Science of Synthesis Knowledge Updates 2017 Vol.1 E-Book

• Herausgeber: Thieme
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch
• Veröffentlichungsjahr: 2017

Seitenzahl: 933

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. Four annual volumes updating content across all categories ensure that you always have access to state-of-the-art synthetic methodology.

• Hot-spot updates across all categories ensure access to state-of-the-art synthetic methodology
• 5% annuals update-rate
• 3 Update volumes

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

3.6.16 Gold-Catalyzed Cycloaddition Reactions

D. Qian and J. Zhang

Since about 2000, a “gold rush” has resulted in the development of numerous gold-catalyzed cycloaddition reactions. Such cycloadditions have now become a powerful and privileged method for the construction of carbo- and heterocycles, in particular those complex polycyclic structures featured in diverse natural products. This chapter is organized according to the key reactive gold intermediate that formally participates in the cycloaddition.

Keywords: gold · cycloaddition · carbocycles · heterocycles · carbophilic activation · alkynes · 1,n-dipolar · allenes · alkenylgold · gold · carbenes · benzopyryliums · furylgold species · cycloisomerization · acyloxy migration · alkyne oxidation · nitrene transfer · carbene transfer · diazo decomposition · σ-Lewis acid · enantioselective

4.4.7 Silylboron Reagents

L. B. Delvos and M. Oestreich

This update describes the development of silylboron chemistry since the initial summary in Science of Synthesis by Hemeon and Singer in 2002. In the first part, an overview of the methods to prepare silylboron reagents by nucleophilic substitution, Si─H bond activation, or reductive coupling is provided, and possibilities for further functionalization are presented. The second section comprehensively covers all aspects of the synthetic applications of silylboron compounds, ranging from transition-metal catalysis to transmetalation reactions and Si─B bond activation with Lewis bases. The presented methodologies include silaboration and silylation of unsaturated carbon–carbon bonds, addition and substitution reactions with nucleophilic silicon reagents, silaboration of strained rings under C─C bond cleavage, and Si─B insertion reactions of carbenoids and related compounds.

Keywords: silicon · boron · interelement compounds · main-group chemistry · silaboration · silylation · borylation · difunctionalization · transition-metal catalysis · asymmetric catalysis · oxidative addition · transmetalation · carbenoid insertion · 1,2-addition · 1,4-addition · allylic substitution · propargylic substitution · aromatic substitution

4.4.11 Silyllithium and Related Silyl Alkali Metal Reagents

C. Kleeberg

This chapter is a revision of the earlier Science of Synthesis contribution describing methods for the synthesis of silyllithium reagents and related compounds of the heavier alkali metals. Various synthetic routes to silyl alkali metal reagents are presented, employing different reaction types including reductive or nucleophilic cleavage of disilanes, reductive metalation of silyl halides, and cleavage of Si─H bonds.

Keywords: silyllithium reagents · lithium compounds · alkali metal compounds · sodium compounds · potassium compounds · reductive cleavage · cleavage reactions · silicon compounds · silanes

4.4.19.4 Silyl Sulfides and Selenides

A. Baker and T. Wirth

This chapter is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of silyl sulfides and silyl selenides. Various efficient synthetic routes to these compounds are shown. The use of disilyl sulfides and disilyl selenides as versatile reagents in synthesis is highlighted.

Keywords: silyl sulfides · silyl selenides · sulfur · silanes

4.4.24.3 Silyl Cyanides

Y. Nishimoto, M. Yasuda, and A. Baba

This chapter is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of silyl cyanides. It focuses on the literature published in the period 1997–2015.

Keywords: silanes · silenes · silicon compounds · cyanides · silyl halides

4.4.47 Silanols

A. M. Hardman-Baldwin and A. E. Mattson

This chapter covers synthetic approaches toward and selected applications of organosilanols. The focus is on the literature published in the period 2000–2015.

Keywords: silanols · silanediols · silanes · metal catalysis · organocatalysis · directing groups

10.22.2 Azaindol-1-ols

J.-Y. Mérour and B. Joseph

This chapter presents the little-known azaindol-1-ol family. Methods for the preparation as well as the reactivity of each isomer are covered.

Keywords: azaindol-1-ols · cyclization · reduction · oxidation · O-alkylation

10.22.3 1,3-Dihydroazaindol-2-ones

J.-Y. Mérour and B. Joseph

This chapter reviews the synthesis and reactivity of 1,3-dihydroazaindol-2-ones described in the literature until mid-2014. Synthetic methods and substituent modifications are reviewed for each isomer.

Keywords: 1,3-dihydroazaindol-2-ones · azaoxindoles · cyclization · reduction · rearrangement · radical cyclization · C3-alkylation · C3-aldolization

10.22.4 1,2-Dihydroazaindol-3-ones

J.-Y. Mérour and B. Joseph

This chapter reviews the synthesis and reactivity of 1,2-dihydroazaindol-3-ones (azaindoxyls) and related 1,2-dihydroazaindol-3-yl acetates. Synthetic preparations are reviewed for all isomers except for 1,2-dihydro-3H-pyrrolo[2,3-c]pyridin-3-ones.

Keywords: 1,2-dihydroazaindol-3-ones · azaindoxyls · 1,2-dihydroazaindol-3-yl acetates · cyclization · C2-aldolization

10.22.5 1H-Azaindole-2,3-diones

J.-Y. Mérour and B. Joseph

This chapter reviews the synthesis and reactivity of 1H-azaindole-2,3-diones (azaisatins). It focuses on the literature published until mid-2014. Synthetic preparations are reviewed for 1H-pyrrolo[3,2-b]pyridine-2,3-diones, 1H-pyrrolo[3,2-c]pyridine-2,3-diones, and 1H-pyrrolo[2,3-b]pyridine-2,3-diones.

Keywords: 1H-azaindole-2,3-diones · azaisatins · cyclization · bromination · oxidation · 1H-pyrrolo[3,2-b]pyridine-2,3-diones · 1H-pyrrolo[3,2-c]pyridine-2,3-diones · 1H-pyrrolo[2,3-b]pyridine-2,3-diones

10.22.6 Azaindol-2- and Azaindol-3-amines

J.-Y. Mérour and B. Joseph

This chapter presents methods for the preparation of azaindol-2-amines and azaindol-3-amines published in the literature until mid-2014. Synthetic methods are described for each isomer.

Keywords: azaindol-2-amines · azaindol-3-amines · cyclization · nitrosation · reduction

21.17 Synthesis of Amides (Including Peptides) in Continuous-Flow Reactors

S. Ramesh, P. Cherkupally, T. Govender, H. G. Kruger, B. G. de la Torre, and F. Albericio

Microreactors are powerful tools which present excellent mass- and heat-transfer performance properties for various kinds of chemical reaction. In this chapter, we present a brief introduction to microreactors, followed by an overview of the different microfluidic methods available for the synthesis of amides (including peptides). The range of peptides obtained via microreactor use includes di- to pentapeptides and also some cyclic analogues. Other continuous-flow reactions involving amide-bond formation are also illustrated, including examples of carbonylation, dendrimer preparation, and drug synthesis. The noteworthy features of these microfluidic reactions include shorter reaction times, high yields, and significantly less wastage. They are thus a step toward environmentally friendly, green reactions.

Keywords: amides · continuous-flow reactions · flow chemistry · green chemistry · microfluidics · microreactors · peptides

27.19.5 Azomethine Imines

I. Atodiresei and M. Rueping

This chapter is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of azomethine imines and focuses on the literature published in the period 2003–2014. As azomethine imines are commonly generated in situ, and subsequently trapped with suitable reaction partners, their applications in synthesis are also presented herein.

Keywords: azomethine imines · cycloaddition reactions · dipolar cycloaddition · hydrazones · intramolecular cycloaddition

35.1.5.1.12 Synthesis of 1-Chloro-n-Heteroatom-Functionalized Alkanes by Addition across C═C Bonds

T. Wirth and F. V. Singh

Chlorination of alkenes is an important synthetic process in organic chemistry. Several approaches for the chlorination of alkenes have been developed, including dichlorination, aminochlorination, halochlorination, oxychlorination, sulfanylchlorination, trihalomethylchlorination, and azidochlorination. Various inorganic and organic chlorides have been used as the source of chlorine, including alkali metal chlorides, tetrabutylammonium chloride, N-chlorosuccinimide, and (dichloroiodo)benzene. In this section, numerous approaches for the chlorination of alkenes using different inorganic and organic chlorides as source of chlorine, to give 1-chloro-n-heteroatom-functionalized alkanes, are discussed.

Keywords: alkenes · chlorination · aminochlorination · halochlorination · oxychlorination · sulfanylchlorination · trihalomethylchlorination · azidochlorination

35.2.1.5.7 Synthesis of Bromoalkanes by Substitution of Oxygen Functionalities

M. Braun

This chapter is an update to the earlier Science of Synthesis contribution describing the synthesis of bromoalkanes by substitution of oxygen functionalities. In this update, the focus is the substitution of free hydroxy groups, silyl ethers, tetrahydropyran-2-yl ethers, and sulfonates.

Keywords: bromoalkanes · alcohols · tetrahydropyran-2-yl ethers · silyl ethers · sulfonates · substitution · bromination

35.2.2.2 Propargylic Bromides

M. Braun

This chapter is an update to the earlier Science of Synthesis contribution describing the synthesis of propargylic bromides. The focus in this update is on synthesis by substitution of propargylic alcohols and protected derivatives thereof.

Keywords: propargylic bromides · substitution · propargylic alcohols · bromination

35.2.3.3.3 Synthesis of Benzylic Bromides by Substitution of σ-Bonded Heteroatoms

M. Braun

This chapter is an update to the earlier Science of Synthesis contribution describing the synthesis of benzylic bromides by substitution of σ-bonded heteroatoms. In this update, the focus is on the substitution of hydroxy groups.

Keywords: benzylic bromides · substitution · benzylic alcohols · bromination

35.2.4.2.3 Synthesis of Allylic Bromides by Substitution of σ-Bonded Heteroatoms

M. Braun

This chapter is an update to the earlier Science of Synthesis contribution describing the synthesis of allylic bromides by substitution of σ-bonded heteroatoms. In this update, the focus is on the substitution of other halogens and of hydroxy groups.

Keywords: allylic bromides · substitution · allylic alcohols · allylic chlorides · bromination

Science of Synthesis Knowledge Updates 2017/1

Preface

Abstracts

Table of Contents

3.6.16 Gold-Catalyzed Cycloaddition Reactions

D. Qian and J. Zhang

4.4.7 Product Subclass 7: Silylboron Reagents

L. B. Delvos and M. Oestreich

4.4.11 Product Subclass 11: Silyllithium and Related Silyl Alkali Metal Reagents

C. Kleeberg

4.4.19.4 Silyl Sulfides and Selenides (Update 2017)

A. Baker and T. Wirth

4.4.24.3 Silyl Cyanides (Update 2017)

Y. Nishimoto, M. Yasuda, and A. Baba

4.4.47 Product Subclass 47: Silanols

A. M. Hardman-Baldwin and A. E. Mattson

10.22.2 Product Subclass 2: Azaindol-1-ols

J.-Y. Mérour and B. Joseph

10.22.3 Product Subclass 3: 1,3-Dihydroazaindol-2-ones

J.-Y. Mérour and B. Joseph

10.22.4 Product Subclass 4: 1,2-Dihydroazaindol-3-ones

J.-Y. Mérour and B. Joseph

10.22.5 Product Subclass 5: 1H-Azaindole-2,3-diones

J.-Y. Mérour and B. Joseph

10.22.6 Product Subclass 6: Azaindol-2- and Azaindol-3-amines

J.-Y. Mérour and B. Joseph

21.17 Synthesis of Amides (Including Peptides) in Continuous-Flow Reactors

S. Ramesh, P. Cherkupally, T. Govender, H. G. Kruger, B. G. de la Torre, and F. Albericio

27.19.5 Azomethine Imines (Update 2017)

I. Atodiresei and M. Rueping

35.1.5.1.12 Synthesis of 1-Chloro-n-Heteroatom-Functionalized Alkanes (n ≥2) by Addition across C═C Bonds (Update 2017)

T. Wirth and F. V. Singh

35.2.1.5.7 Synthesis of Bromoalkanes by Substitution of Oxygen Functionalities (Update 2017)

M. Braun

35.2.2.2 Propargylic Bromides (Update 2017)

M. Braun

35.2.3.3.3 Synthesis of Benzylic Bromides by Substitution of σ-Bonded Heteroatoms (Update 2017)

M. Braun

35.2.4.2.3 Synthesis of Allylic Bromides by Substitution of σ-Bonded Heteroatoms (Update 2017)

M. Braun

Author Index

Abbreviations

Table of Contents

Volume 3: Compounds of Groups 12 and 11 (Zn, Cd, Hg, Cu, Ag, Au)

3.6 Product Class 6: Organometallic Complexes of Gold

3.6.16 Gold-Catalyzed Cycloaddition Reactions

D. Qian and J. Zhang

3.6.16 Gold-Catalyzed Cycloaddition Reactions

3.6.16.1 Cycloadditions via Gold-Containing 1,n-Dipolar Intermediates

3.6.16.1.1 Method 1: Gold-Containing Benzopyrylium Intermediates

3.6.16.1.1.1 Variation 1: Gold-Containing Benzopyrylium Azomethine Ylides

3.6.16.1.1.2 Variation 2: Gold-Containing 2-Oxoalkyl Oxonium Species

3.6.16.1.2 Method 2: Furyl–Gold 1,n-Dipole Intermediates

3.6.16.1.2.1 Variation 1: Furyl–Gold 1,3-Dipole Intermediates

3.6.16.1.2.2 Variation 2: Furyl–Gold 1,4-Dipole Intermediates

3.6.16.1.2.3 Variation 3: Furan-Based ortho-Quinodimethane Intermediates

3.6.16.1.3 Method 3: Gold-Containing All-Carbon 1,3-Dipoles

3.6.16.2 Cycloadditions via Gold-Coordinated Allene Intermediates

3.6.16.2.1 Method 1: Cycloadditions Initiated by Gold Activation of Allenes

3.6.16.2.2 Method 2: Cycloadditions Initiated by Gold Activation of Propargylic Carboxylates

3.6.16.3 Cycloadditions via trans-Alkenylgold Intermediates

3.6.16.3.1 Method 1: trans-Alkenylgold Intermediates Generated by Alkyne Activation

3.6.16.3.1.1 Variation 1: Alkynes as Latent Alkenes in Gold-Catalyzed Cycloadditions

3.6.16.4 Cycloadditions via Gold Carbene Intermediates

3.6.16.4.1 Method 1: Gold Carbenes Generated by Cycloisomerization of Alkynes and Alkenes

3.6.16.4.2 Method 2: Gold Carbenes Generated by 1,2-Acyloxy Migration of Propargyl Carboxylates

3.6.16.4.3 Method 3: Gold Carbenes Generated by Alkyne Oxidation

3.6.16.4.3.1 Variation 1: Gold-Catalyzed Cycloaddition Reactions by Nitrene Transfer

3.6.16.4.3.2 Variation 2: Gold-Catalyzed Cycloaddition Reactions by Carbene Transfer

3.6.16.4.4 Method 4: Gold Carbenes Generated by Diazo Decomposition

3.6.16.5 Cycloadditions via Gold-Coordinated Heteroatom Intermediates

Volume 4: Compounds of Group 15 (As, Sb, Bi) and Silicon Compounds

4.4 Product Class 4: Silicon Compounds

4.4.7 Product Subclass 7: Silylboron Reagents

L. B. Delvos and M. Oestreich

4.4.7 Product Subclass 7: Silylboron Reagents

4.4.7.1 Synthesis of Product Subclass 7

4.4.7.1.1 Preparation by Si─B Bond Formation

4.4.7.1.1.1 Method 1: Nucleophilic Substitution at Boron with Silyllithium Reagents

4.4.7.1.1.1.1 Variation 1: Substitution of Amino-Substituted Chloroboranes

4.4.7.1.1.1.2 Variation 2: Substitution of a Diaryl-Substituted Fluoroborane

4.4.7.1.1.1.3 Variation 3: Nucleophilic Substitution of Diol-Substituted Hydro- or Alkoxyboranes

4.4.7.1.1.2 Method 2: Iridium-Catalyzed Borylation of Trialkylsilanes

4.4.7.1.1.3 Method 3: Reductive Coupling of Chlorosilanes and Chloroboranes

4.4.7.1.2 Modification of Si─B Substitution Pattern

4.4.7.1.2.1 Method 1: Ligand Exchange at the Boron Atom

4.4.7.1.2.2 Method 2: Manipulation at the Silicon Atom

4.4.7.2 Applications of Product Subclass 7 in Organic Synthesis

4.4.7.2.1 Method 1: Reactions with Alkynes

4.4.7.2.1.1 Variation 1: Transition-Metal-Catalyzed Silaboration

4.4.7.2.1.2 Variation 2: Palladium-Catalyzed Silaborative Cyclization

4.4.7.2.1.3 Variation 3: Nickel-Catalyzed Silaborative Dimerization

4.4.7.2.1.4 Variation 4: Palladium-Catalyzed (2 + 2 + 1) Cycloaddition with Silylenes

4.4.7.2.1.5 Variation 5: Copper-Catalyzed Silylation

4.4.7.2.2 Method 2: Reactions with Alkenes

4.4.7.2.2.1 Variation 1: Platinum-Catalyzed Silaboration

4.4.7.2.2.2 Variation 2: Base-Catalyzed Silaboration

4.4.7.2.2.3 Variation 3: Photochemical Radical Silylation

4.4.7.2.3 Method 3: Reactions with Conjugated Dienes and Enynes

4.4.7.2.3.1 Variation 1: Transition-Metal-Catalyzed 1,4-Silaboration

4.4.7.2.3.2 Variation 2: Platinum-Catalyzed Silaborative Coupling of 1,3-Dienes and Aldehydes

4.4.7.2.3.3 Variation 3: Nickel-Catalyzed Silylative Coupling of 1,3-Dienes and Aldehydes

4.4.7.2.3.4 Variation 4: Palladium-Catalyzed (4 + 1) Cycloaddition with Silylenes

4.4.7.2.4 Method 4: Reactions with Allenes

4.4.7.2.4.1 Variation 1: Palladium-Catalyzed Silaboration

4.4.7.2.4.2 Variation 2: Copper-Catalyzed Silylation

4.4.7.2.5 Method 5: Reactions with C═X Bonds

4.4.7.2.5.1 Variation 1: 1,2-Silylation of Aldehydes

4.4.7.2.5.2 Variation 2: 1,2-Silylation of Imines

4.4.7.2.5.3 Variation 3: Reaction with Anhydrides

4.4.7.2.6 Method 6: Reactions with α,β-Unsaturated Carbonyl and Carboxy Compounds and Derivatives Thereof

4.4.7.2.6.1 Variation 1: Transition-Metal-Catalyzed 1,4-Silylation of Enones and α,β-Unsaturated Esters

4.4.7.2.6.2 Variation 2: N-Heterocyclic Carbene Catalyzed 1,4-Silylation of Enones, Enals, or Unsaturated Esters

4.4.7.2.6.3 Variation 3: Copper-Catalyzed 1,4-Silylation of Ynones and Derivatives Thereof

4.4.7.2.6.4 Variation 4: Metal-Free Phosphine-Catalyzed Silaboration of Ynoates

4.4.7.2.7 Method 7: Reactions with Allylic and Propargylic Electrophiles

4.4.7.2.7.1 Variation 1: Copper-Catalyzed Allylic Substitution

4.4.7.2.7.2 Variation 2: Silylative Cyclopropanation

4.4.7.2.7.3 Variation 3: Transition-Metal-Catalyzed Propargylic Substitution

4.4.7.2.8 Method 8: Reactions with (Het)arenes

4.4.7.2.8.1 Variation 1: Silaborative Dearomatization of Nitrogen Heterocycles

4.4.7.2.8.2 Variation 2: Nickel/Copper-Catalyzed Silylation

4.4.7.2.8.3 Variation 3: Base-Catalyzed Borylation

4.4.7.2.8.4 Variation 4: Iridium-Catalyzed Borylation

4.4.7.2.9 Method 9: Reactions with Strained Ring Compounds

4.4.7.2.9.1 Variation 1: Silaboration of Methylenecyclopropanes

4.4.7.2.9.2 Variation 2: Silaboration of Vinylcyclopropanes, Vinylcyclobutanes, and Related Compounds

4.4.7.2.10 Method 10: Reactions with Carbenoids and Related Compounds

4.4.7.2.10.1 Variation 1: Insertion of Alkylidene-Type Carbenoids into the Si─B Bond

4.4.7.2.10.2 Variation 2: Insertion of sp3-Carbon-Centered Carbenoids into the Si─B Bond

4.4.7.2.10.3 Variation 3: Insertion of Isocyanides into the Si─B Bond

4.4.7.2.11 Method 11: Miscellaneous Reactions

4.4.7.2.11.1 Variation 1: Stereoselective Deoxygenation of trans-Stilbene Oxides

4.4.7.2.11.2 Variation 2: B─N Bond Formation by Desilacoupling Catalyzed by a Strontium Bisamide Base

4.4.11 Product Subclass 11: Silyllithium and Related Silyl Alkali Metal Reagents

C. Kleeberg

4.4.11 Product Subclass 11: Silyllithium and Related Silyl Alkali Metal Reagents

4.4.11.1 Method 1: Reductive Cleavage of Disilanes with Alkali Metals

4.4.11.2 Method 2: Reduction of Halotriorganosilanes with Alkali Metals

4.4.11.3.1 Variation 1: Si─Si Bond Cleavage

4.4.11.3.2 Variation 2: Si─Sn Bond Cleavage

4.4.11.4 Method 4: Si─H Bond Cleavage

4.4.11.4.1 Variation 1: Si─H Bond Cleavage by Alkali Metals

4.4.11.4.2 Variation 2: Si─H Bond Cleavage by Alkali Metal Hydrides

4.4.11.5 Method 5: Preparation via Disilylmercury Compounds

4.4.19.4 Silyl Sulfides and Selenides

A. Baker and T. Wirth

4.4.19.4 Silyl Sulfides and Selenides

4.4.19.4.1 Synthesis of Silyl Sulfides and Selenides

4.4.19.4.1.1 Method 1: Synthesis by Reaction of Alkali Metals, Chalcogens, and Halosilanes or Alkali Metal Chalcogenides and Halosilanes

4.4.19.4.1.1.1 Variation 1: From Lithium, Sulfur, and Halosilanes

4.4.19.4.1.1.2 Variation 2: From Sodium, Sulfur, and Halosilanes

4.4.19.4.1.1.3 Variation 3: From Lithium Sulfide and Halosilanes

4.4.19.4.1.1.4 Variation 4: From Lithium Selenide and Halosilanes

4.4.19.4.1.1.5 Variation 5: From Lithium Chalcogenides, Generated from Lithium Triethylborohydride and Chalcogens, and Halosilanes

4.4.19.4.1.2 Method 2: Synthesis from Diselenides and Halosilanes

4.4.19.4.1.2.1 Variation 1: From Dimethyl Diselenide, Lithium Aluminum Hydride, and Halosilanes

4.4.19.4.1.2.2 Variation 2: From Diphenyl Diselenide, Sodium, and Halosilanes

4.4.19.4.1.2.3 Variation 3: From Diphenyl Diselenide, Lithium in Liquid Ammonia, and Halosilanes

4.4.19.4.1.3 Method 3: Synthesis from Selanols

4.4.19.4.1.4 Method 4: Synthesis from Alkynes, Butyllithium, Sulfur, and Halosilanes

4.4.19.4.1.5 Method 5: Synthesis Using Phosphorus-Based Reagents

4.4.19.4.1.5.1 Variation 1: From Silylphosphines and Sulfur

4.4.19.4.1.5.2 Variation 2: From Phosphine Sulfides and (Dimethylamino)trimethylsilane

4.4.19.4.1.5.3 Variation 3: From Phosphorus Pentasulfide and Alkoxytrimethylsilanes or (Alkylsulfanyl)trimethylsilanes

4.4.19.4.1.6 Method 6: Synthesis from Grignard Reagents, Selenium, and Halosilanes

4.4.19.4.1.7 Method 7: Synthesis from Existing Silyl Selenides by Substitution of a Group on Selenium

4.4.19.4.2 Applications of Silyl Sulfides and Selenides

4.4.24.3 Silyl Cyanides

Y. Nishimoto, M. Yasuda, and A. Baba

4.4.24.3 Silyl Cyanides

4.4.24.3.1 Tetracoordinate Silyl Cyanides

4.4.24.3.1.1 Method 1: Transmetalation of Silyl Chlorides

4.4.24.3.1.3 Method 3: Insertion of Silylenes into Isocyanides

4.4.24.3.1.4 Method 4: Transformation of Si═C═N─Si Units

4.4.24.3.2 Extracoordinate Silyl Cyanides

4.4.24.3.2.1 Method 1: Reaction of Pentacoordinate Silyl Chlorides with Cyanotrimethylsilane

4.4.24.3.2.2 Method 2: Reaction of Hexacoordinate Silyl Chlorides with Cyanotrimethylsilane

4.4.47 Product Subclass 47: Silanols

A. M. Hardman-Baldwin and A. E. Mattson

4.4.47 Product Subclass 47: Silanols

4.4.47.1 Synthesis of Silanols

4.4.47.1.1 Method 1: Hydrolysis of Chlorosilanes

4.4.47.1.1.1 Variation 1: Biphasic Hydrolysis of Chlorosilanes

4.4.47.1.1.2 Variation 2: Biphasic Hydrolysis of Chlorosilanes with Triethylamine

4.4.47.1.1.3 Variation 3: Synthesis of Bulky Silanediols from Chlorosilanes

4.4.47.1.2 Method 2: Stoichiometric Oxidation of Silanes

4.4.47.1.2.1 Variation 1: Oxidation of Silanes with Ozone

4.4.47.1.2.2 Variation 2: Oxidation of Silanes with Peroxy Acids

4.4.47.1.2.3 Variation 3: Oxidation of Silanes with Dioxiranes or Oxaziridines

4.4.47.1.2.4 Variation 4: Oxidation of Silanes with Potassium Permanganate and Sonication

4.4.47.1.2.5 Variation 5: Oxidation of Silanes with Osmium(VIII) Oxide

4.4.47.1.3 Method 3: Catalytic Oxidation of Silanes

4.4.47.1.3.1 Variation 1: Heterogeneous Catalytic Oxidation of Silanes with Water

4.4.47.1.3.2 Variation 2: Catalytic Oxidation of Silanes with Nanoparticles

4.4.47.1.3.3 Variation 3: Homogeneous Catalytic Oxidation of Silanes with Water

4.4.47.1.3.4 Variation 4: Catalytic Oxidation of Silanes with Peroxides or Oxygen

4.4.47.1.3.5 Variation 5: Organocatalytic Oxidation of Silanes

4.4.47.1.4 Method 4: Hydrolysis of Aromatic C(sp2)─Si Bonds

4.4.47.1.5 Method 5: Cleavage of Siloxy- and Alkoxysilanes

4.4.47.2 Catalytic Activity of Silanols

4.4.47.2.1 Method 1: Hydrogen-Bond-Donor Catalysis Involving Silanediols

4.4.47.2.2 Method 2: Silanediols in Anion-Binding Catalysis

4.4.47.2.3 Method 3: Catalytic Activity of Bissilanols

4.4.47.2.4 Method 4: Catalytic Activity of Monosilanols

4.4.47.3 Silanols as Directing Groups

Volume 10: Fused Five-Membered Hetarenes with One Heteroatom

10.22 Product Class 22: Azaindoles and Their Derivatives

10.22.2 Product Subclass 2: Azaindol-1-ols

J.-Y. Mérour and B. Joseph

10.22.2 Product Subclass 2: Azaindol-1-ols

10.22.2.1 Synthesis by Ring-Closure Reactions

10.22.2.1.1 By Annulation to a Pyridine

10.22.2.1.1.1 With Formation of One N─C Bond

10.22.2.1.1.1.1 With Formation of the 1─2 Bond

10.22.2.1.1.1.1.1 Method 1: From 2-(o-Nitropyridyl)acetates

10.22.2.1.1.1.1.2 Method 2: From an (Alkenylpyridyl)hydroxylamine

10.22.2.1.1.1.1.3 Method 3: From a 2-(3-Nitropyridin-2-yl)ethanone

10.22.2.1.1.1.1.4 Method 4: From 2-(3-Nitropyridin-2-yl)pent-4-enenitrile

10.22.2.1.1.1.2 With Formation of the 1─7a Bond

10.22.2.1.1.1.2.1 Method 1: From 1-(3-Pyridyl)-2-nitropropene and an Isocyanide

10.22.2.2 Synthesis by Substituent Modification

10.22.2.2.1 Substitution of Existing Substituents

10.22.2.2.1.1 Pyrrole Ring Substituents

10.22.2.2.1.1.1 Method 1: Modification of C-Nitrogen at C2

10.22.2.2.1.1.2 Method 2: Modification of N-Oxygen at N1

10.22.3 Product Subclass 3: 1,3-Dihydroazaindol-2-ones

J.-Y. Mérour and B. Joseph

10.22.3 Product Subclass 3: 1,3-Dihydroazaindol-2-ones

10.22.3.1 Synthesis by Ring-Closure Reactions

10.22.3.1.1 By Annulation to a Pyridine

10.22.3.1.1.1 By Formation of Two N─C Bonds

10.22.3.1.1.1.1 With Formation of the 1─7a and 1─2 Bonds

10.22.3.1.1.1.1.1 Method 1: From 2-(2-Chloropyridin-3-yl)acetic Acid

10.22.3.1.1.2 By Formation of One N─C Bond and One C─C Bond

10.22.3.1.1.2.1 With Formation of the 1─2 and 2─3 Bonds

10.22.3.1.1.2.1.1 Method 1: From Lithiated ortho-Methylpyridinamines

10.22.3.1.1.2.2 With Formation of the 1─2 and 3─3a Bonds

10.22.3.1.1.2.2.1 Method 1: From a 2-Pyridylhydrazide

10.22.3.1.1.3 By Formation of Two C─C Bonds

10.22.3.1.1.3.1 With Formation of 2─3 and 3─3a Bonds

10.22.3.1.1.3.1.1 Method 1: From N-Pivaloylpyridinamines

10.22.3.1.1.4 By Formation of One N─C Bond

10.22.3.1.1.4.1 With Formation of the 1─7a Bond

10.22.3.1.1.4.1.1 Method 1: From 2-(2-Chloropyridin-3-yl)acetamide

10.22.3.1.1.4.1.2 Method 2: From 2-(2-Bromopyridin-3-yl)acetonitrile

10.22.3.1.1.4.1.3 Method 3: From 2-Hydroxy-N-morpholino-2-(3-pyridyl)acetamide

10.22.3.1.1.4.2 With Formation of the 1─2 Bond

10.22.3.1.1.4.2.1 Method 1: From a 2-(Nitropyridyl)malonate

10.22.3.1.1.4.2.2 Method 2: From a 2-Cyano-2-(3-nitropyridyl)acetate

10.22.3.1.1.4.2.3 Method 3: From (3-Nitropyridyl)acetonitriles

10.22.3.1.1.4.2.4 Method 4: From (3-Nitropyridyl)acetates

10.22.3.1.1.4.2.5 Method 5: From (2-Aminopyridin-3-yl)acetic Acid

10.22.3.1.1.5 By Formation of One C─C Bond

10.22.3.1.1.5.1 With Formation of the 3─3a Bond

10.22.3.1.1.5.1.1 Method 1: From N-(3-Bromopyridin-2-yl)alk-2-enamides

10.22.3.1.1.5.1.2 Method 2: From N-Pyridylpropanamides

10.22.3.1.1.5.1.3 Method 3: From N-(Halopyridyl) Amides

10.22.3.1.1.5.1.4 Method 4: From N-(2-Chloropyridin-3-yl)acetamides

10.22.3.1.1.5.1.5 Method 5: From a 2-Bromo-N-pyridylacetamide

10.22.3.1.1.5.1.6 Method 6: From a Pyridylcarbamoylmethyl Xanthate

10.22.3.1.1.5.1.7 Method 7: From Diethyl {2-[(2-Bromopyridin-3-yl)amino]-2-oxoethyl}phosphonate and an Aldehyde

10.22.3.2 Synthesis by Ring Transformation

10.22.3.2.1 From Other Heterocyclic Systems

10.22.3.2.1.1 Method 1: 1H-Pyrrolopyridines by 3,3-Dibromination

10.22.3.2.1.2 Method 2: From a 1H-Pyrrolo[2,3-b]pyridine by Enzymatic Oxidation

10.22.3.2.1.3 Method 3: From a 1H-Pyrrolopyridine-2,3-dione

10.22.3.3 Synthesis by Substituent Modification

10.22.3.3.1 Substitution of Existing Substituents

10.22.3.3.1.1 Pyridine Ring Substituents

10.22.3.3.1.1.1 Modification of C-Halogen at C5

10.22.3.3.1.1.1.1 Method 1: Formation of C-Carbon

10.22.3.3.1.1.2 Modification of Nitrogen at N4

10.22.3.3.1.1.2.1 Method 1: Formation of N-Carbon

10.22.3.3.1.2 Pyrrole Ring Substituents

10.22.3.3.1.2.1 Substitution of C-Hydrogen at C3

10.22.3.3.1.2.1.1 Method 1: Formation of C-Carbon (Alkylation)

10.22.3.3.1.2.1.2 Method 2: Formation of C-Carbon (Alkenylation)

10.22.4 Product Subclass 4: 1,2-Dihydroazaindol-3-ones

J.-Y. Mérour and B. Joseph

10.22.4 Product Subclass 4: 1,2-Dihydroazaindol-3-ones

10.22.4.1 Synthesis by Ring-Closure Reactions

10.22.4.1.1 By Annulation to a Pyridine

10.22.4.1.1.1 By Formation of One N─C and One C─C Bond

10.22.4.1.1.1.1 With Formation of the 1─7a and 2─3 Bonds

10.22.4.1.1.1.1.1 Method 1: From a Pyridine Ester with an ortho-Amino Group

10.22.4.1.1.1.2 With Formation of the 3─3a and 1─2 Bonds

10.22.4.1.1.1.2.1 Method 1: From 3-Iodopyridin-2-amines and 1-Methoxyallene

10.22.4.1.1.2 By Formation of One N─C Bond

10.22.4.1.1.2.1 With Formation of the 1─7a Bond

10.22.4.1.1.2.1.1 Method 1: From (2-Chloropyridin-3-yl)(1H-pyrrol-2-yl)methanone

10.22.4.1.1.3 By Formation of One C─C Bond

10.22.4.1.1.3.1 With Formation of the 2─3 Bond

10.22.4.1.1.3.1.1 Method 1: From an N-Pyridylglycine

10.22.4.1.2 By Annulation to a Pyrrole

10.22.4.1.2.1 By Formation of Two C─C Bonds

10.22.4.1.2.1.1 With Formation of the 4─5 and 6─7 Bonds

10.22.4.1.2.1.1.1 Method 1: From a Masked 2-Amino-4-oxo-1H-pyrrole-3-carbaldehyde

10.22.4.2 Synthesis by Ring Transformation

10.22.4.2.1 From Other Heterocyclic Systems

10.22.4.2.1.1 Method 1: From a Tetrazolo[1,5-a]pyridine

10.22.4.2.1.2 Method 2: From a 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde

10.22.4.3 Synthesis by Substituent Modification

10.22.4.3.1 Substitution of Existing Substituents

10.22.4.3.1.1 Pyrrole Ring Substituents

10.22.4.3.1.1.1 Modification of C-Oxygen at C3

10.22.4.3.1.1.1.1 Method 1: Formation of O-Carbon

10.22.4.3.1.1.2 Substitution of C-Hydrogen at C2

10.22.4.3.1.1.2.1 Method 1: Formation of C-Carbon

10.22.4.3.1.1.3 Modification of Nitrogen at N1

10.22.4.3.1.1.3.1 Method 1: Formation of N-Carbon

10.22.5 Product Subclass 5: 1H-Azaindole-2,3-diones

J.-Y. Mérour and B. Joseph

10.22.5 Product Subclass 5: 1H-Azaindole-2,3-diones

10.22.5.1 Synthesis by Ring-Closure Reactions

10.22.5.1.1 By Annulation to a Pyridine

10.22.5.1.1.1 By Formation of One N─C Bond

10.22.5.1.1.1.1 With Formation of the 1─2 Bond

10.22.5.1.1.1.1.1 Method 1: From {4-[(tert-Butoxycarbonyl)amino]pyridin-3-yl}glyoxylate

10.22.5.2 Synthesis by Ring Transformation

10.22.5.2.1 From Other Heterocyclic Systems

10.22.5.2.1.1 Method 1: From a 1,3-Dihydro-2H-pyrrolopyridin-2-one

10.22.5.2.1.2 Method 2: From a Pyrrolopyridine

10.22.5.3 Synthesis by Substituent Modification

10.22.5.3.1 Substitution of Existing Substituents

10.22.5.3.1.1 Pyridine Ring Substituents

10.22.5.3.1.1.1 Substitution of C-Hydrogen at C5

10.22.5.3.1.1.1.1 Method 1: Giving C-Halogen

10.22.5.3.1.2 Pyrrole Ring Substituents

10.22.5.3.1.2.1 Substitution of N-Hydrogen at N1

10.22.5.3.1.2.1.1 Method 1: Formation of N-Carbon

10.22.6 Product Subclass 6: Azaindol-2- and Azaindol-3-amines

J.-Y. Mérour and B. Joseph

10.22.6 Product Subclass 6: Azaindol-2- and Azaindol-3-amines

10.22.6.1 Synthesis by Ring-Closure Reactions

10.22.6.1.1 By Annulation to a Pyridine

10.22.6.1.1.1 By Formation of One N─C and One C─C Bond

10.22.6.1.1.1.1 With Formation of the 1─2 and 3─3a Bonds

10.22.6.1.1.1.1.1 Method 1: From a 2-Halo-3-nitropyridine and a 2-Cyanoacetamide

10.22.6.1.1.1.2 With Formation of the 1─2 and 2─3 Bonds

10.22.6.1.1.1.2.1 Method 1: From Aminopyridine-3-carbonitriles

10.22.6.1.1.2 By Formation of One N─C Bond

10.22.6.1.1.2.1 With Formation of the 1─2 Bond

10.22.6.1.1.2.1.1 Method 1: From an Ethyl 2-Cyano-2-(3-nitropyridyl)acetate

10.22.6.1.1.2.1.2 Method 2: From a 2-[3-(Alkylamino)pyridin-2-yl]acetonitrile

10.22.6.1.1.2.1.3 Method 3: From 3-Ethynyl-N-methylpyridin-2-amine

10.22.6.1.1.3 By Formation of One C─C Bond

10.22.6.1.1.3.1 With Formation of the 2─3 Bond

10.22.6.1.1.3.1.1 Method 1: From Substituted 2-Aminopyridine-3-carbonitriles

10.22.6.2 Synthesis by Ring Transformation

10.22.6.2.1 From Other Heterocyclic Systems

10.22.6.2.1.1 Method 1: From a Pyrrolopyridine

10.22.6.2.1.1.1 Variation 1: From a Halopyrrolopyridine

10.22.6.2.1.1.2 Variation 2: Via Nitrosation

10.22.6.2.1.1.3 Variation 3: Via Diazonium Coupling

10.22.6.2.1.1.4 Variation 4: By Reduction of Nitro Groups

10.22.6.2.1.1.5 Variation 5: Via Azidation

10.22.6.2.1.2 Method 2: From a 1,2,3-Dithiazole

Volume 21: Three Carbon—Heteroatom Bonds: Amides and Derivatives; Peptides; Lactams

21.17 Synthesis of Amides (Including Peptides) in Continuous-Flow Reactors

S. Ramesh, P. Cherkupally, T. Govender, H. G. Kruger, B. G. de la Torre, and F. Albericio

21.17 Synthesis of Amides (Including Peptides) in Continuous-Flow Reactors

21.17.1 Microreactors: A Faster Tool for Synthesis Laboratories

21.17.2 Amide Formation in Microflow Reactors: Exploring Different Possibilities

21.17.2.1 Peptide Synthesis

21.17.2.1.1 Method 1: Synthesis of Di- and Tripeptides in Solution

21.17.2.1.2 Method 2: Synthesis of Di- and Tripeptides Using Immobilized Reagents

21.17.2.1.3 Method 3: β-Peptide Synthesis Using Fluorine-Activated Amino Acids

21.17.2.1.4 Method 4: Peptide Synthesis Using Triphosgene as the Activating Agent

21.17.2.1.5 Method 5: Cyclization of Peptides Driven by Microfluidics

21.17.2.1.6 Method 6: Analysis of Racemization During Peptide Formation

21.17.2.2 Synthesis of Drugs

21.17.2.3 Carbonylation Reactions

21.17.2.4 Lactam Synthesis

21.17.2.5 Dendrimer Synthesis

21.17.2.6 Miscellaneous Syntheses of Amides

Volume 27: Heteroatom Analogues of Aldehydes and Ketones

27.19 Product Class 19: Azomethine Imines

27.19.5 Azomethine Imines

I. Atodiresei and M. Rueping

27.19.5 Azomethine Imines

27.19.5.1 Acyclic Azomethine Imines

27.19.5.1.1 Synthesis and Applications of Acyclic Azomethine Imines

27.19.5.1.1.1 Method 1: In Situ Generation from Hydrazones Followed by [3 + 2] Cycloaddition

27.19.5.1.1.1.1 Variation 1: In Situ Generation from Hydrazones with Boron Trifluoride–Diethyl Ether Complex and Subsequent Intramolecular [3 + 2] Cycloaddition

27.19.5.1.1.1.2 Variation 2: In Situ Generation from Hydrazones with Iodosylbenzene and Subsequent [3 + 2] Cycloaddition with Imines

27.19.5.1.1.2 Method 2: In Situ Generation from Aldehydes and Hydrazides

27.19.5.1.1.2.1 Variation 1: In Situ Generation from Aldehydes and Hydrazides and Reaction with Nucleophiles

27.19.5.1.1.2.2 Variation 2: In Situ Generation from Aldehydes and Hydrazides and Intermolecular [3 + 2] Cycloaddition with Alkynes

27.19.5.2 Azomethine Imines with C─N Incorporated in a Ring

27.19.5.2.1 Synthesis and Applications of Azomethine Imines with C─N Incorporated in a Ring

27.19.5.2.1.1 Method 1: Synthesis of Cyclic Azomethine Imines from 2-(2-Bromoethyl)benzaldehydes and Benzoylhydrazine

27.19.5.2.1.2 Method 2: Synthesis of Cyclic Azomethine Imines by Intramolecular Cyclization

27.19.5.2.1.2.1 Variation 1: Synthesis of Cyclic Azomethine Imines from Alkynyl Hydrazides

27.19.5.2.1.2.2 Variation 2: Synthesis of Cyclic Azomethine Imines from γ,δ-Unsaturated N-Trichloroacetyl and N-Trifluoroacetyl Hydrazones

27.19.5.2.1.3 Method 3: Synthesis of Cyclic Azomethine Imines from Pyridine Derivatives

27.19.5.2.1.3.1 Variation 1: Synthesis of N-Benzoyl- and N-Tosyliminopyridinium Ylides from Pyridines by Amination and Acylation

27.19.5.2.1.3.2 Variation 2: Synthesis of N-Tosyliminopyridinium Ylides from Pyridines by Metal-Catalyzed Imination with [N-(4-Toluenesulfonyl)imino]-phenyliodinane

27.19.5.2.1.4 Method 4: Metal-Catalyzed Synthesis of Cyclic Azomethine Imines from N′-(2-Alkynylbenzylidene) Hydrazides

27.19.5.3 Azomethine Imines with N─N Incorporated in a Ring

27.19.5.3.1 Synthesis and Applications of Azomethine Imines with N─N Incorporated in a Ring

27.19.5.3.1.1 Method 1: Synthesis from Hydrazones and Alkenes

Volume 35: Chlorine, Bromine, and Iodine

35.1 Product Class 1: One Saturated Carbon—Chlorine Bond

35.1.5.1.12 Synthesis of 1-Chloro-n-Heteroatom-Functionalized Alkanes (n ≥2) by Addition across C═C Bonds

T. Wirth and F. V. Singh

35.1.5.1.12 Synthesis of 1-Chloro-n-Heteroatom-Functionalized Alkanes (n ≥2) by Addition across C═C Bonds

35.1.5.1.12.1 Method 1: Dichlorination of Alkenes

35.1.5.1.12.1.1 Variation 1: Using Manganese(III)/Hydrochloric Acid as the Chlorine Source

35.1.5.1.12.1.2 Variation 2: Using an Iodine(III) Reagent as the Chlorine Source

35.1.5.1.12.1.3 Variation 3: Using Organic Chlorides as the Chlorine Source

35.1.5.1.12.1.4 Variation 4: Using Alkali Metal Chlorides as the Chlorine Source

35.1.5.1.12.1.5 Variation 5: Using N-Chlorosuccinimide as the Chlorine Source

35.1.5.1.12.1.6 Variation 6: Using a Carbene–Palladium(IV) Chloride Complex as the Chlorine Source

35.1.5.1.12.1.7 Variation 7: Organocatalyzed Dichlorination of Alkenes

35.1.5.1.12.2 Method 2: Aminochlorination of Alkenes

35.1.5.1.12.2.1 Variation 1: Carbon Dioxide Promoted Aminochlorination of Alkenes Using Chloramine-T as the Source of Chlorine and Nitrogen

35.1.5.1.12.2.2 Variation 2: Transition-Metal-Catalyzed Aminochlorination of Alkenes

35.1.5.1.12.2.3 Variation 3: Asymmetric Catalytic Aminochlorination of α,β-Unsaturated γ-Oxo Esters

35.1.5.1.12.2.4 Variation 4: Selenium-Catalyzed Chloroamidation of Alkenes

35.1.5.1.12.2.5 Variation 5: Photocatalytic Aminochlorination of Alkenes

35.1.5.1.12.3 Method 3: Halochlorination of Alkenes

35.1.5.1.12.3.1 Variation 1: Iodochlorination of Styrene Using Tetramethylammonium Dichloroiodate

35.1.5.1.12.3.2 Variation 2: Copper-Catalyzed Bromochlorination of Styrene Using Tetrabutylammonium Dichlorobromate

35.1.5.1.12.3.3 Variation 3: Catalytic Enantioselective Bromochlorination of Allylic Alcohols

35.1.5.1.12.4 Method 4: Oxychlorination of Alkenes

35.1.5.1.12.4.1 Variation 1: Thiourea Catalyzed Methoxychlorination of Alkenes

35.1.5.1.12.4.2 Variation 2: Iodine(III)-Mediated Methoxychlorination of Alkenes

35.1.5.1.12.4.3 Variation 3: (Diacetoxyiodo)benzene-Mediated Ethoxychlorination of Enamides

35.1.5.1.12.4.4 Variation 4: Organocatalytic Enantioselective Chlorocyclization of Unsaturated Amides

35.1.5.1.12.5 Method 5: Chloroselanylation of Alkenes

35.1.5.1.12.5.1 Variation 1: β-Chloroselanylation of Alkenes with N,N-Diethylbenzeneselenenamide in the Presence of Phosphoryl Chloride or Thionyl Chloride

35.1.5.1.12.5.2 Variation 2: Chloroselanylation of Alkenes with Phenylselenenyl Chloride

35.1.5.1.12.6 Method 6: Sulfanylchlorination of Alkenes

35.1.5.1.12.7 Method 7: Trihalomethylchlorination of Alkenes

35.1.5.1.12.7.1 Variation 1: Trichloromethylchlorination of Alkenes with Trichloromethanesulfonyl Chloride

35.1.5.1.12.7.2 Variation 2: Trichloromethylchlorination of Alkenes in Subcritical Carbon Tetrachloride

35.1.5.1.12.7.3 Variation 3: Copper/Ruthenium-Catalyzed Trifluoromethylchlorination of Alkenes

35.1.5.1.12.8 Method 8: Azidochlorination of Alkenes

35.1.5.1.12.8.1 Variation 1: Azidochlorination of Alkenes with Sodium Azide in the Presence of Sodium Hypochlorite and Acetic Acid

35.1.5.1.12.9 Method 9: Chlorodiacetonylation of Alkenes

35.1.5.1.12.9.1 Variation 1: Chlorodiacetonylation of Cycloalkenes with Acetylacetone and Manganese(III) Acetate in the Presence of Hydrochloric Acid

35.2 Product Class 2: One Saturated Carbon—Bromine Bond

35.2.1.5.7 Synthesis of Bromoalkanes by Substitution of Oxygen Functionalities

M. Braun

35.2.1.5.7 Synthesis of Bromoalkanes by Substitution of Oxygen Functionalities

35.2.1.5.7.1 Method 1: Substitution of Alcoholic Hydroxy Groups

35.2.1.5.7.1.1 Variation 1: Reaction of Alcohols with Oxalyl Chloride and Lithium Bromide under Catalysis by Triphenylphosphine Oxide

35.2.1.5.7.1.2 Variation 2: Reaction of Alcohols with Diethyl Bromomalonate and Diphenylsilane under Catalysis of 5-Phenyldibenzophosphole

35.2.1.5.7.1.3 Variation 3: Reaction of Primary Alcohols with 7,7-Dichlorocyclohepta-1,3,5-triene and Tetrabutylammonium Bromide

35.2.1.5.7.1.4 Variation 4: Reaction of Alcohols with 2,2-Dibromo-1,3-dicyclohexylimidazolidine-4,5-dione

35.2.1.5.7.1.5 Variation 5: Reaction of Alcohols with tert-Butyl Bromide in the Ionic Liquid 3-Methyl-1-pentylimidazolium Bromide

35.2.1.5.7.2 Method 2: Cleavage of Silyl- and Tetrahydropyranyl-Protected Alcohols

35.2.1.5.7.2.1 Variation 1: Reaction of Tetrahydropyranyl Ethers with Dibromotriphenylphosphorane

35.2.1.5.7.2.2 Variation 2: Reaction of Tetrahydropyranyl and Silyl Ethers with N-Bromosaccharin–Triphenylphosphine

35.2.1.5.7.2.3 Variation 3: Reaction of Tetrahydropyranyl and Silyl Ethers in Ionic Liquids

35.2.1.5.7.3 Method 3: Substitution of Sulfonyloxy Groups

35.2.1.5.7.3.1 Variation 1: Reaction of Arene- or Methanesulfonates with Lithium Bromide in Tetrahydrofuran

35.2.1.5.7.3.2 Variation 2: Reaction of Methanesulfonates with Magnesium Bromide–Diethyl Ether Complex

35.2.1.5.7.3.3 Variation 3: Reaction of Arene- or Methanesulfonates with the Ionic Liquid 1-Butyl-3-methylimidazolium Bromide

35.2.2.2 Propargylic Bromides

M. Braun

35.2.2.2 Propargylic Bromides

35.2.2.2.1 Method 1: Synthesis by Heteroatom Substitution: Substitution of Hydroxy or Tetrahydropyranyl Ether Groups

35.2.2.2.1.1 Variation 1: Reaction of Propargylic Alcohols with Phosphorus Tribromide in Perfluorohexane

35.2.3.3.3 Synthesis of Benzylic Bromides by Substitution of σ-Bonded Heteroatoms

M. Braun

35.2.3.3.3 Synthesis of Benzylic Bromides by Substitution of σ-Bonded Heteroatoms

35.2.3.3.3.1 Method 1: Substitution of Oxygen Functionalities

35.2.3.3.3.1.1 Variation 1: Reaction of (Hydroxymethyl)phenols with 2,4,6-Trichloro-1,3,5-triazine and Sodium Bromide

35.2.3.3.3.1.2 Variation 2: Reaction of Benzylic Alcohols with Poly(vinylpyrrolidin-2-one)–Bromine Complex and Hexamethyldisilane

35.2.3.3.3.1.3 Variation 3: Reaction of Benzylic Alcohols with Monolithic Triphenylphosphine Reagent and Carbon Tetrabromide

35.2.4.2.3 Synthesis of Allylic Bromides by Substitution of σ-Bonded Heteroatoms

M. Braun

35.2.4.2.3 Synthesis of Allylic Bromides by Substitution of σ-Bonded Heteroatoms

35.2.4.2.3.1 Method 1: Substitution of Other Halogens

35.2.4.2.3.1.1 Variation 1: Reaction of Allylic Chlorides with 1,2-Dibromoethane under Rhodium Catalysis

35.2.4.2.3.2 Method 2: Substitution of Hydroxy Groups

Author Index

Abbreviations

3.6.16 Gold-Catalyzed Cycloaddition Reactions

D. Qian and J. Zhang

General Introduction

The development of homogeneous gold catalysis has been remarkably rapid since circa 2000.[1–11] Gold salts and complexes show good performance in catalytic transformations involving carbon–carbon unsaturated bonds, where their properties of being strongly carbophilic Lewis acids, yet air- and moisture-tolerant, lead to unparalleled selectivity and mildness. Most gold-catalyzed reactions start with coordination of gold to carbon–carbon multiple bonds, especially triple bonds. The resulting π-alkyne–or π-alkene–gold complexes promote the inter- or intramolecular nucleophilic addition of a variety of functional groups. In this context, gold-catalyzed cycloadditions are particularly attractive for the construction of complex polycyclic structures present in diverse natural products.[6,7,9,10]

Cycloaddition reactions are an efficient route to construct carbo- and heterocycles by forming at least two bonds and one ring in a single operation.[12,13] Importantly, such processes generally involve the simple addition of two or more molecules and, therefore, this represents an atom- and stepeconomical approach that also takes place with high regio- and stereoselectivity. The scope of classical cycloadditions, however, is often limited to substrates with matched electronic properties. Transition-metal complexes frequently promote cycloadditions that are not feasible under thermal or photolytic conditions. Most transition-metal-catalyzed cycloadditions involve the use of rhodium, ruthenium, nickel, or palladium complexes;[12,13] however, a “gold rush” has now resulted in the development of many gold-catalyzed cycloadditions.[6,7,9,10] This chapter is organized according to the key reactive gold intermediate that formally participates in the cycloaddition. Related reactions involving enynes, propargylic carboxylates, allenes, and alkenes were covered in Sections 3.6.11.1, 3.6.12.1, 3.6.14.1, and 3.6.15.1, respectively; thus, only examples reported since 2012 are included here.

3.6.16.1 Cycloadditions via Gold-Containing 1,n-Dipolar Intermediates

As strong Lewis acids for π-systems, gold complexes can be utilized in a wide range of transformations by electrophilic activation of carbon–carbon multiple bonds toward a variety of nucleophiles.[1–11] Although gold catalysis is well-developed for both cyclizations[1–3] and cycloisomerizations,[4] its potential for 1,n-dipolar cycloaddition is still emerging. Charge-separated carbon chains (i.e., all-carbon 1,n-dipoles) are usually transient species and are often difficult to harness in cycloaddition/annulation reactions; however, the negatively charged end of such a dipole can be masked by a gold species, thus substantially tempering its nucleophilicity, resulting in polycyclic frameworks in a highly regio- and stereoselective fashion (▶ Scheme 1).

Scheme 1 Gold-Catalyzed 1,n-Dipolar Cycloaddition Reactions

3.6.16.1.1 Method 1: Gold-Containing Benzopyrylium Intermediates

When the nucleophile is an aldehyde, ketone, imine, or nitro group, the addition of the nucleophile to a gold-activated alkyne results in a cation that can be trapped by various dipolarophiles, including alkynes, alkenes, enol ethers, imines, or carbonyl compounds. Of particular interest are gold-containing benzopyrylium intermediates 1, which can lead to a rapid increase in molecular complexity by intra- or intermolecular cycloadditions with dipolarophiles. A pioneering example is the use of 2-alk-1-ynylbenzaldehyde derivatives 2, which undergo a tandem addition–cycloaddition process with terminal alkynes catalyzed by gold(III) chloride leading to naphthalenes 3 and 4 (▶ Scheme 2).[14] The synthetic utility of this chemistry has been showcased in the total synthesis of rubiginone B2.[15] Furthermore, the gold-containing benzopyrylium species, generated in situ, are readily trapped by other dipolarophiles including carbonyl compounds/enol ethers [e.g., heptanal (6)],[16] 2,3-dimethylbut-2-ene (8),[17] benzo[b]furan (9),[17] and benzyne [generated from benzenediazonium-2-carboxylate (12)].[18]

Scheme 2 [4 + 2] Cycloaddition of Gold-Containing Benzopyrylium Intermediates with Various Dienophiles[14–18]

R

1

R

2

R

3

Ratio (

3/4

)

Yield (%)

Ref

H

Ph

Ph

>99:1

96

[

14

]

H

Ph

Ac

<1:99

75

[

14

]

Me

Ph

Ph

3

only

40

[

14

]

R

1

R

2

Time (h)

Yield (%)

Ref

4-Tol

Ph

7

81

[

18

]

4-F

3

CC

6

H

4

Ph

9

62

[

18

]

4-Tol

Pr

4

87

[

18

]

Ph

t

-Bu

9

73

[

18

]

An efficient gold-catalyzed cycloaddition reaction of oxoalkynes with norbornenes produces a variety of structurally symmetrical propeller-like molecules. For example, the reaction of 2-(cyclopropylethynyl)benzaldehyde (14) and norbornene (15) catalyzed by chloro(1,3-dimesitylimidazol-2-ylidene)gold(I) [AuCl(IMes)] and Selectfluor [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] gives polycycle 16 (▶ Scheme 3).[19] The reaction is proposed to occur through a gold-catalyzed tandem [4 + 2] reaction via trapping of benzopyrylium intermediates of type 1 and highly reactive cyclic o-quinodimethane species. Similarly, the highly strained benzotricyclo[3.2.1.02,7]octane skeletons 19 are obtained by trapping of the cyclic o-quinodimethane intermediate from the reaction of oxoalkynes 17 and 1,3-dienes, such as 18, using chloro(1,3-dimesitylimidazol-2-ylidene)gold(I) [AuCl(IMes)] or chloro(1,3-dimesitylimidazolidin-2-ylidene)gold(I) [AuCl(SIMes)] as the catalyst.[20] The features of this transformation, such as mild reaction conditions, excellent substrate scope, and high functional-group tolerance, hold considerable potential for the construction of complex molecules with fan-like and tricyclic skeletons.

Scheme 3 [4 + 2] Cycloaddition of Gold-Containing Benzopyrylium Intermediates with Norbornene and Diene Dienophiles[19,20]

R

1

Catalyst

Yield (%)

Ref

H

AuCl(SIMes)

30

[

20

]

Ph

AuCl(IMes)

96

[

20

]

1-Oxo-5-ynes 20 undergo formal [4 + 2] cycloaddition catalyzed by AuCl(JohnPhos)/AgNTf2 to give 9-oxabicyclo[3.3.1]nona-4,7-dienes 21 in high yields (▶ Scheme 4).[21] This reaction, in contrast to those discussed above, is proposed to go through an alternative reactive species of type 22 that functions as a zwitterionic species 23. The 1-oxo-5-ynes undergo an exo-dig cyclization process to give benzopyrylium intermediates 22 that undergo formal [4 + 2] cycloaddition with enol ethers, leading to interesting 9-oxabicyclo[3.3.1]nona-4,7-dienes in good yields. The origin of this high diastereoselectivity is likely to arise from the [3 + 2] cycloaddition of the enol ether with s-trans-methylene(vinyl)oxonium species 23, followed by 1,2-migration (▶ Scheme 4).

Scheme 4 Gold-Catalyzed Synthesis of 9-Oxabicyclo[3.3.1]nona-4,7-dienes via a Formal [4 + 2] Cycloaddition[21]

R

1

R

2

R

3

R

4

Time (h)

Yield (%)

Ref

Ac

H

H

H

2

68

[

21

]

Ac

H

H

Me

2

76

[

21

]

MOM

H

H

Me

1

82

[

21

]

MOM

OMe

OMe

Me

2

95

[

21

]

MOM

Cl

H

Me

1

78

[

21

]

Bu

H

H

Me

1.5

42

[

21

]

However, when the substrate features an internal alkyne, such as in alkynyl acetates 24, the reaction involves an alternative oxacyclization/[4 + 2] cycloaddition cascade (▶ Scheme 5).[22] The cationic gold species catalyzes an initial 1,3-acyloxy shift in 24 to generate initial oxoallenes 25, which subsequently undergo 6-endo-dig cyclization to form a new type of benzopyrylium intermediates 26. The benzopyrylium intermediates 26 then react with an enol ether to give isolable [4 + 2] cycloadducts, highly substituted oxacyclic systems 27, as a mixture of two diastereomers.

Scheme 5 Gold-Catalyzed Tandem Oxacyclization/[4 + 2] Cycloaddition[22]

R

1

R

2

R

3

R

4

Time (h)

Yield

a

(%)

Ref

Bu

Me

H

Bu

2.5

79

[

22

]

Bu

Pr

H

Bu

2

69

[

22

]

Bu

Me

(CH

2

)

3

1

82

[

22

]

Ph

Me

(CH

2

)

3

5

58

[

22

]

a

dr >20:1.

Naphthyl Ketones 3 and 4; General Procedure:[14]

The reaction was performed using 2-alk-1-ynylbenzaldehydes 2 (1.0 equiv) and an alkyne (3.0 equiv) in the presence of AuCl3 (3 mol%) in 1,2-dichloroethane at 80°C. The mixture was concentrated and the residue was purified by flash chromatography (silica gel).

(3-Pentylnaphthalen-1-yl)(phenyl)methanone (7); Typical Procedure:[16]

To a suspension of AuBr3 (22 mg, 0.05 mmol, 10 mol%) in 1,4-dioxane (2 mL) were added 2-alk-1-ynylbenzaldehyde 5 (103 mg, 0.5 mmol) and heptanal (6; 0.084 mL, 0.6 mmol) at rt under an argon atmosphere. The resulting homogeneous soln was stirred at 100°C for 3 h and then cooled to rt. The mixture was passed through a silica gel pad using Et2O, and the resulting crude product was purified by column chromatography (silica gel, hexane/EtOAc 25:1) to give a pale-yellow liquid; yield: 122 mg (81%).

(5aR*,6R*,11R*,11aS*)-11-Benzoyl-6-hydroxy-5a,6,11,11a-tetrahydronaphtho[2,3-b]benzofuran (10); Typical Procedure:[17]

A soln of aldehyde 5 (103 mg, 0.5 mmol), benzo[b]furan (9; 59 mg, 0.5 mmol), H2O (9.0 μL, 0.5 mmol), and AuCl3 (5.0 mg, 0.015 mmol) in MeCN (5 mL) was stirred for 3 h at 80°C. The mixture was concentrated and the residue was fractionated by flash chromatography; TLC (silica gel, hexanes/t-BuOMe 4:1, Rf 0.70, 0.42, 0.33, 0.17, 0.00). The fraction with Rf 0.33 was isolated and dried under reduced pressure at 50°C/0.3 Torr to give the product as colorless crystals; yield: 105 mg (61%); mp 180–190°C.

Fan-Like Compounds, e.g. Cyclopropyl{1,3,4,4a,9a,10-hexahydro-9,10-[2]bicyclo-1,4-methanoanthracen-9(2H)-yl}methanone (16); General Procedure:[19]

To a soln of AuCl(IMes) (5.4 mg, 0.01 mmol, 5 mol%) and Selectfluor (10.6 mg, 0.03 mmol, 10 mol%) in 1,2-dichloroethane (4 mL; 0.05 M) was added the corresponding enynal or enynone (e.g., 14; 0.2 mmol) and norbornene (188.3 mg, 2.0 mmol). The mixture was stirred under a N2 atmosphere at 80°C for 24 h. When the reaction was complete, the mixture was filtered through a short silica gel pad, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography (silica gel).

Benzotricyclo[3.2.1.02,7]octanes 19; General Procedure:[20]

The enynal or enynone (e.g., 17; 0.1 mmol) and 1,3-diene 18 (0.5 mmol) were added to a soln of the catalyst combination of AuCl(SIMes) (2.7 mg, 0.005 mmol) and Selectfluor (5.3 mg, 0.015 mmol) in 1,2-dichloroethane (2 mL; 0.05 M). The mixture was stirred under a N2 atmosphere at 80°C for 14 h. When the reaction was complete, the mixture was filtered through a short silica gel column, and then the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (silica gel).

9-Oxabicyclo[3.3.1]nona-4,7-dienes 21; General Procedure:[21]

A soln of AuCl(JohnPhos) (4.8 mg, 8.2 μmol, 3 mol%) and AgNTf2 (3.5 mg, 9 μmol, 3 mol%) in CH2Cl2 (2.0 mL) was stirred at 30°C for 10 min and then a soln of 1-oxo-5-yne 20 (0.30 mmol) and ethyl vinyl ether (86.5 mg, 1.2 mmol) in CH2Cl2 (1.0 mL) was added. The resulting mixture was stirred for a further 2 h and then it was filtered through a short silica gel column. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel).

(Z)-1-[3-Alkoxy-1-alkyl-1,2,3,4-tetrahydro-1,4-(epoxymethano)naphthalen-9-ylidene]alkyl Acetates 27; General Procedure:[22]

A soln of AuCl(JohnPhos) (4.8 mg, 8.2 μmol, 3 mol%) and AgNTf2 (3.5 mg, 9 μmol, 3 mol%) in CH2Cl2 (2.0 mL) was stirred at 25°C for 10 min and then a soln of alkynyl acetate 24 (0.30 mmol) and vinyl ether (0.90 mmol) in CH2Cl2 (1.0 mL) was added. The resulting mixture was stirred for a further 2.5 h and then it was filtered through a short silica gel column. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel).

3.6.16.1.1.1 Variation 1: Gold-Containing Benzopyrylium Azomethine Ylides

A gold-containing azomethine ylide 29 is formed by gold-mediated heterocyclization of 28 (▶ Scheme 6). Subsequent [3 + 2] cycloaddition with an external alkene followed by 1,2-migration of the R1 group affords the corresponding tricyclic indole derivatives 30 in good yields.[23]

Scheme 6 Gold-Catalyzed [3 + 2] Cycloaddition via an Azomethine Ylide[23]

R

1

Time (h)

Ratio (

cis

/

trans

)

Yield (%)

Ref

Me

22

55:45

81

[

23

]

Pr

2.5

54:42

80

[

23

]

Cy

2

73:27

89

[

23

]

Ph

0.5

49:51

62

[

23

]

Gold-containing azomethine ylides are also intermediates in the one-pot synthesis of azabicyclo[3.2.1]octane skeletons 33 from 1,6-enynes 31 containing a nitrone moiety (▶ Scheme 7).[24] Addition of the imine nitrogen to the in situ generated carbenes affords the azomethine ylides 32, which upon [3 + 2] cycloaddition with the pendent alkene of the starting material produce the tetracyclic ketones 33 in good yields with high diastereoselectivity and excellent atom economy.

Scheme 7 Gold-Catalyzed Internal Redox/[3 + 2] Cycloaddition Cascade[24]

Z

R

1

R

2

R

3

R

4

Time (h)

Yield (%)

Ref

C(CO

2

Et)

2

Bn

H

H

H

1

82

[

24

]

C(CO

2

Et)

2

Bn

H

H

Me

1.5

59

[

24

]

C(CO

2

Et)

2

Me

H

H

H

2.5

75

[

24

]

NTs

Bn

H

H

H

1

85

[

24

]

1-tert-Butoxy-3-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indoles 30; General Procedure:[23]

To a mixture of an imine derivative 28 (0.30 mmol), tert-butyl vinyl ether (1.2 mmol, 4 equiv), and 4-Å molecular sieves (60 mg per 1 mL of toluene) in toluene (3 mL; 0.1 M for 28) was added AuBr3 (9.0 μmol, 3 mol%) at rt, and then the mixture was stirred at rt. After the disappearance of the starting material, the reaction was quenched with sat. aq NaHCO3 and the mixture was filtered through a short pad of Celite. The organic layer was extracted with EtOAc (3 ×) and the combined organic layers were washed with brine and then dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by preparative TLC (silica gel, toluene/hexane 2:1 to 5:1, or toluene/EtOAc 40:1).

Tricyclic Ketones 33; General Procedure:[24]

CAUTION:

Nitromethane is flammable, a shock- and heat-sensitive explosive, and an eye, skin, and respiratory tract irritant.

AuCl3 (0.5 mg, 1.8 μmol, 2 mol%; for a lower catalyst loading, 0.02 M stock solutions in respective solvents were used) was added to a soln of alkyne/nitrone 31 (40 mg, 0.089 mmol) in MeNO2 (0.8 mL). The resulting mixture was heated to 70°C for 1 h. (At this point the mixture turned blue-green and TLC indicated complete conversion. However, there was no appreciable amount of precipitate or metallic gold.) The solvent was removed under reduced pressure and the residue was purified by chromatography (silica gel).

3.6.16.1.1.2 Variation 2: Gold-Containing 2-Oxoalkyl Oxonium Species

A stereoselective synthesis[25] of azatricyclic frameworks 38 begins from 1-ethynyl-2-nitrobenzenes 34 and electron-rich alkenes (▶ Scheme 8).[22] This catalytic transformation involves a formal [2 + 2 + 1] cycloaddition between an α-carbonyl carbene intermediate, a nitroso species, and an external alkene. It is proposed that the α-carbonyl carbene 35 is generated by a gold-catalyzed redox process. Intramolecular oxygen attack on this gold carbene 35 gives 2-oxoalkyl oxonium 36, which then tautomerizes to its enol form 37. Subsequent intermolecular [3 + 2]-cycloaddition reaction of intermediate 37 with an external alkene in a concerted exo-addition mode produces the final product 38.

Scheme 8 Gold-Catalyzed [2 + 2 + 1] Cycloaddition via 2-Oxoalkyl Oxonium Species[25]

R

1

R

2

R

3

Yield (%)

Ref

H

H

OEt

89

[

25

]

H

H

OTMS

77

[

25

]

H

H

SPh

92

[

25

]

H

H

4-MeOC

6

H

4

73

[

25

]

CF

3

H

OEt

84

[

25

]

H

Cl

OEt

82

[

25

]

3.6.16.1.2 Method 2: Furyl–Gold 1,n-Dipole Intermediates

3.6.16.1.2.1 Variation 1: Furyl–Gold 1,3-Dipole Intermediates

Various procedures have been reported for the transformation of 2-(alk-1-ynyl)alk-2-en-1-ones (ynenones) 42 into polar furyl–gold intermediates 44, which are able to undergo various intermolecular [3 + n] cycloadditions with diverse dipolarophiles (▶ Schemes 9 and 10).[26–32]

The furyl–gold 1,3-dipole species 44 reacts well with nitrones to generate intermediates 45 that undergo subsequent ring closure to furnish highly substituted fused heterobicyclic furo[3,4-d][1,2]oxazines 46 in a regio- and diastereoselective fashion (▶ Scheme 9).[26–28] An asymmetric variant of this annulation strategy uses chiral bis- or monophosphine ligands, including (R)-MeO-DTBM-BIPHEP [(R)-39],[27] (R)-C1-TunePhos [(R)-40],[27] and (S,RS)-MingPhos [(S,RS)-41].[28] Interestingly, in this asymmetric [3 + 3]-cycloaddition reaction both enantiomers, with opposite configuration, are obtained in high yields and with excellent diastereo- and enantioselectivity using the diastereomers (R,RS)- or (S,RS)-MingPhos.[28]

Scheme 9 Gold(I)-Catalyzed [3 + 3] Cycloaddition Reaction of Ynenones and C,N-Diphenylnitrone[26–28]

R

1

Catalyst

Solvent

Temp (°C)

ee (%)

Yield (%)

Ref

Ph

AuCl(PPh

3

) (2.5 mol%), AgOTf (2.5 mol%)

CH

2

Cl

2

25

–

a

98

[

26

]

Bu

AuCl(PPh

3

) (2.5 mol%), AgOTf (2.5 mol%)

CH

2

Cl

2

25

–

b

82

[

26

]

Ph

AuCl(SMe

2

) (5 mol%), (

R

)-

39

(2.5 mol%), AgOTf (2.5 mol%)

1,2-dichloroethane

–10

95

97

[

27

]

Bu

AuCl(SMe

2

) (5 mol%), (

R

)-

39

(2.5 mol%), AgOTf (2.5 mol%)

1,2-dichloroethane

–10

55

77

[

27

]

Ph

AuCl(SMe

2

) (5 mol%), (

R

)-

40

(2.5 mol%), AgOTf (2.5 mol%)

1,2-dichloroethane

0

99

94

[

27

]

Bu

AuCl(SMe

2

) (5 mol%), (

R

)-

40

(2.5 mol%), AgOTf (2.5 mol%)

1,2-dichloroethane

–10

32

59

[

27

]

Bu

AuCl(SMe

2

) (5 mol%), (

S

,

R

S

)-

41

(5.5 mol%), AgNTf

2

(5 mol%)

1,2-dichloroethane

–10

94

86

[

28

]

(CH

2

)

3

Cl

AuCl(SMe

2

) (5 mol%), (

S

,

R

S

)-

41

(5.5 mol%), AgNTf

2

(5 mol%)

1,2-dichloroethane

–10

99

99

[

28

]

a

dr >99:1.

b

dr 86:14.

A series of dipolarophiles, such as electron-rich alkenes, α,β-unsaturated imines, and 1,3-diphenylbenzo[c]furan, can also trap the gold 1,3-dipole intermediates 44, leading to 3,4-furan-fused carbocycles or heterocycles with good diastereoselectivity (▶ Scheme 10). Examples are the [3 + 2] annulation of such 1,3-dipoles with 3-styryl-1H-indoles (e.g., 48) to give cyclopenta[c]furans (e.g., 49);[29] [3 + 4] annulation with α,β-unsaturated imines, including an unexpected alkyl migration, to give N-heterocycle-fused furans (e.g., imine 50 gives furo[3,4-c]azepine 51);[30] and [3 + 4] annulation with 1,3-diphenylbenzo[c]furan (52) to give polyfuran 53.[31] Diarylethenes also trap gold 1,3-dipoles 44, leading to the corresponding [3 + 2]-cycloaddition products in good yields; for example, 1,1-diphenylethene (54) gives cyclopenta[c]furan 55.[32]

Scheme 10 Gold-Catalyzed 1,3-Dipolar Cycloaddition Reactions of (E)-3-Benzylidene-5-phenylpent-4-yn-2-one and Dipolarophiles[29–32]

1-Methyl-3-[(4R*,5R*,6S*)-1-methyl-3,5,6-triphenyl-5,6-dihydro-4H-cyclopenta[c]furan-4-yl]-1H-indole (49); Typical Procedure:[29]

AgOTf (3.8 mg, 5.0 mol%) was added to a soln of AuCl(PCy3) (7.8 mg, 5.0 mol%) in 1,2-dichloroethane (1.0 mL) under an argon atmosphere and the mixture was stirred for 10 min at rt. Then the soln of ynenone 47 (73.8 mg, 0.30 mmol) and 3-styryl-1H-indole (48; 84.0 mg, 0.36 mmol) in 1,2-dichloroethane (2.0 mL) was added to this mixture. After being stirred for 2 h at rt, the mixture was passed through a short column (silica gel) and then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to give the product as a white solid; yield: 133.2 mg (93%).

(4R*,8S*)-5-(4-Methoxyphenyl)-1,7-dimethyl-3,4,8-triphenyl-5,8-dihydro-4H-furo[3,4-c]azepine (51); Typical Procedure:[30]

To a soln of AuCl(PPh3) (12.4 mg, 0.025 mmol, 5.0 mol%) in CH2Cl2 (2.0 mL) was added AgOTf (6.4 mg, 0.025 mmol, 5.0 mol%) under an argon atmosphere, and the mixture was stirred for 10 min at rt. Then, 4-Å molecular sieves (200 mg), ynenone 47 (123 mg, 0.50 mmol), imine 50 (150.6 mg, 0.60 mmol), and further CH2Cl2 (3.0 mL) were added to this mixture. The resulting mixture was stirred for 12 h, and then the mixture was passed through a short silica gel column. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a white solid; yield: 228.8 mg (92%).

3.6.16.1.2.2 Variation 2: Furyl–Gold 1,4-Dipole Intermediates

Cyclopropyl-containing alkynyl ketones undergo transition-metal-catalyzed cycloisomerizations into furans.[33] For example 1-alk-1-ynylcyclopropyl ketone 56 and C,N-diphenylnitrone (43) in the presence of a gold(I) catalyst give the [4 + 3]-cycloaddition product, 5,7-fused bicyclic furo[3,4-d][1,2]oxazepine 59 (▶ Scheme 11).[34,35] The proposed mechanism begins with a 5-endo-dig cyclization of the carbonyl group onto the gold-activated alkyne to give 1,4-dipole 57, followed by ring-opening of the cyclopropane ring through nucleophilic attack of the nitrone to give 58. Further studies on the kinetic resolution of racemic rac-56 and transformation experiments on optically active (1S,2R)-56 provide strong supportive evidence for the proposed SN2 reaction pathway.[35]

Scheme 11 Gold-Catalyzed [4 + 3]-Cycloaddition Reaction of a 1-Alk-1-ynylcyclopropyl Ketone and C,N-Diphenylnitrone[35]

The use of polarized alkenes involving indoles, carbonyls, imines, or silyl enol ethers instead of nitrones as the cycloaddition component gives [4 + 2] cycloadducts in good yields with notable regioselectivity.[36]

The reaction of ω-(2-acetyl-2-alk-1-ynylcyclopropyl)alkanals and -alkanimines has been used in a general strategy for the construction of structurally diverse bridged oxa/aza-[n.3.1] skeletons, such as 62, by a fascinating intramolecular [4 + 2]-cycloaddition reaction of the 2-alk-1-ynylcyclopropyl unit with the carbonyl group or imine (▶ Scheme 12). The reaction of the geminal carbonyl group in 60 with the activated triple bond as the first step of this transformation gives the furan moiety in 61.[37]

Scheme 12 Gold-Catalyzed Intramolecular [4 + 2]-Cycloaddition Reaction of a 4-(2-Acetyl-2-alk-1-ynylcyclopropyl)butanal[37]

In addition, a related gold-triggered formal [4 + 3] cycloaddition between 1-acyl-1-(alk-1-ynyl)oxiranes 63 and nitrones using AuCl(RuPhos) gives heterobicyclic products of type 64 in a highly diastereoselective fashion (▶ Scheme 13); this represents the first example of metal-catalyzed, chemoselective C─C bond cleavage of epoxides by introducing an alkyne.[38]

Scheme 13 Gold-Catalyzed [4 + 3] Cycloaddition of 2-Acyl-1-(alk-1-ynyl)oxiranes with C,N-Diphenylnitrone[38]

R

1

R

2

R

3

Time (h)

Yield (%)

Ref

Ph

Ph

Ph

1

93

[

38

]

4-ClC

6

H

4

Ph

Ph

1

98

[

38

]

Ph

4-MeOC

6

H

4

Ph

1.5

71

[

38

]

Ph

Ph

Bu

2

84

[

38

]

(1R*,4R*)-6-Methyl-1,2,4,8-tetraphenyl-1,2,4,5-tetrahydrofuro[3,4-d][1,2]oxazepine (cis-59); Typical Procedure:[35]

A 0.01 M soln of Au(OTf)(PPh3) in CH2Cl2 (1 mL, 0.01 mmol, 2.0 mol%) was added to a soln of ketone rac-56 (130 mg, 0.5 mmol) and nitrone 43 (102.9 mg, 0.55 mmol, 1.1 equiv) in CH2Cl2 (1 mL) at rt. The resulting mixture was stirred for 10 min at rt (TLC monitoring). After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (silica gel, hexanes/Et2O 50:1) to afford the pure product as a white solid; yield: 219.1 mg (96%).

(4R*,8S*)-1-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-4,8-epoxycycloocta[c]furan (62); Typical Procedure:[37]

To an oven-dry flask filled with argon gas was added AuCl(PPh3) (16.1 mg, 0.032 mmol, 10 mol%) and AgOTf (8.0 mg, 0.031 mmol, 10 mol%), and then 1,2-dichloroethane (10 mL) was added. The resulting soln was stirred for 10 min and then substrate 60 (80 mg, 0.31 mmol) was added. After being stirred at 60°C for 40 min, the soln was cooled to rt and passed through a short silica gel column. Purification by column chromatography (petroleum ether/EtOAc 20:1) gave the product; yield: 69 mg (86%).

4,5-Diphenyl-4,5-dihydrofuro[3,4-d][1,6,2]dioxazepines 64; General Procedure:[38]

A soln of AuCl(RuPhos) (10.5 mg, 0.015 mmol, 5 mol%) and AgSbF6 (5.2 mg, 0.015 mmol, 5 mol%) in 1,2-dichloroethane (1.0 mL) was stirred for 10 min under N2. The mixture was transferred into a soln of ketone 63 (0.3 mmol) and nitrone 43 (65.1 mg, 0.33 mmol) in anhyd 1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred at rt for 1 h under N2