Science of Synthesis Knowledge Updates 2013 Vol. 1 E-Book

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

Seitenzahl: 1048

Veröffentlichungsjahr: 2014

Beschreibung

Science of Synthesis is a reference work for preparative methods in synthetic chemistry. Its product-based classification system enables chemists to easily find solutions to their synthetic problems.

Key Features:

• Critical selection of reliable synthetic methods, saving the researcher the time required to find procedures in the primary literature.
• Expertise provided by leading chemists.
• Detailed experimental procedures.
• The information is highly organized in a logical format to allow easy access to the relevant information.

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.

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 expert-evaluated 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

5.2.1 Product Subclass 1: Tin Hydrides

K. Tchabanenko

This chapter is a revision of an earlier Science of Synthesis contribution describing methods for the synthesis and synthetic applications of tin hydrides. Synthetic methods based on free-radical chain reactions promoted by tin hydrides are discussed, including cascade reactions that proceed with rearrangement of radical intermediates. Free-radical and transition-metal-catalyzed hydrostannylations of multiple carbon—carbon bonds are also discussed in the chapter.

Keywords: stannanes · radical reactions · cyclizations · rearrangements · C—C bond formation · C—Sn bond formation · transition-metal catalysis · cascade reactions

7.6.11.21 Grignard Reagents with Transition Metals

Z. Song and T. Takahashi

This chapter is an update to Science of Synthesis Section 7.6.11, which describes the reactions of Grignard reagents in conjunction with transition metals. This update briefly summarizes the related publications that appeared from 2004 onwards.

Keywords: Grignard reagents · C—C coupling · enantioselectivity · transition metals · transmetalation

7.7 Product Class 7: Calcium Compounds

M. Hatano

This chapter is a revision of the earlier Science of Synthesis contribution describing methods for the synthesis of calcium compounds. Recent interest in this area has in part been generated by the observation that complexes of calcium with chiral diols, diamines, or phosphoric acids possess potent activity in asymmetric catalysis.

Keywords: alkylation · amination · arylation · 1,1′-binaphthalene-2,2′-diols · bis(oxazo-lines) · C—C bond formation · cyclization · diamines · diols · oxidation · phosphoric acids · pybox ligands

9.13.5 1H-Pyrroles

W. D. Lubell, D. J. St-Cyr, J. Dufour-Gallant, R. Hopewell, N. Boutard, T. Kassem, A. Dörr, and R. Zelli

This chapter updates the previous Science of Synthesis contribution on 1H-pyrroles, which covers the literature up to 1998. This update includes the literature to 2011, with coverage of >900 references. Modern advances in pyrrole synthesis, reactivity, and functional-group modification, are described, including syntheses of nitrogen-, oxygen-, and sulfur-substituted pyrroles, multicomponent and annulation reactions, selective modifications at the 1-, 2-, and 3-positions of the pyrrole ring, and enantioselective additions of chiral side chains. Various annulation, ring-contraction, and ring-expansion approaches to the heterocycle, as well as modifications of pyrrole by carbon—hydrogen, carbon—halogen, carbon—heteroatom, and carbon—carboxylate transformations, and substituent migration strategies, all are covered in detail, along with many other recent synthetic developments. In addition, examples of various applications of pyrrole chemistry are presented to illustrate the growing importance of this heterocycle in fields such as medicinal chemistry, materials science, and natural product synthesis.

Keywords: pyrrole · Paal–Knorr condensation · Knorr-type reactions · tosylmethyl isocyanide · Barton–Zard type reactions · 1,3-dipolar cycloaddition · halopyrroles · cross coupling · direct arylation · Vilsmeier reaction · enantioselective alkylation · lamellarins · distamycin · prodigiosin · netropsin

16.9.5 Cinnolines

R. Krishnamoorthy

This chapter is an update to the earlier published Science of Synthesis report on the synthesis of cinnolines. The literature on cinnolines published from 2000 onwards is covered.

Keywords: cinnolines · fused cinnolines · diazotization · cyclization · arenediazonium salts · arylhydrazones · alkynyltriazenes · N-oxides · Richter reaction · Suzuki reaction · Sonogashira reaction

16.23.4 Diphosphinines

J. W. Lippert, III

This chapter is an update to the earlier Science of Synthesis contribution describing the methods for the preparation of various diphosphinines. The focus is on the literature published in the period 2003–2011.

Keywords: diphosphinines · dimerization · palladium complexes

Science of Synthesis Knowledge Updates 2013/1

Preface

Abstracts

Table of Contents

5.2.1 Product Subclass 1: Tin Hydrides

K. Tchabanenko

7.6.11.21 Grignard Reagents with Transition Metals (Update 2013)

Z. Song and T. Takahashi

7.7 Product Class 7: Calcium Compounds

M. Hatano

9.13.5 1H-Pyrroles (Update 2013)

W. D. Lubell, D. J. St-Cyr, J. Dufour-Gallant, R. Hopewell, N. Boutard, T. Kassem, A. Dörr, and R. Zelli

16.9.5 Cinnolines (Update 2013)

R. Krishnamoorthy

16.23.4 Diphosphinines (Update 2013)

J. W. Lippert, III

Author Index

Abbreviations

Table of Contents

Volume 5: Compounds of Group 14 (Ge, Sn, Pb)

5.2 Product Class 2: Tin Compounds

5.2.1 Product Subclass 1: Tin Hydrides

K. Tchabanenko

5.2.1 Product Subclass 1: Tin Hydrides

Synthesis of Product Subclass 1

5.2.1.1 Method 1: Reduction of Tin Halides

5.2.1.1.1 Variation 1: Reduction of Tin Halides with Lithium Aluminum Hydride

5.2.1.1.2 Variation 2: Reduction of Tin Halides with Sodium Borohydride

5.2.1.2 Method 2: Synthesis from Organotin Oxides, Alkoxides, or Amides by Reduction

5.2.1.3 Method 3: Synthesis from Organotin Lithium, Sodium, Potassium, or Magnesium Compounds by Reactions with Electrophiles

Applications of Product Subclass 1 in Organic Synthesis

5.2.1.4 Tin-Mediated Radical Chain Reactions Not Involving Rearrangement of Intermediate Radicals

5.2.1.4.1 Method 1: Reduction of Carbon—Heteroatom Bonds

5.2.1.4.1.1 Variation 1: Reduction of Carbon—Halogen Bonds

5.2.1.4.1.2 Variation 2: Reduction of C—O Bonds

5.2.1.4.1.3 Variation 3: Reduction of C—N Bonds

5.2.1.4.2 Method 2: Formation of C—C Bonds by Radical Additions to Alkenes

5.2.1.4.2.1 Variation 1: Formation of C—C Bonds by Intermolecular Reactions with Alkenes

5.2.1.4.2.2 Variation 2: Formation of C—C Bonds by Intramolecular Addition of Carbon Radicals to Double Bonds

5.2.1.4.3 Method 3: Formation of C—N Bonds by Reactions of Nitrogen-Centered Radicals

5.2.1.5 Tin-Mediated Radical Reactions That Proceed with Rearrangement of Intermediate Radicals

5.2.1.5.1 Method 1: Radical Reactions That Proceed with Opening of Small Rings

5.2.1.5.2 Method 2: Radical Reactions That Proceed with 1,2- and 1,4-Group Transfer

5.2.1.5.3 Method 3: Radical Translocation through Intramolecular Hydrogen Abstraction

5.2.1.6 Hydrostannylation

5.2.1.6.1 Method 1: Hydrostannylation of Alkynes

5.2.1.6.1.1 Variation 1: Radical Hydrostannylation of Terminal Alkynes

5.2.1.6.1.2 Variation 2: Transition-Metal-Catalyzed Hydrostannylation of Terminal Alkynes

5.2.1.6.1.3 Variation 3: Palladium-Catalyzed Sequential Hydrostannylation and Stille Cross Coupling of Terminal Alkynes

5.2.1.6.1.4 Variation 4: Radical Hydrostannylation of Internal Alkynes

5.2.1.6.1.5 Variation 5: Transition-Metal-Catalyzed Hydrostannylation of Internal Alkynes

5.2.1.6.2 Method 2: Hydrostannylation of C=C, C=O, and C=N Bonds

5.2.1.6.2.1 Variation 1: Hydrostannylation of Alkenes

5.2.1.6.2.2 Variation 2: Addition Reactions of Tin Hydrides to C=O Bonds

5.2.1.6.2.3 Variation 3: Additions of Tin Hydrides to C=N Bonds

Volume 7: Compounds of Groups 13 and 2 (Al, Ga, In, Tl, Be •••Ba)

7.6 Product Class 6: Magnesium Compounds

7.6.11.21 Grignard Reagents with Transition Metals

Z. Song and T. Takahashi

7.6.11.21 Grignard Reagents with Transition Metals

7.6.11.21.1 Method 1: Mercury-Catalyzed Addition of Grignard Reagents to Aldehydes

7.6.11.21.2 Method 2: Nickel-Catalyzed Cross Coupling of Grignard Reagents

7.6.11.21.2.1 Variation 1: Reaction with Alkyl Halides

7.6.11.21.2.2 Variation 2: Reaction with Organosulfur Compounds

7.6.11.21.2.3 Variation 3: Reaction with Aryl Fluorides under Microwave Irradiation

7.6.11.21.3 Method 3: Palladium-Catalyzed Cross Coupling of Grignard Reagents

7.6.11.21.3.1 Variation 1: Reaction with Aryl Halides

7.6.11.21.3.2 Variation 2: Reaction with Aryl Fluorides under Microwave Irradiation

7.6.11.21.3.3 Variation 3: Reaction with Aryl Halides Promoted by Zinc(II) Bromide

7.6.11.21.3.4 Variation 4: Reaction with Hetaryl Sulfonates

7.6.11.21.4 Method 4: Copper-Catalyzed Reactions of Grignard Reagents

7.6.11.21.4.1 Variation 1: Cross Coupling with Hetaryl Halides

7.6.11.21.4.2 Variation 2: Carbometalation of Propargylic Alcohols

7.6.11.21.4.3 Variation 3: Reaction with α,β-Unsaturated Carbonyl Compounds

7.6.11.21.4.4 Variation 4: Allylic Substitution Reactions

7.6.11.21.4.5 Variation 5: Ring Opening of Chiral Epoxides

7.6.11.21.4.6 Variation 6: Cross Coupling with Allylic Chlorides

7.6.11.21.5 Method 5: Iron-Catalyzed Cross Coupling of Grignard Reagents

7.6.11.21.5.1 Variation 1: Reaction with Aryl Halides

7.6.11.21.5.2 Variation 2: Reaction with Alkynyloxiranes

7.6.11.21.5.3 Variation 3: Reaction with Primary and Secondary Alkyl Halides

7.6.11.21.6 Method 6: Iron-Catalyzed Reduction of Organic Halides

7.6.11.21.7 Method 7: Iridium-Catalyzed Allylic Substitution Reactions

7.6.11.21.8 Method 8: Titanium-Catalyzed Cross Coupling of Grignard Reagents

7.6.11.21.8.1 Variation 1: Reaction with Aryl Fluorides

7.6.11.21.8.2 Variation 2: Reaction with O,N-Acetals

7.6.11.21.9 Method 9: Zirconium-Catalyzed Reaction with Alkynes

7.7 Product Class 7: Calcium Compounds

M. Hatano

7.7 Product Class 7: Calcium Compounds

7.7.1 Product Subclass 1: Organocalcium Hydrides

Synthesis of Product Subclass 1

7.7.1.1 Method 1: Synthesis of Phenylcalcium Hydride from Calcium Metal

Applications of Product Subclass 1 in Organic Synthesis

7.7.1.2 Method 2: Reaction of Phenylcalcium Hydride with Electrophiles

7.7.2 Product Subclass 2: Heterobimetallic Calcium Compounds

Synthesis of Product Subclass 2

7.7.2.1 Method 1: Synthesis of Heterobimetallic Calcium Compounds with Alkaline Earth and Transition Metals

7.7.2.2 Method 2: Synthesis of Calcium Borates

Applications of Product Subclass 2 in Organic Synthesis

7.7.2.3 Method 3: Intramolecular Hydroamination of Amino-Substituted Alkenes

7.7.2.4 Method 4: Baeyer–Villiger Oxidation of Ketones

7.7.3 Product Subclass 3: Organocalcium Halides

Synthesis of Product Subclass 3

7.7.3.1 Method 1: Synthesis of Methylcalcium Iodide from Calcium Metal

Applications of Product Subclass 3 in Organic Synthesis

7.7.3.2 Method 2: Reaction of Organocalcium Halides with Electrophiles

7.7.4 Product Subclass 4: Calcium Alkoxides

Synthesis of Product Subclass 4

7.7.4.1 Method 1: Synthesis of Calcium Alkoxides from Calcium Metal

7.7.4.2 Method 2: Synthesis of Calcium Alkoxides from Calcium(II) Compounds

Applications of Product Subclass 4 in Organic Synthesis

7.7.4.3 Method 3: Asymmetric Baylis–Hillman Reactions

7.7.4.4 Method 4: Asymmetric Aldol Reactions

7.7.4.5 Method 5: Asymmetric 1,4-Addition Reactions

7.7.4.6 Method 6: Asymmetric Epoxidation Reactions

7.7.5 Product Subclass 5: Calcium Phosphates

Synthesis of Product Subclass 5

7.7.5.1 Method 1: Synthesis of Chiral Calcium Phosphates from Calcium(II) Compounds

Applications of Product Subclass 5 in Organic Synthesis

7.7.5.2 Method 2: Asymmetric Mannich Reactions of Aldimines

7.7.5.2.1 Variation 1: Reaction with Acyclic Nucleophiles

7.7.5.2.2 Variation 2: Reaction with Cyclic Nucleophiles

7.7.5.3 Method 3: Asymmetric Reactions of Indolin-2-ones

7.7.5.3.1 Variation 1: Oxidation of 3-Arylindolin-2-ones

7.7.5.3.2 Variation 2: Chlorination of 3-Arylindolin-2-ones

7.7.5.4 Method 4: Asymmetric Amination of Enamines

7.7.5.5 Method 5: Asymmetric Carbonyl-Ene Reactions

7.7.5.6 Method 6: Asymmetric Friedel–Crafts Alkylation

7.7.6 Product Subclass 6: Calcium Amides

Synthesis of Product Subclass 6

7.7.6.1 Method 1: Synthesis of Calcium–Bis(4,5-dihydrooxazole) Complexes from Calcium(II) Compounds

Applications of Product Subclass 6 in Organic Synthesis

7.7.6.2 Method 2: Asymmetric 1,4-Addition Reactions with α,β-Unsaturated Carbonyl Derivatives

7.7.6.3 Method 3: Asymmetric [3 + 2]-Cycloaddition Reactions

7.7.6.4 Method 4: Asymmetric 1,4-Addition/Protonation Reactions

7.7.6.5 Method 5: Asymmetric 1,4-Addition Reactions of Oxazolones

7.7.6.6 Method 6: Asymmetric 1,4-Addition Reactions to Nitroalkenes

7.7.6.7 Method 7: Asymmetric Hydroamination Reactions

7.7.6.8 Method 8: Friedel–Crafts Addition to Arenes

7.7.7 Product Subclass 7: Diorganocalcium Compounds

Synthesis of Product Subclass 7

7.7.7.1 Method 1: Synthesis of Bis(phenylethynyl)calcium from Calcium Metal

7.7.7.2 Method 2: Synthesis of Diallylcalcium from Calcium Iodide

7.7.7.3 Method 3: Synthesis of Calcium Metallocenes

7.7.7.4 Method 4: Synthesis of Dibenzylcalcium Complexes

Applications of Product Subclass 7 in Organic Synthesis

7.7.7.5 Method 5: Hydrogenation of Alkenes

7.7.7.6 Method 6: Hydrosilylation of Ketones

Volume 9: Fully Unsaturated Small Ring Heterocycles and Monocyclic Five-Membered Hetarenes with One Heteroatom

9.13 Product Class 13: 1H-Pyrroles

9.13.5 1H-Pyrroles

W. D. Lubell, D. J. St-Cyr, J. Dufour-Gallant, R. Hopewell, N. Boutard, T. Kassem, A. Dörr, and R. Zelli

9.13.5 1H-Pyrroles

9.13.5.1 Synthesis by Ring-Closure Reactions

9.13.5.1.1 By Formation of Two N—C and Two C—C Bonds

9.13.5.1.1.1 Fragments N, C—C, and Two C Fragments

9.13.5.1.1.1.1 Method 1: Reaction of Nitroalkanes, Aldehydes, 1,3-Dicarbonyl Compounds, and Amines

9.13.5.1.1.1.2 Method 2: Solid-Phase Synthesis of Pyrrole-3-carboxamides from Enaminones and Nitroalkenes

9.13.5.1.1.1.3 Method 3: Combination of an Alkyl Propynoate, Aldehyde, and an Amine

9.13.5.1.1.1.4 Method 4: Samarium-Catalyzed Three-Component Coupling Reaction

9.13.5.1.1.1.5 Method 5: Titanium-Catalyzed Three-Component Coupling Reaction

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

9.13.5.1.2.1 Fragment N and Two C—C Fragments

9.13.5.1.2.1.1 Method 1: Reaction of Amines and Two Carbonyl Compounds

9.13.5.1.2.1.2 Method 2: Reaction of Amines, 1,3-Dicarbonyl Compounds, and Alkenes or Alkynes

9.13.5.1.2.1.3 Method 3: Reaction of Amines, Carbonyl Compounds, and Alkenes or Alkynes

9.13.5.1.2.1.4 Method 4: Reaction of Amines and Combinations of Alkanes, Alkenes, and Alkynes

9.13.5.1.2.2 Fragments N, C—C—C, and C

9.13.5.1.2.2.1 Method 1: Reaction of Amines, α,β-Unsaturated Carbonyl Compounds, and Carbon Nucleophiles

9.13.5.1.2.2.1.1 Variation 1: Reactions with Aldehydes and Acylsilanes as Umpolung Nucleophiles under Stetter Conditions

9.13.5.1.2.2.1.2 Variation 2: Reactions with Nitroalkanes as Nucleophiles for Conjugate Addition

9.13.5.1.2.2.2 Method 2: Reaction of Amines, 1,3-Diketones, and Aldehydes

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

9.13.5.1.3.1 Fragments N—C, C—C, and C

9.13.5.1.3.1.1 Method 1: Reaction of Imines, Acid Chlorides, and Alkynes

9.13.5.1.3.1.2 Method 2: Synthesis of Pyrrole-3,4-dicarboxylates by Multicomponent Reactions Involving Dimethyl Acetylenedicarboxylate

9.13.5.1.3.1.2.1 Variation 1: Reaction of Dimethyl Acetylenedicarboxylate with Amino Acids and Acid Chlorides

9.13.5.1.3.1.2.2 Variation 2: Reaction of Dimethyl Acetylenedicarboxylate with Imines and Diazoacetonitrile or an Isocyanide

9.13.5.1.3.1.3 Method 3: Synthesis of N—C2 Benzo-Fused Pyrroles from Isoquinolines, Quinolines, or Pyridines

9.13.5.1.3.1.4 Method 4: Reactions of Aryl and Alkyl Acetylenes in Stoichiometric Metal-Mediated Pyrrole Syntheses

9.13.5.1.3.1.5 Method 5: Pyrrol-2-amine Synthesis from Nitriles, Aldehydes, and α-(Tosylamino)acetophenones

9.13.5.1.4 By Formation of Three C—C Bonds

9.13.5.1.4.1 Fragments C—N—C and Two C Fragments

9.13.5.1.4.1.1 Method 1: By Transformation of Benzylic Alcohols, Nitroalkanes, and tert-Butyl Isocyanoacetate Using Solid-Supported Reagents

9.13.5.1.4.1.2 Method 2: Reaction of Aldehydes, Ethyl (Diethoxyphosphoryl)acetate, and Tosylmethyl Isocyanide

9.13.5.1.5 By Formation of Two N—C Bonds

9.13.5.1.5.1 Fragments N and C—C—C—C

9.13.5.1.5.1.1 Method 1: Paal–Knorr Reaction

9.13.5.1.5.1.2 Method 2: Reaction of Amines with γ-Modified Carbonyl Compounds as 1,4-Dicarbonyl Equivalents

9.13.5.1.5.1.3 Method 3: Reaction of Alka-2,3-dienyl Carbonyl Compounds and Cyclopropyl Ketones with Amines

9.13.5.1.5.1.4 Method 4: Reaction of Alk-3-ynyl Carbonyl Compounds with Amines

9.13.5.1.5.1.5 Method 5: Reaction of Buta-1,3-dienes and Related Compounds with Amines

9.13.5.1.5.1.6 Method 6: Reactions of 1,3-, 1,4-, and 1,5-Diynes with Amines

9.13.5.1.5.1.7 Method 7: Reaction of 1-En-3-yne Analogues and Amines

9.13.5.1.5.1.8 Method 8: Reaction of Enynol Analogues and Amine Derivatives

9.13.5.1.5.1.9 Method 9: Reaction of (Z)-1,4-Dichlorobut-2-ene with Amines

9.13.5.1.5.1.10 Method 10: Reaction of 2-Allylbuta-2,3-dienoates with Sodium Azide

9.13.5.1.5.1.11 Method 11: Reactions of 1,6-Dicarbonyl-2,4-diene Equivalents with Amines

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

9.13.5.1.6.1 Fragments N—C—C—C and C

9.13.5.1.6.1.1 Method 1: Phosphine-Mediated Reaction of α,β-Unsaturated Imines with Acid Chlorides

9.13.5.1.6.1.2 Method 2: Rhodium(I)-Catalyzed [4 + 1]-Cycloaddition Reactions of α,β-Unsaturated Imines with Terminal Alkynes

9.13.5.1.6.1.3 Method 3: Reaction of α,β-Unsaturated Imines with Isocyanides or Carbenes

9.13.5.1.6.1.4 Method 4: Reaction of Acid Chlorides with Propargylamines and Sodium Iodide

9.13.5.1.6.2 Fragments N—C—C and C—C

9.13.5.1.6.2.1 Method 1: Reactions of 2H-Azirines and 1,3-Dicarbonyl Compounds

9.13.5.1.6.2.1.1 Variation 1: Reaction of Vinyl Azides with 1,3-Dicarbonyl Compounds

9.13.5.1.6.2.1.2 Variation 2: Reaction of Isolated 2H-Azirines with 1,3-Dicarbonyl Compounds

9.13.5.1.6.2.2 Method 2: Knorr-Type Reaction of Oximes and 1,3-Dicarbonyl Compounds

9.13.5.1.6.2.3 Method 3: Reaction of Enamines and Alkynes

9.13.5.1.6.2.4 Method 4: Reactions of 1,2-Diazabuta-1,3-dienes and Enol Derivatives

9.13.5.1.6.2.5 Method 5: Reactions of Imines and Alkenes

9.13.5.1.6.2.6 Method 6: Rearrangement Mechanisms

9.13.5.1.6.3 Fragments N—C and C—C—C

9.13.5.1.6.3.1 Method 1: Reaction of Amines with 1,3-Dicarbonyl Compounds and Equivalents

9.13.5.1.6.3.2 Method 2: Reactions of Imine Derivatives with α-Functionalized Alkenes and Alkynes

9.13.5.1.6.3.3 Method 3: Reactions of Substrates such as Cyclopropenes, Nitriles, Amino Chromium Carbenes, and α,β-Unsaturated Carbonyl Compounds and Derivatives

9.13.5.1.7 By Formation of Two C—C Bonds

9.13.5.1.7.1 Fragments C—N—C—C and C

9.13.5.1.7.1.1 Method 1: Reaction of α-Amido Ketones with Ynolates

9.13.5.1.7.1.2 Method 2: Reaction of 4-(Trifluoroacetyl)münchnones with Wittig Reagents

9.13.5.1.7.2 Fragments C—N—C and C—C

9.13.5.1.7.2.1 Method 1: Reactions of α-Functionalized Isocyanides and Alkenes or Alkynes

9.13.5.1.7.2.1.1 Variation 1: Tosylmethyl Isocyanide and Alkenes

9.13.5.1.7.2.1.2 Variation 2: α-Substituted Tosylmethyl Isocyanides and Alkenes

9.13.5.1.7.2.1.3 Variation 3: Active Methylene Isocyanides and Alkynes

9.13.5.1.7.2.1.4 Variation 4: Active Methylene Isocyanides and Alkynes under Phosphine Catalysis with Reversal of Regioselectivity

9.13.5.1.7.2.1.5 Variation 5: Reactions with Alkenes Possessing Leaving Group Substituents

9.13.5.1.7.2.2 Method 2: Cycloaddition of Azomethine Ylides and Alkenes or Alkynes

9.13.5.1.7.2.2.1 Variation 1: N-α-Functionalized Amides (Thioamides), or N-α-Active Methylene Imines as Azomethine Ylide Precursors

9.13.5.1.7.2.2.2 Variation 2: N-Acylamino Acids as Azomethine Ylide Precursors in the Form of Münchnones

9.13.5.1.8 By Formation of One N—C Bond

9.13.5.1.8.1 Fragment N—C—C—C—C

9.13.5.1.8.1.1 Method 1: Paal–Knorr-Type Cyclizative Condensation

9.13.5.1.8.1.2 Method 2: 5-endo-Cyclization Reactions

9.13.5.1.8.1.2.1 Variation 1: Cyclization of Alk-3-ynylamines and Homopropargyl Azides

9.13.5.1.8.1.2.2 Variation 2: α-Alkynyl Imine Isomerization and Cyclization

9.13.5.1.8.1.2.3 Variation 3: Cyclization of Dienyl Azides and Dienyl Amines

9.13.5.1.8.1.3 Method 3: 5-exo-Cyclization Reactions

9.13.5.1.8.1.3.1 Variation 1: Cyclization of (Z)-(Alk-2-en-4-ynyl)amines and Analogues

9.13.5.1.8.1.3.2 Variation 2: Cyclization of (Z)-Alk-2-en-4-ynyl Imines

9.13.5.1.8.1.3.3 Variation 3: Cyclization of Alk-4-ynyl and Alk-4-enyl Imines

9.13.5.1.9 By Formation of One C—C Bond

9.13.5.1.9.1 Fragment C—N—C—C—C

9.13.5.1.9.1.1 Method 1: Reaction Involving Cyclization of Functionalized Ketene N,S-Acetals

9.13.5.1.9.1.2 Method 2: Metalation of Allyl Isothiocyanate

9.13.5.1.9.1.3 Method 3: Decarboxylative Cyclization of β-Enaminones

9.13.5.1.9.1.4 Method 4: Enamine Cyclization

9.13.5.1.9.2 Fragment C—C—N—C—C

9.13.5.1.9.2.1 Method 1: Lewis Acid Catalyzed Ring Closure

9.13.5.1.9.2.2 Method 2: Palladium-Catalyzed Synthesis from Enamines

9.13.5.1.9.2.3 Method 3: Synthesis from N-Propargyl β-Enaminones

9.13.5.1.9.2.4 Method 4: Synthesis Based on a Staudinger/Aza-Wittig Reaction

9.13.5.1.9.2.5 Method 5: Ring Closure To Give 3,4-Bis(lithiomethyl)dihydropyrroles and Subsequent Functionalization

9.13.5.1.9.2.6 Method 6: Metathesis-Based Approaches

9.13.5.2 Synthesis by Ring Transformation

9.13.5.2.1 By Ring Enlargement

9.13.5.2.1.1 Method 1: Aziridine Ring Expansion

9.13.5.2.1.2 Method 2: Azetidine, β-Lactam, and Cyclopropane Ring Expansions

9.13.5.2.2 By Ring Contraction

9.13.5.2.2.1 Method 1: Nitrogen Extrusion from Pyridazines

9.13.5.2.2.2 Method 2: Sulfur Extrusion from N,S-Heterocycles

9.13.5.3 Synthesis by Aromatization

9.13.5.3.1 By Elimination

9.13.5.3.1.1 Method 1: Dihydropyrrolol Dehydration by Stoichiometric Copper(II)

9.13.5.3.2 By Dehydrogenation

9.13.5.3.2.1 Method 1: Dihydropyrrole Oxidation Using 2,3-Dichloro-5,6-dicyanobenzo-1,4-quinone

9.13.5.3.2.2 Method 2: Photochemical Dihydropyrrole Dehydrogenation

9.13.5.3.3 By Combinations of Elimination, Dehydrogenation, Isomerization, Ring Substitution, and Substituent Modification Reactions

9.13.5.3.3.1 Method 1: Elimination in Conjunction with Dehydrogenation

9.13.5.3.3.2 Method 2: Elimination in Conjunction with Isomerization

9.13.5.3.3.3 Method 3: Dihydropyrrole Dehydrogenation in Conjunction with Cross Coupling

9.13.5.3.3.4 Method 4: Elimination from Pyrrolidin-4-ones in Conjunction with Isomerization and 4-Amination

9.13.5.3.3.5 Method 5: Decarboxylative Oxidation in Conjunction with Elimination/Isomerization and Ring Substitution

9.13.5.3.3.5.1 Variation 1: 5-Halogenated and 2,4-Diformylated Pyrroles from 5-Oxopyrrolidine-2-carboxylates

9.13.5.3.3.5.2 Variation 2: 1-(2-Oxo-1,3-dihydroindol-3-yl)pyrrole from 4-Hydroxypyrrolidine-2-carboxylate

9.13.5.4 Synthesis by Substituent Modification

9.13.5.4.1 Substitution of Existing Substituents

9.13.5.4.1.1 Substitution of C-Hydrogen, Halogens, and Other Heteroatoms

9.13.5.4.1.1.1 C-Acylation and C-Formylation

9.13.5.4.1.1.1.1 Method 1: Formylation under Vilsmeier Conditions

9.13.5.4.1.1.1.2 Method 2: Formylation via Metalated Pyrrole Intermediates

9.13.5.4.1.1.1.3 Method 3: Electrophilic Pyrrole Acylation

9.13.5.4.1.1.2 C-Alkylation

9.13.5.4.1.1.2.1 Method 1: Pyrrole Alkylation with Electrophilic Alkanes

9.13.5.4.1.1.2.2 Method 2: Pyrrole Alkylation with Alkenes

9.13.5.4.1.1.2.2.1 Variation 1: Intermolecular Alkylation with Electrophilic Alkenes

9.13.5.4.1.1.2.2.2 Variation 2: Intramolecular Alkylation with Nonactivated Alkenes

9.13.5.4.1.1.2.3 Method 3: Pyrrole Alkylation with Imines

9.13.5.4.1.1.2.4 Method 4: Pyrrole Alkylation with Aldehydes and Ketones

9.13.5.4.1.1.3 C-Alkenylation

9.13.5.4.1.1.3.1 Method 1: Reaction of Halopyrroles with Alkenes under Heck Conditions

9.13.5.4.1.1.3.2 Method 2: Reaction of Pyrroles with Alkenes under Oxidative Heck Conditions

9.13.5.4.1.1.3.3 Method 3: Reaction of Pyrroles with Alkynes and Equivalents

9.13.5.4.1.1.4 C-Alkynylation

9.13.5.4.1.1.4.1 Method 1: Sonogashira Reaction of Halopyrroles with Alkynes

9.13.5.4.1.1.4.2 Method 2: Reaction of 1-Halogenated Alkynes with Pyrroles

9.13.5.4.1.1.5 C-Arylation

9.13.5.4.1.1.5.1 Method 1: Cross Coupling of Aryl Halides with Pyrrolylboronates, or Arylboronic Acids with Halopyrroles

9.13.5.4.1.1.5.2 Method 2: Cross Coupling at Pyrrole CH with Aryl Halides and Arylboronic Acids

9.13.5.4.1.1.5.3 Method 3: Decarboxylative Arylation of Pyrrole C-Carboxylates

9.13.5.4.1.1.6 C-Cyanation

9.13.5.4.1.1.6.1 Method 1: Oxidative α-Cyanation with Hypervalent Iodine(III)

9.13.5.4.1.1.6.2 Method 2: Oxidative Vilsmeier Cyanation

9.13.5.4.1.1.6.3 Method 3: Anodic Cyanation of 1-Aryl-1H-pyrroles

9.13.5.4.1.1.7 C-Trifluoromethylation

9.13.5.4.1.1.8 C-Halogenation

9.13.5.4.1.1.8.1 Method 1: Direct Substitution of Pyrrole CH by Halogen

9.13.5.4.1.1.8.1.1 Variation 1: Electrophilic Mono CH Substitution

9.13.5.4.1.1.8.1.2 Variation 2: Multiple Electrophilic CH Substitutions

9.13.5.4.1.1.8.2 Method 2: Halogenation via Metalated Pyrrole Intermediates

9.13.5.4.1.1.8.3 Method 3: Electrophilic Substitution of Pyrrole C-Carboxylate by Halogen

9.13.5.4.1.1.8.4 Method 4: Electrophilic Substitution of C-Trimethylsilyl Groups by Halogen

9.13.5.4.1.1.9 Functionalization with Nitrogen-Based Groups

9.13.5.4.1.1.9.1 Method 1: Electrophilic Nitration of Pyrroles

9.13.5.4.1.1.9.2 Method 2: Electrophilic Nitrosation of Pyrroles

9.13.5.4.1.1.9.3 Method 3: Reactions of Pyrroles with Arenediazonium Salts

9.13.5.4.1.1.9.4 Method 4: Azidation of Halo- and Aminopyrroles

9.13.5.4.1.1.9.5 Method 5: Amination and Amidation of Halopyrroles by Metal-Catalyzed Cross Coupling and Nucleophilic Aromatic Substitution

9.13.5.4.1.1.9.6 Method 6: Aryl- and Fluoroalkylsulfonamidation of Pyrroles

9.13.5.4.1.1.10 Functionalization with Silicon-Based Groups

9.13.5.4.1.1.10.1 Method 1: Pyrrole C-Silylation

9.13.5.4.1.1.11 Functionalization with Phosphorus-Based Groups

9.13.5.4.1.1.11.1 Method 1: Pyrrole Phosphorylation and Phosphinylation with Electrophilic Halophosphorus Reagents

9.13.5.4.1.1.11.2 Method 2: Pyrrole Phosphorylation and Phosphinylation via Lithiopyrrole Generation

9.13.5.4.1.1.12 Functionalization with Sulfur- and Selenium-Based Groups

9.13.5.4.1.1.12.1 Method 1: Electrophilic Pyrrolesulfonate Synthesis

9.13.5.4.1.1.12.2 Method 2: Chlorosulfonylation of Pyrroles with Chlorosulfonic Acid

9.13.5.4.1.1.12.3 Method 3: Pyrrolyl Sulfone Synthesis from Sulfonyl Chlorides

9.13.5.4.1.1.12.4 Method 4: Pyrrolyl Sulfoxide Synthesis

9.13.5.4.1.1.12.5 Method 5: Pyrrolylsulfonium Salt Synthesis

9.13.5.4.1.1.12.6 Method 6: Sulfanylpyrrole Synthesis

9.13.5.4.1.1.12.6.1 Variation 1: Synthesis of Sulfanylpyrroles Using Electrophilic Sulfenylation

9.13.5.4.1.1.12.6.2 Variation 2: Sulfanylpyrroles from Reactions of Metalated Pyrroles with Sulfur Sources

9.13.5.4.1.1.12.6.3 Variation 3: Sulfanylpyrroles from Nucleophilic Aromatic Substitution

9.13.5.4.1.1.12.6.4 Variation 4: Thiocyanation of Pyrroles

9.13.5.4.1.1.12.6.5 Variation 5: Dipyrrolyl Sulfide Synthesis

9.13.5.4.1.1.12.6.6 Variation 6: Preparation of Pyrroles with Multiple Sulfur Substituents

9.13.5.4.1.1.12.7 Method 7: Selanylpyrrole Synthesis

9.13.5.4.1.2 Substitution of N-Hydrogen

9.13.5.4.1.2.1 Method 1: N-Acylation

9.13.5.4.1.2.2 Method 2: N-Alkylation and -Allylation

9.13.5.4.1.2.3 Method 3: N-Alkenylation

9.13.5.4.1.2.4 Method 4: N-Arylation

9.13.5.4.1.2.5 Method 5: N-Amination and -Phosphinylation

9.13.5.4.2 Modification of Substituents

9.13.5.4.2.1 Modification of C-Acyl Substituents

9.13.5.4.2.1.1 Method 1: Reduction of 2- or 3-Acylpyrroles to 2- or 3-Alkylpyrroles with Hydrides, Zinc, or Hydrazine as Reductant

9.13.5.4.2.1.2 Method 2: Addition and Condensation Reactions of Acyl Groups

9.13.5.4.2.1.3 Method 3: Rearrangement of Acyl Groups

9.13.5.4.2.2 Modification of C-Alkyl Substituents

9.13.5.4.2.2.1 Method 1: Substitution Reactions of Mannich Bases

9.13.5.4.2.2.2 Method 2: Alkylation of α-Methylene Substituents

9.13.5.4.2.2.3 Method 3: Oxidation of α-Methylene Substituents

9.13.5.4.2.3 Modification of C-Vinyl Substituents

9.13.5.4.2.3.1 Method 1: Arylation by Heck Reaction

9.13.5.4.2.3.2 Method 2: Pyrrolecarbaldehyde Synthesis via Osmium(VIII) Oxide Oxidation

9.13.5.4.2.4 Modification of C-Nitropyrroles by Reductive Acylation

9.13.5.4.2.4.1 Method 1: Synthesis of 2- and 3-(Acylamino)-1H-pyrroles from 2- and 3-Nitro-1H-pyrroles and Acid Anhydrides

9.13.5.4.2.5 Modification of N-Substituents

9.13.5.4.2.5.1 Method 1: Synthesis of 1-(Hydroxymethyl)pyrrole Derivatives by Nucleophilic Addition to 1-Acylpyrroles

9.13.5.4.2.5.2 Method 2: Conjugate Addition to α,β-Unsaturated 1-Acylpyrroles

9.13.5.4.2.5.2.1 Variation 1: Chiral Epoxide Synthesis

9.13.5.4.2.5.2.2 Variation 2: Enantioselective Addition of Carbon Nucleophiles

9.13.5.4.2.5.3 Method 3: Hydroformylation of 1-Allylpyrrole

Volume 16: Six-Membered Hetarenes with Two Identical Hetero-atoms

16.9 Product Class 9: Cinnolines

16.9.5 Cinnolines

R. Krishnamoorthy

16.9.5 Cinnolines

16.9.5.1 Synthesis by Ring-Closure Reactions

16.9.5.1.1 By Annulation to an Arene

16.9.5.1.1.1 By Formation of Two N—C Bonds

16.9.5.1.1.1.1 Fragments Arene—C—C and N—N

16.9.5.1.1.1.1.1 Method 1: Condensation of Quinones with Hydrazine

16.9.5.1.1.1.1.2 Method 2: Condensation of 1-Acyl-8-nitronaphthalenes with Hydrazine

16.9.5.1.1.1.1.3 Method 3: Cinnolin-3-amines via a Diels–Alder–Ene Sequence

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

16.9.5.1.1.2.1 Fragments Arene—N—N and C—C

16.9.5.1.1.2.1.1 Method 1: Synthesis of Cinnoline-3-carboxylates

16.9.5.1.1.2.1.2 Method 2: Synthesis of Pyridazinocinnolines

16.9.5.1.1.3 By Formation of One N—N Bond

16.9.5.1.1.3.1 Fragment N—Arene—Arene—N

16.9.5.1.1.3.1.1 Method 1: Condensation of Substituted Biaryls

16.9.5.1.1.3.1.1.1 Variation 1: Condensation of 2-Amino-2′-Nitrobiaryls

16.9.5.1.1.3.1.1.2 Variation 2: Cyclization of 2-Amino-3-(2-nitroaryl)quinolines

16.9.5.1.1.3.1.2 Method 2: Cyclization of 2,2′-Dinitrobiaryls

16.9.5.1.1.3.1.2.1 Variation 1: Reductive Cyclization of 2,2′-Dinitrobiaryls

16.9.5.1.1.3.1.2.2 Variation 2: Base-Catalyzed Cyclization of 2,2′-Dinitrobiphenyls

16.9.5.1.1.3.1.3 Method 3: Photooxidation of 3-(2-Aminophenyl)quinolin-2-amines

16.9.5.1.1.3.2 Fragment N—Arene—C—C—N

16.9.5.1.1.3.2.1 Method 1: Synthesis of Cinnoline Betaines

16.9.5.1.1.3.2.2 Method 2: Cyclization of 2-(Dinitrophenyl)alk-1-ene-1,1-diamines

16.9.5.1.1.4 By Formation of One N—C Bond

16.9.5.1.1.4.1 Fragment N—N—Arene—C—C

16.9.5.1.1.4.1.1 Method 1: Cyclization of Diazotized Anilines

16.9.5.1.1.4.1.1.1 Variation 1: Cyclization of Diazotized 2-Arylanilines

16.9.5.1.1.4.1.1.2 Variation 2: Cyclization of 2-(2,2-Difluorovinyl)anilines

16.9.5.1.1.4.1.2 Method 2: Cyclization of Diazotized 2-Acylanilines

16.9.5.1.1.4.1.3 Method 3: Cyclization of Diazotized Aryldifurylmethanes

16.9.5.1.1.4.1.4 Method 4: Cyclization of Alkynylanilines

16.9.5.1.1.4.1.4.1 Variation 1: Cyclization of Diazotized 2-Alkynylanilines

16.9.5.1.1.4.1.4.2 Variation 2: Cyclization of Diazotized 2-Diynylanilines

16.9.5.1.1.4.1.5 Method 5: Cyclization of (2-Alkynylaryl)- or (2-Acylaryl)triazenes

16.9.5.1.1.4.1.5.1 Variation 1: Cyclization of (2-Alkynylaryl)triazenes

16.9.5.1.1.4.1.5.2 Variation 2: Cyclization of (2-Acylaryl)triazenes

16.9.5.1.1.4.1.6 Method 6: Cyclization of (6-Oxocyclohexa-2,4-dienylidene)malononitrile Hydrazones

16.9.5.1.1.4.2 Fragment N—N—C—C—Arene

16.9.5.1.1.4.2.1 Method 1: Cyclization of Aryl-Substituted Heterocyclic Amines

16.9.5.1.1.4.2.1.1 Variation 1: Cyclization of Diazotized 3-Aminothiophenes

16.9.5.1.1.4.2.1.2 Variation 2: Cyclization of Diazotized 5-Amino-4-arylpyrazoles

16.9.5.1.1.4.2.1.3 Variation 3: Cyclization of Diazotized 3-Amino-4-arylmaleimides

16.9.5.1.1.4.2.2 Method 2: Cyclization of 2-Diazo-3-(haloaryl)-3-hydroxypropanoates

16.9.5.1.1.5 By Formation of One C—C Bond

16.9.5.1.1.5.1 Fragment Arene—N—N—C—C

16.9.5.1.1.5.1.1 Method 1: Cyclization of Phenylhydrazones

16.9.5.1.1.5.1.1.1 Variation 1: Cyclization of Oxomalonic Acid Derivatives

16.9.5.1.1.5.1.1.2 Variation 2: Synthesis of 3-Aroyl- or 4-Arylcinnolines

16.9.5.1.1.5.1.1.3 Variation 3: Synthesis of 3-Azolylcinnolines from Chloromethyl Ketones

16.9.5.1.1.5.1.1.4 Variation 4: Synthesis of 4-Alkyl-Substituted Cinnolines

16.9.5.2 Synthesis by Ring Transformation

16.9.2.1 Method 1: From 2H-Indazole Ring Enlargement

16.9.5.3 Synthesis by Aromatization

16.9.5.3.1 Method 1: Aromatization of Dihydrocinnolines

16.9.5.4 Synthesis by Substituent Modification

16.9.5.4.1 Substitution of Existing Substituents

16.9.5.4.1.1 Of Hydrogen

16.9.5.4.1.1.1 Method 1: By Lithiation

16.9.5.4.1.2 Of Heteroatoms

16.9.5.4.1.2.1 Method 1: By Metal–Halogen Exchange

16.9.5.4.1.2.2 Method 2: By Carbon Substituents via Cross-Coupling Reactions

16.9.5.4.1.2.3 Method 3: By Heteroatom Nucleophiles via Nucleophilic Substitution

16.9.5.4.1.2.3.1 Variation 1: Substitution of a Hydroxy Group by a Halogen

16.9.5.4.1.2.3.2 Variation 2: Introduction of Chalcogen Substituents

16.9.5.4.1.2.3.3 Variation 3: Introduction of Nitrogen Substituents

16.9.5.4.2 Modification of Existing Substituents

16.9.5.4.2.1 Of Carbon Substituents

16.9.5.4.2.1.1 Method 1: Of Carboxylic Acids and Derivatives

16.9.5.4.2.1.2 Method 2: Of Ketones, Aldehydes, and Derivatives

16.9.5.4.2.2 Of Heteroatom Substituents

16.9.5.4.2.2.1 Method 1: Of Sulfur-Containing Groups

16.9.5.4.2.2.2 Method 2: Of Amines

16.9.5.4.3 Addition Reactions

16.9.5.4.3.1 Method 1: Addition of Organic Groups

16.9.5.4.3.2 Method 2: Addition of Heteroatoms

16.23 Product Class 23: Diphosphinines

16.23.4 Diphosphinines

J. W. Lippert, III

16.23.4 Diphosphinines

16.23.4.1 1,2-Diphosphinines

16.23.4.1.1 Method 1: Synthesis of a 1,2-Dihydro-1,2-diphosphinine Derivative by Dimerization

16.23.4.1.2 Method 2: Synthesis of a 1,2-Dihydro-1,2-diphosphinine Chelate Complex with Palladium(II) Chloride

16.23.4.2 1,3-Diphosphinines

16.23.4.3 1,4-Diphosphinines

Author Index

Abbreviations

5.2.1 Product Subclass 1: Tin Hydrides

K. Tchabanenko

General Introduction

Like silicon and carbon, tin is a group 14 element, but with a more metallic character. This is reflected in the nomenclature of organotin compounds, which can be regarded as derivatives of the metal and named by using “tin” as a suffix, so that, for example, Bu4Sn can be named “tetrabutyltin” and Bu3SnH can be named “tributyltin hydride”. In an alternative system recommended by the International Union of Pure and Applied Chemistry, organotin compounds are named as derivatives of stannane [tin(IV) hydride], so that, for example, Ph3SnH is named “triphenylstannane”. Both the tin- and stannane-type nomenclature are used throughout this section, in common with practice in the general literature.

The compounds discussed in this section contain up to three alkyl or aryl groups bonded to a tin atom, with the remainder of the four valences being occupied by hydrogen atoms.[1,2] Whereas stannane (SnH4), the parent compound, is highly unstable, even at room temperature, and undergoes rapid decomposition to tin and molecular hydrogen,[3] its alkyl or aryl derivatives are somewhat more stable. Monoorganostannanes (R1SnH3) can be stored for a few days at room temperature, whereas diorganostannanes (R12SnH2) are stable for several weeks, and triorganostannanes (R13SnH) can be stored almost indefinitely. Alkylstannanes are generally more stable than the corresponding arylstannanes, and an increase in the bulk of the alkyl substituents leads to greater thermal stability.

The usefulness of organotin hydrides is to some degree limited by the toxic hazards they present, which depend on their volatility and degree of substitution.[1,4] Tributylstannane (tributyltin hydride; Bu3SnH) is less toxic than the more volatile triethyl and trimethyl analogues, and it is therefore the most widely used organostannane. This compound is best prepared by the reduction of hexabutyldistannoxane [bis(tributylstannyl) ether] with poly(methylhydrosiloxane) (▶ Scheme 1).[5] Other alkyl- and arylstannanes are usually prepared by the reduction of the corresponding organotin halides with lithium aluminum hydride[6–15] or sodium borohydride.[16–18] Another useful approach to organostannanes involves the treatment of organostannylated metal derivatives (R13SnLi, R13SnNa, or R13SnMgBr) with water.[12,19–23] This method can be used to prepare tributylstannane-d1 (tributyltin deuteride).[24] Alternatively, triorganostannanes can be prepared by reduction of the corresponding hexaorganodistannanes with metal hydrides (▶ Scheme 1).[25]

▶ Scheme 1 Methods for the Preparation of Tin Hydrides[5–25]

The principal applications of organotin hydrides in organic synthesis include mediation of free-radical dehalogenation, deoxygenation, addition, cyclization, and rearrangement reactions, and hydrostannylation of unsaturated functional groups (▶ Scheme 2). The chemistry, preparation, and reactions of organostannanes have been reviewed many times;[1,2,26–29] in particular, organotin-mediated radical reactions[30–35] and transition-metal-catalyzed hydrostannylation reactions[36–39] have received a great deal of attention.

▶ Scheme 2 Some Applications of Tin Hydrides in Organic Chemistry[30–39]

In general, stannanes are clear, colorless liquids that are frequently purified by distillation at reduced pressures. All show intense, sharp Sn—H IR absorption bands (e.g., SnH4, 1898 cm−1; BuSnH3, 1862 cm−1; Bu2SnH2, 1835 cm−1; and BuSnH3, 1813 cm−1).[40] In the 1H NMR spectra of alkylstannanes, resonances of hydrogen atoms bound to tin occur in the region δ 3.85–4.80.[40–44] The addition of electronegative substituents to the tin atom shifts the signal to higher values of δ [e.g., δ 7.42 for Bu2SnHCl]. 119Sn NMR spectra and 119Sn–13C coupling constants are also useful in the characterization of organotin compounds. Because tin has 10 naturally occurring isotopes, tin-containing compounds can be easily recognized by mass spectrometry.

SAFETY:

Organotin compounds exhibit a range of toxicities,[1,4] with a general tendency for heavier and less volatile tributyl- and triphenylstannanes to be less toxic than the corresponding lighter and more volatile triethyl or trimethyl analogues, which should not be used in large-scale experiments. Tributylstannanes cause skin burns and can be absorbed through the skin. It is recommended that all organotin hydrides are handled with care in an adequate fume hood, and that protective clothing and gloves are worn at all times. Appropriate waste-disposal procedures should be followed for all tin-contaminated chemicals and solvents.

The boiling points of commonly used stannanes are collected in ▶ Table 1.

▶ Table 1 Boiling Points of Common Tin Hydrides[5–8,15,45,46]

Tin Hydride

bp (°C)

Pressure (Torr)

Ref

MeSnH

3

0

760

[

6

]

Me

2

SnH

2

35

760

[

6

]

Me

3

SnH

59

760

[

6

]

Et

3

SnH

142

760

[

7

]

Pr

3

SnH

59–54

4

[

5

]

BuSnH

3

99–101

760

[

8

]

Bu

2

SnH

2

75–76

12

[

45

]

Bu

3

SnH

68–74

0.3

[

15

]

65–67

0.6

[

45

]

Bu

3

SnD

70–74

0.5

[

46

]

Ph

3

SnH

168–172

0.5

[

8

]

Although many organotin hydrides are commercially available, better results are generally obtained with freshly prepared reagents. Some convenient and reliable methods for the synthesis of tin hydrides, including the most commonly used of these reagents, are discussed below.

Synthesis of Product Subclass 1

5.2.1.1 Method 1: Reduction of Tin Halides

Organotin hydrides are generally synthesized by reduction of the corresponding organotin halides with metal hydrides. Lithium aluminum hydride is by far the most commonly used reducing agent,[6–15] although other hydride sources such as dialkylaluminum hydrides,[47] aluminum amalgam,[48] sodium borohydride,[17–19] or potassium borohydride[49] can also be used.

5.2.1.1.1 Variation 1: Reduction of Tin Halides with Lithium Aluminum Hydride

The reduction of alkyl- and aryltin chlorides or bromides by lithium aluminum hydride in ethereal solvents can be used to prepare the corresponding mono-, di-, or triorganostannanes (▶ Table 2).[6,10,13–15] In general, the reactions proceed smoothly at room temperature to give products of high purity. Diethyl ether is normally the solvent of choice, but other ethereal solvents such as dibutyl ether, diglyme, or 1,4-dioxane can be used if separation of the products from diethyl ether is difficult or if high reaction temperatures are required. The preparation of volatile tin hydrides or the parent stannane requires the use of specialized vacuum lines.[14] Deuterated forms of tin hydrides can be readily prepared by reduction with lithium aluminum deuteride.[50]

▶ Table 2 Reduction of Tin Chlorides with Lithium Aluminum Hydride[6–8,12,15]

Entry

Reactant

Solvent

Product

Yield (%)

Ref

1

SnCl

4

Et

2

O

SnH

4

55

[

12

]

2

Me

2

SnCl

2

1,4-dioxane

Me

2

SnH

2

72

[

6

]

3

Et

2

SnCl

2

Et

2

O

Et

2

SnH

2

90

[

7

]

4

Et

3

SnCl

Et

2

O

Et

3

SnH

56

[

7

]

5

BuSnCl

3

Et

2

O

BuSnH

3

37

[

8

]

6

Bu

2

SnCl

2

Et

2

O

Bu

2

SnH

2

66

[

8

]

7

Bu

3

SnCl

Et

2

O

Bu

3

SnH

74

[

8

]

8

Ph

3

SnCl

Et

2

O

Ph

3

SnH

83

[

15

]

Stannane (▶ Table 2, Entry 1); Typical Procedure for Volatile Stannanes:[12]

CAUTION:

Solid lithium aluminum hydride reacts vigorously with a variety of substances, and can ignite on rubbing or vigorous grinding.

A frozen soln of LiAlH4 (10 g, 0.26 mmol) in Et2O (200 mL) was added to a slurry of SnCl4•OEt2 (33.3 g, 0.1 mmol) and Et2O (200 mL) frozen at liq-N2 temperature. A stream of N2 (containing 0.1% of O2 to inhibit decomposition of the product) was passed through the cold mixture, which was warmed to −78 °C until all the soln liquefied. As the mixture warmed to −63.5 °C it turned brown. It was then allowed to warm to −20 °C over 1 h. The gas that evolved during the reaction was collected in a trap cooled in liq N2 and purified by repeated passage through a trap cooled to −112 °C; yield: 6.7 g (55%).

Triphenylstannane (▶ Table 2, Entry 8); Typical Procedure for Nonvolatile Stannanes:[15]

CAUTION:

Solid lithium aluminum hydride reacts vigorously with a variety of substances, and can ignite on rubbing or vigorous grinding.

CAUTION:

Because of the low thermal stability of tin hydrides, a low distillation pressure and temperature are required, and rapid distillation with an efficient, high-capacity vacuum pump is essential.

LiAlH4 (1.56 g, 41 mmol) and Ph3SnCl (38.5 g, 100 mmol) were added to Et2O (150 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 15 min and then at rt for 3 h. The mixture was then cooled in an ice–water bath and hydrolyzed by slow addition of H2O (100 mL). The Et2O layer was washed with ice water (2 × 100 mL) and the crude hydride was distilled very rapidly using an oil bath preheated to 200 °C to give a colorless oil: yield: 29 g (83%); bp 162–168 °C/0.5 Torr.

5.2.1.1.2 Variation 2: Reduction of Tin Halides with Sodium Borohydride

Although the reactions using lithium aluminum hydride discussed above in ▶ Section 5.2.1.1.1 provide good yields of tin hydrides, they must be performed under strictly anhydrous and inert conditions, even though this is not required for the tin derivatives themselves. For this reason, alternative procedures have been developed that use the less reactive reagents sodium borohydride[17–19] or potassium borohydride.[49] Solutions of sodium borohydride in diethyl ether or tetrahydrofuran do not react with organotin halides at room temperature or above; however, the use of solutions in 1,2-dimethoxyethane (monoglyme) or in diglyme results in smooth reductions. Yields are generally similar to or higher than those obtained from reactions with lithium aluminum hydride (▶ Table 3).[18] Stannanes that boil below 100 °C should be prepared in the higher-boiling solvent (diglyme), whereas less volatile hydrides should be prepared in the more volatile solvent (1,2-dimethoxyethane).

▶ Table 3 Reduction of Tin Chlorides with Sodium Borohydride[18]

Entry

Reactant

Solvent

Product

Yield (%)

Ref

1

MeSnCl

3

diglyme

MeSnH

3

92

a

[

18

]

2

Me

2

SnCl

2

diglyme

Me

2

SnH

2

96

b

[

18

]

3

Bu

2

SnCl

2

DME

Bu

2

SnH

2

56

[

18

]

4

Bu

3

SnCl

DME

Bu

3

SnH

96

[

18

]

5

Ph

3

SnCl

DME

Ph

3

SnH

82

[

18

]

a

The solvent was retained in a trap at 0 °C, the product at −126 °C.

b

The product was retained in a trap at −80 °C.

The parent stannane can be prepared in good yield by reaction of aqueous tin(II) chloride with sodium borohydride under acidic conditions (▶ Scheme 3).

▶ Scheme 3 Preparation of Stannane from Tin(II) Chloride and Sodium Borohydride[17]

Tributylstannane (▶ Table 3, Entry 4); Typical Procedure:[18]

A soln of Bu3SnCl (19.2 g, 59.0 mmol) in DME (140 mL) was added dropwise to a soln of NaBH4 (6.2 g, 163 mmol) in DME (230 mL) while the temperature was maintained at −10 °C. When the addition was complete, the mixture was allowed to stand for a few minutes at −10 °C and then, without filtration, the entire crude mixture was concentrated at 0 °C/2 Torr. The residue was extracted with Et2O and the soln was filtered. The Et2O was then removed by evaporation at 180 Torr, and remaining volatiles were removed from the resulting clear, colorless oil by evaporation at 0 °C/<1 Torr for 30 min; yield: 16.4 g (96%).

Stannane (1):[17]

A soln of SnCl2 (0.87 g, 4.6 mmol) in 0.6 M HCl (10 mL) was added to a flask connected to a series of traps suitable for the collection of condensable products. The apparatus was swept with N2, and a steady stream of N2 was maintained while 5% aq NaBH4 (20 mL) was added dropwise over 20 min. The gases that formed were passed through a trap at −23 °C, to remove H2O vapor, and then through a trap at −196 °C to collect the crude product. This was further purified by fractionation into a trap maintained at −112 °C; yield: 0.48 g (85%).

5.2.1.2 Method 2: Synthesis from Organotin Oxides, Alkoxides, or Amides by Reduction

Reduction of tin oxides [bis(stannyl) ethers] or alkoxystannanes by silanes is the preferred method for the synthesis of some of the most common organostannanes, such as tributylstannane or dibutylstannane (▶ Table 4).[5] The most efficient reducing agent is poly(methylhydrosiloxane), which is usually mixed with the tin compound at room temperature; the resulting stannanes are then removed by distillation. When other silicon reducing agents, such as triethylsilane, are used, little if any tributylstannane is produced; instead, large amounts of hexabutyldistannane (Bu3SnSnBu3) are isolated. Silanes are also good reducing agents for tin amides (▶ Scheme 4).[51,52]

▶ Table 4 Reduction of Bis(stannyl) Ethers and Alkoxystannanes with Various Reducing Agents[5]

Entry

Reactant

Silane

Ratio (Reactant/Silane)

Temp

Product

Yield (%)

Ref

1

(Bu

3

Sn)

2

O

(MeSiHO)

n

1:2

rt

Bu

3

SnH

79

[

5

]

2

(Bu

3

Sn)

2

O

(Ph

2

SiH)

2

O

1:1

rt

Bu

3

SnH

64

[

5

]

3

(Bu

3

Sn)

2

O

Ph

3

SiH

1:2

rt

Bu

3

SnH

41

[

5

]

4

(Bu

2

SnO)

m

(MeSiHO)

n

1:2

rt

Bu

2

SnH

2

51

[

5

]

5

(Bu

2

SnO)

m

(Ph

2

SiH)

2

O

1:1

120 °C

Bu

2

SnH

2

78

[

5

]

6

(Bu

2

SnO)

m

Ph

3

SiH

1:2

120 °C

Bu

2

SnH

2

4

[

5

]

7

Bu

3

SnOEt

(MeSiHO)

n

1:1

rt

Bu

3

SnH

86

[

5

]

8

Bu

2

Sn(OEt)

2

(MeSiHO)

n

1:2

rt

Bu

2

SnH

2

66

[

5

]

▶ Scheme 4 Reduction of a Tin Amide with a Silane[52]

Tributylstannane (▶ Table 4, Entry 1); Typical Procedure:[5]

(Bu3Sn)2O (40 g, 67 mmol) and (MeSiHO)n (8.0 g) were mixed together at rt. A slightly exothermic reaction occurred. After 30 min, the mixture was vacuum distilled to give two colorless fractions, bp 80–114 °C/6 Torr (2.8 g) and bp 114–116 °C/6 Torr (31.2 g). Redistillation of the major fraction gave Bu3SnH of 97.6% purity; yield: 15.4 g (79%); bp 105–106 °C/6 Torr.

5.2.1.3 Method 3: Synthesis from Organotin Lithium, Sodium, Potassium, or Magnesium Compounds by Reactions with Electrophiles

Organostannanes can be effectively prepared by treatment of an organotin metal compound with an electrophile.[12,20–24] Thus, treatment of stannane with metallic sodium gives stannylsodium (NaSnH3), which reacts with alkyl halides to give the corresponding lower alkylstannanes, as demonstrated by the synthesis of methylstannane (▶ Scheme 5).[22]

Organostannanes can also be prepared directly by hydrolysis of Sn—Li, Sn—Na, or Sn—MgX bonds with ammonium salts, dilute hydrochloric acid, water, or deuterium oxide (▶ Scheme 5 and ▶ Table 5, entries 2–4).[19–21,24] Trialkyltin deuterides, which are widely used in mechanistic studies, are most conveniently prepared by treatment of the corresponding stannane with a Grignard reagent bearing a bulky substituent such as a cyclohexyl, tert-butyl, or isopropyl group, followed by quenching with deuterium oxide (▶ Scheme 5).[24] The organometallic species can also be prepared from the corresponding organotin halide by treatment with a group 1 metal in liquid ammonia or tetrahydrofuran (▶ Scheme 5).[19–21]

▶ Scheme 5 Reactions of Tin–Metal Bonds with Electrophiles[12,19–24]

▶ Table 5 Preparation of Tin Hydrides by Treatment of Tin–Metal Compounds with Electrophiles[19–22,24]

Entry

Reactant

Electrophile

Product

Yield (%)

Ref

1

NaSnH

3

EtI

EtSnH

3

35

[

22

]

2

NaSnH

3

NH

4

Cl

SnH

4

80

[

22

]

3

(Ph

3

Sn)

2

Mg

NH

4

Cl

Ph

3

SnH

82

[

19

]

4

Bu

3

SnLi

H

2

O

Bu

3

SnH

54

[

21

]

Triphenylstannane (2):[20]

A soln of Ph3SnCl (38.6 g, 100 mmol) in dry THF (110 mL) was added over 3 min to Li clippings (6.9 g, 1.0 mol) in dry THF (100 mL). The reaction was slightly exothermic and gave an olive-brown soln. After 1 h, the mixture was filtered through glass wool to give a soln of Ph3SnLi, which was poured into excess 1 M aq HCl. The mixture was extracted with Et2O and the extracts were dried (Na2SO4) and concentrated. The residue was filtered to remove solid (Ph3Sn)2 and purified by distillation; yield: 12.1 g (34.5%); bp 145–149 °C/0.1 Torr.

Tributylstannane-d1 (3):[24]

Bu3SnH (29.1 g, 100.0 mmol) was added dropwise to a 1 M soln of CyMgBr in Et2O (110 mL) containing galvinoxyl (0.42 g, 0.01 mmol) at 0 °C. The mixture was stirred at rt for 1 h while the progress of the reaction was monitored by IR spectroscopy until the peak at 1812 cm−1, corresponding to the Sn—H bond, was no longer present. D2O (6 mL, 0.3 mol) was then added slowly at 0 °C. After 2 h, the organic layer was separated and the aqueous phase was washed with Et2O. The organic phases were combined, dried (MgSO4), and concentrated under reduced pressure to give a crude residue, which was purified by distillation; yield: 26.0 g (89%); bp 50–55 °C/0.001 Torr.

Tributylstannane (▶ Table 5, Entry 4):[21]

Bu3SnCl (65.1 g, 200 mmol) was added to Li clippings (15.0 g, 2 mol), and the mixture was stirred for 1 h. Dry THF (100 mL) was slowly added and the reaction became slightly exothermic, giving a dark green soln. After 2 h, the mixture was filtered through glass wool to give a soln of Bu3SnLi, which was added to excess H2O. The mixture was extracted with Et2O, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by distillation; yield: 31.4 g (54%); bp 46–49 °C/0.18 Torr.

Applications of Product Subclass 1 in Organic Synthesis

5.2.1.4 Tin-Mediated Radical Chain Reactions Not Involving Rearrangement of Intermediate Radicals

The reduction of alkyl halides with tin hydrides was first discovered in 1957, by accident, by van der Kerk and co-workers.[53] An attempted hydrostannylation of allyl bromide did not give the expected (3-bromopropyl)triphenylstannane [Br(CH2)3SnPh3] but, instead, gave bromotriphenylstannane and propene in excellent yields (▶ Scheme 6). The mechanism of this radical chain reaction, which is initiated by oxygen, was proposed by Kuivila.[26]

▶ Scheme 6 Reduction of Allyl Bromide by Triphenylstannane[26]

The ability of trialkyl- and triaryltin hydrides to reduce halides under mild conditions extends to various other groups. However, it is the deoxygenation of alcohols through their xanthates[54] that has attracted the attention of synthetic chemists, as this reaction can be applied in the synthesis of complex molecules, including natural products. The discovery of C—C bond-forming reactions, which readily occur by means of radical reactions,[55,56] has made tin hydride mediated free-radical chemistry one of the most innovative and productive fields in organic synthesis, especially in the construction of five-membered rings.

Radical chain reactions, such as the reaction shown in ▶ Scheme 6, are initiated by the formation of an organostannyl radical. One of the most common ways of achieving this is by the use of a thermally unstable compound, which can be an azo compound, such as 2,2′-azobisisobutyronitrile (AIBN), or a peroxide, such as di-tert-butyl peroxide, dibenzoyl peroxide, or dilauroyl peroxide. On heating, these compounds form alkyl radicals that abstract hydrogen from the stannane (▶ Scheme 7). Photoinitiation[57] or the use of aerobic initiation (usually involving triplet “biradical” oxygen) in such reagent combinations as triethylborane/tributylstannane,[58] 9-borabicyclo[3.3.1]nonane/tributylstannane,[59] or diethylzinc/tributylstannane[60] are among the preferred methods for initiating radical reactions (▶ Scheme 7). Other methods include the use of zinc(II) chloride/tributylstannane,[61] copper(I) chloride/tributylstannane,[62] or indium(III) chloride/tributylstannane.[63]

▶ Scheme 7 Some Common Radical-Initiation Reactions[30,55,58,59]

The radical initiators are usually present in 5–10 mol% amounts. To compensate for radical chain termination through coupling reactions, addition is performed slowly over the course of the reaction by means of a syringe pump or by portionwise addition. The choice of the initiator is crucial for successful radical reactions and is generally governed by radical-initiation conditions and the optimal conditions for the chain process. The half-life of the initiator is a key factor in choosing the reaction temperature; the half-lives in toluene at 100 °C of AIBN, dibenzoyl peroxide, and di-tert-butyl peroxide are 0.1, 0.5, and 200 h, respectively.[64] 2,2′-Azobis(4-methoxy-2,4-dimethylpentanenitrile), which can initiate radical reactions at room temperature, is frequently used with sensitive substrates that require mild conditions.[65]

By analogy to the radical reduction of allyl bromide (▶ Scheme 6), a general radical-chain process for tin hydride mediated reduction of C—X bonds can be presented in the form of a continuous cycle (▶ Scheme 8).

▶ Scheme 8 Tin Hydride Mediated Reduction of C—X Bonds

The reaction of tin radicals with R1—X species occurs fastest with alkyl iodides and diminishes in the order alkyl iodides > aryl iodides ≈ vinyl iodides > alkyl bromides > aryl bromides ≈ vinyl bromides ≈ α-chloro esters ≈ alkyl phenyl selenides > alkyl chlorides ≈ alkyl phenyl sulfides.[66]

For the same X group, the rate will increase with increasing stability of the radical that is produced: aryl < vinyl < primary alkyl < secondary alkyl < tertiary alkyl. The stability of the intermediate alkyl, vinyl, or aryl radical determines the choice of reaction conditions, as these intermediates are highly reactive and can undergo one of several competing reactions, including homodimerization (rate constant k1), reaction with the solvent [reversible addition to an aromatic solvent (k2) and elimination (k3), where k3>>k2], and (desired) reduction through hydrogen abstraction (rate constant k4) (▶ Scheme 9).

▶ Scheme 9 Competing Radical Reactions

The concentration of the organostannyl radicals and the substrate carbon-based radicals must be kept low to minimize undesired radical–radical combination reactions, which are usually responsible for termination of the radical chain. This can be achieved by slow addition of the radical initiator during the course of the reaction, as discussed previously. Addition of substrate carbon-based radicals to aromatic solvents, which are the solvents most commonly used for these reactions, is reversible[67] and therefore this reaction does not usually interfere with the desired reduction through hydrogen abstraction. The latter reaction has a wide range of rate constants (▶ Table 6) that depend on the nature of the R1 group,[68–70] and this is an important factor to bear in mind when planning a successful radical reaction.

▶ Table 6 Rates of Reactions between Some Carbon-Centered Radicals and Organostannanes[68–70]

Radical

Stannane

Temp (°C)

Rate Constant (M

−1

•s

−1

)

Ref

Me•

Bu

3

SnH

30

1.2 × 10

7

[

68

]

R

2

CH

2

•

Bu

3

SnH

30

2.7 × 10

6

[

68

]

R

2

CH

2

•

Ph

3

SnH

25

2.7 × 10

6

[

70

]

iPr•

Bu

3

SnH

30

1.5 × 10

6

[

68

]

t

-Bu

Bu

3

SnH

30

1.7 × 10

6

[

68

]

Bu

3

SnH

30

8.5 × 10

7

[

70

]

Me

2

C=CH•

Bu

3

SnH

30

3.5 × 10

8

[

68

]

Ph•

Bu

3

SnH

30

5.9 × 10

8

[

69

]

Bn•

Bu

3

SnH

25

3.6 × 10

4

[

69

]

When planning a successful radical chain reaction, it is important to know, or at least to be able to estimate, the rate constants of all competing reactions and to arrange to make the rate constant for the desired process as high as possible.

An important problem in tin hydride mediated radical reactions is the removal of residues of tin compounds from the final products. Tin hydrides (which are often used in excess) and tin chlorides are normally difficult to remove from products by means of column chromatography. The choice of a suitable workup is therefore an important factor in the development of a new tin-mediated radical-chain process. Methods that have been developed by chemists over the years include partitioning between methanol or acetonitrile and petroleum ether, which permits the separation of polar reaction products from nonpolar organotin compounds.[71] This approach has been elaborated by the use of polyfluorinated tin hydrides, which can be easily removed by partitioning the reaction mixtures between organic and polyfluorinated solvents.[72] When the products of radical reactions are nonpolar, another type of stannane can be used. Water-soluble polyethers can be successfully used in some radical reactions,[73] and polymer-supported reagents can simplify product separation.[74–77] In some instances the stannane can be used in a catalytic amount in combination with a second reducing agent, such as poly(methylhydrosiloxane),[10] a borohydride,[78] or a cyanoborohydride.[79] Another type of approach involves simple chemical reactions to convert tin byproducts in the crude reaction mixtures into more readily separated forms. For example, the tin byproduct can be converted into an insoluble precipitate that can be separated by filtration or, in the case of organotin halides, converted into the corresponding phenylsulfanyl derivatives (R13SnSPh), which can be readily separated by column chromatography. The most popular methods include treatment of product mixtures with 1,8-diazobicyclo[5.4.0]undec-7-ene and iodine,[80] with potassium fluoride,[81] or with potassium fluoride impregnated silica.[82]

For the removal of tin residues from reaction mixtures by reaction with 1,8-diazobicyclo[5.4.0]undec-7-ene and iodine,[80] reagent-grade diethyl ether is added to the crude reaction mixture (note: anhydrous diethyl ether should not be used). This is followed by addition of 1.5 equivalents of 1,8-diazobicyclo[5.4.0]undec-7-ene, based on the amount of tin hydride used in the original reaction. The mixture is then titrated with a 0.1 M solution of iodine. A white precipitate of 1,8-diazobicyclo[5.4.0]undec-7-ene hydroiodide forms, and addition of iodine is continued until its color just persists. The mixture is then filtered through a small silica plug with elution by diethyl ether, and the solvent is removed from the filtrate under reduced pressure.

For the removal of tin residues from reaction mixtures by reaction with potassium fluoride,[81] the crude mixture is taken up in diethyl ether and the solution is treated with an excess of an aqueous solution of potassium fluoride (~10 g/100 mL). The colorless precipitate that forms is filtered off and the filtrate is collected, dried over magnesium sulfate, and concentrated to give the crude product that can be further purified by column chromatography.

5.2.1.4.1 Method 1: Reduction of Carbon—Heteroatom Bonds

5.2.1.4.1.1 Variation 1: Reduction of Carbon—Halogen Bonds

Reduction of alkyl, vinyl, or aryl halides to the corresponding hydrocarbons using tin hydrides is one of the mildest and best-yielding methods for this important transformation. Although the general reaction is best demonstrated by reduction of simple substrates such as 4-bromotoluene[57] or 5-bromooctahydronaphthalen-1(2H)-one (5),[83] the reduction can be successfully performed on complex substrates, such as the penicillin derivative 7,[84] with excellent yields (▶ Scheme 10). The stereoselectivity of this reaction is determined by the shape of the intermediate radical 8, and not by the stereochemistry of the starting bromide 7, which is employed as a mixture of two epimers. Hydrogen abstraction by 8 occurs on the less hindered exo-face of the cup-shaped radical. This example also shows that this method can tolerate a wide range of functional groups (for example, the hydroxy group does not require protection). Note also that the C—S bonds are not cleaved because the C—Br bond undergoes much more rapid homolytic cleavage.[66]

▶ Scheme 10 Reduction of C—Br Bonds with Tin Hydrides[57,83,84]

The chemoselectivity of this reaction is further demonstrated by the selective reduction of a C—Br bond in the presence of a C—Cl bond in 7-bromo-7-chlorobicyclo[4.1.0]heptane (9).[85] Furthermore, chemoselectivity can be observed with atoms of the same halogen if the radicals resulting from the cleavage of the different C—X bonds differ significantly in their stability. The reduction of trichloride 10 with 2 equivalents of tributylstannane results in reaction at the C—Cl bonds α to the carbonyl group, reflecting the greater stability of the radicals conjugated to the carbonyl group compared with that of a simple tertiary radical (▶ Scheme 11). The product 11 of this reaction can be further converted into the bicyclic lactone 12.[86]

In another example of selective reduction, the bridgehead bromine atoms in polycycle 13 (▶ Scheme 11) are selectively reduced while the vinylic ones remain unaffected; this is possible because of the greater difficulty in generating vinylic radicals.[87]

The direct reduction of a radical generated by homolytic cleavage of a C—X bond can compete with a rearrangement reaction, as demonstrated in the case of bromocyclopropaindene 14, which on treatment with tributylstannane gives the rearranged product 15. The rearrangement of the intermediate radical can, however, be suppressed by minimizing its lifetime by the changing the stannane to a better hydrogen-atom donor; thus, use of triphenylstannane as the reducing agent gives the dehalogenated cyclopropane derivative 16 (▶ Scheme 11).[88]

▶ Scheme 11 Chemoselectivity in Tin Hydride Reductions of Carbon—Halogen Bonds[85–88]

The stereoselectivity of tin hydride reductions is generally poor because of the planar (or rapidly interconverting tetrahedral) nature of the intermediate carbon-centered radicals. Thus, reduction of enantiomerically pure [(R)-1-chloroethyl]benzene (17) with triphenylstannane-d1 gives racemic deuterated ethylbenzene (±)-18.[89] Attempts at asymmetric reductions using chiral tin hydrides have resulted in modest enantioselectivities at best.[90–93]

Chiral Lewis acid catalysts can be used in asymmetric reductions of α-halogenated carbonyl compounds.[94] An enantiomeric excess of 62% is achieved in the reduction of coumarin 19 in the presence of magnesium iodide and the chiral bispyrrolidine 20 (▶ Scheme 12).[95] Combinations of chiral stannanes and chiral Lewis acids can also be used.[96]

The diastereoselectivity of the reduction, on the other hand, can be effectively controlled by steric factors present elsewhere in the molecule, as illustrated for the case of the penicillin analogue 7 (▶ Scheme 10). Many other examples of diastereoselective reductions of alkyl iodides and bromides have been reported.[32,97–100] Of particular interest is the effect of chelating Lewis acids on the diastereoselectivity of the radical reductions.[78,79,101–105] Radical reduction of the α-halo-β-methoxy ester 21 by tributylstannane at low temperatures gives the anti-product anti-22, whereas in the presence of a bidentate Lewis acid, syn-22 is formed (▶ Scheme 12). The observed stereoselectivities can be explained in terms of the transition states for the reaction by taking into account a number of stereoelectronic factors.[106]

▶ Scheme 12 Stereoselectivity in Reductions of Alkyl Halides with Stannanes[89,95]

Finally, in a convenient procedure, tin hydrides can be generated catalytically from the corresponding tin chlorides by mild reduction with a borohydride in an alcoholic solvent.[107,108] An example of this type of reaction is the catalytic reduction of iodide 23 to give the corresponding deiodinated derivative 24 (▶ Scheme 13).[107]

▶ Scheme 13 Use of a Catalytic Amount of a Tin Compound To Reduce a Carbon—Halogen Bond[107]

Toluene (4); Typical Procedure:[57]

CAUTION:

Volatile alkylstannanes are potent neurotoxins; take all appropriate precautions.

A mixture of neat Et3SnH (32.6 mL, 200 mmol) and 4-bromotoluene (25.7 g, 152 mmol) in a quartz flask under argon was irradiated at rt using a 125-W high-pressure Hg lamp. When the reaction was complete (GC), the product was separated by distillation; yield: 9.9 g (72%); bp 110 °C.

Octahydronaphthalen-1(2H)-one (6); Typical Procedure:[83]

Bu3SnH (0.29 g, 1 mmol) and AIBN (1 mg) were added to a soln of bromo compound 5 (107 mg, 0.46 mmol) in dry benzene (220 mL) (CAUTION:carcinogen) under N2. The mixture was refluxed for 24 h and then cooled and concentrated under reduced pressure. The crude residue was dissolved in MeCN (50 mL) and extracted with hexane (5 × 10 mL) to remove tin residues. The MeCN layer was concentrated to give a colorless oil; yield: 68 mg (97%).

(3aS,4S,5S,6aR)-4-(Methoxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl Acetate (24); Typical Procedure:[107]

CAUTION:

Trimethyltin chloride is very neurotoxic and is an excitotoxicant at high levels of exposure. It is an eye and skin irritant, and toxic to other target organs including the liver and immune system.

A soln of NaBH4 (7.6 mg, 0.195 mmol) in EtOH (1.5 mL) was added from a syringe to a soln of iodide 23 (53 mg, 0.16 mmol) and Me3SnCl (6.3 mg, 0.032 mmol) in degassed EtOH (3 mL) at 15 °C. The mixture was irradiated for 20 min with a 100-W Hg floodlight and then oxalic acid (10 mg, 0.1 mmol) was added to convert any unreacted Me3SnH into the corresponding ester. The mixture was stirred for 5 min, CH2Cl2 was added, and the resulting mixture was poured into sat. aq NaHCO3. The organic layer was collected, dried (MgSO4), and concentrated to give an oil, which was purified by column chromatography [benzene (CAUTION:carcinogen)/Et2O 1:1]; yield: 34 mg (94%).

5.2.1.4.1.2 Variation 2: Reduction of C—O Bonds

In general, alcohols cannot be reduced directly to the corresponding alkanes by organotin hydrides. The most general method for the homolytic cleavage of C—O bonds involves the use of thiocarbonyl derivatives 25, for example xanthates, in the Barton–McCombie reaction (▶ Scheme 14).[54] The addition of a tributylstannyl radical to the thiocarbonyl group in 25 is rapid and reversible.[109] The formation of the intermediate adduct radical 26 can be demonstrated by reaction with an internal alkene.[110] The slow rate-determining step is β-scission of the relatively strong C—O bond in 26 to give an alkyl radical that is further reduced by tributylstannane.

▶ Scheme 14 The Barton–McCombie Deoxygenation Reaction[54,109–111]