Science of Synthesis Knowledge Updates 2010 Vol. 3 E-Book

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

Seitenzahl: 1018

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 you always have access to state-of-the-art synthetic methodology.

Content of this volume: Aryl Grignard Reagents, Magnesium Halides, Magnesium Halides, Magnesium Oxide, Alkoxides, and Carboxylates, Magnesium Amides, Oxazoles, Acyclic and Semicyclic O/O Acetals, 1,3-Dioxetanes and 1,3-Dioxolanes, Spiroketals, Glycosyl Oxygen Compounds (Di- and Oligosaccharides), Oligosaccharides, Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates, Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates.

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

7.6.5.6 Aryl Grignard Reagents

H. Yorimitsu

Halogen–magnesium exchange between aryl iodides or bromides and an isopropylmagnesium chloride–lithium chloride complex or lithium trialkylmagnesates is now recognized as a useful method for the preparation of aryl Grignard reagents in addition to the conventional Grignard method. The exchange reactions lead to a wide variety of functionalized aryl Grignard reagents containing, for example, a carbonyl or a cyano group. Directed ortho-magnesiation reactions of arenes with bulky magnesium amide complexes, such as (2,2,6,6-tetramethylpiperidin-1-yl)magnesium chloride–lithium chloride complex and bis(2,2,6,6-tetramethylpiperidin-1-yl)magnesium–bis(lithium chloride) complex, are also useful.

Keywords: amination · “ate” complexes · carbomagnesiation · carbometalation · Grignard reagents · homocoupling · magnesates · magnesium compounds · metalation

7.6.10.9 Alkyl Grignard Reagents

H. Yorimitsu

While the conventional preparation of Grignard reagents from alkyl halides and metallic magnesium remains reliable, halogen–magnesium and sulfoxide–magnesium exchange have emerged as useful methods for the preparation of functionalized alkyl Grignard reagents that are otherwise difficult to synthesize. Carbomagnesiation reactions of alkenes are also useful for preparing alkyl Grignard reagents of some complexity. The formation of “ate” complexes gives a significant improvement in the utility of alkyl Grignard reagents and can lead to higher efficiency in nucleophilic addition to carbonyl compounds.

Keywords: “ate” complexes · carbomagnesiation · carbometalation · cyclization · magnesium compounds · magnesates · metalation · Grignard reagents · nucleophilic addition · sulfoxides

7.6.12.13 Magnesium Halides

M. Shimizu

This manuscript is an update to the earlier Science of Synthesis contribution describing reactions involving magnesium halides. It focuses on the literature published in the period 2001–2009. In particular, magnesium bromide and magnesium iodide are used frequently as promoters for specific transformations of important molecules.

Keywords: Friedel–Crafts reaction · Knoevenagel reaction · magnesium bromide · magnesium chloride · magnesium enolates · magnesium fluoride · magnesium iodide · Morita–Baylis–Hillman reaction

7.6.13.17 Magnesium Oxide, Alkoxides, and Carboxylates

M. Shimizu

This manuscript is an update to the earlier Science of Synthesis contribution describing reactions involving magnesium oxide, alkoxides, and carboxylates. It focuses on the literature published in the period 2001–2009. In particular, magnesium oxide and magnesium alkoxides are used for useful chemoselective transformations.

Keywords: Baeyer–Villiger oxidation · Diels–Alder reaction · ethyl magnesium malonate · magnesium alkoxides · magnesium bis[2-(alkoxycarbonyl)acetate] · magnesium carboxylates · magnesium monoperoxyphthalate · magnesium oxide · Mannich-type reaction · Michael addition · Oppenauer oxidation

7.6.14 Product Subclass 14: Magnesium Amides

M. Shimizu

This manuscript is a revision of the earlier Science of Synthesis contribution describing reactions involving magnesium amides. Synthesis of a series of magnesium amides, bis(amides), and their lithium chloride complexes is described. The use of magnesium amides as bases enables the regioselective deprotonation of a variety of molecules. Chiral magnesium amides are also discussed.

Keywords: amidomagnesium halide–lithium chloride complexes · amidomagnesium halides · magnesium bis(amide)–lithium chloride complexes · magnesium bis(amides) · magnesium dialkylamides · deprotonation

11.12.5 Oxazoles

A. Khartulyari and M. E. Maier

This manuscript is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of oxazoles. This heterocyclic system is of particular interest, since many oxazole-containing natural products and their synthetic analogues possess interesting biological activities. In addition, oxazoles and related compounds serve as building blocks and reagents for organic synthesis.

Keywords: oxazoles · cyclization · multicomponent reaction · gold catalysis · heterocycles · N-propargylamides · cycloisomerization · coupling reactions

29.6.2 Acyclic and Semicyclic O/O Acetals

L. S. Fowler and A. Sutherland

This manuscript is an update to the previous Science of Synthesis contribution describing methods for the synthesis of acyclic and semicyclic acetals. It focuses on the literature published in the period 2007 to mid-2010.

Keywords: acyclic acetals · semicyclic acetals · aldehydes · ketones · trialkyl orthoformates · enol ethers · cycloaddition · dehydration · acetalization

29.7.3 1,3-Dioxetanes and 1,3-Dioxolanes

D. Carbery

This manuscript is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of 1,3-dioxetanes and 1,3-dioxolanes. It focuses on the synthesis and synthetic applications of 1,3-dioxolanes covered in the literature over the period 2008–2010.

Keywords: dioxolane · carbonyls · diols · protecting groups · deprotection

29.9.2 Spiroketals

E. A. Anderson and B. Gockel

This manuscript is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of spiroketals. It focuses on the literature published in the period 2005–2010.

Keywords: spiroketal · acetalization · benzannulation · carbon–-oxygen bonds · cyclic compounds · diastereoselectivity · intramolecular reactions · oxiranes · oxygen heterocycles · synthesis design · spiro compounds

29.16 Product Class 16: Glycosyl Oxygen Compounds (Di- and Oligosaccharides)

A. V. Demchenko and C. De Meo

This manuscript is a revision of the earlier Science of Synthesis contribution describing methods for the synthesis of di- and oligosaccharides. Recent new developments and important improvements of fundamental concepts are the particular focus of this update.

Keywords: carbohydrates · enzyme catalysis · glycosidases · glycosidation · glycosides · glycosylation · halides · imidates · neighboring-group participation · neuraminic acids · nucleophilic substitution · oligosaccharides · protecting groups · solid-phase synthesis · saccharides · stereoselective synthesis · sugars · thioglycosides · thioimidates

29.17 Product Class 17: Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates

S. C. Coote, L. H. S. Smith, and D. J. Procter

Acyclic hemiacetals are in most cases unstable and exist only as transient intermediates, in contrast with cyclic hemiacetals (lactols), which are often stable, isolable compounds. Lactols may be prepared using various different methods, including the reduction of lactones, reduction of dicarbonyl compounds, or the selective oxidation of diols, as well as by addition of carbon nucleophiles to lactones or dicarbonyl compounds, deprotection of O-protected cyclic hemiacetals, or from enol ethers. Carbonyl hydrates are generally short-lived intermediates, although a limited number of stable carbonyl hydrates (generally derived from strained carbonyl compounds or carbonyl compounds bearing electron-withdrawing groups) have been documented.

Keywords: carbonyl additions · carbonyl compounds · dicarbonyl compounds · diols · hydroxycarbonyl compounds · lactols · lactonization · oxidation · reduction

29.18 Product Class 18: 1,1-Diacyloxy Compounds

L. H. S. Smith, S. C. Coote, and D. J. Procter

1,1-Diacyloxy compounds can be accessed from a variety of starting materials including aldehydes, ketones, and O/O, O/Hal, and Hal/Hal acetals under a variety of reaction conditions. This product class encompasses Meldrum's acid, several natural products, and acyloxy ester prodrugs; in addition, acyl acetals are useful protecting groups for aldehydes and can be cleaved orthogonally to alkyl acetals.

Keywords: acetals · acylation · alkylation · carbonyl compounds · carboxylic acids · esters · Lewis acid catalysts · oxidation

Science of Synthesis Knowledge Updates 2010/3

Preface

Abstracts

Table of Contents

7.6.5.6 Aryl Grignard Reagents (Update 2010)

H. Yorimitsu

7.6.10.9 Alkyl Grignard Reagents (Update 2010)

H. Yorimitsu

7.6.12.13 Magnesium Halides (Update 2010)

M. Shimizu

7.6.13.17 Magnesium Oxide, Alkoxides, and Carboxylates (Update 2010)

M. Shimizu

7.6.14 Product Subclass 14: Magnesium Amides

M. Shimizu

11.12.5 Oxazoles (Update 2010)

A. Khartulyari and M. E. Maier

29.6.2 Acyclic and Semicyclic O/O Acetals (Update 2010)

L. S. Fowler and A. Sutherland

29.7.3 1,3-Dioxetanes and 1,3-Dioxolanes (Update 2010)

D. Carbery

29.9.2 Spiroketals (Update 2010)

E. A. Anderson and B. Gockel

29.16 Product Class 16: Glycosyl Oxygen Compounds (Di- and Oligosaccharides)

A. V. Demchenko and C. De Meo

29.17 Product Class 17: Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates

S. C. Coote, L. H. S. Smith, and D. J. Procter

29.18 Product Class 18: 1,1-Diacyloxy Compounds

L. H. S. Smith, S. C. Coote, and D. J. Procter

Author Index

Abbreviations

Table of Contents

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

7.6 Product Class 6: Magnesium Compounds

7.6.5.6 Aryl Grignard Reagents

H. Yorimitsu

7.6.5.6 Aryl Grignard Reagents

7.6.5.6.1 Method 1: Synthesis by Reaction of Aryl Halides and Magnesium in the Presence of Lithium Chloride

7.6.5.6.2 Method 2: Synthesis by Halogen–Magnesium Exchange with Alkyl Grignard Reagents

7.6.5.6.2.1 Variation 1: Synthesis by Halogen–Magnesium Exchange with Lithium Triorganomagnesates

7.6.5.6.3 Method 3: Synthesis by Deprotonative ortho-Magnesiation

7.6.5.6.4 Method 4: Application to Synthesis of Biaryls by Dimerization

7.6.5.6.5 Method 5: Application to Synthesis of Amines

7.6.5.6.6 Method 6: Application to Addition to C—C Multiple Bonds Bearing a Directing Group

7.6.5.6.7 Method 7: Application to Transmetalations with Metal Halides

7.6.5.6.8 Method 8: Application to Addition to Carbonyl Compounds

7.6.5.6.8.1 Variation 1: Highly Efficient Addition of Lithium Triphenylmagnesate to Benzophenone

7.6.5.6.8.2 Variation 2: Zinc(II)-Catalyzed Addition of Aryl Grignard Reagents to Carbonyl Species

7.6.10.9 Alkyl Grignard Reagents

H. Yorimitsu

7.6.10.9 Alkyl Grignard Reagents

7.6.10.9.1 Method 1: Synthesis by Halogen–Magnesium Exchange

7.6.10.9.1.1 Variation 1: Synthesis by Sulfoxide–Magnesium Exchange

7.6.10.9.2 Method 2: Synthesis by Carbomagnesiation of C—C Multiple Bonds

7.6.10.9.3 Method 3: Application to Addition to Carbonyl Compounds

7.6.10.9.3.1 Variation 1: Highly Efficient Addition of Lithium Trialkylmagnesates to Acetophenone

7.6.10.9.3.2 Variation 2: Zinc(II)-Catalyzed Addition of Alkyl Grignard Reagents to Carbonyl Groups

7.6.12.13 Magnesium Halides

M. Shimizu

7.6.12.13 Magnesium Halides

7.6.12.13.1 Method 1: Applications of Magnesium Fluoride

7.6.12.13.1.1 Variation 1: Magnesium Fluoride Catalyzed Knoevenagel Reactions

7.6.12.13.1.2 Variation 2: Magnesium Fluoride/Chiral Phosphoric Acid Catalyzed Friedel–Crafts Reactions

7.6.12.13.2 Method 2: Applications of Magnesium Chloride as a Lewis Acid

7.6.12.13.2.1 Variation 1: Magnesium Chloride Promoted Claisen Reactions

7.6.12.13.2.2 Variation 2: Magnesium Chloride/Potassium Borohydride Promoted Reductions

7.6.12.13.3 Method 3: Applications of Other Magnesium Halides as Lewis Acids

7.6.12.13.3.1 Variation 1: Reaction of Organometallics in the Presence of Magnesium Bromide

7.6.12.13.3.2 Variation 2: Magnesium Halide Promoted Dipolar Cycloaddition Reactions

7.6.12.13.4 Method 4: Applications of Magnesium Halide/Base Systems to Enolate Formation and Subsequent Addition Reactions

7.6.12.13.5 Method 5: Applications of Magnesium Halides in Morita–Baylis–Hillman Reactions

7.6.12.13.6 Method 6: Applications of Magnesium Iodide in Ring-Expansion Reactions

7.6.13.17 Magnesium Oxide, Alkoxides, and Carboxylates

M. Shimizu

7.6.13.17 Magnesium Oxide, Alkoxides, and Carboxylates

7.6.13.17.1 Method 1: Applications of Magnesium Oxide

7.6.13.17.2 Method 2: Applications of Magnesium Methoxide as a Base

7.6.13.17.3 Method 3: Applications of Magnesium Alkoxides to the Oppenauer Oxidation

7.6.13.17.4 Method 4: Applications of Magnesium Alkoxides in Diastereo- and Enantioselective Reactions

7.6.13.17.5 Method 5: Applications of Magnesium Alkoxides in Elimination Reactions

7.6.13.17.6 Method 6: Applications of Magnesium Carboxylates

7.6.13.17.7 Method 7: Applications of Magnesium Monoperoxyphthalate

7.6.14 Product Subclass 14: Magnesium Amides

M. Shimizu

7.6.14 Product Subclass 14: Magnesium Amides

Synthesis of Product Subclass 14

7.6.14.1 Method 1: Synthesis of Methylmagnesium N-Cyclohexyl-N-isopropylamide

7.6.14.2 Method 2: Synthesis of (2,2,6,6-Tetramethylpiperidino)magnesium Chloride–Lithium Chloride Complex

7.6.14.3 Method 3: Synthesis of Magnesium Bis(diisopropylamide)

7.6.14.4 Method 4: Synthesis of Magnesium Bis(2,2,6,6-tetramethylpiperidide)

7.6.14.4.1 Variation 1: Synthesis of Magnesium Bis(2,2,6,6-tetramethylpiperidide)–Bis(lithium chloride) Complex

7.6.14.5 Method 5: Synthesis of Other Magnesium Bis(amide)s

7.6.14.6 Method 6: Synthesis of Chiral Magnesium Bis(dialkylamide)s

Applications of Product Subclass 14 in Organic Synthesis

7.6.14.7 Method 7: Reactions Involving Methylmagnesium N-Cyclohexyl-N-isopropylamide

7.6.14.8 Method 8: Reactions Involving (Diisopropylamino)magnesium Bromide

7.6.14.9 Method 9: Reactions Involving (2,2,6,6-Tetramethylpiperidino)magnesium Chloride–Lithium Chloride Complex

7.6.14.10 Method 10: Reactions Involving Magnesium Bis(diisopropylamide)

7.6.14.11 Method 11: Reactions Involving Magnesium Bis(2,2,6,6-tetramethylpiperidide)

7.6.14.12 Method 12: Reactions Involving Magnesium Bis(2,2,6,6-tetramethylpiperidide)–Bis(lithium chloride) Complex

7.6.14.13 Method 13: Reactions Involving Other Magnesium Bis(amide)s

7.6.14.14 Method 14: Reactions Involving Chiral Magnesium Bis(dialkylamide)s

Volume 11: Five-Membered Hetarenes with One Chalcogen and One Additional Heteroatom

11.12 Product Class 12: Oxazoles

11.12.5 Oxazoles

A. Khartulyari and M. E. Maier

11.12.5 Oxazoles

11.12.5.1 Synthesis by Ring-Closure Reactions

11.12.5.1.1 By Formation of One O—C and One N—C Bond

11.12.5.1.1.1 Fragments O—C—N and C—C

11.12.5.1.1.1.1 Method 1: From Vinyl Halides and Amides

11.12.5.1.1.2 Fragments O—C—C and C—N

11.12.5.1.1.2.1 Method 1: From Carbonyl Compounds and Nitriles

11.12.5.1.1.2.2 Method 2: From Acylcarbenes and Nitriles

11.12.5.1.1.2.3 Method 3: From Benzylamines and 1,3-Dicarbonyl Compounds

11.12.5.1.1.2.4 Method 4: From Amides and Propargylic Alcohols

11.12.5.1.1.3 Fragments N—C—C and C—O

11.12.5.1.1.3.1 Method 1: From 2-Amino-1-bromoethanesulfonamide and Acid Chlorides

11.12.5.1.1.4 Fragments O—C—C—N and C

11.12.5.1.1.4.1 Method 1: From Nitroethanones and Orthobenzoate

11.12.5.1.1.4.2 Method 2: From α-Cyano-β-hydroxy Enamines and Orthoformate

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

11.12.5.1.2.1 Fragments C—N—C and C—O

11.12.5.1.2.1.1 Method 1: From Isocyanides and Acyl Chlorides

11.12.5.1.3 By Formation of One O—C Bond

11.12.5.1.3.1 Fragment O—C—N—C—C

11.12.5.1.3.1.1 Method 1: Cyclodehydration of α-Acylamino Aldehydes or Ketones

11.12.5.1.3.1.2 Method 2: From (Acylamino)acetaldehyde Dimethyl Acetals

11.12.5.1.3.1.3 Method 3: From Oxazolones via Friedel–Crafts Acylation and Subsequent Cyclization

11.12.5.1.3.1.4 Method 4: Oxazoles from N-Propargylamides

11.12.5.1.3.1.5 Method 5: From Enamides

11.12.5.1.3.1.6 Method 6: From Amides and Diazocarbonyl Compounds

11.12.5.1.3.2 Fragment O—C—C—N—C

11.12.5.1.3.2.1 Method 1: Oxidative Cyclization of Schiff Bases Derived from Glycine Methyl Ester

11.12.5.1.3.2.2 Method 2: From Isocyanoacetamides and Imines

11.12.5.1.3.2.3 Method 3: Trifluoromethanesulfonic Anhydride Mediated Cyclocondensation of N-Acyl Amino Acid Esters

11.12.5.1.3.2.4 Method 4: From Aldehydes and Isocyanides

11.12.5.2 Aromatization

11.12.5.2.1 Method 1: By Dehydrogenation of Dihydrooxazoles

11.12.5.2.2 Method 2: Elimination of Hydrogen Chloride from Dihydrooxazoles

11.12.5.3 Synthesis by Substituent Modification

11.12.5.3.1 Substitution Reactions

11.12.5.3.1.1 Method 1: Reactions of Metalated Oxazoles with Electrophiles

11.12.5.3.1.2 Method 2: Oxazoles via Substitution of Leaving Groups through Transition-Metal-Catalyzed Reactions

11.12.5.3.1.3 Method 3: Coupling Reactions of Oxazolones

11.12.5.4 Applications of Oxazoles in Organic Synthesis

Volume 29: Acetals: Hal/X and O/O, S, Se, Te

29.6 Product Class 6: Acyclic and Semicyclic O/O Acetals

29.6.2 Acyclic and Semicyclic O/O Acetals

L. S. Fowler and A. Sutherland

29.6.2 Acyclic and Semicyclic O/O Acetals

29.6.2.1 Synthesis from Compounds of Higher Oxidation State

29.6.2.1.1 Method 1: Synthesis by Cycloaddition of Ketene Acetals

29.6.2.1.1.1 Variation 1: From Ketene Acetals and Alkenes via Cycloaddition

29.6.2.1.1.2 Variation 2: From Ketene Acetals and Alkynes via Cycloaddition

29.6.2.2 Synthesis from Compounds of the Same Oxidation State

29.6.2.2.1 Method 1: Synthesis from Hal/OR Acetals

29.6.2.2.2 Method 2: Synthesis from Aldehydes or Ketones and Alcohols

29.6.2.2.2.1 Variation 1: From Alcohols without Removal of Water

29.6.2.2.2.2 Variation 2: From Alcohols with Removal of Water by Physical Methods

29.6.2.2.2.3 Variation 3: From Alcohols with Removal of Water by Chemical Means

29.6.2.2.2.4 Variation 4: From Hemiacetals and Alkylating Agents

29.6.2.2.2.5 Variation 5: From Alcohols and Alkenyl Ketones

29.6.2.2.3 Method 3: Synthesis from Aldehydes or Ketones and Alcohol Derivatives

29.6.2.2.3.1 Variation 1: From Trialkyl Orthoformates

29.6.2.2.3.2 Variation 2: From Other Acetals

29.6.2.2.4 Method 4: Synthesis from Other O/O Acetals

29.6.2.2.4.1 Variation 1: By Exchange of Both Alkoxy Groups

29.6.2.2.4.2 Variation 2: By Exchange of One Alkoxy Group

29.6.2.2.5 Method 5: Synthesis from Acetals with Other Heteroatoms

29.6.2.2.5.1 Variation 1: From O/Se Acetals

29.6.2.2.5.2 Variation 2: From S/S Acetals

29.6.2.2.6 Method 6: Synthesis from Oximes

29.6.2.2.7 Method 7: Synthesis from Heterosubstituted Alkenes

29.6.2.2.7.1 Variation 1: From Acyclic Enol Ethers and Alcohols

29.6.2.2.7.2 Variation 2: From Cyclic Enol Ethers and Alcohols

29.6.2.2.7.3 Variation 3: From Allenyl Ethers and Alcohols

29.6.2.2.7.4 Variation 4: Dimerization of Enol Ethers

29.6.2.2.7.5 Variation 5: From Enol Ethers and Cyclic Carbonyl Ylides

29.6.2.3 Synthesis from Compounds of Lower Oxidation State

29.6.2.3.1 Method 1: Synthesis from Heterosubstituted Alkanes

29.6.2.3.1.1 Variation 1: From Alcohols

29.6.2.3.1.2 Variation 2: From Alcohols and Ethers

29.6.2.3.1.3 Variation 3: From Alcohols and Alkyl Halides

29.6.2.3.2 Method 2: Synthesis from Alkynes with Electron-Withdrawing Substituents

29.6.2.3.3 Method 3: Synthesis from Alkenes

29.6.2.3.4 Method 4: Synthesis from Peroxy Esters

29.7 Product Class 7: 1,3-Dioxetanes and 1,3-Dioxolanes

29.7.3 1,3-Dioxetanes and 1,3-Dioxolanes

D. Carbery

29.7.3 1,3-Dioxetanes and 1,3-Dioxolanes

29.7.3.1 1,3-Dioxetanes

29.7.3.2 1,3-Dioxolanes

29.7.3.2.1 Method 1: Synthesis by Formation of Two C—O Bonds

29.7.3.2.1.1 Variation 1: Reactions of Carbonyl Compounds with 1,2-Diols

29.7.3.2.1.2 Variation 2: Reactions of Acetals and Ketals with 1,2-Diols

29.7.3.2.1.3 Variation 3: Reactions of Enol Ethers with 1,2-Diols

29.7.3.2.1.4 Variation 4: Reactions of Carbonyl Compounds with 1,2-Bis(trimethylsilyl) Ethers

29.7.3.2.1.5 Variation 5: Reactions of Epoxides with Ketones

29.7.3.2.1.6 Variation 6: By Double Michael Addition of 1,2-Diols to Electron-Deficient Alkynes

29.7.3.2.1.7 Variation 7: Reaction of 1,1-Dihalo Compounds with 1,2-Diols

29.7.3.2.1.8 Variation 8: Reactions of Ketones and 2-Halo Alcohols

29.7.3.2.2 Method 2: Synthesis by Formation of One C—O Bond

29.7.3.2.2.1 Variation 1: From Monoprotected 1,2-Diols

29.7.3.2.2.2 Variation 2: By Oxidation of Electron-Rich Arenes and Hetarenes and Cyclization

29.7.3.2.2.3 Variation 3: By Cyclization of Hydroxy-Substituted Enol Ethers

29.7.3.2.2.4 Variation 4: By Intramolecular Transacetalization

29.7.3.2.2.5 Variation 5: Additions to Activated Alkenes

29.7.3.2.3 Method 3: Exchange of Ligands on Existing Acetals

29.7.3.2.3.1 Variation 1: Radical Reactions

29.7.3.2.3.2 Variation 2: From Metalated Dioxolanes

29.7.3.2.3.3 Variation 3: From Ortho Esters

29.7.3.2.4 Method 4: Deprotection Reactions of 1,3-Dioxolanes

29.7.3.2.5 Method 5: Applications of Chiral 1,3-Dioxolanes in Asymmetric Synthesis

29.9 Product Class 9: Spiroketals

29.9.2 Spiroketals

E. A. Anderson and B. Gockel

29.9.2 Spiroketals

29.9.2.1 Synthesis by Formation of Two C—O Bonds: Cyclization of Dihydroxy Ketones

29.9.2.1.1 Method 1: Nucleophilic Addition to Aldehydes

29.9.2.1.1.1 Variation 1: Using Dithiane-Stabilized Carbanions

29.9.2.1.1.2 Variation 2: Using Lithiated Methoxyallene Followed by Heck Reaction

29.9.2.1.2 Method 2: [3 + 2] Cycloaddition of Nitrile Oxides Followed by Dihydroisoxazole Hydrogenolysis

29.9.2.1.3 Method 3: Reductive Cross Coupling Followed by Oxidative Cleavage

29.9.2.1.4 Method 4: Radical Addition of Xanthates to Alkenes

29.9.2.1.5 Method 5: Kulinkovich Cyclopropanation of Esters Followed by Cyclopropanol Ring Opening

29.9.2.1.6 Method 6: Synthesis from Formyl Dianion Equivalents

29.9.2.1.6.1 Variation 1: Using Tosylmethyl Isocyanide Followed by Hydrolysis

29.9.2.1.6.2 Variation 2: Using Nitroalkanes Followed by Nef Reaction

29.9.2.2 Synthesis by Formation of Two C—O Bonds: Synthesis from Other Precursors

29.9.2.2.1 Method 1: Transition-Metal-Catalyzed Cyclizations

29.9.2.2.1.1 Variation 1: Palladium-Catalyzed Alkyne Cycloisomerization

29.9.2.2.1.2 Variation 2: Gold-Catalyzed Alkyne Cycloisomerization

29.9.2.2.1.3 Variation 3: Alkyne Cycloisomerization Catalyzed by Other Metals

29.9.2.2.1.4 Variation 4: Iron-Catalyzed Cyclization of Hydroxy Oxo Allylic Acetates

29.9.2.2.2 Method 2: Oxidative Cyclization of Phenols

29.9.2.2.3 Method 3: Oxidative Rearrangement of Alkyl Enol Ethers

29.9.2.2.4 Method 4: Iodoetherification of Dihydroxyalkenes Followed by Dehydroiodination

29.9.2.3 Synthesis by Formation of One C—O Bond and One C—C Bond

29.9.2.3.1 Method 1: Cycloaddition Reactions

29.9.2.3.1.1 Variation 1: Hetero-Diels–Alder Reactions of o-Quinomethanes

29.9.2.3.1.2 Variation 2: [3 + 2] Cycloadditions

29.9.2.3.2 Method 2: Metal-Catalyzed Cross Coupling

29.9.2.3.3 Method 3: Propargyl Claisen Rearrangement

29.9.2.4 Synthesis by Formation of One C—O Bond

29.9.2.4.1 Method 1: Oxidative Insertion

29.9.2.4.2 Method 2: Synthesis from Exocyclic Vinyl Ethers

29.9.2.4.2.1 Variation 1: Using Metal Carbenoids

29.9.2.4.2.2 Variation 2: Ring Expansion of Donor–Acceptor-Substituted Cyclopropanes

29.9.2.4.3 Method 3: Oxidation of Furans

29.9.2.4.3.1 Variation 1: Photooxygenation of Furans

29.9.2.4.3.2 Variation 2: Other Oxidation Reagents

29.9.2.4.4 Method 4: Lewis Acid Catalyzed 1,5-Hydride Transfer

29.9.2.5 Synthesis by Formation of One C—C Bond

29.9.2.5.1 Method 1: Reductive Cyclization of Cyano Acetals

29.9.2.5.2 Method 2: [2 +2+2] Cyclotrimerization

29.9.2.6 Synthesis by Formation of Two C—O Bonds and One C—C Bond

29.9.2.6.1 Method 1: Palladium-Catalyzed Three-Component Coupling

29.9.2.7 Synthesis of Spiroepoxides and Related Small-Ring Spiroketals

29.9.2.7.1 Method 1: Synthesis by Formation of Two C—O Bonds

29.9.2.7.2 Method 2: Synthesis by Formation of Four C—O Bonds

29.9.2.7.3 Method 3: Synthesis by Formation of One C—O Bond and One C—C Bond

29.9.2.8 Synthesis of Trioxadispiroketals

29.16 Product Class 16: Glycosyl Oxygen Compounds (Di- and Oligosaccharides)

A. V. Demchenko and C. De Meo

29.16 Product Class 16: Glycosyl Oxygen Compounds (Di- and Oligosaccharides)

29.16.1 Product Subclass 1: Disaccharides

29.16.1.1 Synthesis of Product Subclass 1

29.16.1.1.1 Method 1: Synthesis from Anomeric Halides

29.16.1.1.1.1 Variation 1: From Fluorides

29.16.1.1.1.2 Variation 2: From Chlorides and Bromides

29.16.1.1.1.3 Variation 3: From Iodides

29.16.1.1.2 Method 2: Synthesis from 1-Oxygen-Substituted Derivatives

29.16.1.1.2.1 Variation 1: From Hemiacetals

29.16.1.1.2.2 Variation 2: From O-Acyl, O-Carbonyl, and Related Compounds

29.16.1.1.2.3 Variation 3: From O-Imidates

29.16.1.1.2.4 Variation 4: From Phosphites, Phosphates, and Other O—P Derivatives

29.16.1.1.2.5 Variation 5: From O-Sulfonyl Derivatives

29.16.1.1.2.6 Variation 6: By O-Transglycosidation

29.16.1.1.3 Method 3: Synthesis from 1-Sulfur-Substituted Derivatives

29.16.1.1.3.1 Variation 1: From Alkylsulfanyl and Arylsulfanyl Glycosides (Thioglycosides)

29.16.1.1.3.2 Variation 2: From Thioimidates

29.16.1.1.3.3 Variation 3: From Sulfoxides, Sulfimides, and Sulfones

29.16.1.1.3.4 Variation 4: From Xanthates and Related Derivatives

29.16.1.1.3.5 Variation 5: From Thiocyanates and Other Thio Derivatives

29.16.1.1.4 Method 4: Synthesis from Miscellaneous Glycosyl Donors

29.16.1.1.4.1 Variation 1: From Ortho Esters and Dihydrooxazoles

29.16.1.1.4.2 Variation 2: From 1,2-Dehydro and 1,2-Anhydro Derivatives

29.16.1.1.4.3 Variation 3: From Seleno- and Telluroglycosides

29.16.1.1.4.4 Variation 4: From 1-Diazirine Derivatives

29.16.1.1.5 Method 5: Synthesis by Intramolecular and Indirect Methods

29.16.2 Product Subclass 2: Oligosaccharides

29.16.2.1 Synthesis of Product Subclass 2

29.16.2.1.1 Method 1: Linear Synthesis

29.16.2.1.2 Method 2: Block Synthesis

29.16.2.1.3 Method 3: Synthesis by Selective Activation

29.16.2.1.4 Method 4: Synthesis by Two-Step Activation and In Situ Preactivation

29.16.2.1.5 Method 5: Armed–Disarmed and Related Chemoselective Approaches

29.16.2.1.5.1 Variation 1: Arming and Disarming with Neighboring Substituents

29.16.2.1.5.2 Variation 2: Disarming with Remote Substituents

29.16.2.1.5.3 Variation 3: Disarming by Torsional Effects

29.16.2.1.5.4 Variation 4: Reactivity-Based Programmable Strategy

29.16.2.1.5.5 Variation 5: Superdisarmed Building Blocks

29.16.2.1.5.6 Variation 6: Superarmed Glycosyl Donors

29.16.2.1.6 Method 6: The Active–Latent Approach

29.16.2.1.7 Method 7: Steric Hindrance and Temporary Deactivation

29.16.2.1.8 Method 8: Orthogonal and Semi-Orthogonal Strategies

29.16.2.1.9 Method 9: One-Pot Strategies

29.16.2.1.10 Method 10: Regioselective and Other Acceptor-Reactivity-Based Concepts

29.16.2.1.11 Method 11: Polymer-Supported Synthesis

29.16.2.1.11.1 Variation 1: Automated Synthesis

29.16.2.1.12 Method 12: Fluorous Tag Supported, Ionic Liquid Supported, and Microreactor Synthesis

29.16.2.1.13 Method 13: Surface-Tethered Synthesis

29.16.2.1.14 Method 14: Enzymatic Synthesis

29.16.2.1.14.1 Variation 1: Using Glycosyltransferases

29.16.2.1.14.2 Variation 2: Using Glycosidases (Hydrolases)

29.17 Product Class 17: Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates

S. C. Coote, L. H. S. Smith, and D. J. Procter

29.17 Product Class 17: Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates

29.17.1 Product Subclass 1: Acyclic Hemiacetals

29.17.1.1 Synthesis of Product Subclass 1

29.17.1.1.1 Method 1: Synthesis from Aldehydes or Ketones by Addition of Alcohols

29.17.1.1.2 Method 2: Reduction of Esters

29.17.1.1.3 Method 3: Addition of Carbon Nucleophiles to Esters

29.17.1.1.3.1 Variation 1: Addition of Nucleophiles Bearing Stabilizing Groups

29.17.1.1.3.2 Variation 2: Addition of Nucleophiles Bearing Stabilizing Groups to Esters Bearing Stabilizing Groups

29.17.2 Product Subclass 2: Lactols

29.17.2.1 Synthesis of Product Subclass 2

29.17.2.1.1 Method 1: Reduction of Lactones

29.17.2.1.1.1 Variation 1: Using Diisobutylaluminum Hydride

29.17.2.1.1.2 Variation 2: Using Other Aluminum Hydride Reagents

29.17.2.1.1.3 Variation 3: Metal Hydride Catalyzed Hydrosilylation

29.17.2.1.1.4 Variation 4: Using Borohydride Reagents

29.17.2.1.2 Method 2: Addition of Carbon Nucleophiles to Lactones

29.17.2.1.2.1 Variation 1: Addition of Preformed Alkylmetal Reagents to Lactones

29.17.2.1.2.2 Variation 2: Barbier Additions to Lactones

29.17.2.1.3 Method 3: Oxidation of Diols

29.17.2.1.3.1 Variation 1: By Selective Oxidation of a Primary Hydroxy Group

29.17.2.1.3.2 Variation 2: By Selective Oxidation of a Secondary Hydroxy Group

29.17.2.1.3.3 Variation 3: By Selective Oxidation of Allylic and Benzylic Hydroxy Groups

29.17.2.1.4 Method 4: Reduction of Dicarbonyl Compounds

29.17.2.1.5 Method 5: Addition of Carbon Nucleophiles to Dicarbonyl Compounds

29.17.2.1.6 Method 6: Deprotection of Protected Cyclic Hemiacetals

29.17.2.1.6.1 Variation 1: Deprotection of O-Alkyl Lactols

29.17.2.1.6.2 Variation 2: Deprotection of O-Acyl Lactols

29.17.2.1.6.3 Variation 3: Deprotection of O-Silyl Lactols

29.17.2.1.7 Method 7: Synthesis From Enol Ethers

29.17.2.1.7.1 Variation 1: Acid-Catalyzed Hydration of Enol Ethers

29.17.2.1.7.2 Variation 2: Oxidation of Enol Ethers

29.17.2.1.8 Method 8: Oxidation of Cyclic Ethers

29.17.3 Product Subclass 3: Carbonyl Hydrates

29.17.3.1 Synthesis of Product Subclass 3

29.17.3.1.1 Method 1: Hydration of Carbonyl Compounds

29.17.3.1.1.1 Variation 1: Synthesis from Carbonyl Compounds Bearing Electron-Withdrawing Groups

29.17.3.1.1.2 Variation 2: Synthesis of Carbonyl Hydrates Stabilized by Hydrogen Bonding

29.17.3.1.1.3 Variation 3: Synthesis from Strained Ketones

29.17.3.1.2 Method 2: Oxidation of Activated Methyl or Methylene Groups

29.17.3.1.2.1 Variation 1: Oxidation Using Dimethyldioxirane

29.17.3.1.2.2 Variation 2: Oxidation Using Selenium Dioxide

29.17.3.1.2.3 Variation 3: Other Oxidations

29.18 Product Class 18: 1,1-Diacyloxy Compounds

L. H. S. Smith, S. C. Coote, and D. J. Procter

29.18 Product Class 18: 1,1-Diacyloxy Compounds

29.18.1 Synthesis of Product Class 18

29.18.1.1 Acylation of Carbonyl Compounds

29.18.1.1.1 Method 1: Acylation of Aldehydes

29.18.1.1.1.1 Variation 1: Using a Lewis Acid Catalyst

29.18.1.1.1.2 Variation 2: In the Absence of a Catalyst

29.18.1.1.2 Method 2: Acylation of Ketones

29.18.1.1.2.1 Variation 1: Synthesis of Meldrum's Acid Using a Diacid and a Ketone

29.18.1.1.2.2 Variation 2: Using an Oxo Acid

29.18.1.1.3 Method 3: Synthesis from 1-Acyloxy-1-hydroxy Compounds, Carbonyl Hydrates, or Vinyl Esters

29.18.1.2 Alkylation of Carboxy Groups

29.18.1.2.1 Method 1: Synthesis Using Hal/Hal Acetal Electrophiles

29.18.1.2.2 Method 2: Synthesis Using O/Hal Acetal Electrophiles

29.18.1.3 Oxidative Methods

29.18.1.3.1 Method 1: Synthesis Using Single-Electron-Transfer Reagents

29.18.1.3.1.1 Variation 1: Oxidation of Benzylic Methyl and Methylene Groups

29.18.1.3.2 Method 2: Other Oxidations

29.18.1.3.2.1 Variation 1: Baeyer–Villiger Oxidation of α-Acyloxy Ketones

29.18.1.3.2.2 Variation 2: Oxidation of Furan Derivatives

29.18.1.4 Synthesis from Propargyl Esters

Author Index

Abbreviations

7.6.5.6 Aryl Grignard Reagents (Update 2010)

H. Yorimitsu

General Introduction

The conventional preparation of aryl Grignard reagents from aryl halides and magnesium metal still remains the most important and convenient available method. However, an improved Grignard method was reported in 2008 utilizing lithium chloride as an additive (see ▶ Section 7.6.5.6.1). Recently, halogen–magnesium exchange between aryl halides and alkyl Grignard reagents has been attracting increasing attention as the exchange allows for preparation of functionalized aryl Grignard reagents such as cyano- and carbonyl-substituted species (see ▶ Section 7.6.5.6.2). Furthermore, deprotonation assisted by a directing group is also emerging as a useful method for the preparation of functionalized aryl Grignard reagents (see ▶ Section 7.6.5.6.3).

7.6.5.6.1 Method 1: Synthesis by Reaction of Aryl Halides and Magnesium in the Presence of Lithium Chloride

A critical drawback of the conventional method for obtaining Grignard reagents is the requirement for higher temperatures, in the region of 30–60°C, conditions which many functional groups are unable to survive. The presence of lithium chloride has proved to promote the formation of aryl Grignard reagents, providing a milder method for the preparation of a variety of functionalized aryl Grignard species (▶ Table 1).[1] The lithium chloride mediated magnesiation requires that the magnesium should be activated with diisobutylaluminum hydride (1 mol%), and the method is powerful enough to allow the use of aryl chlorides as starting materials as well as to effect the dimagnesiation of dihaloarenes. It is worth noting that the aryl Grignard reagents complexed with lithium chloride exhibit a higher degree of reactivity toward electrophiles than the conventional aryl Grignard reagents. The functionalized Grignard reagents obtained by this procedure can participate in nucleophilic addition to carbonyl groups as well as in catalytic cross-coupling reactions.

▶ Table 1 Preparation of Arylmagnesium Halides Complexed with Lithium Chloride by Direct Insertion of Magnesium[1]

Entry

Starting Material

Conditions

Product

Ref

1

DIBAL-H (cat.), Mg, LiCl, THF, 25°C, 30 min

[

1

]

2

DIBAL-H (cat.), Mg, LiCl, THF, –50°C, 3 h

[

1

]

3

DIBAL-H (cat.), Mg, LiCl, THF, 0–25°C, 16 h

[

1

]

(2-Cyanophenyl)magnesium Bromide–Lithium Chloride Complex (▶ Table 1, Entry 1):[1]

Mg turnings (0.12 g, 5 mmol) were placed in a dry, argon-flushed Schlenk flask equipped with a magnetic stirrer and a septum. A 0.50 M soln of LiCl in THF (5.0 mL, 2.5 mmol) was added, followed by 0.1 M DIBAL-H in THF (0.2 mL, 0.02 mmol) to activate the Mg. The mixture was stirred for 5 min and 2-BrC6H4CN (0.36 g, 2.0 mmol) was then added in one portion at 25°C. The mixture was stirred for 30 min and then cannulated to a new Schlenk flask for reaction with an electrophile.

7.6.5.6.2 Method 2: Synthesis by Halogen–Magnesium Exchange with Alkyl Grignard Reagents

▶ Scheme 1 Halogen–Magnesium Exchange with Isopropylmagnesium Chloride–Lithium Chloride Complex[2]

Ar

1

Conditions

Ref

4-NCC

6

H

4

THF, 0°C, 2 h

[

2

]

2-iPrO

2

CC

6

H

4

THF/DMPU, –10°C, 3 h

[

2

]

2-BrC

6

H

4

THF, –15°C, 2 h

[

2

]

5-bromo-3-pyridyl

THF, –10°C, 15 min

[

2

]

Isopropylmagnesium Chloride–Lithium Chloride Complex (1):[2]

Mg turnings (2.7 g, 0.11 mol) and anhyd LiCl (4.24 g, 0.10 mol) were placed in a flask under argon. THF (50 mL) was added, followed by slow addition of a soln of iPrCl (7.85 g, 0.10 mol) in THF (50 mL) at rt. The reaction started within a few minutes and, after the addition, the mixture was stirred for 12 h at ambient temperature. The resulting gray soln was transferred by cannula into another flask under argon to remove the remaining excess Mg. The yield of complex 1 was determined to be 95–98%.

A 10-mL flask equipped with a magnetic stirrer and a septum was charged with a 1.05 M soln of complex 1 in THF (1.0 mL, 1.05 mmol) under argon. 3,5-Dibromopyridine (0.24 g, 1.0 mmol) was added to this mixture in one portion at –15°C. The reaction temperature was increased to –10°C and the bromine–magnesium exchange was complete in 15 min.

7.6.5.6.2.1 Variation 1: Synthesis by Halogen–Magnesium Exchange with Lithium Triorganomagnesates

Lithium triorganomagnesates are effective reagents for halogen–magnesium exchange.[3–6] The magnesium “ate” complexes are prepared by mixing an alkylmagnesium halide with 2 equivalents of an alkyllithium reagent. The reactivity is as high as that of the corresponding isopropylmagnesium chloride complex (see ▶ Section 7.6.5.6.2), and the reagents are reliable enough to use on an industrial scale.[5,6] There are many examples of magnesate-mediated halogen–magnesium exchange in modern organic synthesis.[7–10] Although all of the alkyl groups on the magnesate are potentially able to engage in exchange, as in the synthesis of triarylmagnesate 3,[10] in many cases only one of the three groups participates to give dialkyl(aryl)magnesates such as 4[3] (▶ Scheme 2).

▶ Scheme 2 Bromine–Magnesium Exchange with Lithium Tributylmagnesate[3,10]

Lithium Tris(quinolin-3-yl)magnesate (3):[10]

A 1.6 M soln of BuLi in hexanes (0.81 mL, 1.3 mmol) was added to a soln prepared from 2.0 M BuMgCl in Et2O (0.33 mL, 0.65 mmol) and toluene (2 mL) at –10°C. After the mixture had been stirred for 1 h at –10°C, a soln of 3-bromoquinoline (0.23 mL, 1.7 mmol) in toluene (2 mL) was added at –30°C. The mixture was stirred for 2.5 h at –10°C to give the product.

Lithium Dibutyl[4-(dimethylamino)phenyl]magnesate (4):[3]

A 1.6 M soln of BuLi in hexane (1.5 mL, 2.4 mmol) was added to a soln prepared from 1.0 M BuMgBr in THF (1.2 mL, 1.2 mmol) and THF (2 mL) at 0°C. After the mixture had been stirred for 10 min, a soln of 4-Me2NC6H4Br (0.20 g, 1.0 mmol) in THF (2 mL) was added dropwise. Stirring for 30 min at 0°C led to the complete formation of the product.

7.6.5.6.3 Method 3: Synthesis by Deprotonative ortho-Magnesiation

Complexes of bulky magnesium amides with lithium chloride, such as (2,2,6,6-tetramethylpiperidin-1-yl)magnesium chloride–lithium chloride complex (5) and bis(2,2,6,6-tetramethylpiperidin-1-yl)magnesium–bis(lithium chloride) complex (6), have emerged as excellent reagents for deprotonative magnesiation (▶ Table 2).[11–15] Advantageously, the reagents are more reactive than simple (2,2,6,6-tetramethylpiperidin-1-yl)magnesium halides, and the resulting arylmagnesium reagents have milder reactivity compared with those generated by lithium 2,2,6,6-tetramethylpiperidide.

▶ Table 2 Direct Magnesiation with Magnesium Amide–Lithium Chloride Complexes[11,13,15]

Entry

Starting Material

Amide Complex

Conditions

Product

Ref

1

THF, 25°C, 2 h

[

11

]

2

THF, 25°C, 1 h

[

13

]

3

THF, –60°C, 1.5 h

[

15

]

(2,2,6,6-Tetramethylpiperidin-1-yl)magnesium Chloride–Lithium Chloride Complex (5):[15]

A 250-mL flask equipped with a magnetic stirrer bar and a septum was charged with a 1.2 M THF soln of iPrMgCl•LiCl (1; 100 mL, 0.12 mol) under an atmosphere of argon. At rt, TMP (18.7 g, 0.132 mol) was added dropwise and the mixture was stirred for 24 h before use.

Bis(2,2,6,6-tetramethylpiperidin-1-yl)magnesium–Bis(lithium chloride) Complex (6):[15]

Freshly distilled TMP (5.07 mL, 30 mmol) in THF (30 mL) was added to a 250-mL flask equipped with a magnetic stirrer bar and a septum. Then, 2.4 M BuLi in hexane (12.5 mL, 30 mmol) was added dropwise at –40°C, and the mixture was warmed to 0°C and stirred for 30 min. A 1.0 M soln of complex 6 in THF (30 mL, 30 mmol) was then added dropwise, and the resulting mixture was stirred at 0°C for 30 min and then at 25°C for 1 h. The solvents were removed under reduced pressure to leave a yellowish solid. Freshly distilled THF (50 mL) was added slowly with vigorous stirring until a clear soln (0.6 M) of the product was obtained.

(2-Bromopyrimidin-4-yl)magnesium Chloride–Lithium Chloride Complex (▶ Table 2, Entry 3):[15]

A 1.1 M soln of complex 6 in THF (10 mL, 11 mmol) was placed under argon and cooled to –60°C in a Schlenk flask equipped with a magnetic stirrer bar and a septum. A soln of 2-bromopyrimidine (1.6 g, 10 mmol) in THF (10 mL) was added dropwise, and the resulting mixture was stirred at –60°C for 1.5 h to give the product.

7.6.5.6.4 Method 4: Application to Synthesis of Biaryls by Dimerization

In the presence of an organic oxidant, aryl Grignard reagents undergo homocoupling to yield symmetrical biaryl species. 3,3′,5,5′-Tetra-tert-butyl-1,1′-bi(cyclohexylidene)-2,2′,5,5′-tetraene-4,4′-dione (7, 3,3′,5,5′-tetra-tert-butyldiphenoquinone) has been used as an efficient stoichiometric oxidant for this process, as illustrated in the synthesis of biaryl 8 (▶ Scheme 3).[16] 2,2,6,6-Tetramethylpiperidin-1-oxyl (9; TEMPO) can also serve as a highly active oxidant for homocoupling, as in the formation of biphenyl (10) (▶ Scheme 3).[17,18] Notably, both of these processes do not proceed via the formation of the corresponding aryl radicals. TEMPO can also be used as a catalyst in the presence of dioxygen, although the formation of a small amount of phenol is inevitable.[17]

▶ Scheme 3 Biaryls by Oxidative Homocoupling with Stoichiometric Oxidants[16,18]

Diethyl 1,1′-Biphenyl-4,4′-dicarboxylate (8):[16]

Ethyl 4-iodobenzoate (0.552 g, 2.0 mmol) and THF (2 mL) were added to a 10-mL flask equipped with a magnetic stirrer and a septum. After the resulting soln was cooled to –20°C, a 1.05 M soln of iPrMgCl•LiCl in THF (1; 2.0 mL, 2.1 mmol) was added dropwise. The mixture was stirred for 20 min at the same temperature, and dione 7 (0.449 g, 1.1 mmol) in THF (5 mL) was added dropwise. The resulting mixture was stirred at 0°C for 2 h. Aqueous workup followed by column chromatography (silica gel, CH2Cl2/pentane 1:1) gave the product; yield: 0.184 g (93%).

Biphenyl (10):[18]

To a soln of TEMPO (0.261 g, 1.66 mmol) in THF (3 mL) was added 0.77 M PhMgBr in THF (2.00 mL, 1.54 mmol) with stirring at rt. The mixture was then refluxed for 5 min, allowed to cool to rt, and partitioned between t-BuOMe (30 mL) and sat. aq NH4Cl (10 mL). The aqueous layer was extracted with t-BuOMe (2 × 30 mL) and the combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. Chromatographic purification (silica gel, pentane) gave the product; yield: 0.116 g (98%).

7.6.5.6.5 Method 5: Application to Synthesis of Amines

O-Sulfonyloxime derivatives of carbonyl groups react with aryl Grignard reagents to give the corresponding N-arylimines by nucleophilic substitution at the sp2-hybridized nitrogen atom (▶ Scheme 4).[19–21] The resulting imines undergo acidic hydrolysis to yield aniline salts 11.

▶ Scheme 4 Synthesis of Aniline Derivatives from Aryl Grignard Reagents and a 1,3-Dioxolan-2-one O-Sulfonyloxime[21]

Ar

1

Yield (%)

Ref

Ph

92

[

21

]

2-MeOC

6

H

4

96

[

21

]

4-F

3

CC

6

H

4

91

[

21

]

A 0.96 M soln of PhMgBr in Et2O (2.3 mL, 2.2 mmol) was added dropwise to a soln of 4,4,5,5-tetramethyl-1,3-dioxolan-2-one O-(phenylsulfonyl)oxime (0.593 g, 1.98 mmol) in CH2Cl2 (15 mL) at 0°C under argon. The resulting mixture was stirred at rt for 30 min, pH 9 buffer (15 mL) was added at 0°C, and the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried (Na2SO4), and the solvent was removed under reduced pressure. MeOH (10 mL) was added to dissolve the resulting solid and 1.0 M HCl in Et2O (4.0 mL, 4.0 mmol) was added to the MeOH soln at 0°C. The resulting mixture was stirred at rt for 1.5 h, and any volatile materials were removed under reduced pressure. Anhyd Et2O (40 mL) was added to the resulting residue and the insoluble solids were collected by filtration to give the product; yield: 0.236 g (92%).

7.6.5.6.6 Method 6: Application to Addition to C—C Multiple Bonds Bearing a Directing Group

Aryl Grignard reagents undergo anti-addition to propargylic alcohols (▶ Scheme 5).[22,23] The hydroxy-substituent is essential for the selective and efficient arylmagnesiation reaction, serving as a directing group. The vinylic magnesium intermediate reacts with a variety of electrophiles to yield tetrasubstituted alkenes such as 2,3-diphenylbut-2-en-1-ol (12). The protocol is also applicable to efficient synthesis of (Z)-tamoxifen. Dimethyl(2-pyridyl)(vinyl)silane also undergoes reaction with an aryl Grignard, utilizing the 2-pyridyl moiety as a directing group (▶ Scheme 5).[24]

▶ Scheme 5 Addition to C—C Multiple Bonds Utilizing Substrate Direction[22,24]

(Z)-2,3-Diphenylbut-2-en-1-ol (12):[22]

But-2-yn-1-ol (0.350 g, 5.0 mmol) was dissolved in toluene under N2, and 2 M PhMgCl in toluene/THF (1:1; 8.0 mL, 16 mmol) was added dropwise to the soln at rt. This mixture was then heated at reflux for 12 h. Pd(PPh3)4 (0.289 g, 0.25 mmol) was dissolved in THF (5 mL), and this soln and bromobenzene (1.90 mL, 18 mmol) were added via syringes to the reaction mixture. The resulting mixture was heated for an additional 24 h and then allowed to cool to rt, and H2O (20 mL) and 1 M HCl (10 mL) were added. The organic compounds were extracted with Et2O (2 × 20 mL). Chromatography (neutral alumina, petroleum ether/EtOAc 7:1) gave the product; yield: 0.806 g (73%).

7.6.5.6.7 Method 7: Application to Transmetalations with Metal Halides

See also Section 7.6.5.2

Zinc(II) chloride promotes nucleophilic substitution of chlorosilanes with aryl Grignard reagents to give an efficient synthesis of tetraorganosilanes such as dimethyl(phenyl)(4-tolyl)silane (13) (▶ Scheme 6).[25,26] The zinc(II)-catalyzed arylation proceeds under mild reaction conditions and is reliable for large-scale synthesis.[26]

▶ Scheme 6 Zinc(II)-Catalyzed Arylation of a Chlorosilane[25,26]

Dimethyl(phenyl)(4-tolyl)silane (13):[25]

Me2Si(Ph)Cl (85 mg, 0.50 mmol) in 1,4-dioxane (1 mL) was added under argon to a 20-mL flask containing ZnCl2•TMEDA (1.3 mg, 0.005 mmol), followed by the addition of a 1.0 M soln of 4-TolMgBr in THF (0.75 mL, 0.75 mmol). The resulting mixture was stirred for 1 h at 20°C, and then sat. aq NH4Cl (2 mL) was added. The organic compounds were extracted with EtOAc (3 × 10 mL) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, hexane) gave the product; yield: 95 mg (84%).

7.6.5.6.8 Method 8: Application to Addition to Carbonyl Compounds

See also Section 7.6.5.4

7.6.5.6.8.1 Variation 1: Highly Efficient Addition of Lithium Triphenylmagnesate to Benzophenone

Lithium triphenylmagnesate undergoes efficient nucleophilic attack on benzophenone to give triphenylmethanol (▶ Scheme 7).[27] “Ate” complexation enhances nucleophilicity toward carbonyl groups, suppresses the basicity and reducing ability of the nucleophile, and thereby minimizes formation of byproducts.

▶ Scheme 7 Addition of Lithium Triphenylmagnesate to Benzophenone[27]

7.6.5.6.8.2 Variation 2: Zinc(II)-Catalyzed Addition of Aryl Grignard Reagents to Carbonyl Species

A combination of zinc(II) chloride, [(trimethylsilyl)methyl]magnesium chloride, and lithium chloride can catalyze highly efficient nucleophilic arylation of ketones with aryl Grignard reagents (▶ Scheme 8).[28,29] Mixed zincates [(TMSCH2)2Ar1ZnMgCl•nLiCl] are formed in situ and have higher nucleophilicity and lower basicity than the parent aryl Grignard reagents. A similar effect also operates in the addition of alkyl Grignard reagents (see ▶ Section 7.6.10.9.3).

▶ Scheme 8 Highly Efficient Arylation of Ketones under Zinc Catalysis[28,29]

References

[1] Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel, P., Angew. Chem., (2008) 120, 6907; Angew. Chem. Int. Ed., (2008) 47, 6802.

[2] Krasovskiy, A.; Knochel, P., Angew. Chem., (2004) 116, 3396; Angew. Chem. Int. Ed., (2004) 43, 3333.

[3] Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K., Angew. Chem., (2000) 112, 2594; Angew. Chem. Int. Ed., (2000) 39, 2481.

[4] Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K., J. Org. Chem., (2001) 66, 4333.

[5] Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.; Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, J., J. Org. Chem., (2001) 66, 6775.

[6] Iida, T.; Wada, T.; Tomimoto, J.; Mase, T., Tetrahedron Lett., (2001) 42, 4841.

[7] Spring, D. R.; Krishnan, S.; Blackwell, H. E.; Schreiber, S. L., J. Am. Chem. Soc., (2002) 124, 1354.

[8] Higuchi, T.; Ohmori, K.; Suzuki, K., Chem. Lett., (2006) 35, 1006.

[9] Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W., Tetrahedron, (2006), 62 5092.

[10] Dumouchel, S.; Mongin, F.; Trécourt, F.; Quéguiner, G., Tetrahedron Lett., (2003) 44, 2033.

[11] Krasovskiy, A.; Krasovskaya, V.; Knochel, P., Angew. Chem., (2006) 118, 3024; Angew. Chem. Int. Ed., (2006) 45, 2958.

[12] Lin, W. W.; Baron, O.; Knochel, P., Org. Lett., (2006) 8, 5673.

[13] Clososki, G. C.; Rohbogner, C. J.; Knochel, P., Angew. Chem., (2007) 119, 7825; Angew. Chem. Int. Ed., (2007) 46, 7681.

[14] Mosrin, M.; Knochel, P., Org. Lett., (2008) 10, 2497.

[15] Mosrin, M.; Petrera, M.; Knochel, P., Synthesis, (2008), 3697.

[16] Krasovskiy, A.; Tishkov, A.; del Amo, V.; Mayr, H.; Knochel, P., Angew. Chem., (2006) 118, 5132; Angew. Chem. Int. Ed., (2006) 45, 5010.

[17] Maji, M. S.; Pfeifer, T.; Studer, A., Angew. Chem., (2008) 120, 9690; Angew. Chem. Int. Ed., (2008) 47, 9547.

[18] Maji, M. S.; Studer, A., Synthesis, (2009), 2467.

[19] Tsutsui, H.; Ichikawa, T.; Narasaka, K., Bull. Chem. Soc. Jpn., (1999) 72, 1869.

[20] Kitamura, M.; Chiba, S.; Narasaka, K., Bull. Chem. Soc. Jpn., (2003) 76, 1063.

[21] Kitamura, M.; Suga, T.; Chiba, S.; Narasaka, K., Org. Lett., (2004) 6, 4619.

[22] Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A. G., Org. Lett., (2003) 5, 2989.

[23] Fleming, F. F.; Gudipati, V.; Steward, O. W., Org. Lett., (2002) 4, 659.

[24] Itami, K.; Mitsudo, K.; Yoshida, J., Angew. Chem., (2001) 113, 2399; Angew. Chem. Int. Ed., (2001) 40, 2337.

[25] Murakami, K.; Yorimitsu, H.; Oshima, K., J. Org. Chem., (2009) 74, 1415.

[26] Murakami, K.; Yorimitsu, H.; Oshima, K.; Panteleev, J.; Lautens, M., Org. Synth., (2010) 87, 178.

[27] Hatano, M.; Matsumura, T.; Ishihara, K., Org. Lett., (2005) 7, 573.

[28] Hatano, M.; Ito, O.; Suzuki, S.; Ishihara, K., Chem. Commun. (Cambridge), (2010) 46, 2674.

[29] Hatano, M.; Ito, O.; Suzuki, S.; Ishihara, K., J. Org. Chem., (2010) 75, 5008.

7.6.10.9 Alkyl Grignard Reagents (Update 2010)

H. Yorimitsu

General Introduction

The original Grignard method for obtaining alkyl Grignard reagents has been the most reliable for more than a century. However, recently, heteroatom-assisted halogen–magnesium and sulfoxide–magnesium exchange reactions have been developed which have provided a wide range of functionalized alkyl Grignard reagents, including enantiomerically pure compounds.

7.6.10.9.1 Method 1: Synthesis by Halogen–Magnesium Exchange

The equilibrium between an alkyl halide and an alkyl Grignard reagent via halogen–magnesium exchange is not considered a favorable process. However, with the aid of a neighboring heteroatom the exchange becomes practically useful. For example, ethyl cis-2-iodocyclopropanecarboxylate undergoes smooth halogen–magnesium exchange with isopropylmagnesium chloride (▶ Scheme 1).[1] The reaction proceeds to completion within 15 min at –40°C and the cyclopropylmagnesium intermediate 1 obtained reacts with a wide range of electrophiles.

▶ Scheme 1 Formation of a Cyclopropylmagnesium Reagent[1]

▶ Scheme 2 Iodine–Magnesium Exchange in 3- and 4-Heteroatom-Substituted Alkyl Iodides[2,3]

Halogen–magnesium exchange with α-heteroatom-substituted alkyl halides results in the formation of magnesium carbenoids. These carbenoids are so unstable that they require generation and handling at temperatures as low as –78°C. Iodomethyl pivalate and iodomethyl cyclohexanecarboxylate undergo smooth iodine–magnesium exchange with isopropylmagnesium chloride (▶ Scheme 3).[4] The resulting carbenoids 6 react at –78°C with highly reactive electrophiles, such as iminium salts and aldehydes, in the presence of chlorotrimethylsilane.

▶ Scheme 3 Magnesiation of Iodomethyl Esters[4]

Enantioselective iodine–magnesium exchange between 1,1-diiodo-2-phenylethane and a chiral Grignard reagent 7 (>99% ee) has been reported (▶ Scheme 4).[5] Although enantioselectivities are not satisfactory, this investigation is important to understand the reaction mechanism of iodine–magnesium exchange. Furthermore, the radical cyclization of O,O-acetal 8 with ethylmagnesium bromide has been observed to give the corresponding cyclic Grignard reagent, [(tetrahydrofuran-3-yl)methyl]magnesium bromide 9, in high yield (▶ Scheme 4).[6]

▶ Scheme 4 Synthesis of Chiral Alkyl Grignard Reagents[5,6]

Iodine–magnesium exchange also takes place upon treatment of trans-5-butyl-4-(iodomethyl)-3,3-dimethyldihydrofuran-2(3H)-one with isopropylmagnesium bromide (▶ Scheme 5).[7] The resulting alkylmagnesium species undergoes intramolecular nucleophilic substitution to construct a cyclopropane ring.

▶ Scheme 5 Synthesis of a Cyclopropane Ring via Formation of a Grignard Reagent by Iodine–Magnesium Exchange[7]

cis-[2-(Ethoxycarbonyl)cyclopropyl]magnesium Chloride (1):[1]

Ethyl cis-2-iodocyclopropanecarboxylate (0.240 g, 1.0 mmol) in THF (4 mL) was placed in a dry two-necked flask equipped with a magnetic stirrer bar and a septum under argon. The soln was cooled to –40°C and a 1.62 M soln of iPrMgCl in THF (0.67 mL, 1.1 mmol) was added slowly. After the resulting mixture had been stirred for 15 min, the exchange was complete.

A 2.0 M soln of iPrMgCl in THF (0.23 mL, 0.45 mmol) was added to a THF soln of 3-iodopropan-1-ol (75.6 mg, 0.41 mmol) at –78°C. The resulting soln was stirred for 5 min, and then a 2.9 M soln of BuLi in hexane (0.29 mL, 0.85 mmol) was added. The mixture was stirred for 20 min at the same temperature to give the product.

(1,4-Dioxaspiro[4.5]decan-6-ylmethyl)magnesium Chloride–Lithium Chloride Complex (5):[3]

Flame-dried LiCl (7.21 g, 0.17 mol), Mg turnings (5.47 g, 0.225 mol), and THF (45 mL) were placed in a two-necked flask under argon. 1,5-Dichloropentane (10.6 g, 75.0 mmol) in THF (30 mL) was added dropwise, and the resulting mixture was refluxed for 2 h. The resulting soln was transferred to another flask under argon to give the dimagnesiated pentane 3; concentration: 0.67–0.79 M; 92% purity (GC).

Alkyl iodide 4 (0.564 g, 2.0 mmol) was dissolved in THF (2 mL) and cooled to –15°C. A 0.79 M soln of dimagnesiated pentane 3 in THF (2.8 mL, 2.2 mmol) was then added, and stirring at –15°C for 3 h gave the product.

A 0.60 M soln of iPrMgCl in THF (5.5 mL, 3.3 mmol) was placed in a 50-mL Schlenk flask and cooled to –78°C. A soln of iodomethyl pivalate (0.726 g, 3.0 mmol) in THF/N-butylpyrrolidin-2-one (5:1; 5 mL) was added dropwise over 10 min, and the mixture was stirred at –78°C for 10 min to give the product.

trans-[(5-Butoxy-2-butyltetrahydrofuran-3-yl)methyl]magnesium Bromide (9):[6]

The solvent was removed from a 1.0 M ethereal soln of EtMgBr (3.0 mL, 3.0 mmol) under reduced pressure. The residual solid was dissolved in DME (5 mL) and a soln of O,O-acetal 8 (0.354 g, 1.0 mmol) in DME (2 mL) was added at rt. The resulting mixture was stirred for 30 min to give the product.

7.6.10.9.1.1 Variation 1: Synthesis by Sulfoxide–Magnesium Exchange

Magnesium–sulfoxide exchange[8–10] provides a convenient route to obtain thermally unstable alkyl Grignard reagents, and unstable oxiranyl-[11,12] and aziridinylmagnesium[13,14] species are readily prepared by this method (▶ Scheme 6). The oxiranylmagnesium species decompose gradually even at –78°C and show poor reactivity toward electrophiles at such a low temperature. In contrast, the aziridinylmagnesium species (e.g., 11, obtained from aziridine 10) are stable at room temperature and can react with a variety of electrophiles in the presence or absence of a copper catalyst. Also, as the exchange reaction proceeds with retention of configuration, it is possible to synthesize enantiomerically enriched aziridines starting from enantiomerically pure sulfoxides.

▶ Scheme 6 Generation of Oxiranyl- and Aziridinylmagnesium Species by Magnesium–Sulfoxide Exchange[12,14]

A 1-chlorocyclopropyl phenyl sulfoxide has also been reported to undergo sulfoxide–magnesium exchange with an alkyl Grignard reagent in tetrahydrofuran at –78°C to give a cyclopropyl Grignard reagent (▶ Scheme 7).[15] The magnesium carbenoid generated is thermally and configurationally stable below –60°C for 3 hours.

▶ Scheme 7 Generation of a 1-Chlorocyclopropyl Grignard Reagent by Magnesium–Sulfoxide Exchange[15]

When a diastereomerically and enantiomerically enriched 1-chloroalkyl phenyl sulfoxide is used as the starting material, then sulfoxide–magnesium exchange leads to a (1-chloroalkyl)magnesium reagent of high enantiopurity (▶ Scheme 8).[16,17] The exchange proceeds with retention of configuration and little loss of enantiomeric excess. The chiral Grignard reagent obtained reacts stereoselectively at –78°C with benzaldehyde activated by dimethylaluminum chloride to yield the corresponding chlorohydrin.

▶ Scheme 8 Generation of a Chiral (1-Chloroalkyl)magnesium Reagent[16]

[(2R,3R)-2-Decyl-1,3-diphenylaziridin-2-yl]magnesium Bromide (11):[14]

A soln of aziridine 10 (71 mg, 0.15 mmol) in anhyd THF (1 mL) was added dropwise to a 0.53 M soln of EtMgBr in THF (1.0 mL, 0.53 mmol) at –55°C. The resulting mixture was warmed to –35°C and stirred for 2 h to generate the product.

7.6.10.9.2 Method 2: Synthesis by Carbomagnesiation of C—C Multiple Bonds

Nonpolar C—C multiple bonds are generally unreactive toward alkyl Grignard reagents, and carbomagnesiation proceeds only when the multiple bonds bear a directing group or are intramolecularly tethered to the C—Mg bond.[18] For example, methylmagnesiation of a cyclopropenylmethanol has been reported to proceed smoothly with the aid of (S)(–)-(1-methylpyrrolidin-2-yl)methanol (N-methyl-L-prolinol) to yield the chiral cyclopropylmagnesium 12 with high enantiomeric excess (▶ Scheme 9).[19]

▶ Scheme 9 Enantioselective Methylmagnesiation of a Cyclopropenylmethanol[19]

▶ Scheme 10 Carbomagnesiation of Vinylsilanes[20–22]

[(1S,2R,3S)-3-Methyl-2-(oxidomethyl)-2-phenylcyclopropyl]magnesium (12):[19]

A 50-mL flask containing LiCl (65 mg, 1.5 mmol) was flame-dried under vacuum, refilled with N2, and allowed to cool to ambient temperature. THF (2 mL), toluene (5 mL), MeOH (20 μL, 0.50 mmol), and (S)-(–)-(1-methylpyrrolidin-2-yl)methanol (178 μL, 1.5 mmol) were added sequentially, and the mixture was cooled to –50°C. Then, 3.0 M MeMgCl in THF (1.33 mL, 4.0 mmol) was added dropwise, the cold bath was removed, and the mixture was stirred for 1 h while warming to ambient temperature. The flask was then further cooled in a cold bath (–70°C) and a soln of the cyclopropene (73 mg, 0.50 mmol) in toluene (5 mL) was added by syringe pump over 45 min. After the addition was complete, the mixture was stirred at –50°C for 24 h to give the product. The formation of the enantiomerically enriched reagent was evident upon treatment with electrophiles.

A 2.25 M soln of BuMgCl in Et2O (0.24 mL, 0.55 mmol) was added to a soln of dimethyl(2-pyridyl)(vinyl)silane (82 mg, 0.50 mmol) in Et2O (1 mL) under argon. The resulting mixture was stirred at rt for 3 h to give the product.

7.6.10.9.3 Method 3: Application to Addition to Carbonyl Compounds

See also Section 7.6.10.8

7.6.10.9.3.1 Variation 1: Highly Efficient Addition of Lithium Trialkylmagnesates to Acetophenone

Lithium trialkylmagnesates are superior to alkyllithium and alkylmagnesium reagents in nucleophilic addition to hindered or enolizable ketones. Although homomagnesates, such as lithium tributylmagnesate, are useful they transfer only one of three possible alkyl groups effectively and are thus wasteful. Heteromagnesates, such as lithium ethyl(dimethyl)magnesate, are thus more efficient for alkylation since the methyl groups behave as nontransferable dummy ligands. The reaction of both homo- and heteromagnesates with acetophenone, to give alcohols 14 and 15, is illustrated in ▶ Scheme 11.[23]

▶ Scheme 11 Addition of Magnesates to Acetophenone[23]

2-Phenylhexan-2-ol (14):[23]

A 1.0 M soln of Bu2Mg in heptane (1.06 mL, 1.06 mmol) and 1.6 M BuLi in hexane (0.63 mL, 1.0 mmol) were added sequentially to a soln of 2,2′-bipyridyl (172 mg, 1.1 mmol) in THF (1.5 mL) at –78°C under N2. The resulting suspension was stirred at the same temperature for 1 h and acetophenone (120 mg, 1.0 mmol) in THF (1.5 mL) was then added. The resulting mixture was stirred at –78°C for 5 h and then sat. aq NH4Cl (10 mL) was added. The organic compounds were extracted with Et2O (3 × 10 mL) and washed with brine (10 mL). The combined organic layers were concentrated and the resulting residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to afford the product; yield: 171 mg (96%).

2-Phenylbutan-2-ol (15):[23]

A 1.60 M soln of MeLi in Et2O (1.25 mL, 2.0 mmol) and 0.98 M EtMgBr in THF (1.22 mL, 1.2 mmol) were added to THF (1.5 mL) at –78°C under N2. The resulting soln was stirred at the same temperature for 1 h and acetophenone (120 mg, 1.0 mmol) in THF (1.5 mL) was added. The resulting mixture was stirred at –78°C for 5 h and then sat. aq NH4Cl (10 mL) was added. The product was extracted with Et2O (3 × 10 mL) and washed with brine (10 mL). The combined organic layers were concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to give the product; yield: 140 mg (93%).

7.6.10.9.3.2 Variation 2: Zinc(II)-Catalyzed Addition of Alkyl Grignard Reagents to Carbonyl Groups

The reaction of Grignard reagents with ketones and imines to give alcohols and amines (e.g., 16