Science of Synthesis Knowledge Updates 2012 Vol. 1 E-Book

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

Seitenzahl: 1068

Veröffentlichungsjahr: 2014

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 youalways have access to state-of-the-art synthetic methodology.

Content of this volume: Organometallic Complexes of Titanium, Silicon Compounds, Disilenes, Lithium Compounds, 1,4-Dioxins and Benzo- and Dibenzo-Fused Derivatives, 1,2-Dithiins, Seven-Membered Hetarenes with One Heteroatom, Oxepins, Benzoxepins, Azepines, Cyclopentazepines, and Phosphorus Analogues, Three Carbon-Heteroatom Bonds: Nitriles, Isocyanides, and Derivatives, Heteroatom Analogues of Aldehydes and Ketones.

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.

July 2010

The Editorial Board

E. M. Carreira (Zurich, Switzerland)

C. P. Decicco (Princeton, USA)

A. Fuerstner (Muelheim, Germany)

G. A. Molander (Philadelphia, USA)

P. J. Reider (Princeton, USA)

E. Schaumann (Clausthal-Zellerfeld, Germany)

M. Shibasaki (Tokyo, Japan)

E. J. Thomas (Manchester, UK)

B. M. Trost (Stanford, USA)

Abstracts

2.10.19 Organometallic Complexes of Titanium (Update 1)

P. Bertus, F. Boeda, and M. S. M. Pearson-Long

This chapter is an update to the earlier Science of Synthesis contribution describing the synthesis and application of titanium complexes in organic synthesis. This update focuses on the synthesis of cyclopropane derivatives using titanium reagents, with particular emphasis on the preparation of cyclopropanols from carboxylic esters (Kulinkovich reaction) and cyclopropylamines from carboxylic amides or nitriles.

Keywords: amides · bicyclic compounds · carbonates · cyclopropanes · cyclopropanols · cyclopropylamines · esters · Grignard reagents · imides · magnesium · nitriles · titanium

4.4.1 Product Subclass 1: Disilenes

A. Meltzer and D. Scheschkewitz

The syntheses of stable and marginally stable compounds with Si=Si bonds, i.e. linear and cyclic disilenes as well as tetrasilabutadienes, are reviewed. Typical procedures are described including detailed special requirements and precautions.

Keywords: alkene analogues · coupling reactions · cyclic compounds · dehalogenation · disilenes · disilenides · disilynes · photolysis · reductive coupling · silanes · silicon compounds · silylenes · silyl halides · unsaturated compounds

8.1.31 Functionalized Organolithiums by Ring Opening of Heterocycles

M. Yus and F. Foubelo

This manuscript describes the preparation of functionalized organolithium compounds by reductive opening of heterocycles and further reaction of these intermediates with electrophiles.

Keywords: activation of C—O bonds · alkali metal compounds · carbanions · carbon—metal bonds · heterocycles · lithiation · lithium compounds · radical ions · reductive cleavage

8.1.32 Syntheses Mediated by α-Lithiated Epoxides and Aziridines

L. Degennaro, F. M. Perna, and S. Florio

Three-membered ring heterocycles such as epoxides and aziridines, whose structural motif occurs frequently in natural products and biologically active substances, are an uncommon combination of reactivity, synthetic flexibility, and atom economy. Readily accessible, also in enantioenriched form, they are mainly used as electrophiles, undergoing highly regioselective ring-opening reactions when reacted with nucleophiles. There are, however, many other less conventional but useful reactions these small-ring heterocycles may undergo. This chapter surveys a selection of the most recent advances in the chemistry of α-lithiated epoxides and aziridines, which can be simply generated by treatment of the parent epoxide or aziridine with strong bases such as organolithiums or lithium amides. Such lithiated species are relatively stable and can be captured with a number of electrophiles to give more functionalized oxiranes and aziridines or undergo other transformations including 1,2-organo shifts to enolates, eliminative dimerization, β-elimination, intramolecular cyclopropanation onto a double bond (C=C insertion), transannular C—H insertion, and reductive alkylation.

Keywords: oxiranes · aziridines · small-ring heterocycles · α-lithiation · carbenoids · organolithiums · configurational stability · asymmetric synthesis

8.1.33 Transition-Metal-Catalyzed Carbon—Carbon Bond Formation with Organolithiums

G. Manolikakes

Transition-metal-catalyzed reactions with organolithiums are a useful tool for the formation of carbon—carbon bonds. This chapter covers reactions with organolithium compounds catalyzed by various transition metals such as copper, palladium, or iron.

Keywords: lithium compounds · cross coupling · copper catalysis · palladium catalysis · iron catalysis · carbolithiation · asymmetric catalysis

16.2.4 1,4-Dioxins and Benzo- and Dibenzo-Fused Derivatives

S. M. Sakya and J. Yang

This manuscript concerns three types of compound: 1,4-dioxins, 1,4-benzodioxins, and dibenzo[b,e][1,4]dioxins, and covers recent syntheses of these substrates that have not previously been highlighted in Section 16.2 of Science of Synthesis.

Keywords: aromatization · base-induced coupling · 1,4-benzodioxins · Diels–Alder reaction · 1,4-dioxins · dibenzo[b,e][1,4]dioxins · lithium–halogen exchange · ring-closing metathesis · ring-closure reactions · Stille coupling · substituent modification · Vilsmeier reaction

16.3.5 1,2-Dithiins

F. K. Yoshimoto and Q. Li

1,2-Dithiins are six-membered rings with two double bonds and two sulfur atoms within the ring. Related compounds include 3,6-dihydro-1,2-dithiins, 1,4-dihydrobenzo[d][1,2]dithiins, and dibenzo[c,e][1,2]dithiins. A wide variety of compounds observed in nature are found to contain the dithiin motif and the group is implicated in a wide range of biological activity. 1,2-Dithiins have also been used in other fields, for example as organic transistors and ligands for transition metals. This section updates previously published material in Science of Synthesis and in particular focuses on synthesis by ring-closure reactions and applications of the group in reactions with transition metals, Lewis acids, diazo compounds, alkynes, and enzymes.

Keywords: cyclization · diazo compounds · dibenzo[c,e][1,2]dithiins · Diels–Alder reaction · 1,4-dihydrobenzo[d][1,2]dithiins · 3,6-dihydro-1,2-dithiins · dimerization · 1,2-dithianes · 1,2-dithiins · enzymes · Lewis acids · phase-transfer catalysis · photolysis · ring-closing metathesis · ring-closure reactions · sulfonation · transition metals

17.4.1.5 Oxepins

J. Hong

This manuscript is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of oxepins. It focuses on the literature published in the period 2003–2011.

Keywords: cycloaddition · dehydrogenation · isomerization · Michael addition · nucleophilic substitution · ring expansion

17.4.2.5 Benzoxepins

J. Hong

This manuscript is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of benzoxepins. It focuses on the literature published in the period 2003–2011.

Keywords: annulation · condensation reactions · cyclization · cyclocondensation · rearrangement · ring closure · ring expansion · transition metals

17.4.5.5 Azepines, Cyclopentazepines, and Phosphorus Analogues

J. E. Camp

This manuscript is an update of the earlier Science of Synthesis contribution describing methods for the synthesis of fully unsaturated azepines, cyclopentazepines, and their phosphorus analogues. It focuses on the literature published between 2003 and 2010.

Keywords: azepines · cyclopentazepines · electrocyclization · Diels–Alder · photolytic decomposition · rearrangement · C-amination · C-alkoxylation · Friedel–Crafts · azepinium ion

17.4.6.10 Benzazepines and Their Group 15 Analogues

J. E. Camp

This manuscript is an update of the earlier Science of Synthesis contribution describing methods for the synthesis of fully unsaturated benzazepines and their group 15 analogues. It focuses on the literature published between 2003 and 2010.

Keywords: benzazepines · dibenzoheterepins · tribenzoheterepins · condensation · Bischler–Napieralski · tandem reaction · phase-transfer catalysis · ring enlargement · photodimerization · benzoheterepins · Friedel–Crafts

19.5.17 Synthesis of Nitriles Using Cross-Coupling Reactions

D. M. Rudzinski and N. E. Leadbeater

The synthesis of aryl and hetaryl nitriles by metal-catalyzed cross-coupling reactions is presented. Attention is focused mainly on key methodologies published in the period 2003–2011. As well as the use of alkali metal cyanide salts as sources of cyanide, the application of the less toxic and increasingly popular potassium hexacyanoferrate(II) is also discussed.

Keywords: nitriles · cyanide · cyanation · cross coupling · palladium · nickel · copper · aryl halides · hetaryl halides · aryl trifluoromethanesulfonates · aryl methanesulfonates

27.25 Product Class 25: N-Sulfanyl-, N-Selanyl-, and N-Tellanylimines, and Their Oxidation Derivatives

F. Chemla, F. Ferreira, and A. Pérez-Luna

This chapter is devoted to synthetically useful methods for the preparation of N-sulfanylimines and their oxidation derivatives (N-sulfinylimines and N-sulfonylimines), as well as of N-selanylimines and N-tellanylimines and their oxidation derivatives. N-Sulfinylimines and N-sulfonylimines are important compounds which have raised considerable interest over the past 20 years.

Keywords: imines · sulfanylimines · sulfenimines · sulfinylimines · sulfonylimines · sulfinyl compounds · sulfonyl compounds · selanylimines · selenium compounds · tellurium compounds

Science of Synthesis Knowledge Updates 2012/1

Preface

Abstracts

Table of Contents

2.10.19 Organometallic Complexes of Titanium (Update 1, 2012)

P. Bertus, F. Boeda, and M. S. M. Pearson-Long

4.4.1 Product Subclass 1: Disilenes

A. Meltzer and D. Scheschkewitz

8.1.31 Functionalized Organolithiums by Ring Opening of Heterocycles

M. Yus and F. Foubelo

8.1.32 Syntheses Mediated by α-Lithiated Epoxides and Aziridines

L. Degennaro, F. M. Perna, and S. Florio

8.1.33 Transition-Metal-Catalyzed Carbon—Carbon Bond Formation with Organolithiums

G. Manolikakes

16.2.4 1,4-Dioxins and Benzo- and Dibenzo-Fused Derivatives (Update 2012)

S. M. Sakya and J. Yang

16.3.5 1,2-Dithiins (Update 2012)

F. K. Yoshimoto and Q. Li

17.4.1.5 Oxepins (Update 2012)

J. Hong

17.4.2.5 Benzoxepins (Update 2012)

J. Hong

17.4.5.5 Azepines, Cyclopentazepines, and Phosphorus Analogues (Update 2012)

J. E. Camp

17.4.6.10 Benzazepines and Their Group 15 Analogues (Update 2012)

J. E. Camp

19.5.17 Synthesis of Nitriles Using Cross-Coupling Reactions

D. M. Rudzinski and N. E. Leadbeater

27.25 Product Class 25: N-Sulfanyl-, N-Selanyl-, and N-Tellanylimines, and Their Oxidation Derivatives

F. Chemla, F. Ferreira, and A. Pérez-Luna

Author Index

Abbreviations

Table of Contents

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

2.10 Product Class 10: Organometallic Complexes of Titanium

2.10.19 Organometallic Complexes of Titanium (Update 1)

P. Bertus, F. Boeda, and M. S. M. Pearson-Long

2.10.19 Organometallic Complexes of Titanium (Update 1)

2.10.19.1 Titanium-Mediated Synthesis of Cyclopropyl Derivatives

2.10.19.1.1 Synthesis of Cyclopropanes without Heteroatom Substitution

2.10.19.1.1.1 Method 1: Synthesis from Thioacetals and Thioethers

2.10.19.1.1.2 Method 2: Synthesis from 1,1-Dihalides

2.10.19.1.2 Synthesis of Cyclopropanols

2.10.19.1.2.1 Synthesis from Carboxylic Acid Esters

2.10.19.1.2.1.1 Method 1: Use of Grignard Reagents without Ligand Exchange

2.10.19.1.2.1.2 Method 2: Use of Alkenes and Grignard Reagents

2.10.19.1.2.1.2.1 Variation 1: Bicyclo[n.1.0]alkan-1-ols from Unsaturated Carboxylic Acid Esters

2.10.19.1.2.1.2.2 Variation 2: 2-(Hydroxyalkyl)cyclopropanols from Unsaturated Carboxylic Acid Esters

2.10.19.1.2.1.2.3 Variation 3: Cyclopropanols from Carboxylic Acid Esters and Alkenes

2.10.19.1.2.2 Synthesis from Lactones and Other Acid Derivatives

2.10.19.1.2.2.1 Method 1: Synthesis from Lactones

2.10.19.1.2.2.2 Method 2: Synthesis from Other Acid Derivatives

2.10.19.1.3 Synthesis of Cyclopropanone Hemiacetals

2.10.19.1.3.1 Method 1: Synthesis from Cyclic Carbonates

2.10.19.1.4 Synthesis of Cyclopropylamines

2.10.19.1.4.1 Synthesis from Tertiary Amides

2.10.19.1.4.1.1 Method 1: Use of Grignard Reagents without Ligand Exchange

2.10.19.1.4.1.2 Method 2: Use of Organozinc Reagents without Ligand Exchange

2.10.19.1.4.1.3 Method 3: Use of Alkenes and Grignard Reagents

2.10.19.1.4.1.3.1 Variation 1: Bicyclo[n.1.0]alkan-1-amine Derivatives from Unsaturated Carboxylic Amides

2.10.19.1.4.1.3.2 Variation 2: 2-Azabicyclo[n.1.0]alkane Derivatives from Unsaturated Carboxylic Amides

2.10.19.1.4.1.3.3 Variation 3: Cyclopropylamines from Tertiary Amides and Alkenes

2.10.19.1.4.2 Synthesis from Nitriles

2.10.19.1.4.2.1 Method 1: Use of Grignard Reagents without Ligand Exchange

2.10.19.1.4.2.1.1 Variation 1: Alkylcyclopropylamines from Aliphatic Nitriles

2.10.19.1.4.2.1.2 Variation 2: 1-Aryl- and 1-Alkenylcyclopropylamines from Unsaturated Nitriles

2.10.19.1.4.2.2 Method 2: Use of Alkenes and Grignard Reagents

2.10.19.1.4.2.2.1 Variation 1: Bicyclic Cyclopropylamines from Unsaturated Nitriles

2.10.19.1.4.2.2.2 Variation 2: Cyclopropylamines from Nitriles and Alkenes

2.10.19.1.4.3 Synthesis from Imides

2.10.19.1.4.3.1 Method 1: Synthesis from Formimides or Cyclic Imides

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

4.4 Product Class 4: Silicon Compounds

4.4.1 Product Subclass 1: Disilenes

A. Meltzer and D. Scheschkewitz

4.4.1 Product Subclass 1: Disilenes

Synthesis of Product Subclass 1

4.4.1.1 Method 1: Synthesis of Acyclic Disilenes

4.4.1.1.1 Variation 1: Photolysis of Linear Trisilanes

4.4.1.1.2 Variation 2: Photolysis of Cyclotrisilanes

4.4.1.1.3 Variation 3: Reductive Dehalogenation of 1,1-Dihalosilanes

4.4.1.1.4 Variation 4: Reductive Dehalogenation of 1,2-Dihalodisilanes

4.4.1.1.5 Variation 5: Coupling of a 1,1-Dilithiosilane with Dihalosilanes

4.4.1.1.6 Variation 6: Coupling of Alkali Metal Disilenides with Electrophiles

4.4.1.1.7 Variation 7: Addition to Disilynes

4.4.1.1.8 Variation 8: Other Methods

4.4.1.2 Method 2: Synthesis of Tetrasilabutadienes

4.4.1.3 Method 3: Synthesis of Cyclic Disilenes

Volume 8: Compounds of Group 1 (Li…Cs)

8.1 Product Class 1: Lithium Compounds

8.1.31 Functionalized Organolithiums by Ring Opening of Heterocycles

M. Yus and F. Foubelo

8.1.31 Functionalized Organolithiums by Ring Opening of Heterocycles

8.1.31.1 Three-Membered Heterocycles

8.1.31.1.1 Method 1: Oxiranes

8.1.31.1.2 Method 2: Aziridines

8.1.31.2 Four-Membered Heterocycles

8.1.31.2.1 Method 1: Oxetanes

8.1.31.2.2 Method 2: Azetidines

8.1.31.2.3 Method 3: Thietanes

8.1.31.3 Five-Membered Heterocycles

8.1.31.3.1 Method 1: Oxygen-Containing Compounds

8.1.31.3.1.1 Variation 1: Tetrahydrofurans

8.1.31.3.1.2 Variation 2: Dioxolanes and Oxazolidines

8.1.31.3.1.3 Variation 3: Benzo[b]furans

8.1.31.3.1.4 Variation 4: Phthalans

8.1.31.3.2 Method 2: Nitrogen-Containing Compounds: Pyrrolidines

8.1.31.3.3 Method 3: Sulfur-Containing Compounds

8.1.31.4 Six-Membered Heterocycles

8.1.31.4.1 Method 1: Oxygen-Containing Compounds

8.1.31.4.1.1 Variation 1: Saturated Oxygen-Containing Heterocycles

8.1.31.4.1.2 Variation 2: 1-Benzopyrans

8.1.31.4.1.3 Variation 3: 2-Benzopyrans

8.1.31.4.2 Method 2: Nitrogen-Containing Compounds: Tetrahydroisoquinolines

8.1.31.4.3 Method 3: Sulfur-Containing Compounds

8.1.31.5 Seven-Membered Heterocycles

8.1.31.5.1 Method 1: Dibenzo Oxygen-, Nitrogen-, and Sulfur-Containing Seven-Membered Heterocycles

8.1.31.5.2 Method 2: Dinaphtho Oxygen- and Sulfur-Containing Seven-Membered Heterocycles

8.1.31.6 Other Heterocycles

8.1.31.6.1 Method 1: Benzodioxins, Benzoxathiins, Dihydrobenzodioxepins, and Dihydronaphthodioxocins

8.1.31.6.2 Method 2: Phenoxathiin, Phenothiazine, and Thianthrene

8.1.32 Syntheses Mediated by α-Lithiated Epoxides and Aziridines

L. Degennaro, F. M. Perna, and S. Florio

8.1.32 Syntheses Mediated by α-Lithiated Epoxides and Aziridines

8.1.32.1 Oxiranyllithiums

8.1.32.1.1 2-Alkyl-Substituted Oxiranyllithiums

8.1.32.1.1.1 Method 1: Reactions with Electrophiles

8.1.32.1.1.1.1 Variation 1: Stereospecific Trapping

8.1.32.1.1.1.2 Variation 2: Asymmetric Lithiation and Trapping of meso-Oxiranes

8.1.32.1.1.1.3 Variation 3: Coupling with Boronic Esters: Synthesis of Polyoxygenated Compounds

8.1.32.1.1.2 Method 2: Enantioselective α-Deprotonation–Rearrangement of meso-Oxiranes

8.1.32.1.1.2.1 Variation 1: Synthesis of Bicyclic Alcohols by Transannular C—H Insertion

8.1.32.1.1.2.2 Variation 2: Synthesis of (–)-Xialenon

8.1.32.1.1.2.3 Variation 3: Effect of Lewis Acids on Transannular C—H Insertion Reactions

8.1.32.1.1.2.4 Variation 4: Enantioselective Rearrangement of exo-Norbornene Oxide to Nortricyclanol

8.1.32.1.1.2.5 Variation 5: Transannular C—H Insertion in Lithiated 7-(tert-Butoxycarbonyl)-7-azanorbornene Oxide

8.1.32.1.1.3 Method 3: Construction of Nitrogen-Containing Heterocyclic Compounds by Desymmetrization of meso-Epoxides

8.1.32.1.1.4 Method 4: Synthesis of Alkenes by Reductive Alkylation

8.1.32.1.1.4.1 Variation 1: Synthesis of Enantioenriched Unsaturated Diols

8.1.32.1.1.4.2 Variation 2: Synthesis of Enamines from Terminal Epoxides

8.1.32.1.1.5 Method 5: Intramolecular Cyclopropanation of Unsaturated Terminal Epoxides (C=C Insertion)

8.1.32.1.1.5.1 Variation 1: Stereospecific Synthesis of Bicyclic Alcohols

8.1.32.1.1.5.2 Variation 2: Synthesis of (–)-Sabina Ketone

8.1.32.1.1.6 Method 6: Isomerization of α-Lithiated Epoxides to Ketones: 1,2-Hydrogen Migration

8.1.32.1.2 2-Aryl-Substituted Oxiranyllithiums

8.1.32.1.2.1 Method 1: Reactions of 2-Phenyloxiran-2-yllithiums

8.1.32.1.2.1.1 Variation 1: Stereospecific Trapping with Electrophiles

8.1.32.1.2.1.2 Variation 2: Stereoselective Synthesis of Antifungal Agents

8.1.32.1.2.2 Method 2: Reactions of 3-Substituted 2-Phenyloxiran-2-yllithiums

8.1.32.1.2.2.1 Variation 1: Of 3-Methyl-2-phenyloxiran-2-yllithiums

8.1.32.1.2.2.2 Variation 2: Of 2-Lithiated 2,3-Diphenyloxiranes

8.1.32.1.2.3 Method 3: Reactions of 2-Aryloxiran-2-yllithiums

8.1.32.1.2.4 Method 4: Stereoselective Synthesis of Cyclopropanes

8.1.32.1.2.5 Method 5: Stereoselective Synthesis of β,γ-Epoxyhydroxylamines and 4-(Hydroxyalkyl)-1,2-oxazetidines

8.1.32.1.2.6 Method 6: Stereocontrolled Synthesis of 1,2-Diols by Homologation of Boronic Esters with Lithiated 2-Phenyloxirane

8.1.32.1.2.7 Method 7: Oxiranyl Anion Methodology Using Microflow Systems

8.1.32.1.3 Lithiated Dihydrooxazol-2-yloxiranes

8.1.32.1.3.1 Method 1: Reactions of 2-Lithiated 2-(4,5-Dihydrooxazol-2-yl)oxiranes

8.1.32.1.3.1.1 Variation 1: Configurational Stability of α-Lithiated (4,5-Dihydrooxazol-2-yl)oxiranes: Trapping with Electrophiles

8.1.32.1.3.1.2 Variation 2: Synthesis of 2-Acyldihydrooxazoles

8.1.32.1.3.1.3 Variation 3: Synthesis of Cyclopropane-Fused γ-Lactones

8.1.32.1.3.1.4 Variation 4: Synthesis of α-Epoxy-β-amino Acids

8.1.32.1.3.2 Method 2: Reactions of 2-Lithiated 3-(4,5-Dihydrooxazol-2-yl)oxiranes

8.1.32.1.3.2.1 Variation 1: Configurational Stability of 2-Lithiated 3-(4,5-Dihydrooxazol-2-yl)oxiranes: Trapping with Electrophiles

8.1.32.1.3.2.2 Variation 2: Synthesis of α,β-Epoxy-γ-butyrolactones

8.1.32.1.3.2.3 Variation 3: Synthesis of α,β-Epoxy-γ-amino Acids and α,β-Epoxy-γ-butyrolactams

8.1.32.1.3.3 Method 3: 2-Lithiation of Terminal 3-(4,5-Dihydrooxazol-2-yl)oxiranes

8.1.32.1.4 2-Trifluoromethyl-Stabilized Oxiranyllithium

8.1.32.1.4.1 Method 1: 2-(Trifluoromethyl)oxiranyllithium: Stereospecific Trapping with Electrophiles

8.1.32.1.4.2 Method 2: 2-(Trifluoromethyl)oxiranyllithium as Precursor of the Oxiranylzinc

8.1.32.1.5 Lactone-Derived Oxiranyllithiums

8.1.32.1.5.1 Method 1: Reactions of Oxiranyllithiums Derived from α,β-Epoxy-γ-butyrolactones

8.1.32.1.6 Silyloxiranyllithiums

8.1.32.1.6.1 Method 1: Lithiation of 3-Vinyloxiran-2-ylsilanes

8.1.32.1.6.2 Method 2: Lithiation of 3-Alkyloxiran-2-ylsilanes

8.1.32.1.7 2-Sulfonyloxiranyllithiums

8.1.32.1.7.1 Method 1: 2-Sulfonyloxiranyllithiums: Configurational Stability and Trapping with Electrophiles

8.1.32.1.7.2 Method 2: Construction of Polycyclic Ethers

8.1.32.1.8 2-Lithiated 2-(Benzotriazol-1-yl)oxiranes

8.1.32.1.8.1 Method 1: Synthesis of 2-(Benzotriazol-1-yl)oxiranyllithiums with Subsequent Trapping

8.1.32.1.9 2-Lithiated 2-(Benzothiazol-2-yl)oxiranes

8.1.32.1.9.1 Method 1: Synthesis of 2-(Benzothiazol-2-yl)oxiranyllithiums with Subsequent Trapping

8.1.32.1.10 Oxiranyllithiums by Transmetalation

8.1.32.1.10.1 Method 1: Lithium–Tin Transmetalation

8.1.32.1.10.2 Method 2: Lithium–Aluminum and Lithium–Zirconium Transmetalation

8.1.32.1.10.2.1 Variation 1: Synthesis of Alkylated (Triphenylsilyl)alkenes: Reaction of a 2-Lithiated 2-(Triphenylsilyl)oxirane with Organoaluminum Reagents

8.1.32.1.10.2.2 Variation 2: Insertion of Metalated Epoxides into Zirconacycles

8.1.32.1.10.2.3 Variation 3: Insertion of Metalated Epoxynitriles into Chlorobis(η5-cyclopentadienyl)organozirconium Reagents

8.1.32.1.10.2.4 Variation 4: Insertion of 2-Lithiated 2-(Phenylsulfonyl)oxiranes into Alkenylchlorobis(η5-cyclopentadienyl)zirconium Reagents

8.1.32.1.11 Remotely Stabilized Lithiated Epoxides

8.1.32.1.11.1 Method 1: Remotely Stabilized Lithiated Epoxides: Reactions with Aldehydes

8.1.32.1.11.2 Method 2: Synthesis of Xylobovide

8.1.32.2 α-Lithiated Aziridines

8.1.32.2.1 Lithiation–Trapping Sequence of Aziridines with an Electron-Withdrawing Group at the Carbon Atom

8.1.32.2.1.1 Method 1: Synthesis of 1-Alkylaziridine-2-carboxylates

8.1.32.2.1.2 Method 2: Synthesis of 1-Alkylaziridine-2-carbothioates

8.1.32.2.1.3 Method 3: Reactions of 2-(4,5-Dihydrooxazol-2-yl)-Substituted 1-Phenylaziridines

8.1.32.2.1.4 Method 4: Reactions of 2,3-Dihetaryl-Substituted 1-Phenylaziridines

8.1.32.2.1.5 Method 5: Reactions of 2-(4,5-Dihydrooxazol-2-yl)-Substituted 1-Tritylaziridines

8.1.32.2.1.5.1 Variation 1: Synthesis of N-Tritylepimino-γ-butyrolactones

8.1.32.2.1.6 Method 6: Reactions of 2-(4,5-Dihydrooxazol-2-yl)-Substituted 1-Benzylaziridines

8.1.32.2.1.7 Method 7: Reactions of 2-(4,5-Dihydrooxazol-2-yl)-Substituted 1-(1-Phenylethyl)aziridines

8.1.32.2.1.8 Method 8: Synthesis of C-Substituted 1-Phenyl-2-sulfonylaziridines

8.1.32.2.2 Lithiation of Aziridines with an Electron-Withdrawing Group at Nitrogen

8.1.32.2.2.1 Method 1: C-Alkylation of 1-(tert-Butylsulfonyl)-2-phenylaziridine

8.1.32.2.2.1.1 Variation 1: Synthesis of 2-Substituted 1-(tert-Butylsulfonyl)-2-phenylaziridines Using Microreactor Technology

8.1.32.2.2.1.2 Variation 2: Synthesis of (tert-Butylsulfonyl)amino Alcohols

8.1.32.2.2.2 Method 2: Synthesis of 2-Alkyl-Substituted 1-(tert-Butylsulfonyl)-3-(trimethylsilyl)aziridines

8.1.32.2.2.3 Method 3: Synthesis of 2-Substituted 1-(tert-Butylsulfonyl)aziridines

8.1.32.2.2.3.1 Variation 1: Synthesis of 2-Substituted 1-(tert-Butylsulfonyl)aziridines Using Microreactor Technology

8.1.32.2.2.4 Method 4: Synthesis of trans-2,3-Disubstituted 1-(tert-Butylsulfonyl)aziridines

8.1.32.2.2.5 Method 5: Synthesis of C-Substituted 1-(2,4,6-Triisopropylphenylsulfonyl)aziridines

8.1.32.2.2.6 Method 6: Reductive Alkylation (or Alkylative Ring Opening) of 1-Sulfonylaziridinyllithiums

8.1.32.2.2.6.1 Variation 1: Synthesis of Allylic Sulfonamides

8.1.32.2.2.6.2 Variation 2: Synthesis of Alkynylamines

8.1.32.2.2.6.3 Variation 3: Allylic Amino Alcohols and Amino Ethers by Organolithium-Induced Alkylative Ring Opening of 1-Sulfonyl-Protected Aziridinyl Ethers

8.1.32.2.2.6.4 Variation 4: Allylic Amino Alcohols and Amino Ethers by Organolithium-Induced Alkylative Ring Opening of 1,4-Dimethoxybut-2-ene-Derived Aziridines

8.1.32.2.2.7 Method 7: Eliminative Dimerization of Lithiated 1-(tert-Butylsulfonyl)-aziridines

8.1.32.2.2.7.1 Variation 1: Synthesis of 2-Ene-1,4-diamines

8.1.32.2.2.8 Method 8: Intramolecular Cyclopropanation of Lithiated 1-(tert-Butylsulfonyl)aziridines

8.1.32.2.2.8.1 Variation 1: Synthesis of 2-Aminobicyclo[3.1.0]hexanes

8.1.32.2.2.9 Method 9: Lithiation of 1-(tert-Butoxycarbonyl)aziridines

8.1.32.2.2.9.1 Variation 1: Synthesis of 2-Silylaziridines

8.1.32.2.2.9.2 Variation 2: Synthesis of trans-Configured Aziridine-2-carboxylates

8.1.32.2.2.9.3 Variation 3: Synthesis of trans-Configured Aziridin-2-ylphosphonates

8.1.32.2.2.9.4 Variation 4: Synthesis of N-tert-Butoxycarbonyl 1,2-Amino Alcohols

8.1.32.2.3 Lithiation of Aziridines with an Electron-Donating Group on Nitrogen

8.1.32.2.3.1 Method 1: Synthesis of cis- and trans-Configured C-Substituted 1-Alkyl-2,3-diphenylaziridines

8.1.32.2.3.2 Method 2: Synthesis of C-Substituted 1-Alkyl-2-methyleneaziridines

8.1.32.2.3.2.1 Variation 1: Synthesis of Chiral Nonracemic C-Substituted 1-Alkyl-2-methyleneaziridines

8.1.32.2.3.3 Method 3: Synthesis of C-Substituted Aziridine–Borane Complexes

8.1.32.2.3.3.1 Variation 1: Of 1-[2-(tert-Butyldimethylsiloxy)ethyl]aziridine–Borane Complexes

8.1.32.2.3.3.2 Variation 2: Of 1-Alkyl-2-phenylaziridine–Borane Complexes

8.1.33 Transition-Metal-Catalyzed Carbon—Carbon Bond Formation with Organolithiums

G. Manolikakes

8.1.33 Transition-Metal-Catalyzed Carbon—Carbon Bond Formation with Organolithiums

8.1.33.1 Copper-Catalyzed Reactions

8.1.33.1.1 Method 1: Copper-Catalyzed Conjugate Addition

8.1.33.1.2 Method 2: Copper-Catalyzed Alkylation

8.1.33.1.2.1 Variation 1: Copper-Catalyzed Asymmetric Allylation

8.1.33.1.3 Method 3: Copper-Catalyzed Coupling of Organolithium Reagents with α-Lithiated Cyclic Enol Ethers

8.1.33.2 Palladium-Catalyzed Reactions

8.1.33.2.1 Method 1: Palladium-Catalyzed Cross-Coupling Reactions with Aryl and Vinyl Halides

8.1.33.2.2 Method 2: Palladium-Catalyzed Coupling Reaction of Aryllithium Reagents with 1-Bromo-2-methylbut-3-en-2-ol

8.1.33.3 Iron-Catalyzed Reactions

8.1.33.3.1 Method 1: Iron-Catalyzed Cross-Coupling Reactions

8.1.33.3.2 Method 2: Iron-Catalyzed Carbolithiation of Alkynes

Volume 16: Six-Membered Hetarenes with Two Identical Heteroatoms

16.2 Product Class 2: 1,4-Dioxins and Benzo- and Dibenzo-Fused Derivatives

16.2.4 1,4-Dioxins and Benzo- and Dibenzo-Fused Derivatives

S. M. Sakya and J. Yang

16.2.4 1,4-Dioxins and Benzo- and Dibenzo-Fused Derivatives

16.2.4.1 Synthesis by Ring-Closure Reactions

16.2.4.1.1 By Formation of Two O—C Bonds

16.2.4.1.1.1 Fragments O—C—C—O and C—C

16.2.4.1.1.1.1 Method 1: Dibenzo[b,e][1,4]dioxins by Base-Induced Coupling of Benzene-1,2-diols with Activated Fluorobenzenes

16.2.4.1.1.2 Fragments O—C—C and O—C—C

16.2.4.1.1.2.1 Method 1: Substituted 1,4-Dioxins by Reaction of Methyl 3-Chloro-2-oxo-3-phenylpropanoate with Potassium Phthalimide or Sodium Imidazolide

16.2.4.1.2 By Formation of One C—C Bond

16.2.4.1.2.1 Fragment C—O—C—C—O—C

16.2.4.1.2.1.1 Method 1: 1,4-Benzodioxins by Ring-Closing Metathesis of Divinyl Ethers

16.2.4.2 Aromatization

16.2.4.2.1 Method 1: 1,4-Benzodioxins by Isomerization of Exocyclic Alkenes

16.2.4.2.2 Method 2: Dibenzo[b,e][1,4]dioxins from the Diels–Alder Reactions of 1,4-Benzodioxin and Benzo[b]furo[3,4-e][1,4]dioxins

16.2.4.3 Synthesis by Substituent Modification

16.2.4.3.1 Substitution of Existing Substituents

16.2.4.3.1.1 Of Hydrogen

16.2.4.3.1.1.1 Method 1: Vilsmeier Reaction of 2-Phenyl-1,4-benzodioxin

16.2.4.3.1.1.2 Method 2: Diels–Alder Reaction of 2,2′-Bi-1,4-benzodioxin

16.2.4.3.1.2 Of Metals

16.2.4.3.1.2.1 Method 1: Stille Coupling of 2-(Trimethylstannyl)-1,4-benzodioxin with a Bromoalkene

16.2.4.3.1.3 Of Halogens

16.2.4.3.1.3.1 Method 1: Alkylation of 2-Bromo-1,4-benzodioxin by Lithium–Halogen Exchange

16.2.4.3.2 Modification of Substituents

16.2.4.3.2.1 Method 1: Alkylation of 1,4-Benzodioxin-6,7-dicarbaldehyde

16.3 Product Class 3: 1,2-Dithiins

16.3.5 1,2-Dithiins

F. K. Yoshimoto and Q. Li

16.3.5 1,2-Dithiins

16.3.5.1 Synthesis by Ring-Closure Reactions

16.3.5.1.1 By Formation of One S—S and Two S—C Bonds

16.3.5.1.1.1 Fragment C—C—C—C and Two S Fragments

16.3.5.1.1.1.1 Method 1: Addition of Sulfur to 6-Nitroperylo[1,12-bcd]thiophene

16.3.5.1.1.1.2 Method 2: Addition of Sulfur to 2-(Trimethylsiloxy)buta-1,3-diene

16.3.5.1.2 By Formation of One S—S and One S—C Bond

16.3.5.1.2.1 Fragments S—C—C—C—C and S

16.3.5.1.2.1.1 Method 1: Reaction of 2-(2-Phenylvinyl)-3-vinylthiirane Promoted by Acetonitrile(pentacarbonyl)tungsten(0)

16.3.5.1.3 By Formation of One S—S and One C—C Bond

16.3.5.1.3.1 Fragments S—C—C—C and S—C

16.3.5.1.3.1.1 Method 1: Thermal Dimerization of α,β-Unsaturated β-Arylsulfanyl Thioketones

16.3.5.1.3.1.2 Method 2: Cobalt(II)-Mediated Dimerization of α,β-Unsaturated Thioacylsilanes

16.3.5.1.3.1.3 Method 3: Dimerization via Diels–Alder Reaction of Thioaldehydes

16.3.5.1.3.2 Fragments S—C—C and S—C—C

16.3.5.1.3.2.1 Method 1: Thionation–Dimerization of 1,3-Dihydro-2H-indol-2-one

16.3.5.1.3.2.2 Method 2: Manganese(IV) Oxide Promoted Oxidative Dimerization

16.3.5.1.4 By Formation of One S—S Bond

16.3.5.1.4.1 Fragment S—C—C—C—C—S

16.3.5.1.4.1.1 Method 1: Polycyclization of Diynes

16.3.5.1.4.1.2 Method 2: N-Bromosuccinimide-Induced Ring Formation

16.3.5.1.4.1.3 Method 3: Cyclization of Dibromides Promoted by Phase-Transfer Catalysts

16.3.5.1.4.1.4 Method 4: Cyclization of Dichlorides by Tandem Michael–Nucleophilic Substitution Processes

16.3.5.1.5 By Formation of One C—C Bond

16.3.5.1.5.1 Fragment C—C—S—S—C—C

16.3.5.1.5.1.1 Method 1: Cyclization via Ring-Closing Metathesis of Alkenes

16.3.5.2 Synthesis by Ring Transformation

16.3.5.2.1 Method 1: Ring Contraction Promoted by Photolysis

16.3.5.3 Synthesis by Other Methods

16.3.5.3.1 Method 1: Rearrangement Promoted by Photolysis

16.3.5.4 Applications of 1,2-Dithiins in Organic Synthesis

16.3.5.4.1 Reaction with Transition Metals

16.3.5.4.1.1 Method 1: Reaction with Organometallic Complexes

16.3.5.4.1.2 Method 2: Reaction with Copper Metal

16.3.5.4.2 Reaction with Lewis Acids

16.3.5.4.2.1 Method 1: Reaction Promoted by Aluminum Trichloride

16.3.5.4.2.2 Method 2: Reaction Promoted by Boron Trifluoride

16.3.5.4.3 Reaction with Diazo Compounds

16.3.5.4.3.1 Method 1: Reaction Promoted by Rhodium(II) Acetate

16.3.5.4.3.2 Method 2: Reaction Promoted by Copper(I) Chloride

16.3.5.4.4 Reaction with Alkynes

16.3.5.4.4.1 Method 1: Reaction Promoted by Bis(acetylacetonato)nickel(II)

16.3.5.4.5 Reaction with Enzymes

16.3.5.4.5.1 Method 1: Reaction with a Toluene Dioxygenase

Volume 17: Six-Membered Hetarenes with Two Unlike or More than Two Heteroatoms and Fully Unsaturated Larger-Ring Heterocycles

17.4 Product Class 4: Seven-Membered Hetarenes with One Heteroatom

17.4.1.5 Oxepins

J. Hong

17.4.1.5 Oxepins

17.4.1.5.1 Synthesis by Ring-Closure Reactions

17.4.1.5.1.1 By Formation of One O—C and One C—C Bond

17.4.1.5.1.1.1 Method 1: From a 3-(Dimethylamino)-1-phenylprop-2-en-1-one and Arylidenemalononitriles

17.4.1.5.2 Synthesis by Ring Transformation

17.4.1.5.2.1 Method 1: By Valence Isomerization of 3-Oxaquadricyclanes

17.4.1.5.2.2 Method 2: By Valence Isomerization of 7-Oxanorbornadienes

17.4.1.5.2.3 Method 3: By Ring Enlargement of Furans with Diethyl Acetylenedicarboxylate

17.4.1.5.2.4 Method 4: By Valence Isomerization of Benzene Oxide

17.4.1.5.2.5 Method 5: By Ring Enlargement of a 2-[(Prop-2-ynyloxy)methyl]furan

17.4.1.5.2.6 Method 6: By Ring Enlargement of a Cyclohexa-2,5-diene-1,4-diol via SN2′ Reaction

17.4.1.5.3 Aromatization

17.4.1.5.3.1 Method 1: By Dehydrogenation

17.4.2.5 Benzoxepins

J. Hong

17.4.2.5 Benzoxepins

17.4.2.5.1 Synthesis by Ring-Closure Reactions

17.4.2.5.1.1 By Formation of One O—C and Two C—C Bonds

17.4.2.5.1.1.1 Method 1: From a Betaine and Diethyl Acetylenedicarboxylate

17.4.2.5.1.2 By Formation of One O—C and One C—C Bond

17.4.2.5.1.2.1 Method 1: From Dinitrotoluenes and Salicylaldehydes

17.4.2.5.1.3 By Formation of Two C—C Bonds

17.4.2.5.1.3.1 Method 1: By Annulation of a Boronic Acid with Dimethyl Acetylenedicarboxylate

17.4.2.5.1.4 By Formation of One O—C Bond

17.4.2.5.1.4.1 Method 1: From 2-Alkyl-3-[2-(iodoethynyl)phenyl]oxiranes

17.4.2.5.1.4.2 Method 2: By Cyclization of 2-[2-(2-Bromophenyl)vinyl]phenols and Related Compounds

17.4.2.5.1.5 By Formation of One C—C Bond

17.4.2.5.1.5.1 Method 1: By Base-Catalyzed Cyclocondensation of Methyl (2E)-4-(2-Formylphenoxy)but-2-enoate

17.4.2.5.2 Synthesis by Ring Transformation

17.4.2.5.2.1 By Ring Enlargement

17.4.2.5.2.1.1 Method 1: Of a Benzofuran with 1-Phenyl-2-tosylacetylene

17.4.2.5.2.1.2 Method 2: Of Xanthenes by Dehydration

17.4.2.5.2.1.3 Method 3: Of 2-Diazo-3′,6′-bis(diethylamino)spiro[indene-1,9′-xanthen]-3(2H)-one (Rhodamine BBN)

17.4.2.5.2.1.4 Method 4: Of a Dihydrofuran by Rearrangement

17.4.2.5.2.1.5 Method 5: Of Tetrahydrobenzo[b]cyclopropa[e]pyran-1-carboxylates

17.4.2.5.3 Synthesis by Substituent Modification

17.4.2.5.3.1 Substitution of Existing Substituents

17.4.2.5.3.1.1 Method 1: Condensation of Dibenz[b,f]oxepin-10(11H)-one with 3-Methylbut-2-enal

17.4.2.5.3.1.2 Method 2: Vilsmeier-Type Chloroformylation of Dibenz[b,f]oxepin-10(11H)-ones

17.4.2.5.3.1.3 Method 3: Reaction of Dibenz[b,f]oxepin-10(11H)-one with Base and Carbon Disulfide/Iodomethane or Dimethyl Trithiocarbonate; Annulation of the Products

17.4.2.5.3.1.4 Method 4: 1H-Dibenz[2,3:6,7]oxepino[4,5-b]pyrroles by Annulation of 11-(Hydrazonoethylidene)dibenz[b,f]oxepin-10-ones

17.4.2.5.3.1.5 Method 5: 1H-Dibenz[2,3:6,7]oxepino[4,5-d]imidazoles by Oxidation/Annulation of Dibenz[b,f]oxepin-10(11H)-ones

17.4.5.5 Azepines, Cyclopentazepines, and Phosphorus Analogues

J. E. Camp

17.4.5.5 Azepines, Cyclopentazepines, and Phosphorus Analogues

17.4.5.5.1 Synthesis by Ring-Closure Reactions

17.4.5.5.1.1 By Formation of One C—C Bond

17.4.5.5.1.1.1 Method 1: Azepine Formation via Copper-Mediated Cyclization of 2-Azahepta-2,4-dien-6-ynyl Anions

17.4.5.5.1.1.2 Method 2: 3H-Azepines via Deprotonation of 2-Aza-1,3,5-trienes

17.4.5.5.2 Synthesis by Ring Transformation

17.4.5.5.2.1 By Ring Enlargement

17.4.5.5.2.1.1 Of Five-Membered Heterocycles

17.4.5.5.2.1.1.1 Method 1: Thermal Isomerization of 3-Azaquadricyclanes

17.4.5.5.2.1.1.1.1 Variation 1: Thermal Isomerization of a Cyclobutane 3-Azaquadricyclane

17.4.5.5.2.1.2 Of Six-Membered Arenes

17.4.5.5.2.1.2.1 Method 1: Intramolecular Insertion of Arylnitrenes

17.4.5.5.2.1.2.1.1 Variation 1: Photolytic Decomposition of Aryl Azides

17.4.5.5.2.1.2.1.2 Variation 2: Rearrangement of Nitroarenes

17.4.5.5.3 Synthesis by Substituent Modification

17.4.5.5.3.1 Substitution of Existing Substituents

17.4.5.5.3.1.1 Of Hydrogen

17.4.5.5.3.1.1.1 Method 1: Tautomerization

17.4.5.5.3.1.1.1.1 Variation 1: Rearrangement of 2H-to 3H-Azepines

17.4.5.5.3.1.1.2 Method 2: C-Halogenation

17.4.5.5.3.1.1.2.1 Variation 1: C-Halogenation with N-Bromosuccinimide

17.4.5.5.3.1.1.3 Method 3: C-Alkylsulfanylation

17.4.5.5.3.1.1.4 Method 4: C-Amination

17.4.5.5.3.1.1.5 Method 5: C-Alkoxylation

17.4.5.5.3.1.2 Of Heteroatoms

17.4.5.5.3.1.2.1 Method 1: Of Alkoxy Groups

17.4.5.5.3.1.2.1.1 Variation 1: Of Activated Organooxy Groups

17.4.6.10 Benzazepines and Their Group 15 Analogues

J. E. Camp

17.4.6.10 Benzazepines and Their Group 15 Analogues

17.4.6.10.1 1H-1-Benzazepines

17.4.6.10.1.1 Synthesis by Ring-Closure Reactions

17.4.6.10.1.1.1 By Formation of Two C—C Bonds and One C—N Bond

17.4.6.10.1.1.1.1 Method 1: By Condensation between 2-Fluoroaniline and Aryl Methyl Ketones

17.4.6.10.1.1.2 By Formation of One N—C and One C—C Bond

17.4.6.10.1.1.2.1 Method 1: From 5-[(E)-(2-Dimethylamino)vinyl]-2,1,3-benzoselenadiazol-4-amine

17.4.6.10.1.1.3 By Formation of Two C—C Bonds

17.4.6.10.1.1.3.1 Method 1: By Thermal Cycloaddition of Dimethyl Acetylenedicarboxylate with Methylindoles

17.4.6.10.1.1.3.2 Method 2: From the Reaction of Phosphonium Ylides

17.4.6.10.1.1.4 By Formation of One C—N Bond

17.4.6.10.1.1.4.1 Method 1: By Intramolecular Addition of Anilines

17.4.6.10.1.2 Synthesis by Ring Transformation

17.4.6.10.1.2.1 By Ring Enlargement

17.4.6.10.1.2.1.1 Method 1: By Ring Expansion of Activated Quinolines

17.4.6.10.2 2-Benzazepines

17.4.6.10.2.1 Synthesis by Ring-Closure Reactions

17.4.6.10.2.1.1 By Formation of One N—C and One C—C Bond

17.4.6.10.2.1.1.1 Method 1: By a Tandem Ritter/Houben–Hoesch Process

17.4.6.10.2.1.1.2 Method 2: By Reaction of 4-Chloro-2-oxo-2H-1-benzopyran-3-carbaldehyde with Benzylamines

17.4.6.10.2.1.2 By Formation of One C—C Bond

17.4.6.10.2.1.2.1 Method 1: By Cyclization of 2-Azahepta-2,4-dien-6-ynyls

17.4.6.10.3 5H-Dibenz[b,d]azepines

17.4.6.10.3.1 Synthesis by Substituent Modification

17.4.6.10.3.1.1 Method 1: By Rhodium-Catalyzed Decarbonylative Cycloaddition

17.4.6.10.4 11H-Dibenz[b,e]azepines

17.4.6.10.4.1 Synthesis by Ring-Closure Reactions

17.4.6.10.4.1.1 By Formation of One N—C and One C—C Bond

17.4.6.10.4.1.1.1 Method 1: By Condensation of 2,6-Dimethylaniline with Phenanthrene-9,10-dione

17.4.6.10.4.1.2 By Formation of One C—C Bond

17.4.6.10.4.1.2.1 Method 1: By Bischler–Napieralski Cyclodehydration of N-(2-Benzylphenyl)-2-chloroacetamide

17.4.6.10.4.1.2.2 Method 2: By Friedel–Crafts Cyclization of 2-Allyl-N-benzylanilines

17.4.6.10.4.1.2.3 Method 3: By Acid-Mediated Cyclization of Benzylic Alcohols

17.4.6.10.5 5H-Dibenz[c,e]azepines

17.4.6.10.5.1 Synthesis by Ring-Closure Reactions

17.4.6.10.5.1.1 By Formation of Two N—C Bonds

17.4.6.10.5.1.1.1 Method 1: Ring Closure of 2,2′-Difunctionalized Biaryls with Chiral Amines under Acidic Conditions

17.4.6.10.6 5H-Dibenz[b,f]azepines

17.4.6.10.6.1 Synthesis by Ring-Closure Reactions

17.4.6.10.6.1.1 By Formation of One C—C and One C—N Bond

17.4.6.10.6.1.1.1 Method 1: By a Palladium-Catalyzed Tandem Process

17.4.6.10.6.1.2 By Formation of One C—C Bond

17.4.6.10.6.1.2.1 Method 1: By Palladium-Catalyzed Intramolecular Amination

17.4.6.10.6.1.2.2 Method 2: Friedel–Crafts Acylation

17.4.6.10.6.2 Synthesis by Ring Transformation

17.4.6.10.6.2.1 By Ring Enlargement

17.4.6.10.6.2.1.1 Method 1: From 1-Arylindoles

17.4.6.10.6.2.1.1.1 Variation 1: Ring Expansion of 6-Methoxy-1-phenylindole

17.4.6.10.6.3 Aromatization

17.4.6.10.6.3.1 Method 1: Bromination–Dehydrobromination

17.4.6.10.6.3.1.1 Variation 1: Dehalogenation of 5-Acetyl-10,11-dibromo-10,11-dihydro-5H-dibenz[b,f]azepine with 1,2-Diphenylethane-1,2-diyldisodium

17.4.6.10.6.4 Synthesis by Substituent Modification

17.4.6.10.6.4.1 Substitution of Hydrogen

17.4.6.10.6.4.1.1 Method 1: N-Alkylation of 5H-Dibenz[b,f]azepines

17.4.6.10.6.4.1.1.1 Variation 1: By Phase-Transfer Catalysis

17.4.6.10.6.4.1.2 Method 2: N-Acylation of 5H-Dibenz[b,f]azepines

17.4.6.10.6.4.1.2.1 Variation 1: By Reaction with Acid Chlorides

17.4.6.10.6.4.1.2.2 Variation 2: By Reaction with Dimethyl Carbonate

17.4.6.10.6.4.1.2.3 Variation 3: By Palladium-Mediated Carbonylative Benzoylation of 5H-Dibenz[b,f]azepine

17.4.6.10.6.4.1.2.4 Variation 4: By Reaction with Trifluoroacetic Anhydride

17.4.6.10.6.4.1.2.5 Variation 5: N-Formylation of 5H-Dibenz[b,f]azepine

17.4.6.10.6.4.1.3 Method 3: Chlorocarbonylation of 5H-Dibenz[b,f]azepines with Phosgene Equivalents

17.4.6.10.6.4.1.3.1 Variation 1: N-Acylation of 5H-Dibenz[b,f]azepines Followed by Amination

17.4.6.10.6.4.1.4 Method 4: Formation of N—P Bonds

17.4.6.10.6.4.1.5 Method 5: By a Methoxy Group

17.4.6.10.6.4.1.6 Method 6: Palladium-Catalyzed N-Arylation

17.4.6.10.6.4.2 Substitution of Heteroatoms

17.4.6.10.6.4.2.1 Method 1: Substitution of Bromine

17.4.6.10.6.4.3 Addition Reactions

17.4.6.10.6.4.3.1 Method 1: Formation of Epoxides by Oxidation

17.4.6.10.6.4.3.2 Method 2: Formation of Diols by Oxidation

17.4.6.10.6.4.3.3 Method 3: [2 + 2] Photodimerization of 5-Acetyl-5H-dibenz[b,f]azepine

17.4.6.10.6.4.3.3.1 Variation 1: [2 + 2] Photodimerization of 5H-Dibenz[b,f]azepine Derivatives

17.4.6.10.7 9H-Tribenz[b,d,f]azepines

17.4.6.10.7.1 Synthesis by Ring-Closure Reactions

17.4.6.10.7.1.1 By Formation of One N—C Bond

17.4.6.10.7.1.1.1 Method 1: From N-(2-Bromophenyl)biphenyl-2-amine

17.4.6.10.8 Other Group 15 Benzoheterepins

17.4.6.10.8.1 3-Benzoheterepins

17.4.6.10.8.1.1 Synthesis by Ring-Closure Reactions

17.4.6.10.8.1.1.1 By Formation of Two Heteroatom—Carbon Bonds

17.4.6.10.8.1.1.1.1 Method 1: Potassium Hydroxide Catalyzed Addition of Metal Complexed Phosphines to 1,2-Diethynylbenzene

17.4.6.10.8.1.1.1.2 Method 2: From 1,2-Bis[(Z)-2-bromovinyl]benzenes and Metal Halides

Volume 19: Three Carbon—Heteroatom Bonds: Nitriles, Isocyanides, and Derivatives

19.5 Product Class 5: Nitriles

19.5.17 Synthesis of Nitriles Using Cross-Coupling Reactions

D. M. Rudzinski and N. E. Leadbeater

19.5.17 Synthesis of Nitriles Using Cross-Coupling Reactions

19.5.17.1 Preparation of Aryl Cyanides

19.5.17.1.1 Method 1: Use of Alkali Metal Cyanides

19.5.17.1.1.1 Variation 1: Palladium-Catalyzed Approaches

19.5.17.1.1.2 Variation 2: Copper-Catalyzed Approaches

19.5.17.1.1.3 Variation 3: Dual Palladium- and Copper-Catalyzed Approaches

19.5.17.1.1.4 Variation 4: Nickel-Catalyzed Approaches

19.5.17.1.2 Method 2: Use of Zinc(II) Cyanide

19.5.17.1.2.1 Variation 1: Palladium-Catalyzed Approaches: Homogeneous Catalysis

19.5.17.1.2.2 Variation 2: Palladium-Catalyzed Approaches: Heterogeneous Catalysis

19.5.17.1.2.3 Variation 3: Copper-Mediated Approaches

19.5.17.1.3 Method 3: Use of Nickel(II) Cyanide as the Cyanide Source

19.5.17.1.4 Method 4: Use of Copper(I) Cyanide as the Cyanide Source

19.5.17.1.5 Method 5: Use of Potassium Hexacyanoferrate(II) as the Cyanide Source

19.5.17.1.5.1 Variation 1: Palladium-Catalyzed Approaches: Homogeneous Catalysis

19.5.17.1.5.2 Variation 2: Palladium-Catalyzed Approaches: Heterogeneous Catalysis

19.5.17.1.5.3 Variation 3: Copper-Catalyzed Approaches

19.5.17.1.5.4 Variation 4: Dual Palladium- and Copper-Catalyzed Approaches

19.5.17.1.6 Method 6: Use of Organic Cyanide Sources

19.5.17.1.6.1 Variation 1: Use of Cyanohydrins

19.5.17.1.6.2 Variation 2: Use of Trimethylsilyl Cyanide

19.5.17.1.6.3 Variation 3: Use of N-Cyano-N-phenyl-4-toluenesulfonamide

19.5.17.1.7 Method 7: In Situ Generation of Cyanide from Non-Cyanide-Containing Precursors

19.5.17.2 Preparation of Hetaryl Cyanides

19.5.17.2.1 Method 1: Palladium-Catalyzed Coupling Reactions

19.5.17.2.2 Method 2: Copper-Catalyzed Coupling Reactions

19.5.17.2.3 Method 3: Dual Palladium- and Copper-Catalyzed Approaches

19.5.17.3 Preparation of Vinyl Cyanides

19.5.17.3.1 Method 1: Cyanation of Vinyl Halides and Vinylboronic Acids

Volume 27: Heteroatom Analogues of Aldehydes and Ketones

27.25 Product Class 25: N-Sulfanyl-, N-Selanyl-, and N-Tellanylimines, and Their Oxidation Derivatives

F. Chemla, F. Ferreira, and A. Pérez-Luna

27.25 Product Class 25: N-Sulfanyl-, N-Selanyl-, and N-Tellanylimines, and Their Oxidation Derivatives

27.25.1 Product Subclass 1: N-Sulfanylimines

27.25.1.1 Synthesis of Product Subclass 1

27.25.1.1.1 Method 1: Synthesis from Aldehydes or Ketones

27.25.1.1.1.1 Variation 1: From Ammonia and a Thiol

27.25.1.1.1.2 Variation 2: From Ammonia and a Disulfide

27.25.1.1.1.3 Variation 3: From N,N-Bis(trimethylsilyl)sulfenamides

27.25.1.1.1.4 Variation 4: From Sulfenamides

27.25.1.1.2 Method 2: Synthesis from Imines and Imine Derivatives

27.25.1.1.2.1 Variation 1: From N-Unsubstituted Imines

27.25.1.1.2.2 Variation 2: From Oximes

27.25.1.1.2.3 Variation 3: From Oxime Thiocarbamates

27.25.1.1.2.4 Variation 4: From O-Tosyloximes

27.25.1.1.2.5 Variation 5: From N-Chloroimines

27.25.1.1.3 Method 3: Synthesis from α-Aminoalkanoates

27.25.1.1.4 Method 4: Synthesis from Sulfinamides

27.25.1.1.5 Method 5: Synthesis from Nitro Compounds

27.25.2 Product Subclass 2: N-Sulfinylimines

27.25.2.1 Synthesis of Product Subclass 2

27.25.2.1.1 Method 1: Synthesis by Oxidation of N-Sulfanylimines

27.25.2.1.2 Method 2: Synthesis from N-Metalated Imines

27.25.2.1.2.1 Variation 1: From Sulfinate Esters

27.25.2.1.2.2 Variation 2: From a Cyclic Sulfinamide

27.25.2.1.3 Method 3: Synthesis from Ortho Esters

27.25.2.1.4 Method 4: Synthesis from an Aldehyde Hydrate

27.25.2.1.5 Method 5: Synthesis from Carbonyl Derivatives

27.25.2.1.5.1 Variation 1: From 1,2,3-Oxathiazolidine 2-Oxides

27.25.2.1.5.2 Variation 2: From Sulfinate Esters

27.25.2.1.5.3 Variation 3: From an N-Sulfinylbornane-10,2-sultam

27.25.2.1.5.4 Variation 4: From Sulfinamides

27.25.2.1.5.5 Variation 5: From a Phosphazene

27.25.2.1.6 Method 6: Synthesis from Sulfoximides

27.25.2.1.7 Method 7: Synthesis from Other N-Sulfinylimines

27.25.2.2 Applications of Product Subclass 2 in Organic Synthesis

27.25.3 Product Subclass 3: N-Sulfonylimines

27.25.3.1 Synthesis of Products of Subclass 3

27.25.3.1.1 Method 1: Synthesis from Acetals

27.25.3.1.1.1 Variation 1: From O,O-Acetals and Sulfonamides

27.25.3.1.1.2 Variation 2: From N-[(Arylsulfonyl)methyl]arenesulfonamides

27.25.3.1.2 Method 2: Synthesis from Alkenes and Allenes

27.25.3.1.2.1 Variation 1: By Oxidative Amination

27.25.3.1.2.2 Variation 2: From N,N-Dihalosulfonamides

27.25.3.1.2.3 Variation 3: From Sulfonyl Azides

27.25.3.1.2.4 Variation 4: From Oxazolidinones

27.25.3.1.3 Method 3: Synthesis from Alkynes

27.25.3.1.3.1 Variation 1: By a Hydroamination Reaction

27.25.3.1.3.2 Variation 2: From Sulfonyl Azides

27.25.3.1.3.3 Variation 3: Through Iminobismuthane Addition

27.25.3.1.4 Method 4: Synthesis from Aziridines

27.25.3.1.5 Method 5: Synthesis from Carbonyl Compounds

27.25.3.1.5.1 Variation 1: From Sulfonamides

27.25.3.1.5.2 Variation 2: From Isocyanates

27.25.3.1.5.3 Variation 3: From N-Sulfinylsulfonamides

27.25.3.1.5.4 Variation 4: From Chloramine-T

27.25.3.1.6 Method 6: Synthesis from Other Imines

27.25.3.1.6.1 Variation 1: From Oximes

27.25.3.1.6.2 Variation 2: From N-(Trimethylsilyl)imines

27.25.3.1.6.3 Variation 3: From N-Sulfanylimines

27.25.3.1.6.4 Variation 4: From N-Sulfinylimines

27.25.3.1.6.5 Variation 5: From Imidoyl Chlorides

27.25.3.1.7 Method 7: Synthesis from Sulfimides

27.25.3.1.8 Method 8: Synthesis by Oxidation of N-Sulfonylanilines

27.25.3.1.9 Method 9: Synthesis from N-Sulfonylamides

27.25.3.2 Applications of Product Subclass 3 in Organic Synthesis

27.25.4 Product Subclass 4: N-Selanylimines

27.25.4.1 Synthesis of Product Subclass 4

27.25.4.1.1 Method 1: Synthesis from N-Unsubstituted Imines

27.25.4.1.2 Method 2: Synthesis by Oxidation of Phenols

27.25.4.1.3 Method 3: Synthesis from N-Selenamides

27.25.5 Product Subclass 5: N-Seleninylimines and Related Compounds

27.25.5.1 Synthesis of Product Subclass 5

27.25.5.1.1 Method 1: Synthesis from Imines and Imine Derivatives

27.25.5.1.1.1 Variation 1: From Imines

27.25.5.1.1.2 Variation 2: From N-Chloroimines

27.25.6 Product Subclass 6: N-Tellanylimines

27.25.6.1 Synthesis of Product Subclass 6

27.25.6.1.1 Method 1: From N-Metalloimines

27.25.6.1.2 Method 2: From Pentafluorotellurium Isocyanate

Author Index

Abbreviations

2.10.19 Organometallic Complexes of Titanium (Update 1, 2012)

P. Bertus, F. Boeda, and M. S. M. Pearson-Long

2.10.19.1 Titanium-Mediated Synthesis of Cyclopropyl Derivatives

The cyclopropane ring is unique among carbocycles, in both its properties and reactivity, due to its inherent ring strain.[1,2] Thus, cyclopropane derivatives are of great interest for chemists and biochemists since they are used as building blocks or synthetic intermediates and are also present in many biologically active molecules.[3–6]

Until recently, the synthetic routes to heterosubstituted cyclopropanes (such as cyclopropanols and cyclopropylamines) were rather limited.[1,5] The discovery, by O. G. Kulinkovich and co-workers, that titanium(IV) isopropoxide can promote the synthesis of cyclopropanols from carboxylic acid esters and Grignard reagents (▶ Scheme 1) marked the beginning of intense research based on dialkoxytitanacyclopropane reagents and is the subject of several review articles.[7–12]

▶ Scheme 1 Preparation of Cyclopropanols from Carboxylic Acid Esters

Nowadays, the Kulinkovich reaction, as well as variants using carboxylic amides or nitriles (▶ Scheme 2), has become the most widely used method to synthesize cyclopropanols and cyclopropylamines. This success is due to the great functional group compatibility, to the extension of the method, especially by the use of terminal alkenes as coupling partners, and, obviously, to the low cost and easy availability of the reagents.

▶ Scheme 2 Preparation of Cyclopropylamines from Amides and Nitriles

The most widely used reagent for these transformations, titanium(IV) isopropoxide, [Ti(OiPr)4], is indeed commercially available in large quantities, and the two other derived reagents, chlorotriisopropoxytitanium(IV) [TiCl(OiPr)3] and triisopropoxy(methyl)titanium(IV) [TiMe(OiPr)3], are commercially available or easily accessible in a few steps.[13]

In addition to the synthesis of monocyclic cyclopropanols or cyclopropylamines, a large array of fused or spiro polycyclic compounds containing a three-membered ring are also directly accessible.

Non-heterosubstituted cyclopropane derivatives (including alkenyl- and alkynylcyclopropanes) have also been prepared using titanium reagents, but by other methods. Titanocene-derived reagents, generated in situ from commercially available dichlorobis(η5-cyclopentadienyl)titanium(IV) (titanocene dichloride), are able to convert thioacetals (or 1,1-dihalides) and alkenes into three-membered rings.[14]

2.10.19.1.1 Synthesis of Cyclopropanes without Heteroatom Substitution

2.10.19.1.1.1 Method 1: Synthesis from Thioacetals and Thioethers

Conversion of aldehydes into their corresponding thioacetals is a well-known process in organic synthesis. Thus, the titanocene(II)-promoted reaction of thioacetals with a vinylic partner represents an elegant process for the overall conversion of aldehydes into cyclopropanes.[15] In such a way, bis(η5-cyclopentadienyl)bis(triethyl phosphite)titanium(II) (1), generated in situ from dichlorobis(η5-cyclopentadienyl)titanium(IV), magnesium, and triethyl phosphite, is able to convert thioacetals into monosubstituted cyclopropanes 4 with vinyl 2,2-dimethylpropanoate (vinyl pivalate) as the coupling partner (▶ Scheme 3).

▶ Scheme 3 Preparation of Cyclopropanes from Thioacetals[15]

The reaction begins with the formation of the alkylidenetitanocene intermediate 2, followed by the addition of the alkene, and ring contraction. The regioselective formation of titanacyclobutane 3 is important to obtain the expected cyclopropane and to avoid side reactions such as metathesis, degradation, or β-elimination. Indeed, after examination of several vinylic coupling partners, 2,2-dimethylpropanoates (pivalates) proved to be the most efficient. In general, good yields are observed and substrates bearing functionalities such as ethers or silyl ethers are also tolerated (▶ Scheme 4). The main limitation of this methodology is that the yield is dependent on the steric hindrance of the thioacetals employed. Indeed, the use of less hindered substrates (mono-α-substituted) does not result in regioselective formation of titanacyclobutane 3, and as a consequence, furnishes only moderate yields of the desired products.

▶ Scheme 4 Synthesis of Cyclopropanes from Thioacetal Derivatives[15]

R

1

Yield (%)

Ref

CHBn

2

76

[

15

]

73

[

15

]

(CH

2

)

17

Me

43

[

15

]

The above methodology is also applicable to 1,3-dienes (▶ Scheme 5).[15] The use of buta-1,3-diene as well as 2-methylbuta-1,3-diene (isoprene) allows the conversion of thioacetals into vinylcyclopropanes 5 in good yields.

▶ Scheme 5 Synthesis of Vinylcyclopropanes from Thioacetal Derivatives[15]

R

1

R

2

Yield

a

(%)

Ref

CHBn

2

H

82

[

15

]

CHBn

2

Me

64

b

[

15

]

4-Me

2

NC

6

H

4

H

60

[

15

]

4-Me

2

NC

6

H

4

Me

52

[

15

]

a

As a single diastereomer. Unless otherwise mentioned, the

cis

/

trans

relationship was not determined.

b

The relative configuration was determined to be

trans

.

The synthesis of vinylcyclopropanes can also be achieved by titanocene(II)-promoted reaction of unsaturated thioacetals 6, or 1,3-bis(phenylsulfanyl)alkenes 9, with alkenes (▶ Scheme 6).[14,16] In such a process, a common alkylidene–titanocene intermediate 7 is formed from 6 or 9. This carbene, in equilibrium with titanacyclobutene 8, can react with an additional alkene to give the titanacyclobutane 10 and finally the vinylcyclopropane by ring contraction.

▶ Scheme 6 Mechanism for the Formation of Vinylcyclopropanes from Unsaturated Thioacetals or 1,3-Bis(phenylsulfanyl)alkenes[14]

This method has been successfully used to prepare various vinylcyclopropanes (e.g., 11) in moderate to good yields (▶ Schemes 7 and 8). 3-Chloroallyl sulfides also react in a similar manner with alkenes to afford vinylcyclopropane derivatives.[17]

▶ Scheme 7 Synthesis of Vinylcyclopropanes from Unsaturated Thioacetals[14]

R

1

R

2

R

3

Ratio (

E

/

Z

)

Yield (%)

Ref

Ph

Me

Me

1:0

64

[

14

]

Ph

Ph

H

1:0

a

68

[

14

]

Ph

(CH

2

)

5

Me

H

1:0

a

72

[

14

]

(CH

2

)

5

Me

Me

Me

4.6:1

86

[

14

]

(CH

2

)

2

Ph

Me

Me

2.6:1

68

[

14

]

a

Mixture of

cis

/

trans

-isomers.

▶ Scheme 8 Synthesis of Vinylcyclopropanes from 1,3-Bis(phenylsulfanyl)alkenes or 1-Chloro-3-(phenylsulfanyl)alkenes[14,16,17]

R

1

R

2

R

3

X

Ratio (

E

/

Z

)

Yield (%)

Ref

Bn

Me

Me

SPh

11.5:1

83

[

14

]

(CH

2

)

2

Ph

Me

Me

SPh

5.7:1

93

[

14

]

CH

2

TMS

Ph

H

SPh

49:1

a

84

[

16

]

CH

2

SiMe

2

Ph

Pr

H

SPh

15.7:1

a

85

[

16

]

Et

Ph

H

Cl

1:0

a

58

[

17

]

a

Mixture of

cis

/

trans

-isomers.

β,γ-Unsaturated thioacetals and 1,3-bis(phenylsulfanyl)alkenes can also be converted into vinylcyclopropanes using a method employing titanocene–alkene derivatives generated from dichlorobis(η5-cyclopentadienyl)titanium(IV) and alkyllithium reagents.[18] Due to the use of organolithium species, this last method is of more limited scope.

The bis(η5-cyclopentadienyl)bis(triethyl phosphite)titanium(II) (1) based procedure can be extended to 1,1-bis(phenylsulfanyl)alk-2-ynes, giving alkynylcyclopropane derivatives 12 in good yields with a large array of alkynes and alkenes (▶ Scheme 9).[19] The main drawback of this procedure is that it relies on the use of a large excess of the alkene.

▶ Scheme 9 Synthesis of Alkynylcyclopropanes[19]

R

1

R

2

Alkene (Equiv)

dr

a

Yield (%)

Ref

(CH

2

)

3

Ph

Ph

4

>99:1

65

[

19

]

(CH

2

)

3

Ph

(CH

2

)

2

Ph

8

2.1:1

59

[

19

]

(CH

2

)

3

Ph

Bu

8

1.5:1

65

[

19

]

Bu

Ph

4

>99:1

73

[

19

]

Bu

(CH

2

)

2

Ph

8

1.3:1

77

[

19

]

Me

(CH

2

)

2

Ph

8

1.3:1

70

[

19

]

a

The

cis

or

trans

relationship in the major and minor isomers was not determined.

Following a similar strategy, 2-alkynyl-2-(trialkylsilyl)-1,3-dithianes are regioselectively converted into alkynylcyclopropanes in good yields through a formal allylic rearrangement, as exemplified by the conversion of 13 into 14 (▶ Scheme 10).[20] In contrast, the regioisomer 15 gives the same product 14, without any allylic rearrangement, suggesting a common intermediate for these two reactions.

▶ Scheme 10 Preparation of Alkynylcyclopropanes[20]

To a flask charged with finely powdered 4-Å molecular sieves (50 mg), Mg turnings (97 mg, 4 mmol), and Ti(Cp)2Cl2 (249 mg, 1 mmol) were added THF (5 mL), P(OEt)3 (0.34 mL, 2 mmol), and oct-1-ene (224 mg, 2 mmol) successively with stirring at rt. After 2 h, (E)-2-(2-phenylvinyl)-1,3-dithiane (111 mg, 0.5 mmol) in THF (2 mL) was added to the mixture, which was further stirred for 4 h. Then, the mixture was diluted with hexane (30 mL) and the insoluble materials were removed by filtration through Celite. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative TLC (hexane) to give a mixture of cis/trans-isomers; yield: 82 mg (72%).

Mg turnings (24 mg, 1 mmol) and finely powdered 4-Å molecular sieves (100 mg) were placed in a flask and dried by heating with a heat gun under reduced pressure (2–3 Torr). After the mixture had been stirred for 15 h under argon at rt, Ti(Cp)2Cl2 (249 mg, 1 mmol) was added to the mixture, which was further dried by heating under reduced pressure. After cooling, THF (2 mL), P(OEt)3 (0.69 mL, 4 mmol), and styrene (0.23 mL, 2 mmol) were added successively with stirring at rt under argon. After 3 h, 6-phenyl-1,1-bis(phenylsulfanyl)hex-2-yne (187 mg, 0.5 mmol) in THF (1.5 mL) was added to the mixture, and stirring was continued for 3.5 h. The reaction was quenched by addition of 1 M NaOH (10 mL), and the resulting insoluble materials were removed by filtration through Celite, washing with Et2O (10 mL). The organic materials were extracted with Et2O (3 × 30 mL), and the extract was dried (Na2SO4). After removal of the solvent, the residue was purified by preparative TLC (hexane/EtOAc 98:2); yield: 85 mg (65%).

2.10.19.1.1.2 Method 2: Synthesis from 1,1-Dihalides

▶ Scheme 11 Synthesis of Bicyclo[3.1.0]- and Bicyclo[4.1.0]alkanes from Unsaturated 1,1-Dihalides[21]

R

1

R

2

X

m

dr

a

Yield (%)

Ref

(CH

2

)

3

Ph

H

Cl

1

8.1:1

73

[

21

]

(CH

2

)

3

Ph

H

Br

1

8.1:1

73

[

21

]

(CH

2

)

3

Ph

Me

Br

1

32.3:1

70

[

21

]

Ph

Me

Br

1

24:1

72

[

21

]

H

(CH

2

)

2

Ph

Cl

1

–

77

[

21

]

(CH

2

)

3

Ph

Me

Br

2

1.7:1

68

b

[

21

]

a

The

cis

or

trans

relationship in the major and minor isomers was not determined.

b

Reaction performed at rt overnight.

Concerning the mechanism of this reaction, the authors propose the formation of α-haloalkyltitanium intermediates, which undergo insertion of the alkene to form cyclic γ-haloalkyltitanium species, followed by intramolecular reductive coupling (▶ Scheme 12).

▶ Scheme 12 Mechanism of Bicyclo[3.1.0]- and Bicyclo[4.1.0]alkane Formation[21]

To a soln of the titanocene(II) reagent in THF (6.7 mL), prepared from Ti(Cp)2Cl2 (374 mg, 1.5 mmol), Mg turnings (36 mg, 1.5 mmol), P(OEt)3 (0.52 mL, 3 mmol), and finely powdered 4-Å molecular sieves (150 mg), was added a soln of 6,6-dibromo-4-phenylhept-1-ene (166 mg, 0.5 mmol) in THF (10 mL) at 0°C under argon. After the mixture had been stirred for 1.5 h, the reaction was quenched by addition of 1 M NaOH (30 mL). The insoluble materials were removed by filtration through Celite and washed with Et2O (10 mL). The layers were separated, and the aqueous layer was extracted with Et2O (2 × 20 mL). The combined organic extracts were dried (Na2SO4). After removal of the solvent at atmospheric pressure, the residue was dissolved in AcOH (3 mL) and 30% H2O2 (0.8 mL) was added to the soln with cooling (ca. rt). The mixture was stirred for 6 h and then diluted with H2O (20 mL). The organic materials were extracted with Et2O (2 × 20 mL) and the extracts were dried (Na2SO4). The solvent was removed under atmospheric pressure, and the residue was purified by preparative TLC (hexane) to give a mixture of cis/trans-isomers; yield: 63 mg (72%).

2.10.19.1.2 Synthesis of Cyclopropanols

2.10.19.1.2.1 Synthesis from Carboxylic Acid Esters

The titanium-mediated cyclopropanation of carboxylic acid esters was discovered in 1989 by O. G. Kulinkovich and co-workers[24] and is certainly the most direct way to obtain cyclopropanol derivatives.[7] This reaction, now referred as the Kulinkovich reaction, uses inexpensive and simple starting materials and reagents, such as carboxylic acid esters, organomagnesium halides, and titanium(IV) isopropoxide.

Since its discovery, two main methods have emerged: (1) the three-membered ring is obtained from the carboxylic acid ester and a Grignard reagent (method without ligand exchange); (2) the cyclopropane ring is obtained from the carboxylic acid ester and an alkene derivative (method with ligand exchange).

2.10.19.1.2.1.1 Method 1: Use of Grignard Reagents without Ligand Exchange

The Kulinkovich reaction, as depicted in ▶ Scheme 13, is the conversion of carboxylic acid esters into cyclopropanols 17 by the use of Grignard reagents and titanium(IV) isopropoxide in an ethereal solvent, typically diethyl ether or tetrahydrofuran. The reaction, initially performed with 1 equivalent of titanium(IV) isopropoxide and an excess of Grignard reagent (3 equivalents),[24] was rapidly developed to allow a version employing a catalytic amount of titanium(IV) isopropoxide (10 mol%) and 2.1 equivalents of the Grignard reagent.[25,26]

▶ Scheme 13 Synthesis of Cyclopropanols by the Original Catalytic Kulinkovich Reaction[25,26]

R

1

R

2

R

3

Yield (%)

Ref

Pr

Me

H

91

[

25

,

26

]

(CH

2

)

4

Me

Me

H

94

[

25

,

26

]

(CH

2

)

6

Me

Me

H

94

[

26

]

Ph

Et

H

64

[

26

]

(CH

2

)

6

Me

Me

Me

90

a

[

26

]

Et

Me

Et

74

a

[

26

]

Ph

Et

Ph

31

a

[

26

]

a

The diastereomeric ratio was not determined.

As exemplified with ethylmagnesium bromide (▶ Scheme 14), the reaction begins with the formation of a diethyltitanium(IV) species (obtained by transmetalation with the Grignard reagent).[25] At the temperature used for the reaction (room temperature), a β-fragmentation occurs, leading to the formation of ethane and a transient dialkoxytitanacyclopropane 18, which can also be viewed as a dialkoxy(η2-alkene)titanium(II) species 19. The next step is the insertion of the carbonyl group of the ester, leading to the five-membered metallacycle 20. After elimination of an alkoxy group, a β-metalated ketone 21 is formed, which spontaneously undergoes a ring contraction to afford the three-membered ring. When the titanium reagent is used in catalytic quantities, the resulting titanium tetraalkoxide complex 22 can eventually react with the excess of Grignard reagent to regenerate a titanacyclopropane that closes the catalytic cycle. The mechanism has been studied by several groups,[27–30] and probably involves titanium “ate” complexes, as proposed by Kananovich and Kulinkovich.[29,30]

▶ Scheme 14 Simplified Mechanism of the Kulinkovich Cyclopropanation[25]

Titanium(IV) isopropoxide and chlorotriisopropoxytitanium(IV) are the most used titanium reagents, the latter often giving better yields. In some cases, the alternative use of triisopropoxy(methyl)titanium(IV) presents the advantage of requiring a lower amount of the Grignard reagent (1.1–1.5 equiv).[31]

When ethylmagnesium halides are used, 1-substituted cyclopropanols are obtained in generally high yield. With groups larger than ethyl, the corresponding disubstituted cyclopropanols are obtained, generally with high diastereoselectivity in favor of the cis dialkyl relationship. However, the diastereoselectivity decreases with increasing steric hindrance of the carboxylic acid ester (▶ Scheme 15).[29] The presence of free hydroxy groups on the side chain may also affect the diastereoselectivity (see also ▶ Section 2.10.19.1.2.1.2.2).[32]

▶ Scheme 15 Diastereomeric Ratios in the Titanium-Mediated Cyclopropanation of Carboxylic Acid Esters[29]

R

1

R

2

R

3

Solvent

Ratio (

cis

/

trans

)

Yield (%)

Ref

Me

Et

Pr

Et

2

O or THF

20:1

75

[

29

]

Pr

Me

Me

Et

2

O

5.5:1

76

[

29

]

Pr

Me

Me

THF

14:1

84

[

29

]

iPr

Me

Me

Et

2

O

1:1

67

[

29

]

t

-Bu

Me

Me

Et

2

O

1:3

49

[

29

]

The main byproducts in the titanium-catalyzed cyclopropanation of carboxylic acid esters are secondary alcohols with similar Rf values to the desired products (e.g., 23) (▶ Scheme 16). A solution to overcome the problem of purification is to use a methylmagnesium halide in addition to the appropriate Grignard reagent. Under these conditions, only secondary alcohols with lower Rf values are present, and thus, can be separated from the desired cyclopropanols by chromatography.[30]

▶ Scheme 16 Synthesis of Cyclopropanols Avoiding the Formation of Inseparable Byproducts[30]

The reaction proceeds well with a large array of carboxylic acid esters bearing functional groups that are not sensitive to Grignard reagents, such as halogens, tetrahydropyranylor trialkylsilyl-protected alcohols, carbamates, acetals, benzyl-protected amines, phosphinic or phosphonic acid esters, and phosphine oxides (▶ Scheme 17). However, nitriles and tertiary amides may be converted into cyclopropylamines (see ▶ Section 2.10.19.1.4). α,β-Unsaturated esters give poor results,[33] except when the double bond is part of a cyclic system.

▶ Scheme 17 Scope of the Kulinkovich Cyclopropanation[34–40]

R

1

R

2

R

3

Conditions

Yield (%)

Ref

Et

H

Ti(OiPr)

4

(0.5 equiv), EtMgBr (2.5 equiv), Et

2

O, rt, 12 h

64

[

34

]

Me

H

Ti(OiPr)

4

(0.3 equiv), EtMgBr (3 equiv), THF, 0°C, 1 h

64

[

35

]

Me

H

TiCl(OiPr)

3

(1 equiv), EtMgBr (5 equiv), THF, rt, 5 h

99

[

37

]

Et

H

Ti(OiPr)

4

(0.2 equiv), EtMgBr (3 equiv), Et

2

O, rt, 10 h

92

[

38

]

Me

Et

Ti(OiPr)

4

(1 equiv), BuMgBr (2.2 equiv), THF, rt, 4 h

71

a

[

39

]

Me

H

Ti(OiPr)

4

(1 equiv), EtMgBr (2.2 equiv), THF, rt, 4 h

64

[

39

]

Et

Et

Ti(OiPr)

4

(0.2 equiv), BuMgBr (4 equiv), Et

2

O/THF, rt, 2 h

90

b

[

36

]

Me

(CH

2

)

2

OTIPS

TiCl(OiPr)

3

(0.5 equiv), TIPSO(CH

2

)

4

MgCl (5 equiv), THF, rt, 2 h

77

a

[

40

]

a

Ratio (

cis

/

trans

) 1:0.

b

Ratio (

cis

/

trans

) >32.3:1.

Cyclic Grignard reagents can also be used with carboxylic acid esters, leading to bicyclic derivatives (▶ Scheme 18).[41] Whereas cyclopropylmagnesium bromide does not afford the cyclopropanol, cyclobutyl to cycloheptyl Grignard reagents give the corresponding bicyclo[n.1.0]alkanol frameworks with good to excellent exo diastereoselectivity and in good yield, with the notable exception of cyclohexylmagnesium bromide (17%).

▶ Scheme 18 Synthesis of Bicyclo[n.1.0]alkanols from Cyclic Grignard Reagents[41]

m

Ratio (

exo

/

endo

)

Yield (%)

Ref

1

1:0

46

[

41

]

2

2:1

63

[

41

]

3

1:0

17

[

41

]

4

1:0

56

[

41

]

An asymmetric version of the Kulinkovich reaction is possible using TADDOL-derived chiral catalysts (▶ Scheme 19).[42] Starting from ethyl acetate and 2-phenylethylmagnesium bromide, the cyclopropanol 24 is obtained as a single diastereomer with a 70–78% enantiomeric excess, depending on the conditions used. Since there is only one example cited, further studies are required to determine the scope of this asymmetric version of the cyclopropanation.

▶ Scheme 19 Asymmetric Kulinkovich Cyclopropanation[42]

To a stirred soln of methyl hexanoate (3.25 g, 25 mmol) and Ti(OiPr)4 (0.74 mL, 2.5 mmol) in Et2O (80 mL) was added a soln of EtMgBr (53 mmol) in Et2O slowly over a period of 1 h at rt, and stirring was continued for 10 min. The mixture was then poured into cooled (5°C) 10% aq H2SO4 (250 mL) and the products were extracted with Et2O (3 × 50 mL). The combined organic extracts were washed with H2O (50 mL), dried (Na2SO4), and the solvent was removed. The crude oil was purified by chromatography (silica gel, hexane); yield: 3.0 g (94%); bp 88–90°C/25 mbar.

2-Methyl-1-propylcyclopropanol (23); Typical Procedure Avoiding the Formation of Inseparable Byproducts:[30]

A 1.5 M soln of MeMgBr in THF (20 mL, 30 mmol) was added over 5 min at rt to a soln of Ti(OiPr)4 (5.68 g, 20 mmol) in THF (20 mL). The soln was cooled to 0°C and a soln of methyl butanoate (2.27 mL, 20 mmol) in THF (20 mL) was added. A 1.5 M soln of PrMgBr in THF (20 mL, 30 mmol) was added to the mixture over 30–40 min, and the resulting soln was allowed to warm to rt and was stirred for 1 hour. The mixture was quenched by careful addition of 10% H2SO4 (70–80 mL) at 0°C, the aqueous phase was extracted with Et2O (3 × 20 mL), and the combined organic layers were washed with sat. aq NaHCO3 and then brine and dried (MgSO4). After removal of the solvent, the cis- (1.53 g) and trans-isomers (0.18 g) were separated by column chromatography (silica gel, petroleum ether/EtOAc); combined yield: 1.71 g (75%).

2.10.19.1.2.1.2 Method 2: Use of Alkenes and Grignard Reagents

As early as 1993 it was shown that titanacyclopropanes generated from Grignard reagents are able to undergo a ligand exchange process with an added alkene, leading to a new titanacyclopropane complex. This discovery extends the synthetic potential of the reagent, since the three-membered ring can be obtained from carboxylic acid esters and alkenes (▶ Scheme 20).[43] In order for significant ligand exchange to occur, the first titanacyclopropane (generated from the Grignard reagent) must be more substituted than the one obtained from the alkene moiety. Consequently, experimentally, substituted Grignard reagents are required, cyclopentylmagnesium chloride, and cyclohexylmagnesium chloride being the most used. Another consequence is that, generally, only monosubstituted alkenes are able to undergo efficient ligand exchange.

▶ Scheme 20 Alkene Exchange in Titanacyclopropane Complexes

When using carboxylic acid esters, three reactions must be considered (▶ Scheme 21): (1) an intramolecular reaction from an ester bearing an unsaturation in the acyl moiety, leading to bicyclic [n.1.0] compounds; (2) an intramolecular reaction from an ester bearing an unsaturation in the alkoxy moiety, leading to 2-(hydroxyalkyl)-substituted cyclopropanols; (3) an intermolecular reaction between an alkene and a carboxylic acid ester.

▶ Scheme 21 Preparation of Cyclopropanols via Ligand Exchange

2.10.19.1.2.1.2.1 Variation 1: Bicyclo[n.1.0]alkan-1-ols from Unsaturated Carboxylic Acid Esters

Substituted fused bicyclic cyclopropanol compounds are accessible from the corresponding ω-unsaturated carboxylic acid esters when subjected to titanium(IV) isopropoxide or chlorotriisopropoxytitanium(IV) and a suitable Grignard reagent (▶ Scheme 22). Due to a favorable intramolecular process, isopropylmagnesium chloride[44] or butylmagnesium chloride[45] can be used. Cyclic alkylmagnesium halides are also found to be good reagents.[46]

▶ Scheme 22 Preparation of Bicyclic Alkanols from Unsaturated Carboxylic Acid Esters

▶ Table 1 Synthesis of Bicyclic Alkanol Derivatives from Unsaturated Carboxylic Acid Esters[44–48]]

Starting Material

Conditions

Product

a

Yield (%) (dr)

Ref

TiCl(OiPr)

3

(0.5 equiv), BuMgCl (5 equiv), Et

2

O, rt, 1–2 h

55

[

45

]

Ti(OiPr)

4

(2 equiv), iPrMgCl (4 equiv), Et

2

O, –45°C, 1 h, then –45 to 0°C, 2.5 h

77 (1.9:1)

b

[

44

]

TiCl(OiPr)

3

(0.5 equiv), BuMgCl (5 equiv), Et

2

O, rt, 1–2 h

58 (3.5:1)

[

45

]

Ti(OiPr)

4

(0.1 equiv), iPrMgCl (5 equiv), THF/Et

2

O, rt

75 (2.6:1)

[

46

]

Ti(OiPr)

4

(1.3 equiv), iPrMgCl (2.6 equiv), Et

2

O, –78°C to rt, 2.5 h

94

[

47

]

Ti(OiPr)

4

(1.3 equiv), iPrMgCl (2.6 equiv), Et

2

O, –78°C to rt, 2.5 h

80

[

47

]

Ti(OiPr)

4

(2 equiv), iPrMgCl (4 equiv), Et

2

O, –78°C to rt, 2 h

94

[

44

]

TiCl(OiPr)

3

(1 equiv), cyclopentylmagnesium chloride (3–5 equiv), THF, rt

86 (9:1)

b

[

48

]

TiCl(OiPr)

3

(1 equiv), CyMgCl (4 equiv), THF, rt, 5 h

47

[

49

]

TiCl(OiPr)

3

(1 equiv), CyMgCl (4 equiv), THF, rt, 5 h

52

[

49

]

a

Only the major isomer is shown.

b

The relative configuration of each diastereomer was not determined.

Bicyclo[3.1.0]hexan-1-ol (25); Typical Procedure Using Butylmagnesium Chloride:[45]

To a soln of methyl hex-5-enoate (100 mg, 0.78 mmol) in anhyd Et2O (8 mL) was added 1 M TiCl(OiPr)3 in hexane (0.39 mL, 0.39 mmol). A 2 M soln of BuMgCl in THF (1.95 mL, 3.9 mmol) was added at rt over a period of 1 h. The mixture was stirred for an additional 1 h, and then poured into ice-cold 1 M HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined extracts were washed with aq NaHCO3 (10 mL) followed by brine (10 mL) and then dried (MgSO4). Solvents were removed by distillation at atmospheric pressure, and distillation of the residue under reduced pressure (H2O aspirator) gave a colorless oil; yield: 42 mg (55%).

2-Benzylbicyclo[3.1.0]hexan-1-ol (26); Typical Procedure Using Isopropylmagnesium Chloride:[44]

To a stirred soln of methyl 2-benzylhex-5-enoate (0.22 g, 1.0 mmol) and Ti(OiPr)4 (0.568 g, 2.0 mmol) in Et2O (12 mL) was added 1.3 M iPrMgCl in Et2O (3.1 mL, 4.0 mmol) at –45°C. The mixture was stirred for 1 h at –45 to –40°C and then warmed to 0°C over 2.5 h. After addition of THF (3.0 mL) and H2