Organophosphorus Chemistry

Organophosphorus Chemistry

From Molecules to Applications

Edited by Viktor Iaroshenko

Editor

Dr. Viktor IaroshenkoPolish Academy of Sciences, Center ofMolecular and MacromolecularStudies in Lodz, Laboratory ofHomogeneous Catalysis andMolecular Design, Sienkiewicza 112,90-363 Łódz, Poland

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v

Contents

1 Phosphines and Related Tervalent Phosphorus Systems 1Piet W. N. M. van Leeuwen

1.1 Introduction 11.1.1 History 11.1.2 Alternative Ligands 21.1.3 Aim of the Chapter 21.2 Synthesis of Phosphorus Ligands 31.2.1 Introduction 31.2.2 Nucleophilic Substitution by Carbanions at P𝛿+ 31.2.3 Phosphorus–Carbon Bond Cleavage and Phosphido Anion

Preparation 71.2.4 Phosphido Anions as Nucleophiles 91.2.5 P—H Addition to Unsaturates 121.2.6 Reduction of Phosphine Oxides and Sulfides 131.2.7 X/Y-Substitution at Phosphorus 141.2.8 Aryl-X in Metal-Catalyzed Cross-Coupling 151.2.9 Quaternization and Reduction 161.2.10 The Use of R2PCH2

− Anions in Phosphine Synthesis 161.3 Ligand Properties 181.3.1 Electronic Properties 181.3.2 Steric Properties 201.3.3 The Bite Angle of Bidentate Ligands 221.3.4 Chirality 251.3.4.1 P-Stereogenic or P-Chiral Ligands 251.3.4.2 Chiral Backbone 271.3.4.3 Chiral Substituents at Phosphorus 271.3.4.4 Axial Asymmetry or Atropisomery 271.3.4.5 Spiro Diphosphines 281.3.4.6 Planar Asymmetry 281.3.4.7 Helical Symmetry 291.4 Rhodium-Catalyzed Hydroformylation with Xantphos-Type

Ligands 291.4.1 Introduction 29

vi Contents

1.4.2 Monophosphines, Characterization Studies, and Diphosphines 301.5 Cross-Coupling Catalysis with Mono- and Bidentate

Phosphines 331.5.1 Introduction and Simplified Mechanism 331.5.2 Oxidative Addition 341.5.3 Transmetallation 371.5.4 Reductive Elimination 371.6 Decomposition Reactions 431.6.1 Phosphine Decomposition 431.6.1.1 Phosphine Oxidation 431.6.1.2 P–C Cleavage of Ligands 441.6.2 Phosphite Decomposition 47

References 50

2 Recent Developments in Phosphonium Chemistry 59Mathieu Berchel and Paul-Alain Jaffrès

2.1 Introduction 592.2 Synthesis of Phosphonium Salts 602.3 Phosphonium Salts as a Tool for Organic Synthesis 702.3.1 Phosphonium Salts as Ionic Liquids 702.3.2 Phase Transfer Catalysis (PTC) 742.3.3 Coupling Agent for Peptide Synthesis 782.4 Phosphonium Salts for Biological and Medical Applications 842.4.1 Targeting Mitochondria 842.4.1.1 Anticancer Drugs 862.4.1.2 Imaging Agents 902.4.2 Phosphonium Salts for Nucleic Acid Delivery 922.4.3 Phosphonium Salts as Antimicrobial Agents 962.5 Conclusion 102

References 103

3 Phosphorus Ylides and Related Compounds 113Alejandro Presa Soto and Joaquín García-Álvarez

3.1 Introduction 1133.2 Preparation of Phosphorus Ylides 1153.2.1 Synthesis of Phosphorus Ylides from Phosphonium Salts 1163.2.2 One-Pot Three-component Reactions of Phosphines, Dialkyl

Acetylenedicarboxylates, and Various Organic Nucleophiles 1213.2.3 Other Methodologies for the Synthesis of Phosphorus Ylides 1253.3 Applications of Phosphorus Ylides in Organic Synthesis 1303.3.1 Wittig Reaction 1303.3.1.1 Application of Wittig Reaction in Cyclization Processes 1333.3.1.2 Application of Wittig Reaction in Tandem Processes 1353.3.1.3 Application of Wittig Reaction in Total Synthesis of Natural

Products 1403.3.1.4 Wittig Reactions with Nonstabilized Ylides 142

Contents vii

3.3.1.5 Application of Wittig Reaction in Nonconventional Solvents or UnderSolvent-free Conditions 144

3.3.2 Other Organic Reactions of Phosphorus Ylides 1463.4 Conclusions 148

Acknowledgments 148References 148

4 Low-Coordinate Phosphorus Compounds withPhosphaorganic Multiple Bond Systems 163Dietrich Gudat

4.1 Introduction 1634.2 General Considerations on Structure and Bonding of PC Multiple

Bond Systems 1654.2.1 Bonding and Stability 1654.2.2 Structural and Spectroscopic Data 1694.3 Synthetic Approaches 1714.3.1 Acyclic Phosphaalkenes 1714.3.2 Phosphaalkynes 1744.3.3 Delocalized Ring Systems: Phosphinines and Phospholides 1754.4 Reactivity 1774.4.1 Addition and Cycloaddition Reactions 1774.4.2 Reactions with Electrophiles 1794.4.3 Reactions with Nucleophiles 1804.4.4 Oxidation, Reduction, and Metathesis 1814.4.5 Metal Coordination 1814.5 Applications of Phosphorus–Carbon Multiple Bond Systems 1844.5.1 PC Multiple Bond Systems in π-Conjugated Materials 1844.5.2 Oligomerization of PC Multiple Bond Systems: Building Rings and

Cages 1884.5.3 Polymeric Materials from PC Multiple Bond Systems 1924.5.4 Chiral Phosphorus-Containing Multiple Bond Systems 1954.5.5 PC Multiple Bond Systems in Coordination Chemistry and

Catalysis 1984.5.6 PC Multiple Bond Systems for Nanoparticle Stabilization and Surface

Functionalization 206References 209

5 Pentacoordinate Phosphorus Compounds 219Masaaki Yoshifuji

5.1 History of Pentacoordinate Phosphorus Compounds 2195.2 Preparation of Pentacoordinate Phosphorus Compounds 2215.3 Structure of Trigonal Bipyramid and Square Pyramid 2285.4 Interconversion of Pentacoordinate Phosphorus Compounds 2295.5 Apicophilicity 2325.6 Hydrolysis of Phosphate Esters 233

References 235

viii Contents

6 Hexacoordinate Phosphorus Compounds 239Masaaki Yoshifuji

6.1 Preparation and Structure of Hexacoordinate PhosphorusCompounds 239

6.2 Stereochemistry of Hexacoordinate Phosphorus Compounds 2416.3 Hexacoordinate Compounds with Intramolecular Coordination 2426.4 Theoretical Studies on Hexacoordinate Phosphorus Compounds 2456.5 Hexacoordinate Phosphates as Counter Anions for Complex

Ligands 245References 247

7 Methods for the Introduction of the Phosphonate Moiety intoComplex Organic Molecules 249Wouter Debrouwer, Iris Wauters, and Christian V. Stevens

7.1 Introduction 2507.2 P—C (sp3) Bond Formation 2527.2.1 Michaelis–Arbuzov Reaction 2527.2.2 Abramov Reaction 2547.2.3 Michaelis–Becker Reaction 2547.2.4 Pudovik Reaction 2547.2.5 Kabachnik–Fields Reaction 2567.2.6 Transition-metal-Catalyzed Coupling Reactions 2577.2.7 Hydrophosphonylation of Unsaturated C—C Bonds 2587.2.7.1 Palladium-Catalyzed Hydrophosphonylation 2587.2.7.2 Rhodium-Catalyzed Hydrophosphonylation 2597.2.7.3 Manganese-Catalyzed Hydrophosphonylation 2607.2.7.4 Michael Addition 2617.3 P—C (sp2) Bond Formation 2617.3.1 Michaelis–Arbuzov Reaction 2617.3.2 Transition-metal-Catalyzed Coupling Reactions 2647.3.2.1 Palladium-Catalyzed Coupling 2647.3.2.2 Copper-Catalyzed Coupling 2717.3.2.3 Nickel-Catalyzed Coupling 2727.3.3 Hydrophosphonylation 2737.3.4 Other Methods 2757.3.4.1 Insertion of Phosphonylated Zirconacycles into Alkynes 2757.3.4.2 Derivatization of Alkynylphosphonates 2767.3.4.3 Electrophilic Phosphorus Reagents 2767.3.4.4 Radical Trapping with Trialkyl Phosphites 2777.3.4.5 Electrochemical Synthesis of Organophosphorus Compounds 2777.3.4.6 Horner–Wadsworth–Emmons Approach 2787.4 P—C (sp) Bond Formation 2787.4.1 Michaelis–Arbuzov Reaction 2787.4.2 Electrophilic Phosphorus Reagents 2797.4.2.1 Grignard Reagents 2797.4.2.2 Lithiated Reagents 2807.4.2.3 Other Metal Acetylides 280

Contents ix

7.4.3 Transition-metal-Catalyzed Coupling Reactions 2817.4.3.1 Copper-Catalyzed Coupling 2817.4.3.2 Palladium-Catalyzed Coupling 2837.4.4 Other Methods 2847.4.4.1 Isomerization of Allenylphosphonates 2847.4.4.2 Heating of Selenoxides 2857.5 Conclusion 285

References 286

8 Phosphorus Heterocycles 295Viktor Iaroshenko and Satenik Mkrtchyan

8.1 Introduction 2958.2 Five-Membered Phosphorus Heterocycles 2968.3 Five-Membered Phosphorus Heterocycles with One Phosphorus

Atom: 1H-Phospholes and Fused Aromatic Systems ContainingPhosphole Ring 296

8.4 Aromaticity of 1H-Phospholes and 1H-Phosphole-ContainingHeterocyclic Systems 303

8.5 1H-Phospholes 3058.6 Synthesis of 1H-Phospholes Following [4+1] and [2+2+1] Synthetic

Strategies 3078.7 Synthesis of Phospholes by [3+2] Cyclization Reaction 3128.8 Synthesis of 1H-Phospholes by Intramolecular Cyclization

Reactions 3128.9 Synthesis of Phosphorus-Containing Porphyrin Hybrids 3168.10 Fused Heterocycles with 1H-Phosphole Structural Fragment 3178.11 Synthesis-Fused 1H-Phospholes Following [4+1] and [2+2+1]

Synthetic Strategies 3208.12 Synthesis of Fused Phospholes Following [3+2] Synthetic

Strategies 3248.13 Synthesis of Fused Phospholes Following Intramolecular Cyclization

Strategies 3298.14 Application of C—H Bond Activation Protocols for the Synthesis of

Benzo[b]phosphindoles via Intramolecular Cyclization 3398.15 Synthesis of π-Conjugated Benzo[b]phosphindoles Following [2+2+2]

Cycloaddition Synthetic Strategy 3418.16 Five-Membered Phosphorus Heterocycles with One

Heteroatom 3428.16.1 1,2- and 1,3-Heterophospholes: General Overview 3428.17 Synthesis of 1,2- and 1,3-Heterophospholes: General Overview 3458.18 1,2-Azaphospholes 3478.18.1 Synthesis of 1,2-Azaphospholes Following [4+1] Synthetic

Strategies 3478.19 Synthesis of 1,2-Azaphospholes Following [3+2] Synthetic

Strategies 3518.20 Synthesis of Fused 1,2-Azaphospholes via Intramolecular Cyclization

Strategy 353

x Contents

8.21 Synthesis of 1,2-Oxophospholes, 1,2-Thiaphosphols, and1,2-Selenophosphols 356

8.22 1,3-Azaphospholes 3598.22.1 Synthesis of 1,3-Azaphosphole Following [4+1] Synthetic

Strategies 3598.23 Synthesis of 1,3-Azaphospholes by Intramolecular Cyclization

Reactions 3628.24 Synthesis of 1,3-Oxaphospholes, 1,3-Thiaphospholes, and

1,3-Selenophospholes 3658.25 Six-Membered Phosphorus Heterocycles 3728.26 Phosphinines: General Overview 3728.27 Synthesis of λ3- and λ5-Phosphenines: General Overview 3768.28 Synthesis of Phosphenines Following [5+1] Synthetic Strategy 3788.29 Synthesis of Phosphenines Following [4+2] Synthetic Strategy 3818.30 Synthesis of Phosphenines from Phospholes 3888.31 Synthesis of Phosphenines Following 1,6-Electrocyclization

Strategy 3938.32 Synthesis of Fused λ3- and λ5-Phosphenines: General Overview 3968.33 Synthesis of Fused Phosphenines Following [4+2] Synthetic

Strategy 3978.34 Synthesis of Fused Phosphenines by Intramolecular Cyclization 4008.35 Synthesis of Fused Phosphenines Following [5+1] Synthetic

Strategy 4018.36 Six-Membered Phosphorus Heterocycles with One Heteroatom 4048.37 Synthesis 1,2-, 1,3-, and 1,4-Heterophosphinines 4088.38 1,2-Azaphosphenines 4088.39 Synthesis of 1,2-Azaphosphenines Following [3+1+1+1] Synthetic

Strategy 4098.40 Synthesis of 1,2-Azaphosphenines Following [3+3] Synthetic

Strategy 4148.41 Synthesis of 1,2-Azaphosphenines Following [3+2+1] Synthetic

Strategies 4148.42 Synthesis of 1,2-Azaphosphenines Following [5+1] Synthetic

Strategies 4148.43 Synthesis of 1,2-Azaphosphenines Following [4+2] Synthetic

Strategies 4158.44 Synthesis of 1,2-Azaphosphenines Following Intramolecular

Cyclization Strategies 4178.45 1,3-Azaphosphenines 4198.46 Synthesis of 1,3-Azaphosphenines Following [5+1] Synthetic

Strategy 4198.47 Synthesis of 1,3-Azaphosphenines Following [4+2] Synthetic

Strategies 4198.48 1,4-Azaphosphenines 4218.49 Oxygen- and Sulfur-Containing Heterophosphinines 4248.50 Application and Synthesis of Phosphoborine Systems 4298.51 Application and Synthesis of 1,4-Phosphasiline System 432

Contents xi

8.52 Synthesis of Germanium- and Tin-ContainingHeterophosphinines 437References 441

9 Modern Aspects of 31P NMR Spectroscopy 457David S. Glueck

9.1 Introduction 4579.1.1 Properties of the 31P NMR Nucleus and Experimental Details 4579.1.2 31P NMR Chemical Shifts 4589.1.3 Coupling Constants 4589.1.4 What is New About This Review 4599.2 Chemical Shifts 4599.2.1 Chemical Shifts for Common Organophosphorus Compounds 4599.2.2 31P NMR Chemical Shifts for Organophosphorus Heterocycles 4599.2.3 Beyond the Normal Chemical Shift Range 4599.2.4 Isotope Shifts 4609.2.5 From Chemical Shifts to Structure and Bonding 4609.2.6 Prediction of 31P NMR Chemical Shifts 4629.2.6.1 Structural Assignment Assisted by Computation of 31P NMR Chemical

Shifts 4639.3 Coupling Constants 4649.3.1 P–H Couplings 4649.3.1.1 1JPH 4649.3.1.2 Conformational Effects on 3JPH 4649.3.2 P–P Couplings 4669.3.3 P–Se Couplings: Lewis Base Strength 4689.3.4 P–Pt Couplings: Trans Influence 4699.4 Two-Dimensional (2D) 31P NMR Techniques 4699.4.1 Connectivity via 2D Correlation Experiments 4709.4.1.1 Correlation Spectroscopy (COSY) 4709.4.1.2 Semiconstant time COSY 4709.4.1.3 Heteronuclear Multiple-Quantum Correlation Spectroscopy

(HMQC) 4709.4.2 Intramolecular Distances via 31P–1H Heteronuclear Overhauser

Enhancement Spectroscopy (HOESY) 4719.5 Analytical Methods 4719.5.1 Quantification by 31P NMR Integration 4729.5.2 Direct Analysis of Organophosphorus Compounds 4729.5.3 Indirect Analysis via Derivatization of Analytes with

Organophosphorus Compounds 4739.5.4 31P NMR Spectroscopic Probes 4749.5.4.1 Measurement of Enantiomeric or Diastereomeric Purity of Chiral

Phosphines 4749.5.4.2 Phosphorus Labels for Measuring Enantiomeric Purity 4759.5.5 Spectroscopic Probes for Lewis Acidity 4759.6 Diffusion-Ordered NMR Spectroscopy (DOSY) 4769.6.1 DOSY Analysis of Organophosphorus Compounds 476

xii Contents

9.6.1.1 Hydrogen Bonding to Phosphine Oxides 4769.6.1.2 Ion Pairing 4779.6.1.3 Monomer or Dimer? 4779.6.1.4 Polymer Characterization 4779.6.1.5 Quantitative Determination of Molecular Size or Formula

Weight 4779.6.2 DOSY Analysis of Phosphorus-Tagged Analytes 4789.6.2.1 Phosphitylation of Small Molecules 4789.6.2.2 Phosphorus-Labeled Biomolecules 4799.7 Solid-State (SS) 31P NMR 4799.7.1 Probes of Solid-State Structure and Reactivity 4799.7.1.1 Anchoring Phosphines to Solid Supports 4799.7.1.2 Reactions on Surfaces: Sarin 4809.7.1.3 Spectroscopic Probe of Solid Acids 4809.7.2 Solid-State vs Solution Structure 4819.7.2.1 PPh3Cl2 4819.7.2.2 Pt-phosphaalkene Coordination Mode 4819.7.2.3 A Ru–Pyrrolato Complex: Monomer or Dimer? 4819.7.3 Structure and Bonding 4829.7.3.1 P–B Interactions in Phosphine–Borane-Frustrated Lewis Pairs 4829.7.3.2 Ti=P Multiple Bonding in a Phosphinidene Complex 4829.7.3.3 Distance Information from Transferred Echo Double Resonance

(TEDOR) 4839.8 Physical and Chemical Processes of Organophosphorus

Compounds 4839.8.1 Dynamic Processes 4839.8.1.1 Restricted Rotation 4839.8.1.2 Pyramidal Inversion 4849.8.1.3 Pseudorotation 4849.8.2 Chemical Exchange 4859.8.2.1 Tautomerization 4859.8.2.2 Te Exchange in Phosphine Tellurides 4879.8.2.3 Phosphine Dissociation 4879.9 Identification of Intermediates and Monitoring Their Reactivity 4889.9.1 Reaction of a Triarylphosphine with Oxygen 4889.9.2 Phosphonium Intermediates in Asymmetric Appel Oxidation 4889.9.3 Enhanced 31P NMR Spectra via para-Hydrogen-Induced Polarization

(PHIP) 4899.10 Conclusion 490

Acknowledgment 490References 490

10 Phosphorus in Chemical Biology and MedicinalChemistry 499Marlon Vincent V. Duro, Dana Mustafa, Boris A. Kashemirov, andCharles E. McKenna

10.1 Phosphorus and Life: An Introduction 499

Contents xiii

10.2 Unnatural Nucleotides as Chemical Tools in Biology 50010.2.1 Base-Modified Nucleoside Triphosphates 50110.2.2 Modifications Within the Triphosphate 50410.2.3 Modifications at the Terminal Phosphate 51410.3 Prodrugs of Nucleoside Phosphates and Phosphonates 51610.3.1 Approaches for Nucleoside Monophosph(on)ates 51710.3.2 Prodrugs of Nucleoside Di- and Triphosphates 52110.4 Synthesis and Medical Applications of Bisphosphonates 52210.4.1 Pharmacologically Active Bisphosphonates (and

Phosphonocarboxylates) 52310.4.2 Synthesis of Bisphosphonates 52410.4.3 Bisphosphonates in Medical Imaging and Drug Delivery 52710.4.4 Lipophilic Bisphosphonates 52910.4.5 Benefits and Risks of Bisphosphonate Therapies 53010.5 Conclusion: The Future of Phosphorus in Chemical Biology and

Medicinal Chemistry 531References 531

11 Future Trends in Organophosphorus Chemistry 545Shin-ichi Kawaguchi and Akiya Ogawa

11.1 Introduction 54511.2 Facile C—P Bond Formation Methods 54511.2.1 Addition Reactions of Phosphorus Compounds to Unsaturated

Bonds 54511.2.2 Cross-coupling Reactions of Phosphorus Compounds 55011.3 Utilization of Organophosphorus Compounds 55111.3.1 Frustrated Lewis Pairs 55111.3.2 Ionic Liquids 55211.3.3 Fluorinated Phosphine Ligands 552

References 553

Index 557

1

1

Phosphines and Related Tervalent Phosphorus Systems

Organophosphorus Compounds as Ligands in Organometallic CatalysisPiet W. N. M. van Leeuwen

LPCNO, INSA-Toulouse, 135 Av. de Rangueil, 31077 Toulouse, France

1.1 Introduction

1.1.1 History

Phosphines and related phosphorus-containing molecules play a major role inhomogeneous catalysis. The history of homogeneous metal complex catalysis, aswe know it today, started in the 1960s, although there had been even industrialapplications long before that. In the 1920s, a catalytic process was used for theaddition of water to acetylene. The metal mercury was used in a sulfuric acid solu-tion. The reaction was very slow and large volumes were needed; thus, this was farfrom attractive. A related process still in operation is the zinc-salt-catalyzed addi-tion of carboxylic acids to acetylene. With the introduction of petrochemistry, thefeedstock for acetaldehyde production changed to ethene. The reaction used untiltoday is a stoichiometric oxidation of ethene by palladium, the so-called Wackerprocess, in which palladium is reoxidized with oxygen and a copper catalyst. Car-bonylation catalysis came on stream in the 1930s and 1940s, although its appli-cation was retarded by World War II (WWII). Initially, the metals of choice werenickel, e.g. work by Reppe, and cobalt, especially hydroformylation by Roelen,and methanol carbonylation. Probably, Reppe (1948) was the first to use triph-enylphosphine as a modifying ligand in a catalytic reaction, which concerned theaddition of nickel-cyanide-catalyzed carbonylative alcohol addition to alkynes,leading to acrylates [1]. He used nickel cyanide also in the synthesis of polyketonefrom carbon monoxide and ethene in those early years. As of the 1960s, all these“leads” were greatly improved by ligand effects and by changing to the more activesecond-row transition metals palladium and rhodium. Cobalt was also modifiedby phosphine ligands, and in this instance, the catalyst produced more of the lin-ear oxygenate product, which now is mainly the alcohol rather than the aldehyde(Shell) [2]. Early examples of triphenylphosphine-modified group 10 hydrogena-tion catalysis are due to Bailar and Itatani [3]. Ever since, more publications haveappeared that reported phosphine effects on catalytic reactions.

Organophosphorus Chemistry: From Molecules to Applications, First Edition.Edited by Viktor Iaroshenko.© 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.

2 1 Phosphines and Related Tervalent Phosphorus Systems

1.1.2 Alternative Ligands

Before concentrating only on phosphorus ligands, we should mention that in thepast three decades, ligands based on other donor atoms have become equallyimportant and, in some areas, even more important than phosphines. In themid-1980s, the metallocene era started for the early transition metals especiallyin polymerization catalysis, followed by alkoxides, amides, and salen ligands.Meanwhile, metallocene catalysts have found industrial applications. In the latetransition metal area, the diimine ligands stand out together with a shift to thefirst-row metals for alkene polymerization, and they almost made it to a replace-ment of the nickel catalyst in the oligomerization of ethene. They were followeda little later by the outburst of the NHC ligands, which have beaten, in severalinstances, the best phosphines used so far in certain reactions. They have foundcommercial applications in metathesis reactions. A combination of all donorligands in bidentates has further enriched the toolbox of homogeneous catalysis.One should not forget that the “ligand-free” systems are attractive, as they donot suffer from ligand decomposition, but their life can still be limited becauseof precipitation or formation of a compound with the wrong valence state. Thestabilizing ligands in these cases are, for example, carbon monoxide, alkenes,halides, and other anions, for example, the Wacker process, cobalt-catalyzedhydroformylation (Exxon), nickel-catalyzed oligomerization of butene to3-methylheptane (IFP, Dimersol process), rhodium-catalyzed carbonylation ofmethanol (Monsanto, now BP), and ditto for iridium (BP, Cativa process).

1.1.3 Aim of the Chapter

The aim of this chapter is to give an introduction to the use of tervalent phos-phorus compounds as ligands in homogeneous catalysis. Several chapters in thiswork refer to that area and have their own introductions. We have tried to avoidoverlap and provide some basic concepts in a nutshell while referring to thosechapters that deal in more detail with this topic. In Section 1.2, we deal with themost common elementary steps used for the synthesis of phosphorus ligands.In more specific chapters, synthesis will be dealt with in much more detail thanwhat we were able to cover here. The overview is very limited, as, for example,in our laboratories students are introduced to phosphorus ligand synthesis witha series of about 200 synthetic steps of which we think they are worthwhile for astarter in this area! In Section 1.3, the properties of phosphorus ligands will bediscussed by presenting the most common yardsticks used, such as Tolman’s 𝜒and 𝜃 values for the electronic and steric parameters, respectively, and Casey’s 𝛽n,the natural bite angle for bidentate ligands. For the steric and electronic parame-ters, several alternatives have been developed, and all the parameters have founduse particularly in catalysis [4]. Studies on the use of parameters in Linear FreeEnergy Relations and QUALE will be mentioned.

In Section 1.4, chiral phosphorus ligands will be introduced focusing on thetypes of chiral ligands available, involving the most typical phosphorus anddiphosphorus ligands, and heterobidentate ligands.

1.2 Synthesis of Phosphorus Ligands 3

The next two sections will deal with two examples of ligand effects, namely afew highlights in hydroformylation and the next one on modern cross-couplingchemistry. As both are huge areas, these parts also serve as a brief introductionto the fields. We will highlight the crucial issues concerning monodentate andbidentate ligands.

Section 1.6 includes the main decomposition pathways of phosphorus ligands,which are also discussed in dedicated chapters in books and reviews.

1.2 Synthesis of Phosphorus Ligands

1.2.1 Introduction

Clearly, the synthesis of phosphorus ligands involves a library of organic phos-phorus chemistry to which one cannot do justice in just a few pages. Chapter 7by Stevens deals with the most important routes for the introduction of phos-phonates into complex organic molecules, and more details and references canbe found there. Phosphonates can be converted into phosphines, of which thereexist many examples. Here, we will deal with a simple summary of the com-mon elementary steps for making phosphorus ligands. Phosphaalkenes will notbe discussed as they are not yet of proven interest in catalysis. Although phos-phinines have been exploited occasionally in catalysis and have shown interestingproperties, for instance, in rhodium-catalyzed hydroformylation [5], we will notdiscuss their synthesis. We will confine ourselves to a series of elementary stepsthought to be useful for our purposes. Even that will rather be a short list ofless than 40, as, for example, in my group, the students acquainted themselvesin phosphine synthesis using a set of about 150–200 reactions. Although onecould bring down the number as there are less reaction types, it would still betoo large to list for the present purposes. Below we have ordered the reactionsaccording to the main reaction types, which are still feasible, because the num-ber of ways to make a P—C bond is far less numerous than that for making C—Cbonds!

1.2.2 Nucleophilic Substitution by Carbanions at P𝜹+

The ionic approach to the formation of a carbon–phosphorus bond has two pos-sibilities, namely the use of phosphorus as a nucleophile or as an electrophile.The latter seems more in accord with the electronic properties of phosphorus, asa slightly positively charged phosphorus species is common and stable, whereasphosphido anions (Section 1.2.3) tend to show electron transfer reactions in addi-tion to and before entering a nucleophilic attack. Indeed, nucleophilic substitu-tion is the most common reaction used, although both routes have their prosand cons. One might not often directly see potential cons for a certain route.For example, an attack of a benzylic anion at a phosphorus electrophile will pro-ceed smoothly, but the product formed, PhCH2PR2, has an acidic proton at the

4 1 Phosphines and Related Tervalent Phosphorus Systems

benzylic position, and the remaining benzyl anion may be consumed via a sim-ple proton abstraction and, at best, the yield is only half of the expected amount.The nucleophile will often be a relatively simple Grignard or a hydrocarbyllithiumreagent, and it can be used in excess, as during the workup by hydrolysis, it canbe easily removed. If the nucleophile is a more complicated molecule, of whichthe remains can be removed only with difficulty, the use of a large excess must beavoided. Also, the carbonucleophile may substitute other hydrocarbyl groups atphosphorus (Scheme 1.3). Reaction 3 shows a less common nucleophilic substi-tution, but it shows its versatility.

Perfluoroalkyl groups are far less frequently used than simple aromatics, whichwe will encounter below. The first example shows pentafluoroethyl groups, whichare not the most common substituents at phosphorus, but they are highly desir-able in the studies of electronic effects in catalysis (Scheme 1.1) [6]. In this case,the diphosphine was obtained in an excellent yield. It should be borne in mindthat the formation of LiF of such lithium fluoroalkyl intermediates is a highlyexothermic decomposition reaction. Occasionally, such decomposition reactionstake place. For instance, dry spots in the reaction vessel, caused by a flow of aninert gas, might initiate an explosive formation of LiF. Several accidents haveoccurred, even on a large scale, but few have been adequately reported (a safesynthesis of fluoroalkyl-containing organometallics has been reported) [7]. Thephosphorus precursor is not a common reagent either; it is difficult to synthesize,but it is commercially available.

4C2F5ClBuLi

4C2F5Li +PPPCl2Cl2P C2F5

C2F5

C2F5

C2F5

88%

–95 °C –95 °C

Et2O

Scheme 1.1 Reaction 1, alkylation of P—Cl bonds.

A more elaborate lithium reagent that one might not want to spoil is shownin Scheme 1.2, Reaction 2 [8]. In the next step, the amino group can be replacedby a phosphide anion under mild acidic conditions to give the so-called Josiphosligands. Lithiation at the upper ring is facilitated by the amino group and willproceed mainly on one side to give a certain diastereoisomer if the amine consistsof just one enantiomer.

FeMe

NMe2

FeMe

NMe2PPh2

1. nBuLi

2. ClPPh2

(61%) S,RS

–78 °C, then RT

Scheme 1.2 Reaction 2, synthesis of Josiphos.

Examples of hydrocarbyl/hydrocarbyl substitution are given in Scheme 1.3,Reaction 3 [9]. Thus, on the way to the formation of the lithium nucleophiles of

1.2 Synthesis of Phosphorus Ligands 5

10H-phenoxaphosphinine, one has to use the appropriate lithium rearrange-ment. We have pictured this reaction to show another unexpected side reactionof the otherwise successful nucleophilic substitution.

70%

MeLiP

O

P

O

CH3

PhLi

CO2, HCl–H2OP

O

CO2H

Scheme 1.3 Reaction 3, aryl–methyl exchange.

Scheme 1.4, Reaction 4 shows that phosphinates can be the electrophiles andthe phosphonates can be substituted in the same way [10]. A more reactivereagent is obtained by replacing the methoxy group by chlorine. The finalphosphine oxide can be reduced by HSiCl3 or similar reagents such as poly-methylhydrosiloxane (PMHS). Nowadays, on a small-scale synthesis, we oftenuse refluxing PhSiH3. As usual, the diastereoisomers containing the mentholgroup can be separated to eventually yield the P-chiral phosphine. Anotherchiral auxiliary used frequently is ephedrine.

PhP(OMe)2

MeI, cat PCl5(–)-mentholO

P OMePh

Me

O

P ClPh

Me

P

PhMe

O

OMen

RMgBr

InversionP

Ph

Me

O

R

Scheme 1.4 Reaction 4, P-chiral phosphines.

Addition of a Grignard to a carbyne is the first step in the elegant synthesisof Buchwald toward his group of ligands developed for cross-coupling reactions(Scheme 1.5, Reaction 5) [11]. The Grignard reagent adds to the carbyne gener-ating another nucleophile that is made to react with a dihydrocarbylphosphorus

MgBr

NMe2

Br

Cl

NMe2

BrMg

NMe2

PCy2

Mg

2 h

60 °C

CuCl

Cy2PCl+

Scheme 1.5 Reaction 5, Buchwald’s synthetic scheme.

6 1 Phosphines and Related Tervalent Phosphorus Systems

chloride. A wide variety of ligands have been made this way, and the route wasoptimized for use on a larger scale to promote its use in industrial applications.

The lithium reagent, as is well known, can be generated via exchange of arylbromides with, e.g. nBuLi forming nBuBr as the by-product, which may inter-fere in later steps. A clean and more effective way is the often use of the moredangerous tBuLi, of which two equivalents per bromide are needed as it formsthe unreactive isobutane and isobutene and no aliphatic bromide. An example ofcarbanion/carbanion substitution is depicted in Reaction 6 for dilithiobiphenyl(Scheme 1.6) [12]. The product that formed is a dibenzophosphole unless the6,6′ position resists planarization of the molecule. The liberated PhLi reacts withPh2PCl to give triphenylphosphine as the second product, and thus, this is notthe most convenient way to make dibenzophosphole as reaction of the dilithiointermediate with PhPCl2 gives mainly one product.

Li Li+ 2Ph2PCl

Ph2P Ph2P

P

PhLi Li

+ 2Ph2PCl

Ph2P Ph2P

85%

Br Br

4tBuLi

–2LiCl

–PPh3

Scheme 1.6 Reaction 6, phosphole synthesis.

Reaction 7 illustrates the favorable exploitation of carbon nucleophile substitu-tion in disubstituted ferrocene derivatives (Scheme 1.7) [13]. Monosubstitutionof dilithioferrocene is not a clean reaction, but here it is solved by the intro-duction of one extra step, namely the opening of the P—C bond by PhLi. Theresulting lithium reagent can be reacted with a variety of electrophiles, includingP-based ones.

FeLi

Li

PhPCl2Fe PPh

PhLiFe

PPh2

Li

FePPh2

PtBu2

–LiCl–78 °C

then RT50%

t-Bu2PCl

45% two steps

Scheme 1.7 Reaction 7.

1.2 Synthesis of Phosphorus Ligands 7

1.2.3 Phosphorus–Carbon Bond Cleavage and Phosphido AnionPreparation

Phosphorus–carbon bond cleavage aims at the generation of phosphido anionsfor their use as nucleophiles toward carbon electrophiles. A few phosphidoanions can be made from the triarylphosphines by cleavage with sodium inammonia or alkali metals in tetrahydrofuran (THF) or dioxane. In additionto the desired MPAr2, one obtains MAr, or in ammonia, MNH2. Immediatecontinuation with this solution of the phosphido anion requires protonationof the coproduced metal aryl or metal amide. This can be done convenientlyby ammonium chloride (in ammonia), tBuCl, or alcohols. In THF or dioxane,the aryllithium product formed may partially decompose and less than thecalculated amount of alcohol may be required. Alternatively, the crude, cleavedmixture can be added with weak acids to make the diarylphosphine for storage,which is deprotonated with, e.g. nBuLi before its use as a phosphide anion.

The results for the sodium or lithium cleavage reactions, or for phosphinescontaining different aryl groups, are hard to predict. Van Doorn carried out a sys-tematic study of substituted arylphosphines and a few alkylarylphosphines [14].

An inventory of the reductive cleavage of functionalized triphenylphosphinesAr3P has been made in the first publication [14]. The reaction can be controlledin many cases to eventually give preparatively interesting secondary or primaryphosphines (Scheme 1.8). In addition, the reaction of ortho-functionalized sec-ondary phosphines leads to primary phosphines. The reducing agents Na/NH3and Li/THF often give complementary results; reactions such as Birch reduc-tion or multiple cleavage of ortho-functionalized phosphines require protonationby the solvent and do not occur in THF. Lowest unoccupied molecular orbital(LUMO) energies and coefficients were correlated with the experimental results.Both very high and very low LUMO energies impede cleavage. Note that many ofthese reactions were at the time carried out on 10-g scale, which required mod-erate precaution with air and water; today’s procedures on 100-mg scale requiremore stringent conditions.

P

3R

PNa

2R

PH

2R

NH4ClNa/NH3

R = H 2/3/4-Me 2/3-Me2N 2/3-MeO 3-t-Bu 4-Me3Si

100% 55/84/70% 14/37% 88/76% 85% 96%

Scheme 1.8 Reaction 8 [14], P–C cleavage by sodium.

Reductive cleavage of mixed o- and p-functionalized triarylphosphines withNa/NH3 and Li/THF strongly depends on the nature and positions of thesubstituents [14]. Reduction occurs readily with PhPAr2 [Ar = 2,4-(MeO)2C6H3,2,4,6-(MeO)3C6H2, 4-(Me2N)C6H4] and Ph2PAr [Ar = 2,4-(MeO)2C6H=],whereas the corresponding Ar3P is not reduced. Cleavage of p-substituted

8 1 Phosphines and Related Tervalent Phosphorus Systems

compounds leads to the mixtures of secondary phosphines. By contrast, thecleavage of mixed o-substituted triphenylphosphines is very selective. Thefunctionalized Ph group is split off in high yield when it carries Me, Me2N, andMeO substituents. Reaction of [2,4-(MeO)2C6H3]2PPh is not selective, owing toloss of methoxy groups. By contrast, the Ph group is split off when the mixedphosphine contains phenoxide groups, e.g. 2-NaOC6H4. In a number of cases,the product of a Birch reduction with an isolated diene system is formed in NH3via a phosphino-stabilized cyclohexadienyl anion. This reduction does not occurin the aprotic solvent THF. Base-catalyzed isomerization leads to a conjugateddouble-bond system with a vinylphosphine moiety.

Reaction 9 shows an example with the use of Li/THF for the cleavage, which,for many researchers, may be more attractive, especially when working on a smallscale (Scheme 1.9).

P

3R

PLi

2R

Li/THF

R = 2-Me, 4-Ph, 3-Me2N95–95%

16–60 h

RT

Scheme 1.9 Reaction 9, P–C cleavage by lithium [14] .

Phosphides can also be made from Ar2PCl compounds by reacting the latterwith an alkali metal in THF, and thus, this reaction can be done on small scale(Scheme 1.10) [15]. The potential by-product Ar2P-PAr2 also reacts with the alkalimetal to give the phosphido metal derivative. The excess metal can be removedby decantation. The selective synthesis of Ar2PCl often requires the well-knownsequence PCl3, Cl2PNR2, Ar2PNR2, and Ar2PCl.

PCl PLi

2

Li/THF

2

O

O

OTos

TosO

H

H

O

O

Ph2P

PPh2

H

H

35%

RT 0 °C

Scheme 1.10 Reaction 10, P–Cl reduction.

Diphosphines of bis-diphenylphosphino nature give double cleavage, andmono-cleavage has been reported but is not selective. The use of an ultrasonicbath gives the best results (Scheme 1.11, Reaction 11) [16].

The monocleaved diphosphine can be obtained with a certain percentage ofdi-cleaved products. Acidic workup gives the mixture of secondary phosphinesthat can be separated by Kugelrohr distillation. Another route to monocleaved

1.2 Synthesis of Phosphorus Ligands 9

PPh2 PPh2

PPh2 PPh2

PPh2 PPh2

PPh2

HPhP PPhHLi/THF

77%

85%

75%

80%PPh2

Scheme 1.11 Reaction 11, P–C cleavage in diphosphines.

diphosphine for 1,3-bis(diphenylphosphino)propane (dppp) involves the conver-sion of the dicleaved diphosphine to the cyclic 1,2-diphenyl-1,2-diphospholane,which can be ring-opened by carbonucleophiles, especially small aliphaticreagents, and thus, the scope seems limited (Scheme 1.12) [17].

PP

Ph

PhPPh2 PPh2Li

0 °C, THFultrasound

HPhP PPhH

BuLiBuPhP PPhLi

EtBrBuPhP PPhEt

[Cp*2ZrH3Li]3

–H2

88%

60–90%86%

Scheme 1.12 Reaction 12, reactions of 1,2-diphospholane.

Improvements of these examples are continuously reported, and one shouldcheck for more recent examples.

1.2.4 Phosphido Anions as Nucleophiles

The synthetic sequence of starting with an ester, reducing it to an alcohol,tosylating the alcohol, and nucleophilic displacement of the tosylate by phos-phide is very useful and popular, e.g. 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (DIOP) and many look-alikes were made via thisroute. The chiral acids are often natural products or derived thereof. One shouldrealize, looking at the yields of this sequence, that the effectiveness of this routeis limited, in particular the last step, although column separation at the end, orcomplex formation with nickel, always yields the pure product. The efficienciesof the substitution reactions with the use of halides as the leaving group, R2POanion as the nucleophile, or the BH3 complex of the phosphido anion often givemuch better results. Sometimes, these results may be unexpected and, as intransition metal chemistry, it may be worth trying a number of nucleophiles andsolvents. In our view, it often pays off to replace the tosylate by chloride. The sideproducts of the simple nucleophilic substitution are, as always, elimination andradical formation (electron transfer without direct contact between phosphorusand electrophilic carbon atoms occurs; the reaction of electrophilic phosphorushalides and carbon anionic nucleophiles is more in accord with the nature ofboth entities).

10 1 Phosphines and Related Tervalent Phosphorus Systems

Only alkyl halides can be substituted this way, and for aromatic electrophiles,other routes have been developed. An important reaction for the preparationof aromatic and alkene phosphine has become the metal-catalyzed coupling ofsp2-carbon and phosphorus atoms, which is discussed separately.

Ph2PK is commercially available, which avoids several experimental problems.Several dihydrocarbylphosphines such as R2PH are also commercially available,even on a large scale! As one works on a relatively small scale, nowadays theobnoxious odor of Ph2PH does not pose a large problem either, if all glasswareis submerged into a bleach solution in the fume cupboard immediately after use.Alternatively, hydrogen peroxide in water and acetic acid to aid the solubilizationof the organics can be used. The smell of PhPH2 is much worse than that of Ph2PH,let alone PH3 (inflammable in air), and more care should be taken. RPH2 and PH3should be handled by experienced chemists only in well-equipped laboratories.

Scheme 1.13 gives the synthesis of DIOP [18] and 1,2-Bis(diphenylphosphino)propane - Prophos [19] and shows the low yields obtained via the substitution oftosylates. Crude Prophos was converted to a nickel complex, and after crystal-lization, the ligand was recovered by treatment with a cyanide salt.

27%

HO

HO

H

COOEtH

COOEtO

O

H

H

PPh2

PPh2

DIOP

Ph2PLi

24%

Ph2P PPh2

H CH3

TsO OTos

H3C

H

HO OH

H3C

HCOOH

HOH

H3C LiAlH4 TsCl

py

ProphosQuant. Quant.

Scheme 1.13 Reaction 13, synthesis of DIOP via tosylate.

Next, we present two examples of the successful conversion of the ditosylate tothe dichloride for which the substitution by the phosphide salt was much moreeffective, by Tani et al. [20] and Townsend et al. [21], respectively (Scheme 1.14).

O

O OTs

OTs

3LiCl

DMSO O

O Cl

Cl O

O PPh2

PPh2

87%95%

–75 °C THF

Reaction 14

Ph2P–Li

Scheme 1.14 Reactions 14. P–C coupling after conversion of tosylate to halide.

Another approach for obtaining a highly selective substitution was introducedby Livinghouse and others. It involves the conversion of the phosphido anion toits borane adduct, which becomes much less basic and less apt to electron trans-fer. Excellent yields are now achieved, and the borane can be removed simply by

1.2 Synthesis of Phosphorus Ligands 11

treatment with an amine (Scheme 1.15) for the less basic phosphines. Treatmentwith acid (HBF4⋅OMe2) followed by base works well for basic phosphines [22].

OTs

OTs

n[Ph2P–BH3]– [Li]+

DMF, THF

PPh2

PPh2

n

BH3

BH3

DABCO PPh2

PPh2

n

n = 2,88%

PPh2

PPh2

PPh2

Me2Si

PPh2

92% 89%

Scheme 1.15 Reaction 15, synthesis of diphosphines from tosylates via phosphide-boranes.

There are exceptions regarding aryl halides as is shown in Reaction 16 inwhich o-chlorobenzoic acid gives substitution by diphenyl phosphide in liquidammonia. The acid is deprotonated by the sodium amide coproduct, formedfrom PhNa, and thus, this needs no separate destruction. A by-product ofthe substitution is the meta-isomer formed via a benzyne intermediate. Atthe time of its publication by Rauchfuss and coworkers this was already anindustrial process for the synthesis of the ligand of Shell’s higher olefin process(Scheme 1.16) [23].

2Na + PPh3

NH3

NaPPh2

+ NaPh +

Cl

COOH

PPh2

COOH75%

By-product

COONa

NaPPh2

COOH

PPh2

(NaNH2)

Cl

COONa

NaPPh2

NaPPh2

–78 °C

–78 °C, then RT

12%

Scheme 1.16 Reaction 16, synthesis of the SHOP ligand.

Aromatic fluorides can be substituted by phosphide groups either with or with-out a metal catalyst. Reaction 17 is an example of an uncatalyzed reaction. Foralkyl halides, an efficient procedure involves the use of DMSO/KOH/water, andsometimes, this even works for organic fluorides (Scheme 1.17) [24].

Secondary phosphine oxides (SPOs) can also be used for tosylate substitutionas is exemplified in Reaction 18 for the synthesis of 1,2-bis(diphenylphosphino)ethane (dppe). The SPOs are soft nucleophiles and not very basic, and they workwell even for tosylated ethylene glycol. In this instance, the dichloride is readilyavailable as well. A further advantage of the SPO is that it does not have an

12 1 Phosphines and Related Tervalent Phosphorus Systems

+PDME, 85 °C

95%

P

K

F

NH2

NH2

+

–

Scheme 1.17 Reaction 17, substitution of fluoride by phosphide base.

obnoxious smell such as PPh2H. Both phosphide anions and SPOs have beenused for the ring-opening substitution of epoxides (Scheme 1.18) [25].

HP

OMe O X

OTs

TsO

BuLi

THF2 P

OMe

OX

P

MeO

OX

AlH3

THF at RT

P

OMe

X

P

MeO

X

X = H, OMe

90%

Scheme 1.18 Reaction 18, the use of SPOs in diphosphine synthesis.

1.2.5 P—H Addition to Unsaturates

There are three main routes for the addition of secondary phosphines, SPOs, andthe like to alkenes and alkynes. The first one is the Michael addition to activateddouble bonds such as the one shown in Reaction 19 with t-butoxide as the base.Through this route, one can conveniently synthesize 1,2-ethanediyl diphosphineswith different substituents at each side (Scheme 1.19) [26].

PPh2H

t-BuOKLiAlH4

PMe2

S

PMe2

SPh2P

RTQuant.

THFPMe2Ph2P

Quant.

Scheme 1.19 Reaction 19, Michael addition of phosphide anion.

For nonactivated double bonds, one can rely on the radical addition promotedby azobisisobutyronitrile (AIBN) (Reaction 20). One adds AIBN until completeconversion has been reached [27]. Even dendrimeric oligophosphines have beenprepared this way; in this instance, UV irradiation was applied together withAIBN (Scheme 1.20) [28].

The third method involves the transition-metal-catalyzed addition to unsatu-rated C=C bonds of which there are many examples in other chapters of thisbook because like many of the other reactions, it can be applied to phosphinecompounds that are not R2PH or SPO. Interestingly, for the palladium-catalyzedreactions, Xantphos often appears to be the ligand of choice [29, 30]. The example

1.2 Synthesis of Phosphorus Ligands 13

PPh2H

88%

AIBNPPh2 PPh2Ph2P

80 °CCH3CN

Scheme 1.20 Reaction 20, radical addition of R2PH to alkenes.

in Reaction 21 depicts the addition of hypophosphorus acid to 1-octene. This con-tains another P—H bond and could be added to another molecule, the OH groupcan be esterified and substituted, and the P=O group can be reduced to convertit into a phosphine. In the work referred to here by Montchamp, the product wasoxidized to octylphosphonic acid (Scheme 1.21).

H3PO2

Pd/dba/Xantphos

C6H13 C6H13

PH(OH)O

DMF110 °C

100%

Scheme 1.21 Reaction 21, addition of hypophosphorus acid.

1.2.6 Reduction of Phosphine Oxides and Sulfides

The most common method for the reduction of phosphine oxides was the useof trichlorosilane (HSiCl3 or Si2Cl6) and triethylamine in refluxing acetonitrile(not shown). Prolonged refluxing leads to loss of trichlorosilane in that instance,as its boiling point is very low (32 ∘C). In the past decades, a variety of relatedreagents have become available that had a higher boiling point and led to a cleanerworkup than trichlorosilane. For alkylphosphines, often more potent reducingagents were needed, and these have also been developed.

For chiral phosphorus centers, one should be aware that both retention andinversion have been observed for different substrates with the use of otherwisevery similar reaction conditions and the same reagents.

The reducing agent used in Reaction 22, PMHS, is a by-product of the siliconeindustry. It is a cheap, easy-to-handle, and environmentally friendly reducingagent. PMHS is more air and moisture stable than other silanes and can be storedfor long periods of time without loss of activity (www.organic-chemistry.org/chemicals/reductions/polymethylhydrosiloxane-pmhs.shtm). The reduction canbe catalyzed by Lewis acidic metal complexes such as titanium tetraisopropoxide,also a large industrial product. Sulfides of strongly donating phosphines are firstmethylated to give the thiomethylphosphonium derivative, which is then easilyreduced (Scheme 1.22) [33].

For alkylphosphines, the use of metal catalysts is recommended, and forinstance, cerium is an effective metal (Reaction 23). The method of Imamotoet al. is interesting because it directly produces borane-protected phosphines(Scheme 1.23) [34].

One more example concerns the transfer of sulfur from R3P=S toBu3P at 150 ∘C, which only works for nonbasic phosphines (Scheme 1.24,Reaction 24) [35].

14 1 Phosphines and Related Tervalent Phosphorus Systems

Me3SiO

SiO

SiMe3Me H

O

P P

t-But-Bu

OO

PhMe

MePh

O

P P

t-But-Bu

PhMe

MePhPMHS

Ti(i-PrO)4

THF reflux

79%, complete retention

PMHS

Scheme 1.22 Reaction 22, reduction of P=O [31, 32] .

Ph P

O

R2R1

Ph P

R2R1

LiAlH4, NaBH4, CeCl3

R1 R2

Ph Et 93%

tBu H 82%

o-An Me 62%

BH3

THF, RT

Scheme 1.23 Reaction 23, reduction of P=O.

Ph P

S

BzPh

Ph P

BzPh

89%

Bu3P neat

150 °C

Scheme 1.24 Reaction 24, reduction of P=S.

Simple AlH3 is interesting in that many reducible functional groups are notaffected. Not reduced in the presence of P=O/AlH3 are sulfoxides, sulfones, alkylhalides, nitro aromatics, oxiranes, esters, and amides [36]. An aqueous workup isnot required (Scheme 1.25).

O

PEt

PhPh

PEt

PhPh

Functional groups, see text

AlH3

THF, reflux

98%

Scheme 1.25 Reaction 25, reduction of P=O.

1.2.7 X/Y-Substitution at Phosphorus

The transformation of phosphorus halides, alkoxides, and amides with the aid ofC-, O-, and N-centered nucleophiles is a widely used reaction for the formation