walker, B. (4) 145 Walker, B.J. (4) 145 Walker, P.A. (5) 357,358 Waller, C.F. (5) 141 Wallow, T.I. (1) 365 Waltman, R.J. (7) 69 Walton, D.RM. (1) 199 Walton, T.J.(8) 143 Wan, H.(4) 229; (8) 43 Wan, J. (8) 61 W a g , A.-L. (1) 337 Wang, B.(1) 262,454 Wang, F. (1) 234 Wang, H . 4 . (4) 230 W a g , H.-Q. (1) 337 Wang, J. (5) 296; (8) 73, 144
Author Index Wan& J.-C. (8) 107 Wan& L. (6) 69 Wang, P. (5) 242 Wan& Q. (1) 394; (4) 242 Wag, Q.-S. (8) 154 W a g , R.-M. (8) 87 Wang, S.(4) 140 Wmg, S.-L.(1) 364 Wang, W. (5) 12; (6) 139, 140 Wmg, Y.-M. (4) 12,230 Wang, Z.X.(5) 242; (6) 8; (7) 26, 27 Waring, M.J. (5) 65 Warner, I.M. (8) 171 Warren, S.(1) 280,327-329, 333; (6) 122-125 Waschbusch, K.(1) 5 19 Waschbusch, R.(6) 119 Washington, J. (8) 180 Wasielewski, M.R (5) 232 Watahiki, M.(5) 53 Watanabe, F.(4) 52 Watanabe, J. (1) 6 Watanabe, K.A. ( 5 ) 74-76 Watanabe, M. (8) 158 Watanabe, Y.(1) 67; (4) 37 Waterman, S.M. (8) 19 Waters, L.C. ( 5 ) 293 Watkins, D.M. (1) 3 11 Watson, W.H. (6) 81 Watts, A. (4) 47 Watts, J. (8) 137 Wawrzenczyk, C. (1) 33 1 Weakley, T.J.R. (1) 259 Weber, G. (6) 165 Weber, L.(1) 417420,435,471; (8) 30 Weber, M. (7) 190 Wei, C.F.( 5 ) 177 Wei, N. ( 5 ) 261 Wei, X. (6) 90 Weibel, J.-M. (4) 105 Weichman, H. (1) 96 Weidenbruch, M. (1) 450 Weigt, A. (1) 40 Weiler, J. (5) 79 Weiler, L. (4) 120 Weinstein, L.B. (5) 265 Weiser, B.( 5 ) 3 13 Weiser, C. ( 5 ) 123 Weiss, M.A. (5) 323, 324 Weitgenant, J.A. (1) 3 1 Weller, F. (6) 34; (7) 11,21,32 Wells, RL. (1) 85,225 Welzel, P.(4) 77 Wemmer, D.E. (5) 347 Wendeborn, S.( 5 ) 240 Wender, P.A. ( 5 ) 252
Wendler, A. (4) 2 I0 Weng, L.(4) 206 Wengel, J. (3) 29; (5) 151 Wenger, E. (1) 143 Wenzel, T. ( 5 ) 148 Werner, H.(1) 10 Westerhausen, M. (1) 77,80,8 1, 524; (8) 101 Westhof, E.( 5 ) 266,330 Westwood, N.J. (4) 60 Wettling, T.(1) 438 Wheatley, A.E.H. (1) 333; (6) 121,122 Wheeler, J.W. (1) 297 Wheeler, P.(5) 221 Wbitaker, M. (6) 24 White, A.H. (8) 19 White, A.J.P. (1) 271,421,486, 488,489; (6) 155; (8) 95 White, P.S.(1) 225,369; (4) 223; (7) 72; (8) 52 White, S.( 5 ) 248,25 1 Whitehead, B.J. (6) 102 Whitfield, J.N. (5) 22 Whittaker, A.K. (1) 34 1 Whitten, D.G. (4) 236 Wiberg, N. (1) 78 Wicht, D.K. (1) 430 Widhaim, M. (1) 28,149 Wieczorek, M.W. (4) 83,224, 238; (8) 173 Wiegand, T.W. (5) 19 Wiemer, D.F. (4) 67 Wieneke, B.(1) 81 Wieringa, RH.(7) 101 Wieser, C. (1) 11,120; (6) 38 Wiesmuller, L. ( 5 ) 355 Wild, S.B.(1) 272 Wilk, A. (5) 136 Wilke, G. (1) 510 Wilkens, H.(1) 463,478 Will, D.W. (5) 118, 123,207 Wille, U.(5) 233 Willet, G.(8) 133 Williams, D.C. (4)*9 Williams, D.J. (1) 271,421,486, 488,489; (6) 155; (8) 95 Williams, D.M. ( 5 ) 58 Williams, I.D. (1) 285 Williams, J.A.G. (4) 159, 160 Williams, L.D. (5) 340 Williams, M.L.(8) 19 Williams, P.E.(1) 31 Williams, P.G.(4) 9 Williamson, J.R ( 5 ) 47,309 Williard, P.G.46) 107 Willis, A.C. (1)37, 143 Willner, I. ( 5 ) 297
359 Wills, M. (4) 169, 175; (6) 137 Wilson, K.S.( 5 ) 3 14 Wilson, M.(4) 58; ( 5 ) 119 Wilson, N.J. (1) 458 Wilson, S.H.( 5 ) 343 Wilson, S.R(6) 100 (1) 421,443; Wilton-Ely, J.D.E.T. (8) 95 Wimmer, N.(4) 44 Wincott, F.E. (5) 158 Winde, R. (1) 520 Wink, D.J. (4) 71 Winkler, A. (7) 34 Winkler, U.(4) 205 Winssinger, N.(6) 166 Winter, H.( 5 ) 3 Winterhalte, U.(1) 46,48,49,53 Wintermeyer, W. (5) 3 15 Wisian-Neilson, P. (7) 152 Wisniewski, K. (1) 226 Witch, E.M. ( 5 ) 3 1 Witherington, J. (4) 201 Withers, S.G. (4) 120 Witkamp, H.A. (6) 148 Witt, D. (1) 309 Witt, M. (7) 98 Wittchow, E. (1) 427 Wittinghofer, A. ( 5 ) 355 Witucki, L. ( 5 ) 68,69 Wnuk, S.F.(6) 154 Wocadlo, S.(7) 29 Wodicka, L. ( 5 ) 28 1,283 Wiirner, A. (1) 78 Wojcik, M. (5) 133 Wolf, J. (1) 10 Wolf, R.M. (5) 240 Wolfe, B. (I) 275 Wolfe, S.A. ( 5 ) 223 Wolff, E.(4) 81 Wolff, J.A. ( 5 ) 209 Wong, A. (1) 142 Wong Foy, A. (8) 116 Woo, H.G. (1) 87 Woodtoffe, T.M. (8) 17 Woods,A.L. (7) 186 Woodson, S.A. ( 5 ) 308,310 Woody, RW. (4) 170 Woolins, J.D. (1) 468; (4) 173; (7) 36, 125 Woolley, A.T. (5) 292 Worboys, K.(1) 102,103 Workman, D.B. (1) 220 Worle, M. (1) 154 Worlem, M. (8) 110 Wrackmeyer, B. (1) 61 Wright, A. (1) 107 Wright, I.G. (4) 143 Wroblewski, A.E. (4) 115, 123
360
Wroblowski, B.(5) 155 Wronka, J. (5) 242 WU, C.-H. (7) 171 Wu, H. (8) 64 WU, H.-S. (7) 74; (8) 126 Wu, L. (4) 140; (5) 290 WU, M.-Y. (1) 364 Wu, T.F. (5) 232 Wu, T.J. (7) 18 Wu, T.R. (8) 26 WU,X.-W. (4) 140 Wu, Y. (4) 206; (8) 144 Wiirthwein, E.-U. (6) 2 Wuggenig, F. (4) 15 1 Wutzer, B.S.(7) 38,39 Wyatt, P.(1) 123,280; (6) 123 Wyns, L. (5) 332 Xe, X. (1) 394 Xiao, D. (1) 66 Xiao, H. (8) 144 Xiao, W. (5) 141, 142 Xie, D.(1) 303 Xie, 1. (5) 205 Xin, S. (1) 87 Xin, Z. (8) 127 Xu, L.X. (5) 242 Xu, Y.Z. (5) 144 Yablokov, V.A. (8) 125 Yabui, A. (1) 320 Yadav, J.S. (6) 88 Yager, K.M.(4) 201 Yajima, H. (5) 259 Yamada, H. (1) 6 Yamada, N. (1) 416 Yamagishi, T. (4) 112, 1 13 Yamaguchi, K. (1) 6; (4) 150; (6) 114
Yamaguchi, T. (1) 372; (5) 6 1 Yamamoto, I. (1) 290 Yamamoto, K. (1) 372 Yamamoto, M.(7)113 Yamana, K.(5) 216,219 Yamasaki, S.(4) 188 Yamasaki, Y. (5) 368 Yamataka, H. (6) 92 Yamauchi, K. (7) 191, 192 Yamazaki, A. (1) 114,115 Yamazaki, S.(5) 300 Yamazaki, T. (5) 113 Yamshita, M. (1) 320 Yanase, N. (6) 58 Yanez, J. (5) 208 Yang, F. (5) 68,69; (8) 34 Yang, F.-L. (4) 239
Yang, G.(4) 242 Yang, H. (4) 165 Yang, H.-2. (8) 154 Yang, J.-J. (1) 165 Yang, X. (4) 174; (5) 98 Yang, Y.F. (4) 184 Yang, Y.-P. (8) 87 Yangt, G. (4) 166 Yano, S. (7) 83,84 Yanovsky, A.I. (1) 254,352,353 Yao, J.W. (6) 171 Yao, Q.(4) 71 Yao, Y. (8) 181 Yao, Z.-J. (4) 140 Yaouanc, J.-J. (1) 121 Yaoune, J.-J. (4) 180 Yap, G.P.A. (1) 85,86,430 Yarsiminky, A.K. (8) 183 Yashima, E.(7) 12 Yashiro, M.(5) 259 Yassar, A. (5) 298 Yasui, M. (1) 218 Yasui, S.(3) 3 1,32 Yavari, I. (1) 182-184; (6) 93,94 Yazdi, P.T. (4) 74 Yazu, K. (7) 111 Ye, B. (4) 140 Ye, C. (8) 16 Yegge, J. (5) 90 Yerxa, B.R. (5) 72 Yeung, L.-L. (1) 285 Yokomatsu, T. (4) 112, 113; (5) 10 Yokoyama, S.(5) 38, 169 Yoneda, Y. (5) 53 Yonenwa, M.(7) 45 Yoon, T.H. (1) 301,302 Yoshida, A. (5) 100 Yoshida, K. (1) 118 Yoshida, S.(5) 61 Yoshida, Y. (4) 112 Yoshifiji, M. (1) 1,396,398,406, 412,413,416
Yoshihashi, K. (7) 122 Yoshikawa, K. (5) 368 Yoshimura, T.(7)45 Young, V.G.,Jr. (1) 422; (6) 35, 40
Youseti-Salakdeh, E. (5) 18 Yu, B. (4) 41,42; (7) 4 Yu, H. (8) 147 Yu, K.(8) 16 Yu, S. (5) 305 Yuan, C.S. (6) 154 Yuan, G. (1) 394 Yuan, Y. (8) 24 Yuasa, H. (5) 60 Yuck J.I. (1) . ,301 I
Organophosphorus Chemistry Yurchenko. A.A. (3) 19 Yves, E.(8).4,5 Zablocka, M.(1) 34, 129,146 Zaccai, G. (5) 319 Zagala, A.P. (1) 393 Zahn, T.J. (4) 7 Zai, K. (7) 124 Zaidi, M.G.H. (8) 129
*
2. (7) 47-49
Zakharova, I.V.(1) 68 Zalesova, N.N.(8) 122 Zamaratski, E.(5) 218 Zambelli, A. (8) 68 Zammit, M.D. (1) 3 12 Zangrando, E.(8) 29 Zanitti, L. (1) 274 Zanobini, F. (1) 157 Zanotto, L. (6) 27 Zarrinkar, P.P. (5) 309 Zauner, K.P. (5) 306 Zayed, M.F. (2) 12 Zefirov, N.S. (1) 209 Zegers, I. (5) 332 Zehnder, M.(1) 36; (4) 10 Zehnizadeh, B.(1) 388 Zemlicka, J. (5) 3 Zeng, F. (5) 89 Zeng, L. (8) 69 Zhan, C.(8) 20,61 Zhang, B.L. (5) 20 Zhang, C.(7) 152; (8) 20 Zhang, F.J. (5) 37; (6) 161 Zhang, G. (4) 41 Zhang, G.F. (5) 209
Zhang,H.(8) 24 Zhang, J. (4) 55,56
Zhang, J.C. (5) 105 Zhang, L. (8) 97 Zhang, L.H. (5) 269 Zhang, N.-J. (2) 16 Zhang, P.M. (5) 188 Zhang, T.Y. (6) 104 Zhang, W. (1) 139 Zhang, X. (1) 66,95; (4) 102 Zhang, X.H. (5) 89 Zhang, X.L. (5) 168 Zhang, Y. (1) 297; (4) 70, 172; (8) 24,34
Zhang, Y.F. (5) 232 Zhang, Y.-j. (4) 239 Zhang, Z.D. (5) 102 Zhang, 2.-Y. (4) 140 Zhang, z . 2 . (1) 45 Zhao, C.-Q. (4) 230 Zhao, K. (3) 24; (4) 42, 166; (7) 4, 5
Author Index Zhao, M. (5) 324; (6) 156; (7) 116 Zhao, Y. (8) 144 Zhao, Y.-F. (2) 16 Zhao, Z.Y. (5) 104 Zheng, H. (4) 206 Zheng, N. (5) 322 Zhong, R .G. (2) 16 Zhou, D.M.(5) 269 Zhou, H. (5) 245 Zhou, J. (4) 48 Zhou, W.Q. (5) 205
361
Zhou, X. (1) 33 Zhu, C. (4) 110 Zhu, G. (1) 95 Zhu, J. (6) 19 Zhuo, R. (8) 16 Ziessel, R. (1) 55 Zijlstra, RW. (8) 55 Zimmermann, K.(5) 157 Zinic, M.(3) 27 Zon, J. (1) 331 Zonouzi, A. (1) 183; (6) 93
Zozolin, A.N. (4) 54; (8) 47 Zsolnai, L. (1) 47,291; (6) 41 Zuber, J.-F. (4) 214 Zubin, E.M.(5) 159 Zundel, G. (7) 52; (8) 76 Zuurmond, H.M. (6) 150 Zverev, D.V. (6) 21 Zwierzak, A. (4) 66 Zyablikova, T.A. (4) 240
