Science of Synthesis Knowledge Updates: 2016/2 E-Book

• Herausgeber: Thieme
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 843

Veröffentlichungsjahr: 2016

Beschreibung

The Science of Synthesis Editorial Board, together with the volume editors and authors, is constantly reviewing the whole field of synthetic organic chemistry as presented in Science of Synthesis and evaluating significant developments in synthetic methodology. Several annual volumes updating content across all categories ensure that you always have access to state-of-the-art synthetic methodology.

Leseprobe

Science of Synthesis

Science of Synthesis is the authoritative and comprehensive reference work for the entire field of organic and organometallic synthesis.

Science of Synthesis presents the important synthetic methods for all classes of compounds and includes:

Methods critically evaluated by leading scientists

Background information and detailed experimental procedures

Schemes and tables which illustrate the reaction scope

Preface

As the pace and breadth of research intensifies, organic synthesis is playing an increasingly central role in the discovery process within all imaginable areas of science: from pharmaceuticals, agrochemicals, and materials science to areas of biology and physics, the most impactful investigations are becoming more and more molecular. As an enabling science, synthetic organic chemistry is uniquely poised to provide access to compounds with exciting and valuable new properties. Organic molecules of extreme complexity can, given expert knowledge, be prepared with exquisite efficiency and selectivity, allowing virtually any phenomenon to be probed at levels never before imagined. With ready access to materials of remarkable structural diversity, critical studies can be conducted that reveal the intimate workings of chemical, biological, or physical processes with stunning detail.

The sheer variety of chemical structural space required for these investigations and the design elements necessary to assemble molecular targets of increasing intricacy place extraordinary demands on the individual synthetic methods used. They must be robust and provide reliably high yields on both small and large scales, have broad applicability, and exhibit high selectivity. Increasingly, synthetic approaches to organic molecules must take into account environmental sustainability. Thus, atom economy and the overall environmental impact of the transformations are taking on increased importance.

The need to provide a dependable source of information on evaluated synthetic methods in organic chemistry embracing these characteristics was first acknowledged over 100 years ago, when the highly regarded reference source Houben–Weyl Methoden der Organischen Chemie was first introduced. Recognizing the necessity to provide a modernized, comprehensive, and critical assessment of synthetic organic chemistry, in 2000 Thieme launched Science of Synthesis, Houben–Weyl Methods of Molecular Transformations. This effort, assembled by almost 1000 leading experts from both industry and academia, provides a balanced and critical analysis of the entire literature from the early 1800s until the year of publication. The accompanying online version of Science of Synthesis provides text, structure, substructure, and reaction searching capabilities by a powerful, yet easy-to-use, intuitive interface.

From 2010 onward, Science of Synthesis is being updated quarterly with high-quality content via Science of Synthesis Knowledge Updates. The goal of the Science of Synthesis Knowledge Updates is to provide a continuous review of the field of synthetic organic chemistry, with an eye toward evaluating and analyzing significant new developments in synthetic methods. A list of stringent criteria for inclusion of each synthetic transformation ensures that only the best and most reliable synthetic methods are incorporated. These efforts guarantee that Science of Synthesis will continue to be the most up-to-date electronic database available for the documentation of validated synthetic methods.

Also from 2010, Science of Synthesis includes the Science of Synthesis Reference Library, comprising volumes covering special topics of organic chemistry in a modular fashion, with six main classifications: (1) Classical, (2) Advances, (3) Transformations, (4) Applications, (5) Structures, and (6) Techniques. Titles will include Stereoselective Synthesis, Water in Organic Synthesis, and Asymmetric Organocatalysis, among others. With expertevaluated content focusing on subjects of particular current interest, the Science of Synthesis Reference Library complements the Science of Synthesis Knowledge Updates, to make Science of Synthesis the complete information source for the modern synthetic chemist.

The overarching goal of the Science of Synthesis Editorial Board is to make the suite of Science of Synthesis resources the first and foremost focal point for critically evaluated information on chemical transformations for those individuals involved in the design and construction of organic molecules.

Throughout the years, the chemical community has benefited tremendously from the outstanding contribution of hundreds of highly dedicated expert authors who have devoted their energies and intellectual capital to these projects. We thank all of these individuals for the heroic efforts they have made throughout the entire publication process to make Science of Synthesis a reference work of the highest integrity and quality.

The Editorial Board

July 2010

E. M. Carreira (Zurich, Switzerland)

C. P. Decicco (Princeton, USA)

A. Fuerstner (Muelheim, Germany)

G. Koch (Basel, Switzerland)

G. A. Molander (Philadelphia, USA)

E. Schaumann (Clausthal-Zellerfeld, Germany)

M. Shibasaki (Tokyo, Japan)

E. J. Thomas (Manchester, UK)

B. M. Trost (Stanford, USA)

Abstracts

1.2.7 Radical-Based Palladium-Catalyzed Bond Constructions

Y. Li, W. Xie, and X. Jiang

Palladium(0) and palladium(II) species are frequently used as catalysts and are considered to be active intermediates in traditional palladium-catalyzed coupling reactions, participating in oxidative addition and reductive elimination via two-electron-transfer processes. Meanwhile, the catalytic modes involving palladium(I) and palladium(III) have been gradually developed. Single-electron-transfer pathways are thought to be involved via related catalytic cycles. Various palladium(I) and palladium(III) complexes have been synthesized and characterized. The palladium(I) precatalysts in Suzuki coupling and Buchwald–Hartwig amination exhibit higher reactivity than traditional palladium(0) and palladium(II) catalysts. Palladium-catalyzed single-electron-transfer conditions allow alkyl halides to participate in a series of cross-coupling, carbonylation, atom-transfer, and cyclization reactions, in which the palladium(I) species and various alkyl radicals are thought to be key intermediates. Palladium(III) species have been proposed as active intermediates in various directed C—H activation reactions. Moreover, it has been proved that palladium(III) intermediates can catalyze C—F bond formation and asymmetric Claisen rearrangement reactions. Beyond these systems, it is thought that palladium(I) and palladium(III) species might take part in the same system. In summary, radical-type palladium-catalyzed systems possess new properties which help to realize various otherwise difficult transformations.

Keywords: bond construction · palladium(I) catalysis · palladium(III) catalysis · radical processes

2.11.15 C(sp3)—H Functionalization by Allylic C—H Activation of Zirconocene Complexes

A. Vasseur and J. Bruffaerts

Zirconocene-assisted allylic C(sp3)—H activation allows the remote functionalization of alkenes through multipositional migration of the olefinic double bond as a communicative process between two distant sites. The transformation involves the successive formation of zirconacyclopropane species along an alkyl chain. This C—H activation promoted migration proceeds rapidly under mild conditions. Moreover, it occurs in a unidirectional manner if associated with thermodynamically favored termination steps such as elimination, selective carbon–carbon bond activation, or ring expansion. The remotely formed zirconocene species can subsequently react with a variety of electrophilic carbon, oxygen, or nitrogen reagents to give a wide range of added-value products from simple substrates. Transmetalation processes further increase the synthetic potential by allowing the remote formation of a new carbon–carbon bond. The global transformation is not only stereo- and regioselective, but also enables the relay of stereochemical information. Alternatively, a ziconacyclopropane/crotylzirconocene hydride equilibrium can be promoted under particular reaction conditions, leading to direct regio- and stereoselective allylation reactions with acid chloride, aldehyde, diketone and imine derivatives.

Keywords: zirconocenes · allylic C—H activation · alkenes · conjugated dienes · trienes · homoallylic alcohols · homoallylic amines · alkenylcyclopropanes · cyclopropanols · diastereoselectivity · quaternary stereocenters

2.11.16 Synthesis and Reactivity of Heteroatom-Substituted Vinylzirconocene Derivatives and Hetarylzirconocenes

J. Bruffaerts and A. Vasseur

Reactive and stereodefined vinylzirconocene derivatives are efficiently prepared from a variety of different heterosubstituted alkenes in the presence of a stoichiometric amount of the Negishi reagent. This chapter describes the synthesis of these compounds along with their applications in the synthesis of various substituted alkenes.

Keywords: organometallic compounds · zirconocenes · alkenes · vinyl compounds · stereoselective synthesis · elimination

2.12.17 The Role of Solvents and Additives in Reactions of Samarium(II) Iodide and Related Reductants

T. V. Chciuk and R. A. Flowers, II

The use of additives with samarium(II) iodide (SmI2) greatly impacts the rate, diastereoselectivity, and chemoselectivity of its reactions. Additives that are commonly utilized with samarium(II) iodide and other samarium(II)-based reductants can be classified into three major groups: (1) Lewis bases such as hexamethylphosphoric triamide (HMPA) and other electron-donor ligands and chelating ethers; (2) proton donors, such as water, alcohols, and glycols; and (3) inorganic additives such as nickel(II) iodide, iron(III) chloride, and lithium chloride. In addition, the solvent milieu can also play an important role in the reactivity of samarium(II) reductants, predominantly through changes in the coordination sphere of the metal. The main focus of this chapter is on the use of additives and solvent milieu to provide selective and efficient reactions, with at least one example being given for each subclass of samarium(II)-promoted reaction.

Keywords: cross-coupling reactions · electron transfer · hexamethylphosphoric triamide · inorganic additives · intramolecular cyclization · Lewis bases · proton donors · reductive coupling · ring expansion · samarium(II) iodide · solvent effects

30.1.3 Carbohydrate Derivatives (Including Nucleosides)

T. Nokami

O,N-Acetals are found in various types of organic molecules and are core motifs in carbohydrates, including nucleosides. This chapter summarizes the synthetic methods to prepare N-linked glycopeptides, ribonucleosides, 2-deoxyribonucleosides, and others. Glycosylation between the anomeric carbon and the nitrogen atom of a nucleophile is a conventional method for the synthesis of these molecules, but stereoselectivity highly depends on the structures of the substrates. Glycosylamines are also important precursors for the stereoselective synthesis of N-linked glycopeptides and ribonucleosides.

Keywords: aminoglycosides · carbohydrates · glycopeptides · glycosylation · nucleosides

30.2.3 O,P-Acetals

K. Murai and H. Fujioka

This chapter is an update to the earlier Science of Synthesis contribution (Section 30.2) describing methods for the synthesis of O,P-acetals. It focuses on the literature published in the period 2006–2015. Key methods covered include the addition of phosphorus compounds to carbonyl groups (including enantioselective variations), kinetic resolution of α-hydroxyphosphonates, oxidation of α,β-unsaturated phosphorus compounds, addition of phosphorus compounds to O,O-acetals, reduction of acylphosphonates and related compounds, and aldol-type reactions of keto phosphonates.

Keywords:O,P-acetals · asymmetric synthesis · diastereoselectivity · enantioselectivity · kinetic resolution · hydrogenation · organocatalysis · oxidation · epoxidation · reduction · phosphorus compounds · Pudovik reaction

30.3.1.3 Acyclic S, S-Acetals

A. Tsubouchi

This chapter is an update to the earlier Science of Synthesis contribution (Section 30.3.1) describing methods for the preparation of acyclic S,S-acetals. It focuses on the literature published in the period 2006–2014, presenting complementary information with respect to new developments and transformations. It also contains an important extension of the coverage of the previous contribution. Key methods covered include the thioacetalization of carbonyl compounds using a variety of catalysts, conversion of O,O-acetals, addition of thiols to C—C multiple bonds, addition of disulfides to methylenecyclopropanes, and ring opening of 1,2-cyclopropanated 3-oxo sugars with thiols.

Keywords: acetals · carbonyl compounds · chemoselectivity · Lewis acid catalysts · S,S-acetals · supported catalysis · surfactants · thiols · ring opening

30.3.6.3 Acyclic and Cyclic S, S-Acetal S-Oxides and S, S′-Dioxides

A. Ishii

This chapter is an update to the earlier Science of Synthesis contribution (Section 30.3.6) published in 2007. S,S-Acetal S-oxides and S,S′-dioxides are synthesized by the reaction of sulfanyl- or sulfinyl-stabilized carbanions with electrophiles or by the (asymmetric) oxidation of S,S-acetals. Reaction of a carbanion with an aldehyde or ketone followed by dehydration provides ketene S,S-acetal oxides. Recent advances in synthetic application have been seen in conjugate additions of nucleophiles or radicals to ketene S,S-acetal oxides and in reactions utilizing reactive sulfonium intermediates generated by treatment with acid anhydrides (Pummerer conditions).

Keywords: sulfur-stabilized carbanions · asymmetric oxidation · condensation · ketene dithioacetals · conjugate addition · cyclopropanation · cross-coupling reaction · hydrolysis · Pummerer conditions · benzo[b]chalcogenophenes

30.5.6 Selenium- and Tellurium-Containing Acetals

M. Yoshimatsu

This chapter is an update to the earlier Science of Synthesis contribution (Section 30.5) concerning the synthesis and reactions of selenium- and tellurium-containing acetals. Recent interest has changed to the new field of Se,N- and Te,N-acetals including 4′-selenonucleosides, which may be used as unique building blocks for new DNA and RNA analogues. The published methods for Se,N- and Te,N-acetals could open up new applications in this field.

Keywords:Se,Se-acetals · Se,Te-acetals · Se,N-acetals · 4′-selenonucleosides · seleno-Pummerer reactions

30.7.3 N,P-and P, P-Acetals

T. Kimura

This chapter is an update to the earlier Science of Synthesis contribution (Section 30.7) describing methods for the synthesis of N,P- and P,P-acetals. It focuses on the literature published in the period 2007–2014. As well as covering the synthesis of the title compounds, their applications in organic synthesis are also briefly reviewed.

Keywords: α-aminophosphonates · hydrophosphorylation · imines · Pudovik addition · Kabachnik–Fields three-component condensation · Horner–Wadsworth–Emmons alkenation · gem-bisphosphonates · phospha-Claisen condensation · Michaelis–Becker substitution · Michaelis–Arbuzov rearrangement

Science of Synthesis Knowledge Updates 2016/2

Preface

Abstracts

Table of Contents

1.2.7 Radical-Based Palladium-Catalyzed Bond Constructions

Y. Li, W. Xie, and X. Jiang

2.11.15 C(sp3)—H Functionalization by Allylic C—H Activation of Zirconocene Complexes

A. Vasseur and J. Bruffaerts

2.11.16 Synthesis and Reactivity of Heteroatom-Substituted Vinylzirconocene Derivatives and Hetarylzirconocenes

J. Bruffaerts and A. Vasseur

2.12.17 The Role of Solvents and Additives in Reactions of Samarium(II) Iodide and Related Reductants

T. V. Chciuk and R. A. Flowers, II

30.1.3 Carbohydrate Derivatives (Including Nucleosides)

T. Nokami

30.2.3 O,P-Acetals (Update 2016)

K. Murai and H. Fujioka

30.3.1.3 Acyclic S,S-Acetals (Update 2016)

A. Tsubouchi

30.3.6.3 Acyclic and Cyclic S,S-Acetal S-Oxides and S,S′-Dioxides (Update 2016)

A. Ishii

30.5.6 Selenium- and Tellurium-Containing Acetals (Update 2016)

M. Yoshimatsu

30.7.3 N,P- and P,P-Acetals (Update 2016)

T. Kimura

Author Index

Abbreviations

Table of Contents

Volume 1: Compounds with Transition Metal–Carbon π-Bonds and Compounds of Groups 10–8 (Ni, Pd, Pt, Co, Rh, Ir, Fe, Ru, Os)

1.2 Product Class 2: Organometallic Complexes of Palladium

1.2.7 Radical-Based Palladium-Catalyzed Bond Constructions

Y. Li, W. Xie, and X. Jiang

1.2.7 Radical-Based Palladium-Catalyzed Bond Constructions

1.2.7.1 Method 1: Reactions Involving Palladium(I) Species

1.2.7.1.1 Variation 1: Synthesis of Organometallic Palladium(I) Complexes

1.2.7.1.2 Variation 2: Reactions Involving Palladium(I) Precatalysts

1.2.7.1.3 Variation 3: Cross-Coupling Reactions

1.2.7.1.4 Variation 4: Carbonylation Reactions

1.2.7.1.5 Variation 5: Cyclization Reactions

1.2.7.1.6 Variation 6: Atom-Transfer Reactions

1.2.7.2 Method 2: Reactions Involving Palladium(III) Species

1.2.7.2.1 Variation 1: Synthesis of Organometallic Palladium(III) Complexes

1.2.7.2.2 Variation 2: C—H Activation Reactions Involving Palladium(III)

1.2.7.2.3 Variation 3: C—F Bond-Constructing Reactions Involving Palladium(III)

1.2.7.2.4 Variation 4: Reactions Involving Phenyl or Benzoyl Radicals

1.2.7.2.5 Variation 5: Asymmetric Aza-Claisen Rearrangements

1.2.7.3 Method 3: Reactions Involving Palladium(I) and Palladium(III) Species

1.2.7.4 Method 4: Miscellaneous Reactions

Volume 2: Compounds of Groups 7–3 (Mn…, Cr…, V…, Ti…, Sc…, La…, Ac…)

2.11 Product Class 11: Organometallic Complexes of Zirconium and Hafnium

2.11.15 C(sp3)—H Functionalization by Allylic C—H Activation of Zirconocene Complexes

A. Vasseur and J. Bruffaerts

2.11.15 C(sp3)—H Functionalization by Allylic C—H Activation of Zirconocene Complexes

2.11.15.1 Method 1: Synthesis of Conjugated Dienes from Nonconjugated Dienes

2.11.15.1.1 Variation 1: From Nonheteroatom-Substituted Alkenes

2.11.15.1.2 Variation 2: From Nonconjugated Dienes Bearing an Alkoxy Substituent

2.11.15.2 Method 2: Synthesis of Trienes

2.11.15.3 Method 3: Synthesis of Homoallylic Alcohols

2.11.15.3.1 Variation 1: From Acid Chlorides without Ligand Exchange

2.11.15.3.2 Variation 2: From Acid Chlorides with Ligand Exchange

2.11.15.3.3 Variation 3: From Aldehydes without Ligand Exchange

2.11.15.3.4 Variation 4: From Aldehydes with Ligand Exchange

2.11.15.4 Method 4: Diastereoselective Synthesis of Homoallylic Amines

2.11.15.5 Method 5: Diastereoselective Synthesis of 1,4-Homoallylic Diols

2.11.15.5.1 Variation 1: From Grignard Reagents

2.11.15.5.2 Variation 2: From Terminal Alkenes

2.11.15.6 Method 6: Synthesis of 1,2-Disubstituted Cyclopropanols

2.11.15.7 Method 7: Synthesis of Substituted Allylic Derivatives from Unsaturated Fatty Alcohols

2.11.15.8 Method 8: Selective Reduction of the Double Bond of ω-Ene Dihydrofurans and Dihydropyrans

2.11.15.9 Method 9: Synthesis of Acyclic Fragments Possessing an All-Carbon Quaternary Stereogenic Center

2.11.15.9.1 Variation 1: From ω-Ene Cyclopropanes

2.11.15.9.2 Variation 2: From Alkylidenecyclopropanes

2.11.15.9.3 Variation 3: From ω-Alkenylcyclopropanes Bearing a Leaving Group

2.11.16 Synthesis and Reactivity of Heteroatom-Substituted Vinylzirconocene Derivatives and Hetarylzirconocenes

J. Bruffaerts and A. Vasseur

2.11.16 Synthesis and Reactivity of Heteroatom-Substituted Vinylzirconocene Derivatives and Hetarylzirconocenes

2.11.16.1 General Preparation of Vinylzirconocene Derivatives

2.11.16.2 General Reactivity of Vinylzirconocene Derivatives

2.11.16.3 Preparation of Vinylzirconocene Derivatives from Heteroatom-Substituted Alkenes

2.11.16.3.1 Method 1: From Alkenyl Halides

2.11.16.3.2 Method 2: From Aryl Halides

2.11.16.3.3 Method 3: From Enol Sulfonates

2.11.16.3.4 Method 4: From Enol Ethers and Silyl Enol Ethers

2.11.16.3.5 Method 5: From Sulfides, Sulfoxides, and Sulfones

2.11.16.3.6 Method 6: From Carbamates

2.11.16.3.7 Method 7: From Dienyl Systems

2.12 Product Class 12: Organometallic Complexes of Scandium, Yttrium, and the Lanthanides

2.12.17 The Role of Solvents and Additives in Reactions of Samarium(II) Iodide and Related Reductants

T. V. Chciuk and R. A. Flowers, II

2.12.17 The Role of Solvents and Additives in Reactions of Samarium(II) Iodide and Related Reductants

2.12.17.1 Synthesis of Samarium(II) Reductants

2.12.17.1.1 Samarium(II) Iodide

2.12.17.1.1.1 Method 1: Synthesis in Tetrahydrofuran from Samarium and 1,2-Diiodoethane

2.12.17.1.1.2 Method 2: Synthesis in Tetrahydrofuran from Samarium and Iodine

2.12.17.1.1.3 Method 3: Synthesis in Tetrahydropyran

2.12.17.1.1.4 Method 4: Synthesis in 1,2-Dimethoxyethane

2.12.17.1.1.5 Method 5: Synthesis in Acetonitrile and Other Nitriles

2.12.17.1.1.6 Method 6: Synthesis in Benzene/Hexamethylphosphoric Triamide

2.12.17.1.2 Samarium(II) Bromide and Samarium(II) Chloride

2.12.17.1.2.1 Method 1: Synthesis of Samarium(II) Bromide from Samarium(III) Oxide and Hydrobromic Acid

2.12.17.1.2.2 Method 2: Synthesis of Samarium(II) Bromide from Samarium and 1,1,2,2-Tetrabromoethane

2.12.17.1.2.3 Method 3: Synthesis of Samarium(II) Bromide from Samarium(II) Iodide and Lithium Bromide

2.12.17.1.2.4 Method 4: Synthesis of Samarium(II) Chloride from Samarium(III) Chloride

2.12.17.1.2.5 Method 5: Synthesis of Samarium(II) Chloride from Samarium(II) Iodide and Lithium Chloride

2.12.17.1.2.6 Method 6: Synthesis of Samarium(II) Chloride in Water from Samarium(III) Chloride and Samarium

2.12.17.1.3 Samarium(II) Trifluoromethanesulfonate

2.12.17.1.3.1 Method 1: Synthesis from Samarium(III) Trifluoromethanesulfonate, Samarium Metal, and Ethylmagnesium Bromide

2.12.17.1.3.2 Method 2: Synthesis from Samarium(III) Trifluoromethanesulfonate and sec-Butyllithium

2.12.17.1.3.3 Method 3: Synthesis from Samarium Metal and 1,5-Dithioniabicyclo[3.3.0]octane Bis(trifluoromethanesulfonate)

2.12.17.1.3.4 Method 4: Mercury-Catalyzed Reduction of Samarium(III) Trifluoromethanesulfonate

2.12.17.1.3.5 Method 5: Synthesis from Samarium(III) Trifluoromethanesulfonate and Samarium Metal

2.12.17.1.4 Samarium(II) Amides

2.12.17.1.5 (η5-Cyclopentadienyl)samarium(II) Complexes

2.12.17.1.5.1 Method 1: Synthesis of Bis(η5-cyclopentadienyl)samarium(II)

2.12.17.1.5.2 Method 2: Synthesis of Bis(η5-pentamethylcyclopentadienyl) samarium(II)

2.12.17.2 Use of Lewis Bases in Samarium(II)-Based Reactions

2.12.17.2.1 Hexamethylphosphoric Triamide

2.12.17.2.1.1 Method 1: Reduction of Alkyl and Aryl Halides

2.12.17.2.1.2 Method 2: Reduction of α-Oxygenated Carbonyl Compounds

2.12.17.2.1.3 Method 3: Reduction of 4-Methylbenzoates

2.12.17.2.1.4 Method 4: Grignard and Barbier Reactions

2.12.17.2.1.4.1 Variation 1: Intermolecular Samarium Grignard Reactions

2.12.17.2.1.4.2 Variation 2: Intermolecular Samarium Barbier Reactions

2.12.17.2.1.4.3 Variation 3: Intramolecular Samarium Barbier Reactions

2.12.17.2.1.5 Method 5: Reformatsky- and Aldol-Type Reactions

2.12.17.2.1.6 Method 6: Halide–Alkene Coupling Reactions

2.12.17.2.1.7 Method 7: Spirocyclization via Intramolecular Aryl Iodide Radical Addition

2.12.17.2.1.8 Method 8: Carbonyl–Alkene Coupling

2.12.17.2.1.8.1 Variation 1: Intramolecular Cyclization of Unactivated Alkenyl Ketones

2.12.17.2.1.8.2 Variation 2: Sequential Intramolecular Cyclization with Intermolecular Electrophilic Addition

2.12.17.2.1.8.3 Variation 3: Intermolecular Ketone–Allene Coupling

2.12.17.2.1.8.4 Variation 4: Sequential Intramolecular Cyclization with Electrophilic Addition to 1H-Indole Derivatives

2.12.17.2.1.9 Method 9: Intramolecular Pinacol Coupling of Carbonyl Compounds

2.12.17.2.1.10 Method 10: Intramolecular Pinacol-Type Coupling of Ketones and Imines

2.12.17.2.1.11 Method 11: Tandem Epoxide-Opening/Cyclization To Afford γ-Lactones

2.12.17.2.1.12 Method 12: Tandem Elimination and Coupling of Aliphatic Imides with Carbonyl Compounds

2.12.17.2.1.13 Method 13: Intermolecular and Intramolecular Reductive Dimerization

2.12.17.2.2 Additives Related to Hexamethylphosphoric Triamide

2.12.17.2.2.1 Method 1: Tri(pyrrolidin-1-yl)phosphine Oxide in Reductive Coupling Reactions

2.12.17.2.2.2 Method 2: N-Methyl-P,P-di(pyrrolidin-1-yl)phosphinic Amide in Reductive Cyclization Reactions

2.12.17.2.2.3 Method 3: Hydroxylated Hexamethylphosphoric Triamide in Reductive Coupling Reactions

2.12.17.3 Use of Proton Donors in Samarium(II)-Based Reactions

2.12.17.3.1 Water

2.12.17.3.1.1 Method 1: Reduction of Alkyl Iodides

2.12.17.3.1.2 Method 2: Reduction of Aromatic Carboxylic Acids, Esters, Amides, and Nitriles

2.12.17.3.1.3 Method 3: Reduction of Azido Oligosaccharides to Amino Sugars

2.12.17.3.1.4 Method 4: Reduction of Six-Membered Lactones

2.12.17.3.1.5 Method 5: Reduction of Cyclic Esters

2.12.17.3.1.6 Method 6: Reductive Cyclization of Lactones

2.12.17.3.1.7 Method 7: Reduction of Sodium S-Alkyl Thiosulfates and Alkyl Thiocyanates

2.12.17.3.1.8 Method 8: Reduction of Cyclic 1,3-Diesters

2.12.17.3.1.9 Method 9: Cross Coupling of N-Acyloxazolidinones to Acrylamides and Acrylates

2.12.17.3.1.10 Method 10: Coupling To Produce α,α-Disubstituted Pyrrolidin-2-ylmethanols

2.12.17.3.1.11 Method 11: Reductive Coupling of Nitrones and Acrylates

2.12.17.3.2 Water and Amines

2.12.17.3.2.1 Method 1: Reduction of Ketones

2.12.17.3.2.2 Method 2: Reduction of β-Hydroxy Ketones

2.12.17.3.2.3 Method 3: Reduction of Alkyl Halides

2.12.17.3.2.4 Method 4: Reduction of Double and Triple Bonds in Conjugated Alkenes

2.12.17.3.2.5 Method 5: Deprotection of Allyl Ether Protected Alcohols

2.12.17.3.2.6 Method 6: Deprotection of Toluenesulfonamides

2.12.17.3.2.7 Method 7: Reduction of Nitroalkanes

2.12.17.3.2.8 Method 8: Reductive Cleavage of Benzyl–Heteroatom Bonds

2.12.17.3.2.9 Method 9: Reduction of Nitriles

2.12.17.3.2.10 Method 10: Reduction of Unactivated Esters

2.12.17.3.2.11 Method 11: Reduction of Amides to Alcohols

2.12.17.3.2.12 Method 12: Reduction of Carboxylic Acids to Alcohols

2.12.17.3.2.13 Method 13: Intramolecular Coupling of Aryl Iodides with Alkenyl and Alkynyl Groups

2.12.17.3.3 Methanol

2.12.17.3.3.1 Method 1: Stereoselective Reduction of β-Hydroxy Ketones to anti- 1,3-Diols

2.12.17.3.3.2 Method 2: Reductive Cyclization of δ-Halo α,β-Unsaturated Esters

2.12.17.3.3.3 Method 3: Ring Expansion of Alkyl (n + 1)-Oxobicyclo[n.1.0]alkane-1-carboxylates

2.12.17.3.3.4 Method 4: Cyclization of γ,δ-Unsaturated Ketones To Afford syn-Cyclopentanols

2.12.17.3.4 tert- Butyl Alcohol

2.12.17.3.4.1 Method 1: Reductive Cyclization of Carbodiimides to Indolin-2-amines

2.12.17.3.4.2 Method 2: Cross Coupling of Chiral N-(tert-Butylsulfinyl)imines with Aldehydes

2.12.17.3.5 Glycols

2.12.17.3.5.1 Method 1: Synthesis of Uracils

2.12.17.3.6 2-(Dimethylamino)ethanol

2.12.17.3.6.1 Method 1: Reductive Ring Opening of Aziridine-2-carboxylates and Aziridine-2-carboxamides to β-Amino Esters and Amides

2.12.17.3.6.2 Method 2: Simple Functional Group Reductions Using Samarium(II) Iodide/2-(Dimethylamino)ethanol

2.12.17.4 Use of Inorganic Additives in Samarium(II)-Based Reactions

2.12.17.4.1 Transition-Metal Additives

2.12.17.4.1.1 Method 1: Carbonyl–Alkene Coupling Reactions

2.12.17.4.1.2 Method 2: Barbier Coupling Reactions

2.12.17.4.2 Lithium Halide Salts

2.12.17.4.2.1 Method 1: Intramolecular Coupling of Isocyanates and Cyclic α,β-Unsaturated Ketones

2.12.17.4.2.2 Method 2: Cross Coupling of Nitrones with Allenoates

2.12.17.5 Impact of Solvents on Reactivity in Samarium-Mediated Reductions and Coupling Reactions

2.12.17.5.1 Coordinating Solvents (Other than Tetrahydrofuran)

2.12.17.5.1.1 Method 1: Coupling of Ketones with Acid Chlorides in Tetrahydropyran

2.12.17.5.1.2 Method 2: Coupling of Allylic and Benzylic Samarium Compounds with Ketones and Esters in Tetrahydropyran

2.12.17.5.1.3 Method 3: Reduction of β-Hydroxy Ketones in 1,2-Dimethoxyethane

2.12.17.5.1.4 Method 4: Reductive Intramolecular Ketyl–Alkene Coupling in Acetonitrile

2.12.17.5.1.5 Method 5: 2,3-Wittig Rearrangement by Partial Reduction of Diallyl Acetals in Acetonitrile

2.12.17.5.1.6 Method 6: Coupling of α-Chloro α,β-Unsaturated Aryl Ketones to Aldehydes in Acetonitrile

2.12.17.5.1.7 Method 7: Coupling of Carbonyls in Pivalonitrile

2.12.17.5.2 Non-coordinating Solvents

2.12.17.5.2.1 Method 1: Barbier-Type Coupling of Aryl Halides and Ketones in Benzene/Hexamethylphosphoric Triamide

2.12.17.5.2.2 Method 2: Coupling of Iodoalkynes and Carbonyl Compounds in Benzene/Hexamethylphosphoric Triamide

2.12.17.5.2.3 Method 3: Reduction of Dithioacetals to Sulfides in Benzene/Hexamethylphosphoric Triamide

2.12.17.5.2.4 Method 4: Reductive Defluorination in Hexane

Volume 30: Acetals: O/N, S/S, S/N, and N/N and Higher Heteroatom Analogues

30.1 Product Class 1: O,N-Acetals

30.1.3 Carbohydrate Derivatives (Including Nucleosides)

T. Nokami

30.1.3 Carbohydrate Derivatives (Including Nucleosides)

30.1.3.1 Glycosyl Asparagine Derivatives

30.1.3.1.1 Method 1: Synthesis from Glycosyl Imidates

30.1.3.1.2 Method 2: Synthesis from Pent-4-enyl Glycosides

30.1.3.1.3 Method 3: Synthesis from Thioglycosides

30.1.3.1.4 Method 4: Synthesis from Glycals

30.1.3.1.4.1 Variation 1: Other C—N Bonds from Glycals

30.1.3.1.5 Method 5: Synthesis from Glycosyl Halides

30.1.3.1.6 Method 6: Synthesis from Glycosyl Isothiocyanates

30.1.3.1.7 Method 7: Synthesis from N-Glycosyl Hydroxylamines

30.1.3.1.8 Method 8: Synthesis from Glycosyl Azides

30.1.3.2 Ribonucleosides

30.1.3.2.1 Method 1: Synthesis from Glycosyl Acetates

30.1.3.2.2 Method 2: Synthesis from Glycosyl Halides

30.1.3.2.3 Method 3: Synthesis from Glycosyl Imidates

30.1.3.2.4 Method 4: Synthesis from Thioglycosides

30.1.3.2.5 Method 5: Synthesis from Glycosyl 2-Alk-1-ynylbenzoates

30.1.3.2.6 Method 6: Synthesis from Glycosylamines

30.1.3.3 2-Deoxyribonucleosides

30.1.3.3.1 Method 1: Synthesis from Glycosyl Halides

30.1.3.3.2 Method 2: Synthesis from Thioglycosides

30.1.3.4 Other Deoxyfuranosides

30.1.3.4.1 Method 1: Synthesis from Glycals

30.1.3.4.2 Method 2: Synthesis from Thioglycosides

30.2 Product Class 2: O,P- and S,P-Acetals

30.2.3 O,P-Acetals

K. Murai and H. Fujioka

30.2.3 O,P-Acetals

30.2.3.1 Method 1: Addition of Phosphorus Compounds to Ketones or Aldehydes

30.2.3.1.1 Variation 1: Diastereoselective Hydrophosphonylation

30.2.3.1.2 Variation 2: Enantioselective, Metal-Catalyzed Addition of Phosphites to Aldehydes (Pudovik Reaction)

30.2.3.1.3 Variation 3: Enantioselective, Organocatalyzed Addition of Phosphites to Aldehydes (Pudovik Reaction)

30.2.3.1.4 Variation 4: Enantioselective, Metal-Catalyzed Addition of Phosphites to Ketones (Pudovik Reaction)

30.2.3.1.5 Variation 5: Enantioselective, Organocatalyzed Addition of Phosphites to Ketones (Pudovik Reaction)

30.2.3.2 Method 2: Kinetic Resolution of α-Hydroxy Phosphonates

30.2.3.3 Method 3: Oxidation of α,β-Unsaturated Phosphorus Compounds

30.2.3.4 Method 4: Addition of Phosphorus Compounds to O,O-Acetals

30.2.3.5 Method 5: Reduction/Hydrogenation

30.2.3.6 Method 6: Aldol-Type Reactions and Other Reactions Using Carbon Nucleophiles

30.3 Product Class 3: S,S-Acetals

30.3.1.3 Acyclic S,S-Acetals

A. Tsubouchi

30.3.1.3 Acyclic S,S-Acetals

30.3.1.3.1 Method 1: Thioacetalization of Carbonyl Compounds

30.3.1.3.1.1 Variation 1: With Metal Salt Based Lewis Acid Catalysts

30.3.1.3.1.2 Variation 2: With Non-Metal Lewis Acid Catalysts

30.3.1.3.1.3 Variation 3: With Solid-Supported Lewis Acid Catalysts

30.3.1.3.1.4 Variation 4: With Solid Acid Catalysts

30.3.1.3.1.5 Variation 5: In Micelles

30.3.1.3.1.6 Variation 6: Without Acid Catalysis

30.3.1.3.2 Method 2: Conversion of O,O-Acetals

30.3.1.3.2.1 Variation 1: In Micelles

30.3.1.3.2.2 Variation 2: With Odorless Thiol Equivalents

30.3.1.3.3 Method 3: Addition of Thiols to C—C Multiple Bonds

30.3.1.3.3.1 Variation 1: Addition to Propargyl Alcohols

30.3.1.3.3.2 Variation 2: Addition to Allenes

30.3.1.3.3.3 Variation 3: Addition to Alkynes

30.3.1.3.4 Method 4: Addition of Disulfides to Methylenecyclopropanes

30.3.1.3.5 Method 5: Ring Opening of 1,2-Cyclopropanated 3-Oxo Sugars with Thiols

30.3.6.3 Acyclic and Cyclic S,S-Acetal S-Oxides and S,S′-Dioxides

A. Ishii

30.3.6.3 Acyclic and Cyclic S,S-Acetal S-Oxides and S,S′-Dioxides

30.3.6.3.1 Synthesis of Acyclic and Cyclic S,S-Acetal S-Oxides and S,S′-Dioxides

30.3.6.3.1.1 Method 1: Reactions of α-Sulfanyl α-Sulfinyl Carbanions

30.3.6.3.1.1.1 Variation 1: Monoalkylation with Alkyl or Hetaryl Halides, Epoxides, or Enones

30.3.6.3.1.1.2 Variation 2: Condensation with Carbonyl Compounds

30.3.6.3.1.2 Method 2: Oxidation Reactions

30.3.6.3.1.2.1 Variation 1: Oxidation of S,S-Acetals

30.3.6.3.1.2.2 Variation 2: Oxidation of Ketene S,S-Acetals

30.3.6.3.1.2.3 Variation 3: Oxidation of α-Sulfanyl Vinyl Sulfenates

30.3.6.3.1.3 Method 3: Addition of S,S-Acetal S,S′-Dioxides to Carbonyl Compounds

30.3.6.3.1.4 Method 4: Conjugate Addition to Ketene S,S-Acetal S-Oxides and S,S′-Dioxides

30.3.6.3.1.6 Method 6: Cross-Coupling of Ketene S,S-Acetal S-Oxides

30.3.6.3.2 Applications of Acyclic and Cyclic S,S-Acetal S-Oxides and S,S′-Dioxides in Organic Synthesis

30.3.6.3.2.1 Method 1: Synthesis of Aldehydes from S,S-Acetal S,S′-Dioxides

30.3.6.3.2.2 Method 2: Synthesis of Carboxylic Acid Derivatives from S,S-Acetal S,S′-Dioxides

30.3.6.3.2.3 Method 3: Synthesis of α-Amino Acid Derivatives

30.3.6.3.2.4 Method 4: Synthesis of Heteroaromatic Compounds

30.3.6.3.2.5 Method 5: Miscellaneous Reactions of S,S-Acetal S-Oxides and S,S-Acetal S,S′-Dioxides

30.5 Product Class 5: Selenium- and Tellurium-Containing Acetals

30.5.6 Selenium- and Tellurium-Containing Acetals

M. Yoshimatsu

30.5.6 Selenium- and Tellurium-Containing Acetals

30.5.6.1 S,Se- and S,Te-Acetals

30.5.6.1.1 Method 1: Reaction between Selenium Dihalides and Divinyl Sulfide or Divinyl Sulfone

30.5.6.1.2 Method 2: Selanylation–Deselanylation Process To Introduce a C=C Bond

30.5.6.1.3 Method 3: Electrochemical Fluoroselanylation of Vinyl Sulfones

30.5.6.2 Se,Se- and Se,Te-Acetals

30.5.6.2.1 Method 1: Palladium-Catalyzed Double Hydroselanylation of Alkynes

30.5.6.2.2 Method 2: Lewis Acid Catalyzed Conversion of Methylenecyclopropanes into 1,1-Bis(organoselanyl)cyclobutanes

30.5.6.2.3 Method 3: Indium/Chlorotrimethylsilane Promoted Selenoacetalization of Aldehydes Using Diorganyl Diselenides

30.5.6.2.4 Method 4: Diselanylation of Dihaloalkanes with 1-(Organoselanyl)perfluoroalkanols

30.5.6.2.5 Method 5: Diselanylation of Dihaloalkanes Using Selenolate Anions

30.5.6.3 Te,Te-Acetals

30.5.6.3.1 Method 1: In Situ Generation and Reaction of Tellurocarbamates with Dihaloalkanes

30.5.6.4 Se,N-Acetals

30.5.6.4.1 Method 1: Phosphoric Acid Catalyzed Addition of Benzeneselenol to an N-Acylimine

30.5.6.4.2 Method 2: 1,3-Dipolar Cycloaddition Reactions between Azidomethyl Aryl Selenides and Alkynes (Click Reactions)

30.5.6.4.3 Method 3: Base-Promoted Selanylation Using Se-[2-(Trimethylsilyl)ethyl] 4-Methylbenzoselenoate

30.5.6.4.4 Method 4: Synthesis of 4′-Selenonucleosides by Pummerer Condensation

30.5.6.4.5 Method 5: Synthesis of 3′-Azido-4′-selenonucleosides and Related Derivatives

30.5.6.4.6 Method 6: [2 + 2] Cyclization of S,Se-Diphenyl Carbonimidoselenothioates with Ketene Equivalents

30.5.6.4.7 Method 7: Reactions of Selenoamide Dianions with N,N-Disubstituted Thio- or Selenoformamides

30.5.6.4.8 Method 8: Photoinduced Di-π-methane Rearrangement of 3-(Organoselanyl)-5H-2,5-methanobenzo[f][1,2]thiazepine 1,1-Dioxide

30.5.6.4.9 Method 9: Decarboxylative Selanylation of Acids

30.5.6.4.10 Method 10: Base-Promoted Alkylation of α-Selanyl Nitroalkanes

30.5.6.4.11 Method 11: Reaction of Bromoalkanes with Selenium/Sodium Borohydride

30.5.6.4.12 Method 12: Selanylation of (Chloromethyl)benzotriazoles

30.5.6.4.13 Method 13: Synthesis of (Arylselanyl)methyl-Functionalized Imidazolium Ionic Liquids

30.5.6.4.14 Method 14: Application of N-[(Phenylselanyl)methyl]phthalimide as a Reagent for Protecting Alcohols as Phthalimidomethyl Ethers

30.5.6.5 Se,P- and Te,P-Acetals

30.5.6.5.1 Method 1: Diels–Alder Reaction of Selenoaldehydes and Phosphole Chalcogenides

30.5.6.5.2 Method 2: Michaelis–Arbuzov Reaction of Chloromethyl Phenyl Selenide

30.5.6.5.3 Method 3: Reaction between a Phosphorylmethyl 4-Toluenesulfonate and Sodium Selenide or Telluride

30.5.6.5.4 Method 4: Base-Promoted Reaction between Bis[(diphenylphosphoryl)methyl] Telluride and Chalcones

30.7 Product Class 7: N,P- and P,P-Acetals

30.7.3 N,P- and P,P-Acetals

T. Kimura

30.7.3 N,P- and P,P-Acetals

30.7.3.1 N,P-Acetals

30.7.3.1.1 Synthesis of N,P-Acetals

30.7.3.1.1.1 Method 1: Cross Dehydrogenative Coupling of Amines and Phosphonates

30.7.3.1.1.1.1 Variation 1: Using a Copper Catalyst under an Oxygen Atmosphere

30.7.3.1.1.1.2 Variation 2: Using an Iron Catalyst and tert-Butyl Hydroperoxide as Co-oxidant

30.7.3.1.1.2 Method 2: Aldehyde-Induced C—H Substitution with Phosphine Oxides

30.7.3.1.1.3 Method 3: Electrophilic Amination

30.7.3.1.1.4 Method 4: Aldehyde-Induced Decarboxylative Coupling of α-Amino Acids and Phosphonates

30.7.3.1.1.4.1 Variation 1: Using Copper/N, N-Diisopropylethylamine Catalyst

30.7.3.1.1.4.2 Variation 2: Without Catalyst

30.7.3.1.1.5 Method 5: Substitution of α-Hydroxyphosphonates with Amines

30.7.3.1.1.5.1 Variation 1: Under Microwave Irradiation

30.7.3.1.1.5.2 Variation 2: Using Trifluoromethanesulfonic Acid

30.7.3.1.1.6 Method 6: Substitution of α-Amido Sulfones with Organophosphorus Compounds

30.7.3.1.1.7 Method 7: Substitution of Dichloromethane with Tertiary Amines and Organophosphorus Compounds

30.7.3.1.1.8 Method 8: Asymmetric Hydrogenation of α-Enamido Phosphonates

30.7.3.1.1.9 Method 9: Reduction of α-Iminophosphonates

30.7.3.1.1.10 Method 10: 1,4-Addition of Aryltrifluoroborates to α-Enamido Phosphonates

30.7.3.1.1.11 Method 11: Addition of Carbon Nucleophiles to α-Iminophosphonates

30.7.3.1.1.11.1 Variation 1: Using Terminal Alkynes

30.7.3.1.1.11.2 Variation 2: Using Pyruvonitrile

30.7.3.1.1.12 Method 12: Hydrophosphorylation of Imines (Pudovik Reaction)

30.7.3.1.1.12.1 Variation 1: Using a Chiral Aluminum–Salalen Catalyst

30.7.3.1.1.12.2 Variation 2: Using a Chiral Tethered Bis(quinolin-8-olato)aluminum Catalyst

30.7.3.1.1.12.3 Variation 3: Using Cinchona Alkaloid Catalysts

30.7.3.1.1.12.4 Variation 4: Using a Chiral Copper Catalyst

30.7.3.1.1.12.5 Variation 5: Using a Chiral Auxiliary

30.7.3.1.1.13 Method 13: Three-Component Coupling Reaction of Amines, Carbonyl Compounds, and Phosphonates (Kabachnik–Fields Reaction)

30.7.3.1.1.13.1 Variation 1: Using a Magnesium Perchlorate Catalyst

30.7.3.1.1.13.2 Variation 2: Using a Chiral Phosphoric Acid Catalyst

30.7.3.1.1.14 Method 14: Reductive Phosphorylation of Amides

30.7.3.1.1.15 Method 15: Hydroamination and Hydrophosphorylation of Alkynes

30.7.3.1.1.16 Method 16: Asymmetric Isomerization of α-Iminophosphonates

30.7.3.1.1.17 Method 17: Consecutive Reaction of Methyleneaziridines with Organomagnesium Chlorides, Organic Bromides, and Phosphonates

30.7.3.1.1.18 Method 18: Three-Component Coupling of α-Diazophosphonates, Anilines, and Aldehydes

30.7.3.1.2 Applications of N, P-Acetals in Organic Synthesis

30.7.3.1.2.1 Method 1: Horner–Wadsworth–Emmons Alkenation

30.7.3.1.2.2 Method 2: Intramolecular Hydroamination of α-Aminophosphonates Possessing an Alkynyl Group

30.7.3.1.2.2.1 Variation 1: Via 5-exo-dig Cyclization Using a Palladium Catalyst

30.7.3.1.2.2.2 Variation 2: Via 6-endo-dig Cyclization Using a Silver Catalyst

30.7.3.1.2.3 Method 3: [3 + 2] Cycloaddition with Alkenes

30.7.3.2 P,P-Acetals

30.7.3.2.1 Synthesis of P, P-Acetals

30.7.3.2.1.1 Method 1: Consecutive Phosphorylation of Carbanions

30.7.3.2.1.2 Method 2: Phosphorylation of α-Phosphoryl Carbanions

30.7.3.2.1.2.1 Variation 1: Generated from Alkylphosphonates

30.7.3.2.1.2.2 Variation 2: Via Phospha-Claisen Condensation

30.7.3.2.1.2.3 Variation 3: Generated from Phosphine Sulfides

30.7.3.2.1.2.4 Variation 4: Generated from Phosphine–Boranes

30.7.3.2.1.3 Method 3: Synthesis from α-Chloroalkylphosphonates, Organoboranes, and Chlorophosphines

30.7.3.2.1.4 Method 4: Substitution of α-Silylphosphines with Chlorophosphines

30.7.3.2.1.5 Method 5: Consecutive Substitution of Dihaloalkanes with Organophosphorus Nucleophiles

30.7.3.2.1.5.1 Variation 1: Using Phosphides

30.7.3.2.1.5.2 Variation 2: Using Phosphites (Michaelis–Arbuzov Reaction)

30.7.3.2.1.6 Method 6: Substitution of Organophosphorus Compounds Possessing a Leaving Group at the α-Position with Organophosphorus Nucleophiles

30.7.3.2.1.6.1 Variation 1: Using Phosphides

30.7.3.2.1.6.2 Variation 2: Using Phosphites (Michaelis–Arbuzov Reaction)

30.7.3.2.1.7 Method 7: Conjugate Addition to Vinylidenebisphosphonates

30.7.3.2.1.7.1 Variation 1: Using Aldehydes in the Presence of an Organocatalyst

30.7.3.2.1.7.2 Variation 2: Using Boronic Acids in the Presence of a Copper Catalyst

30.7.3.2.2 Applications of P, P-Acetals in Organic Synthesis

30.7.3.2.2.1 Method 1: Alkylation of gem-Bisphosphorus Compounds

30.7.3.2.2.2 Method 2: Horner–Wadsworth–Emmons Alkenation

Author Index

Abbreviations

1.2.7 Radical-Based Palladium-Catalyzed Bond Constructions

Y. Li, W. Xie, and X. Jiang

General Introduction

During the evolution of organic chemistry, palladium catalysts have played an important and irreplaceable role in studies on carbon–carbon[1–7] and carbon–heteroatom[8–10] bond formation. Beyond the methodological studies, palladium-catalyzed reactions have also been widely applied in the preparation of natural products,[11] pharmaceuticals, agrochemicals, and materials, even on large scale.[12] Palladium(0) and palladium(II) species are frequently used as the catalysts and considered as active intermediates, participating in oxidative addition and reductive elimination steps in two-electron-transfer processes.[1–15] Throughout the development of palladium chemistry, an increasing number of single-electron-transfer procedures have been proposed and carefully studied, which mainly involve palladium(I)[16] and palladium(III)[17] species. The focus of this chapter is on radical-based palladium-catalyzed bond constructions in organic synthesis.

1.2.7.1 Method 1: Reactions Involving Palladium(I) Species

1.2.7.1.1 Variation 1: Synthesis of Organometallic Palladium(I) Complexes

Various palladium(I) complexes have been successfully synthesized, most of which exist as dimers. In previously reported reactions starting from palladium(I) complexes, the palladium species tended to undergo a single-electron oxidation to generate the corresponding palladium(II) complexes in monomeric or dimeric form. Besides the common ligandexchange reactions, palladium(I) complexes have been transformed with hydrogen, carbon monoxide,[18,19] oxygen,[20] and even ammonia gas,[21] which has helped to further the understanding of palladium chemistry.

Scheme 1 Typical Reactions of Palladium(I) Dimers[18,19]

X

Yield (%)

Ref

Br

74

[

19

]

I

58

[

19

]

Scheme 2 Reaction of a Palladium(I) Dimer with Oxygen[20]

Scheme 3 Synthesis of (PNP)Pd—Pd(PNP) Dimers[21]

Scheme 4 Oxidative Addition to Palladium(I) Dimers[21]

Scheme 5 Oxidation of a Palladium(I) Dimer with Oxygen[22]

Scheme 6 Formation of C—H Activated Complexes[23]

1.2.7.1.2 Variation 2: Reactions Involving Palladium(I) Precatalysts

Most commonly, palladium complexes have been introduced into reaction systems as palladium(0) or palladium(II) species. Since the investigation of palladium(I) catalysts, it has been shown that palladium(I) generally exhibits more efficiency in C—C and C—N bond-forming transformations, which is attributed to the easy generation of active palladium(0) species from the palladium(I) dimer complexes.[24–27] Suzuki couplings, Buchwald–Hartwig aminations, carbonylation couplings, and α-arylation of carbonyl compounds can all be achieved using palladium(I) precatalysts under mild conditions (room temperature) in shortened time (minutes). However, the development of other common cross coupling, oxidative coupling, reductive coupling, and C—H activation reactions is still to be achieved.

The seminal report of a reaction involving a palladium(I) precatalyst is that from Hartwig's group in 2002.[24] Air-stable palladium(I) dimers have been utilized to catalyze the coupling between various aryl bromides/chlorides and amines to give arylamines 12 (▶ Scheme 7). The reactions are complete within minutes at room temperature, with excellent yields. The aryl halides can have an electron-withdrawing or electron-donating substituent; ortho-substitution is also tolerated. The amines can be secondary aliphatic ones, or primary or secondary aryl ones. Furthermore, the coupling between aryl bromides and phenylboronic acid has been presented, resulting in biaryls 13 (▶ Scheme 8).

Scheme 7 Cross Coupling between Aryl Halides and Amines Using Palladium(I) Dimer Catalysts[24]

Ar

1

X

R

1

R

2

Catalyst

Yield (%)

Ref

4-Tol

Cl

(CH

2

)

2

O(CH

2

)

2

{PdBr[P(

t

-Bu)

2

(1-adamantyl)]}

2

92

[

24

]

4-NCC

6

H

4

Cl

Bu

Bu

{PdBr[P(

t

-Bu)

2

(1-adamantyl)]}

2

93

[

24

]

4-O

2

NC

6

H

4

Cl

Bu

Bu

{PdBr[P(

t

-Bu)

3

]}

2

97

[

24

]

4-

t

-BuO

2

CC

6

H

4

Cl

Bu

Bu

{PdBr[P(

t

-Bu)

3

]}

2

>99

[

24

]

4-

t

-BuC

6

H

4

Br

Bu

Bu

{PdBr[P(

t

-Bu)

3

]}

2

96

[

24

]

4-

t

-BuC

6

H

4

Br

Me

Ph

{PdBr[P(

t

-Bu)

2

(1-adamantyl)]}

2

98

[

24

]

4-

t

-BuC

6

H

4

Br

Ph

Ph

{PdBr[P(

t

-Bu)

3

]}

2

96

[

24

]

Scheme 8 Suzuki Coupling Catalyzed by a Palladium(I) Dimer[24]

Ar

1

Yield (%)

Ref

4-Tol

95

[

24

]

2-NCC

6

H

4

92

[

24

]

2-F

3

CC

6

H

4

90

[

24

]

2-MeOC

6

H

4

96

[

24

]

In 2004, new palladium(I)–palladium(I) dinuclear complexes 14 with one bridging halide were synthesized, in which only one phosphine is retained in the dinuclear core.[25] An unprecedented μ2-η3:η3 coordination mode between a phenyl ring of the biphenyl-2-yldi-tert-butylphosphine ligand and the palladium(I) unit was present in the complexes (▶ Scheme 9). Furthermore, the catalytic ability in the amination of aryl halides was concisely investigated (▶ Scheme 10); both complexes efficiently catalyze the coupling between an aryl bromide/chloride and primary or secondary arylamines to give diarylamines 15.

Scheme 9 Synthesis of a Palladium(I)–Palladium(I) Dinuclear Complex[25]

Scheme 10 Application of a Palladium(I)–Palladium(I) Dinuclear Complex in Cross Coupling between Aryl Halides and Amines[25]

The palladium(I)-catalyzed amination of aryl bromides has been investigated with a focus on the use of secondary alkyl(aryl)amines and aryl bromides bearing electron-donating and electron-withdrawing groups (▶ Scheme 11).[26] The reactions using the palladium(I) dimer were conducted in parallel with the use of palladium(II) acetate/tri-tert-butylphosphine; generally, the reactions with the palladium(I) dimer as catalyst afford better yields of amines 16.

Scheme 11 Cross Coupling between Aryl Halides and Aryl(alkyl)amines[26]

Ar

1

R

1

Yield

a

(%)

Ref

Ph

Cy

93 (86)

[

26

]

3-MeOC

6

H

4

Cy

94 (89)

[

26

]

4-FC

6

H

4

Cy

77 (71)

[

26

]

2-Tol

Cy

60 (52)

[

26

]

Ph

t

-Bu

92 (87)

[

26

]

3-MeOC

6

H

4

t

-Bu

91 (90)

[

26

]

4-FC

6

H

4

t

-Bu

87 (87)

[

26

]

2-Tol

t

-Bu

61 (12)

[

26

]

a

Yields using Pd(OAc

2

) (1 mol%) and

t

-Bu

3

P (1 mol%) are given in parentheses.

Scheme 12 Suzuki Coupling of 4-Chlorophenyl Trifluoromethanesulfonate Using a Palladium(I) Catalyst in Different Solvents[27]

Solvent

X

Yield (%)

Ref

THF

OTf

76

[

27

]

MeCN

Cl

78

[

27

]

Table 1 Selective Couplings of Dihalogenated Heterocycles[27]

Starting Materials

Product

Yield (%)

Ref

Hetarene

Boronic Acid

90

[

27

]

92

[

27

]

82

[

27

]

91

[

27

]

87

[

27

]

94

[

27

]

Scheme 13 Reactivity of 4-Chlorophenyl Trifluoromethanesulfonate with Bis(tri-tert-butylphosphine)palladium(0)[27]

The palladium(I)-catalyzed carbonylative coupling of aryl halides and amines has been achieved under an atmospheric pressure of carbon monoxide (▶ Scheme 14).[28] The reactions yield the desired products 20 in moderate to good yields within 10 minutes. Aryl iodides are better substrates than aryl bromides, and can be transformed with a lower catalyst loading and at a lower temperature. In light of the high efficiency, this system has been successfully applied in synthesizing radiolabeled amides 21 using11CO gas (▶ Scheme 15).

Scheme 14 Palladium(I)-Catalyzed Carbonylative Coupling of Aryl Halides and Amines[28]

Ar

1

X

R

1

R

2

Solvent

Catalyst (%)

Temp (°C)

Yield (%)

Ref

Ph

Br

H

Bn

mesitylene

10

150

46

[

28

]

4-MeOC

6

H

4

Br

H

Bn

mesitylene

10

150

46

[

28

]

2-MeOC

6

H

4

Br

H

Bn

mesitylene

10

150

46

[

28

]

I

(CH

2

)

5

toluene

2.2

100

82

[

28

]

Scheme 15 Palladium(I)-Catalyzed Carbonylative Coupling of Aryl Halides and Amines Using 11CO[28]

The cross coupling between aryl bromides and esters can also be catalyzed by {PdBr[P(t-Bu)3]}2 in a process promoted by lithium dicyclohexylamide (▶ Scheme 16).[29] The catalyst loading is 0.05–0.5 mol%. The aryl bromides can be substituted by electron-withdrawing or electron-donating groups. In addition, pyridyl and thienyl bromides are also compatible. However, the choice of esters is limited to tert-butyl propanoate, methyl 2-methylpropanoate, and tert-butyl acetate. It is worth noting that reactions with all three esters can be conducted on a 10-gram scale.

Scheme 16 α-Arylation of Esters Catalyzed by Palladium(I)[29]

R

1

R

2

R

3

Ar

1

{PdBr[P(

t

-Bu)

3

]}

2

(mol%)

Yield (%)

Ref

H

H

t

-Bu

4-

t

-BuC

6

H

4

0.20

83

[

29

]

H

H

t

-Bu

4-F

3

CC

6

H

4

0.40

73

[

29

]

H

H

t

-Bu

4-FC

6

H

4

0.40

82

[

29

]

Me

H

t

-Bu

4-

t

-BuC

6

H

4

0.04

87

a

[

29

]

Me

H

t

-Bu

4-FC

6

H

4

0.20

88

[

29

]

Me

H

t

-Bu

2,4,6-Me

3

C

6

H

2

0.05

72

[

29

]

Me

Me

Me

4-

t

-BuC

6

H

4

0.05

72

[

29

]

Me

Me

Me

4-F

3

CC

6

H

4

0.50

60

[

29

]

Me

Me

Me

2-pyridyl

0.50

71

[

29

]

Me

Me

Me

3-thienyl

0.50

75

[

29

]

a

Reaction was performed on a 40-mmol scale.

Arylamines 12; General Procedure:[24]

In a drybox, the Pd catalyst (0.005 M in THF), t-BuONa (144.0 mg, 1.50 mmol), an aryl halide (1.00 mmol), and an amine [1.05 mmol in THF (1 mL)] were added to a vial containing a stirrer bar. The vial was sealed with a cap containing a PTFE septum and removed from the drybox. The mixture was then stirred at rt for 15 min. After this time, H2O (1 mL) was added into the vial, and the mixture was extracted with CH2Cl2. The organic layer was dried (MgSO4) and concentrated, and the residue was purified by column chromatography.

Biaryls 13; General Procedure:[24]

In a drybox, {PdBr[P(t-Bu)3]}2 (0.005 M in THF), KOH (168.0 mg, 3.0 mmol), PhB(OH)2(1.08 mmol), and an aryl bromide [1.00 mmol in THF (1.5 mL)] were added to a vial containing a stirrer bar. The vial was sealed with a cap containing a PTFE septum and removed from the drybox. The mixture was then stirred at rt for 15 min. After this time, H2O (1 mL) was added into the vial, and the mixture was extracted with CH2Cl2. The organic layer was dried (MgSO4) and concentrated, and the residue was purified by column chromatography.

Arylamines 15; General Procedure:[25]

To an argon-filled Schlenk tube containing a mixture of the catalyst 14 (0.01 mmol), t-BuONa (1.4 mmol), an aryl halide (1.0 mmol), and an amine (1.2 mmol) was added THF (1 mL). The resulting mixture was stirred at rt until the aryl halide was consumed, and then it was extracted with CH2Cl2. The organic layer was dried (MgSO4) and concentrated, and the residue was purified by column chromatography (silica gel, hexane/EtOAc).

Alkyldiarylamines 16; General Procedure:[26]

To an argon-flushed, three-necked flask, containing Pd(OAc)2 (12.8 mg, 0.057 mmol) or {PdBr[P(t-Bu)3]}2 (22.0 mg, 0.0285 mmol), t-BuONa (1.64 g, 17.1 mmol), an aniline (5.7 mmol), and an aryl bromide (6.9 mmol), was added dry, degassed toluene (20 mL). After stirring at rt for 15 min, t-Bu3P [only in the cases where Pd(OAc)2 was used; 11.5 mg, 0.057 mmol] dissolved in toluene was added. Then, the mixture was heated to 108–110 °C and kept at the same temperature for 1 h. After cooling to rt, the reaction was quenched with H2O (10 mL), and then the organic layer was washed with H2O and concentrated. The crude product was purified by chromatography (silica gel).

A N2-filled dry reaction vessel was charged with 4-chlorophenyl trifluoromethanesulfonate (276.0 mg, 1.1 mmol), 2-tolylboronic acid (146 mg, 1.1 mmol), and KF (186 mg, 3.2 mmol). After the vessel was transferred to a drybox, THF or MeCN (2 mL; previously deoxygenated for 30 min) and H2O (3.0 equiv) were added and the mixture was stirred for 5 min. Then, {PdBr[P(t-Bu)3]}2 (12.4 mg, 0.016 mmol) was added and the mixture was stirred at rt for 30 min. The resulting mixture was subsequently diluted with Et2O and filtered through silica using Et2O as the eluant. The filtrate was concentrated in vacuo and purified by column chromatography.

Hetarenes 19; General Procedure:[27]

In a glovebox, to a N2-filled dry reaction vessel containing the heterocyclic substrate (0.5 mmol) was added recrystallized, deoxygenated, and dried boronic acid (0.5 mmol), KF (87.0 mg, 1.5 mmol), and deoxygenated THF (1 mL). The mixture was stirred for 5 min and then {PdBr[P(t-Bu)3]}2 (4.1 mg, 0.005 mmol), THF (0.5 mL), and H2O (3.0 equiv) were added (THF and H2O were deoxygenated prior to use). After this, the mixture was stirred for an additional 30 min. Then, the mixture was quenched with Et2O and filtered through silica gel, the filtrate was concentrated, and the residue was purified by column chromatography.

Benzamides 20; General Procedure:[28]

CAUTION:

Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma.

To a CO-filled Schlenk tube, containing the catalyst complex (2.2 or 10 mol%), was added the aryl halide (0.45 mmol) and the amine (BnNH2 or piperidine; 4.6 mmol) in the stated solvent. The mixture was stirred in a preheated oil bath for the desired time. Then, the reaction was quenched with 1 M aq HCl (4.5 mL). The rubber septum was removed and the unreacted CO was vented into the fumehood. The crude product mixture was extracted with CH2Cl2 (2 × 5 mL), the extracts were filtered and concentrated, and the residue was purified by column chromatography (silica gel).

For the preparation of11C-radiolabeled benzamides, the procedure was as described above but with the use of11CO instead of CO.

α-Aryl Esters 22; General Procedure with tert-Butyl Propanoate:[29]

In a drybox, to a 4-mL, screw-capped vial containing Cy2NLi (0.243 g, 1.30 mmol) dissolved in toluene (2 mL), was slowly added the ester (1.10 mmol). After stirring at rt for 10 min, the soln was added to another 4-mL, screw-capped vial containing the aryl bromide (1.00 mmol) and catalyst {PdBr[P(t-Bu)3]}2. The vial was sealed with a cap containing a PTFE septum and removed from the drybox. After stirring at rt for 4 h, the mixture was diluted with Et2O (30 mL) and then washed with 0.1 M HCl (10 mL). The aqueous phase was extracted with Et2O (3 × 10 mL). To the combined organic layers was added sat. aq NaHCO3(30 mL), and the aqueous layer was back-extracted with Et2O (3 × 10 mL). The combined organic layers were washed with H2O (30 mL), the aqueous layer was extracted with Et2O(3× 10 mL), and the combined organic layers were dried (MgSO4), and concentrated. The crude product was purified by flash column chromatography (silica gel, 2.5% EtOAc in hexanes).

To a N2-filled, 500-mL, three-necked round-bottomed flask equipped with a rubber septum, a glass stopper, and a stirrer-bar, was added Cy2NH (10.3 mL, 0.052 mol) dissolved in toluene (300 mL). The mixture was stirred for 10 min at 0 °C, and then a 2.5 Msoln of BuLi in hexane (20.7 mL, 0.052 mol) was added slowly to the cooled soln. Then, the mixture was stirred for 30 min at 0 °C. tert-Butyl acetate (5.93 mL, 0.044 mol) was added slowly over 20 min. The mixture was stirred for an additional 50 min at 0 °C. To another N2-filled, pear-shaped, 10-mL flask, containing {PdBr[P(t-Bu)3]}2 (0.062 g, 0.0790 mmol), were added 1-bromo-4-tert-butylbenzene (6.93 mL, 0.040 mol) and toluene (5 mL). The mixture was transferred via cannula to the round-bottomed flask containing the lithium enolate of tert-butyl acetate. Toluene (2 × 5 mL) was used to wash the pear-shaped flask, and the wash was transferred to the round-bottomed flask. The mixture was stirred for 4 h at rt, and then concentrated until the reaction volume was reduced to half by rotary evaporation. A sat. aq soln of NH4Cl (300 mL) was added, and the aqueous phase was washed with Et2O (5 × 200 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and purified; yield: 7.90 g (79.5%).

1.2.7.1.3 Variation 3: Cross-Coupling Reactions

Palladium-catalyzed cross-coupling reactions have been studied for about half a century. The typical mechanism involves oxidative addition and reductive elimination via two-electron transfer. Cross-coupling reactions involving alkyl halides, especially those with β-hydrogen atoms, are a challenge because of the slow rate of oxidative addition and the rapid rate of β-hydrogen elimination.[30] At the same time, cross-coupling reactions of the related alkylmetal compounds are also difficult because of the slow rate of transmetalation.[31] Recently, reactions that proceed via single-electron transfer processes have been developed, which have partially solved these problems. Generally, the radical properties of the reaction systems are supported by various radical-trapping experiments.

Cross coupling between 9-alkyl-9-borabicyclo[3.3.1]nonane (9-alkyl-9-BBN) derivatives and alkyl iodides has been achieved in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (▶ Scheme 17).[30] Primary iodides, even including iodomethane, deliver the products 23 in 45–71% yield; neopentyl iodide (1-iodo-2,2-dimethylpropane) also reacts successfully. However, reactions with secondary iodides are not successful. In terms of the boranes, various functionalized compounds are tolerated, including the presence of alkene, ester, and acetal groups.

Scheme 17 Cross-Coupling Reactions of 9-Alkyl-9-borabicyclo[3.3.1]nonane Derivatives with Alkyl Iodides[30]

R

1

R

2

Yield (%)

Ref

Me

(CH

2

)

10

CO

2

Me

71

[

30

]

(CH

2

)

5

Me

(CH

2

)

7

Me

64

[

30

]

(CH

2

)

5

Me

58

[

30

]

(CH

2

)

5

Me

(CH

2

)

10

CO

2

Me

54

[

30

]

(CH

2

)

3

CN

61

[

30

]

(CH

2

)

3

CO

2

Me

57

[

30

]

(CH

2

)

9

Me

(

E

)-CH=CHBu

64

[

30

]

(CH

2

)

9

Me

Ph

55

[

30

]

In 1987, reactions of polyfluoroalkyl iodides with organostannanes in a tetrakis(triphenylphosphine)palladium(0)-catalyzed Negishi coupling were reported (▶ Table 2).[32] The stannane can be allyl-, alkenyl-, and alkynyl-substituted. It is worthy to note that even trifluoroiodomethane leads to the desired product, albeit with lower yield (entry 3). Both the E- and Z-isomers of alkenylstannanes react with an iodide to afford only products with E configuration (entries 1, 2, 9, and 10). A possible mechanism is the addition of a polyfluoroalkyl radical to the alkenylstannane, followed by the elimination of tributyliodostannane; the palladium(0) species is thought to act as a radical initiator (▶ Scheme 18).

Table 2 Cross Coupling of Polyfluoroalkyl Iodides and Organostannanes[32]

Entry

Starting Materials

Equiv of Iodide

Temp

Time (h)

Product

Yield (%)

Ref

Stannane

Alkyl Iodide

1

F

3

C(CF

2

)

3

I

2

70 °C

4

70

[

32

]

2

F

3

C(CF

2

)

3

I

2

70 °C

4

70

[

32

]

3

CF

3

I

excess

80 °C

3

11

a

[

32

]

4

F

3

C(CF

2

)

5

I

1.2

rt

1

100

[

32

]

5

F

3

C(CF

2

)

5

I

3

70°C

3

64

32

6

F

3

C(CF

2

)

3

I

2

70°C

4

68

[

32

]

7

F

3

C(CF

2

)

5

I

2

70 °C

6

55

[

32

]

8

F

3

C(CF

2

)

3

I

2

70 °C

6

60

[

32

]

9

F

3

CCH

2

I

2

80 °C

4

38

a

[

32

]

10

F

3

CCH

2

I

2

80 °C

4

35

a

[

32

]

a

Benzene was used as solvent.

Scheme 18 Possible Mechanism for the Introduction of a Polyfluoroalkyl Group to (E)-Tributyl(styryl)stannane[32]

Alkyl iodides can also participate in a palladium-catalyzed Heck-type reaction (▶ Table 3).[33] This intramolecular procedure results in five- or six-membered rings 24, which contain various functional groups. Preliminary investigations into the corresponding intermolecular reactions have also been undertaken (▶ Scheme 19). Three kinds of 1-aryl-2-cyclohexylethene are obtained in moderate yields. Radical-trapping reactions have helped to disclose the radical nature of this system (▶ Scheme 20). A mechanism was proposed, as shown in ▶ Scheme 21, whereby a palladium(0) species initiates the reaction via a single-electron transfer to generate carbon radical 25, which subsequently cyclizes onto the intramolecular alkene to provide another carbon radical 26. Then, radical 26 adds to palladium(I) and subsequent β-hydride elimination of the alkylpalladium(II) complex 27 leads to the product.

Table 3 Palladium-Catalyzed Carbocyclization[33]

Substrate

Product(s)

Yield (%)

Ref

80

[

33

]

70

[

33

]

73 (dr 83:17)

[

33

]

74

[

33

]

70

[

33

]

62 (dr 58:42)

[

33

]

66 (dr >95:5)

[

33

]

Scheme 19 Intermolecular Reactions of Iodocyclohexane and Styrenes[33]

R

1

Yield (%)

Ref

Ph

55

[

33

]

4-AcC

6

H

4

60

[

33

]

4-(HOCH

2

)C

6

H

4

51

[

33

]

Scheme 20 Radical-Trapping Reaction of Diethyl 2-(2-Iodoethyl)-2-(4-methylpent-3-enyl)malonate[33]

Scheme 21 Proposed Mechanism of the Intramolecular Heck-Type Reaction[33]

Recently, intermolecular Heck reactions catalyzed by palladium that involve inactive alkyl halides have also been developed (▶ Scheme 22).[34] The method enables various primary and secondary alkyl iodides, including those with β-hydrogen atoms, to react with aryl-, hetaryl-, and electron-withdrawing-group-substituted alkenes. The observed reactivity of these reactions is consistent with a hybrid organometallic–radical pathway, which might be the reason for the avoidance of undesired dehydrohalogenation of the simple alkyl halide substrates. This method has been applied in the late-stage functionalization of a modified steroid to release 29 (▶ Scheme 23).[34] A radical clock reaction produces the cyclic substrate with no linear product observed (▶ Scheme 24); this result has helped to confirm the radical properties of this system. A mechanism has been proposed that is similar to the corresponding intermolecular reactions (▶ Scheme 25).

Scheme 22 Palladium-Catalyzed Heck Reactions of Inactive Alkyl Halides[34]

R

1

R

2

R

3

Yield (%)

Ratio (

E

/

Z

)

Ref

Ph

H

Cy

84

E

only

[

34

]

4-F

3

CC

6

H

4

H

Cy

82

E

only

[

34

]

4-MeOC

6

H

4

H

Cy

66

E

only

[

34

]

2-pyridyl

H

Cy

35

E

only

[

34

]

CN

H

Cy

70

a

29:71

[

34

]

CN

H

61

a

33:66 (dr 1:1)

[

34

]

CN

Me

79

a

,

b

,

c

66:33

[

34

]

Ph

H

80

88:12 (dr 95:5)

[

34

]

Ph

H

79

E

only

[

34

]

Ph

H

42

d

,

e

E

only

[

34

]

a

K

3

PO

4

(2.0 equiv) was used instead of Cy

2

NMe.

b

Pd(PPh

3

)

4

(10 mol%) was used as the catalyst.

c

Crotononitrile (3.0 equiv) was used.

d

Reaction temperature was 130 °C.

e

Yield determined by NMR.

Scheme 23 Late-Stage Functionalization of a Modified Steroid[34]

Scheme 24 Radical Clock Reaction of 6-Iodohex-1-ene and Styrene[34]

Scheme 25 Proposed Mechanism of the Intermolecular Heck Reaction of Unactivated Alkyl Halides[34]

A tetrakis(triphenylphosphine)palladium(0)/1,1′-bis(diphenylphosphino)ferrocene system could also be used to realize the intermolecular Heck reaction of unactivated alkyl halides (▶ Scheme 26).[35] The desired alkenes are produced from various primary and secondary alkyl halides with improved E/Z selectivity (2:1 to 82:1); even a primary chloride reacts in 74% yield and with 4:1 (E/Z) selectivity. Secondary halides afford better E/Z selectivity than primary ones. Radical-trapping experiments have also been conducted with 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO). The trapped product 31 is obtained (▶ Scheme 27) and a proposed mechanism is presented in ▶ Scheme 28.

Scheme 26 Heck Reaction of Alkyl Halides and Arylalkenes[35]

R

1

X

Ar

1

Yield (%)

Ratio (

E

/

Z

)

Ref

I

Ph

75

a

10:1

[

35

]

I

Ph

86

10:1

[

35

]

(CH

2

)

3

Ph

I

Ph

75

a

4:1

[

35

]

(CH

2

)

3

NPhth

I

Ph

76

a

17:1

[

35

]

Cy

I

4-ClC

6

H

4

82

38:1

[

35

]

Cy

I

3-Tol

70

30:1

[

35

]

CHEt

2

I

Ph

80

38:1

[

35

]

Br

Ph

64

82:1

[

35

]

(CH

2

)

11

Me

Cl

Ph

74

a

4:1

[

35

]

a

Pd(dba)

2

(10 mol%) and dppf (14 mol%) were used.

Scheme 27 Radical-Trapping Experiments with 2,2,6,6-Tetramethylpiperidin-1-oxyl[35]

Pd(PPh

3

)

4

(mol%)

dppf (mol%)

Yield (%)

Ref

10

14

20

[

35

]

20

28

41

[

35

]

50

70

100

[

35

]

Scheme 28 Proposed Mechanism for the Heck Reaction with Unactivated Alkyl Halides[35]

In addition to the various cross-coupling reactions described above, the palladium-catalyzed C—H activation of hetarenes has also been achieved in reactions with unactivated alkyl halides (▶ Scheme 29).[36] The substrate scope is quite broad (86 examples; 50–96% yield), with common heterocycles generally tolerated. The use of secondary and tertiary iodides and bromides are the main focus, while only three examples employing primary halides are reported. Radical-trapping products have been isolated and identified, and based on these results and DFT studies a radical mechanism has been proposed (▶ Scheme 30). Single-electron transfer from [1,3-bis(diphenylphosphino)propane]palladium(0) [Pd(dppp)] to the alkyl halide produces an alkyl radical and PdI(X)(dppp); subsequent radical addition to the heterocycle generates a hetarene radical, which undergoes single-electron oxidation followed by deprotonation to finally deliver the product.

Scheme 29 Palladium-Catalyzed C—H Activation of Hetarenes with Unactivated Alkyl Halides[36]

Ar

1

R

1

X

Yield (%)

Ref

t

-Bu

Br

58

a

[

36

]

Br

62

a

[

36

]

I

61

a

,

b

[

36

]

1-adamantyl

I

80

a

[

36

]

Cy

I

92

c

[

36

]

Cy

I

98

[

36

]

Cy

I

76

[

36

]

Cy

I

80

[

36

]

Cy

I

75

d

[

36

]

1-adamantyl

I

82

a

,

e

,

f

[

36

]

CH

2

Cy

I

82

a

,

e

[

36

]

CH

2

Cy

I

51

a

[

36

]

a

NaI (2 equiv) was also added.

b

dr 4:1.

c

Ratio (C2/C4) 32:1.

d

Ratio (mono-/dialkylation) 10:1.

e

10 mol% Pd(PPh

3

)

4

and 14 mol% dppp were used.

f

Ratio (C5/C3 alkylation) 23:1.

Scheme 30 Proposed Mechanism of Palladium-Catalyzed C—H Activation of Hetarenes with Unactivated Alkyl Halides[36]

(E)-3,3,4,4,5,5,6,6,6-Nonafluoro-1-phenylhex-1-ene (▶ Table 2, Entry 1):[32]

To a tube containing a mixture of (E)-1-phenyl-2-(tributylstannyl)ethene (0.4 g, 1.0 mmol) and Pd(PPh3)4 (0.11 g, 0.10 mmol) in hexane (3.0 mL), was added a soln of F3C(CF2)3I (0.70 g, 2.0 mmol) in hexane (2.0 mL) dropwise. The mixture was stirred for 4 h at 70 °C. Et2O and sat. aq KF (10 mL) were added, and then the mixture was extracted with Et2O. The organic layer was dried (Na2SO4) and concentrated, and the residue was purified by chromatography (silica gel); yield: 0.23 g (70%).

Carbo- and Heterocycles 24; General Procedure:[33]

CAUTION:

Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma.

Alkyl iodide, Pd(PPh3)4 (10 mol%), 1,2,2,6,6-pentamethylpiperidine (PMP; 2.0 equiv), and benzene (0.5 M) (CAUTION:carcinogen) were added to a 22-mL Parr reactor in a glovebox. The reactor was removed from the glovebox, and then charged with CO (10 atm) twice. Then, the mixture was stirred for 24 h at 110 °C. The reactor was cooled and slowly depressurized, and then Et2O was added and the mixture was washed with 1 M HCl. The mixture was extracted with Et2O, and the organic layers were dried (MgSO4) and concentrated. The residue was dissolved in CH2Cl2 and treated with CuCl to remove Ph3P. The crude products were purified by flash column chromatography.

Alkenes 28; General Procedure:[34]

The alkyl iodide (0.87 mmol), alkene (1.31 mmol), PdCl2(dppf) (0.087 mmol), Cy2NMe (1.74 mmol), and PhCF3