Modern Alkyne Chemistry E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
A comprehensive and up-to-date overview of alkyne chemistry, taking into account the progress made over the last two decades. The experienced editors are renowned world leaders in the field, while the list of contributors reads like a "Who's Who" of synthetic organic chemistry. The result is a valuable reference not only for organic chemists at universities and in the chemical industry, but also for biologists and material scientists involved in the modern synthesis of organic compounds and materials.
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Seitenzahl: 608
Veröffentlichungsjahr: 2014
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Table of Contents
Cover
Related Titles
Title Page
Copyright
List of Contributors
Preface
Chapter 1: Introduction
1.1 History of Alkynes
1.2 Structure and Properties of Alkynes
1.3 Classical Reactions of Alkynes
1.4 Modern Reactions
1.5 Conclusion
References
Part I: Catalytic Isomerization of Alkynes
Chapter 2: Redox Isomerization of Propargyl Alcohols to Enones
2.1 Introduction
2.2 Base Catalysis
2.3 Ru Catalyzed
2.4 Rh Catalysis
2.5 Palladium Catalysis
2.6 Miscellaneous
2.7 Conclusions
References
Chapter 3: Carbophilic Cycloisomerization Reactions of Enynesand Domino Processes
3.1 Introduction and Reactivity Principles
3.2 Skeletal Rearrangement Reactions in the Absence of Nucleophiles
3.3 Enyne Domino Processes
3.4 Conclusion
References
Chapter 4: Alkyne Metathesis in Organic Synthesis
4.1 Introduction
4.2 Mechanistic Background and Classical Catalyst Systems
4.3 State-of-the-Art Catalysts
4.4 Basic Reaction Formats and Substrate Scope
4.5 Selected Applications
4.6 Conclusions
References
Part II: Catalytic Cycloaddition Reactions
Chapter 5: Alkyne–Azide Reactions
5.1 Introduction
5.2 Reviews on Cu-Catalyzed Azide–Alkyne Cycloaddition
5.3 Mechanistic Considerations on the Cu(1) Catalysis
5.4 The Substrates for CuAAC
5.5 The Environment
5.6 Modified 1,2,3-Triazoles and CuAAC Side Reactions
5.7 The Catalyst
5.8 Optimizing Conditions for CuAAC Reactions
5.9 CuAAC in Biological Applications
5.10 Biocompatibility of the CuAAC Reaction
References
Chapter 6: Catalytic Cycloaddition Reactions
6.1 Introduction
6.2 (2 + 2) Cycloaddition
6.3 (3 + 2) and (2 + 1) Cycloaddition
6.4 (4 + 2) Cycloaddition
6.5 (5 + 1) and (4 + 1) Cycloadditions
6.6 (5 + 2) Cycloaddition
6.7 (6 + 2) Cycloaddition
6.8 (2 + 2 + 1) Cycloaddition
6.9 (2 + 2 + 2) Cycloaddition
6.10 (3 + 2 + 1) Cycloaddition
6.11 (3 + 2 + 2) Cycloaddition
6.12 (4 + 2 + 1) and (4 + 2 + 2) Cycloaddition
6.13 (4 + 3 + 2) Cycloaddition
6.14 (5 + 2 + 1) and (5 + 1 + 2 + 1) Cycloadditions
6.15 (2 + 2 + 1 + 1) and (2 + 2 + 2 + 1) Cycloadditions
6.16 (2 + 2 + 2 + 2) Cycloaddition
6.17 Conclusions
References
Part III: Catalytic Nucleophilic Additions and Substitutions
Chapter 7: Catalytic Conjugate Additions of Alkynes
7.1 Introduction
7.2 Metal Alkynylides as Nucleophiles
7.3 Direct Use of Terminal Alkynes as Pronucleophiles
7.4 Summary and Conclusions
References
Chapter 8: Catalytic Enantioselective Addition of Terminal Alkynes to Carbonyls
8.1 Introduction
8.2 Metallation of Terminal Alkynes: Formation of Alkynyl Nucleophiles
8.3 Ligand-Catalyzed Alkyne Additions with Stoichiometric Quantities of Metal
8.4 Alkyne Additions with Catalytic Amounts of Metal
8.5 Concluding Remarks
References
Chapter 9: Catalytic Nucleophilic Addition of Alkynes to Imines: The A3 (Aldehyde–Alkyne–Amine) Coupling
9.1 A
3
Couplings Involving Primary Amines
9.2 A
3
Couplings Involving Secondary Amines
9.3 Alkyne Additions with Reusable Catalysts
9.4 Asymmetric Alkyne Addition Reactions
9.5 Alkyne Additions to Imines in Tandem Reactions
9.6 Conclusion
References
Chapter 10: The Sonogashira Reaction
10.1 Introduction
10.2 Palladium–Phosphorous Catalysts
10.3 Palladium–Nitrogen Catalysts
10.4 N-Heterocyclic Carbene (NHC)-Palladium Catalysts
10.5 Palladacycles as Catalysts
10.6 Ligand-Free Palladium Salts as Catalysts
10.7 Palladium Nanoparticles as Catalysts
10.8 Non-Palladium-Based Catalysts
10.9 Mechanistic Considerations
10.10 Summary and Conclusions
References
Part IV: Other Reactions
Chapter 11: Catalytic Dimerization of Alkynes
11.1 Introduction
11.2 Dimerization of Alkynes Catalyzed by Iron, Ruthenium, and Osmium Complexes
11.3 Dimerization of Alkynes Catalyzed by Cobalt, Rhodium, and Iridium Complexes
11.4 Dimerization of Alkynes Catalyzed by Nickel, Palladium, and Platinum Complexes
11.5 Dimerization of Alkynes Catalyzed by Group 3, Lanthanide, and Actinide Complexes
11.6 Dimerization of Alkynes Catalyzed by Titanium, Zirconium, and Hafnium Complexes
11.7 Dimerization of Alkynes Catalyzed by Other Compounds
11.8 Summary and Conclusions
Acknowledgments
References
Chapter 12: The Oxidative Dimerization of Acetylenes and Related Reactions: Synthesis and Applications of Conjugated 1,3-Diynes
12.1 Introduction
12.2 Syntheses of Conjugated 1,3-Diynes
12.3 Scope and Limitation of the Alkyne Dimerization Reaction
12.4 Scope and Limitation of Copper-Catalyzed Hetero-Coupling Reactions
12.5 The Cadiot–Chodkiewicz Reaction
12.6 Palladium-Catalyzed Acetylenic Coupling Reactions
12.7 Alternative Methods for the Synthesis of Diynes
12.8 Mechanism of Alkyne Homo-Coupling Reactions
12.9 Mechanism of Alkyne Hetero-Coupling Reactions
12.10 Utility of 1,3-Diynes in the Synthesis of Natural Products
12.11 Synthetic Utility of Conjugated 1,3-Diynes
12.12 Utility of 1,3-Diynes in Materials Science
12.13 Conclusion
References
Chapter 13: The Alkyne Zipper Reaction in Asymmetric Synthesis
13.1 Introduction
13.2 Mechanism of KNH
2
/NH
3
Isomerization
13.3 Mechanism of KAPA Isomerization
13.4 Applications in Natural Products
13.5 Conclusion
References
Index
End User License Agreement
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Guide
Cover
Table of Contents
Preface
Part I: Catalytic Isomerization of Alkynes
Chapter 1: Introduction
List of Illustrations
Figure 2.1
Scheme 2.1
Scheme 2.2
Scheme 3.1
Scheme 3.2
Scheme 3.3
Scheme 3.4
Scheme 3.5
Scheme 3.6
Scheme 3.7
Scheme 3.8
Scheme 3.9
Scheme 3.10
Scheme 3.11
Scheme 3.12
Scheme 3.13
Scheme 3.14
Scheme 3.15
Scheme 3.16
Scheme 3.17
Scheme 3.18
Scheme 3.19
Scheme 3.20
Scheme 3.21
Scheme 3.22
Scheme 3.23
Scheme 3.24
Scheme 3.25
Scheme 3.26
Scheme 3.27
Scheme 3.28
Scheme 3.29
Scheme 3.30
Scheme 3.31
Scheme 3.32
Scheme 3.33
Scheme 3.34
Scheme 3.35
Scheme 3.36
Scheme 3.37
Scheme 3.38
Scheme 3.39
Scheme 3.40
Scheme 3.41
Scheme 4.1
Scheme 4.2
Scheme 4.3
Scheme 4.4
Scheme 4.5
Scheme 4.6
Figure 4.1
Scheme 4.7
Scheme 4.8
Scheme 4.9
Scheme 4.10
Scheme 4.11
Scheme 4.12
Scheme 4.13
Scheme 4.14
Scheme 4.15
Scheme 4.16
Scheme 4.17
Scheme 4.18
Scheme 4.19
Scheme 4.20
Scheme 4.21
Scheme 4.22
Scheme 4.23
Scheme 4.24
Scheme 4.25
Scheme 4.26
Scheme 4.27
Scheme 4.28
Scheme 4.29
Scheme 4.30
Scheme 4.31
Scheme 4.32
Scheme 4.33
Figure 5.1
Figure 5.2
Scheme 5.1
Figure 5.3
Figure 5.4
Figure 5.5
Figure 5.6
Figure 5.7
Figure 5.8
Figure 5.9
Figure 5.10
Scheme 6.1
Scheme 6.2
Scheme 6.3
Scheme 6.4
Scheme 6.5
Scheme 6.6
Scheme 6.7
Scheme 6.8
Scheme 6.9
Scheme 6.10
Scheme 6.11
Scheme 6.12
Scheme 6.13
Scheme 6.14
Scheme 6.15
Scheme 6.16
Scheme 6.17
Scheme 6.18
Scheme 6.19
Scheme 6.20
Scheme 6.21
Scheme 6.22
Scheme 6.23
Scheme 6.24
Scheme 6.26
Scheme 6.25
Scheme 6.27
Scheme 6.28
Scheme 6.29
Scheme 6.30
Scheme 6.31
Scheme 6.32
Scheme 7.1
Figure 7.1
Scheme 7.2
Scheme 7.3
Scheme 7.4
Scheme 7.5
Scheme 7.6
Scheme 7.7
Scheme 7.8
Scheme 7.9
Scheme 7.10
Scheme 7.11
Scheme 7.12
Scheme 7.13
Scheme 7.14
Scheme 7.15
Scheme 7.16
Scheme 7.17
Scheme 7.18
Scheme 7.19
Scheme 7.20
Scheme 7.21
Scheme 7.22
Scheme 7.23
Scheme 7.24
Scheme 7.25
Scheme 7.26
Scheme 7.27
Scheme 7.28
Figure 7.2
Figure 8.1
Figure 8.2
Figure 8.3
Scheme 8.1
Figure 8.4
Scheme 8.2
Scheme 8.3
Scheme 8.4
Scheme 8.5
Scheme 8.6
Scheme 8.7
Scheme 8.8
Scheme 8.9
Scheme 8.10
Figure 8.5
Scheme 8.11
Scheme 8.12
Scheme 8.13
Scheme 8.14
Scheme 8.15
Scheme 8.17
Scheme 8.16
Scheme 8.18
Scheme 8.19
Scheme 8.20
Scheme 8.21
Scheme 8.22
Scheme 8.23
Scheme 8.24
Scheme 8.25
Scheme 8.26
Scheme 8.27
Scheme 8.28
Scheme 8.29
Scheme 8.30
Scheme 8.31
Scheme 8.32
Scheme 8.33
Scheme 8.34
Scheme 8.35
Scheme 8.36
Scheme 8.37
Scheme 8.38
Scheme 8.39
Scheme 8.40
Scheme 8.41
Scheme 8.42
Scheme 8.43
Scheme 8.44
Scheme 8.45
Scheme 9.1
Scheme 9.2
Scheme 9.3
Scheme 9.4
Scheme 9.5
Scheme 9.6
Scheme 9.7
Scheme 9.8
Scheme 9.9
Scheme 9.10
Scheme 9.11
Scheme 9.12
Scheme 9.13
Scheme 9.14
Scheme 9.15
Scheme 9.16
Scheme 9.17
Scheme 9.18
Scheme 9.19
Scheme 9.20
Scheme 9.21
Scheme 9.22
Scheme 9.23
Scheme 9.24
Scheme 9.25
Scheme 9.26
Scheme 10.1
Scheme 10.2
Scheme 10.3
Scheme 10.4
Scheme 10.5
Scheme 10.6
Scheme 10.7
Scheme 10.8
Scheme 10.9
Scheme 10.10
Scheme 10.11
Scheme 10.12
Scheme 10.13
Scheme 10.14
Scheme 10.15
Scheme 10.16
Scheme 10.17
Scheme 10.18
Scheme 10.19
Scheme 10.20
Scheme 10.21
Scheme 10.22
Scheme 10.23
Scheme 10.24
Scheme 10.25
Figure 10.1
Figure 10.2
Figure 11.1
Scheme 11.1
Scheme 11.2
Scheme 11.3
Scheme 11.4
Scheme 11.5
Scheme 11.6
Scheme 11.7
Scheme 11.8
Scheme 11.9
Scheme 11.10
Scheme 11.11
Scheme 11.12
Scheme 11.13
Scheme 11.14
Scheme 11.15
Scheme 11.16
Scheme 11.17
Scheme 11.18
Scheme 11.19
Scheme 11.20
Scheme 11.21
Scheme 11.22
Figure 11.2
Scheme 11.23
Scheme 11.24
Scheme 11.25
Scheme 11.26
Scheme 11.27
Scheme 11.28
Scheme 11.29
Scheme 11.30
Scheme 12.1
Scheme 12.2
Scheme 12.3
Scheme 12.4
Scheme 12.5
Scheme 12.6
Scheme 12.7
Scheme 12.8
Scheme 12.9
Scheme 12.10
Scheme 12.11
Scheme 12.12
Scheme 12.13
Figure 12.1
Scheme 12.14
Scheme 12.15
Scheme 12.16
Scheme 12.17
Scheme 12.18
Scheme 12.19
Scheme 12.20
Scheme 12.21
Scheme 12.22
Scheme 12.23
Scheme 12.24
Scheme 12.25
Scheme 12.26
Scheme 12.27
Scheme 13.1
Scheme 13.2
Scheme 13.3
Scheme 13.4
Scheme 13.5
Scheme 13.6
Scheme 13.7
Scheme 13.8
Scheme 13.9
Scheme 13.10
Scheme 13.11
Scheme 13.12
Scheme 13.13
Scheme 13.14
Scheme 13.15
Scheme 13.16
Scheme 13.17
Scheme 13.18
Scheme 13.19
Scheme 13.20
Scheme 13.21
Schemes 13.22
Figure 13.23
Scheme 13.24
Scheme 13.25
Scheme 13.26
Scheme 13.27
Scheme 13.28
Scheme 13.29
Scheme 13.30
Scheme 13.31
Scheme 13.32
List of Tables
Table 3.1
Table 4.1
Table 4.2
Table 4.3
Table 9.1
Table 9.2
Table 9.3
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Edited by
Barry M. Trost and Chao-Jun Li
Modern Alkyne Chemistry
Catalytic and Atom-Economic Transformations
The Editors
Prof. Dr. Barry M. Trost
Stanford University
Department of Chemistry
330 Roth Way
Stanford
CA 94305-5080
USA
Prof. Dr. Chao-Jun Li
McGill University
Department of Chemistry
801 Sherbrook Street West
Montreal
Quebec H3A 0B8
Canada
All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.
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List of Contributors
Kenneth Avocetien
Northeastern University
Department of Chemistry and Chemical Biology
Hurtig Hall
Huntington Ave
Boston
MA 02115
USA
Mark J. Bartlett
University of California Berkeley
Department of Chemistry
Berkeley
CA 94720-1460
USA
Rafael Chinchilla
University of Alicante
Department of Organic Chemistry
Faculty of Sciences and Institute of Organic Synthesis
ctra San Vicente s/n
Alicante
Spain
Alois Fürstner
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1
Mülheim an der Ruhr
Germany
Sergio E. García-Garrido
Universidad de Oviedo
Laboratorio de Compuestos Organometálicos y Catálisis
Red ORFEO-CINQA - Centro de Innovación en Química Avanzada
IUQOEM, Facultad de Química
C/Julián Clavería 8
Oviedo
Spain
Jean-Pierre Genet
PSL Research University
Chimie ParisTech - CNRS
Institut de Recherche de Chimie Paris
rue P. et M. Curie
Paris Cedex 05
France
Naoya Kumagai
Institute of Microbial Chemistry (Bikaken)
Laboratory of Synthetic Organic Chemistry
3-14-23 Kamiosaki
Shinagawa-ku
Tokyo 141-0021
Japan
Chao-Jun Li
McGill University
Department of Chemistry
Sherbrook Street West
Montreal
Quebec H3A 0B8
Canada
Yu Li
Northeastern University
Department of Chemistry and Chemical Biology
Hurtig Hall
Huntington Ave
Boston
MA 02115
USA
Jean-Philip Lumb
McGill University
Department of Chemistry
Sherbrooke Street West, Room 322
Montreal
Quebec H3A 0B8
Canada
Giovanni Maestri
Institut de Chimie des Substances Naturelles
CNRS-UPR 2301
1, avenue de la Terrasse-Bât.27
Gif/Yvette Cedex
France
Max Malacria
Institut de Chimie des Substances Naturelles
CNRS-UPR 2301
1, avenue de la Terrasse-Bât.27
Gif/Yvette Cedex
France
Morten Meldal
University of Copenhagen
Department of Chemistry
Center for Evolutionary Chemical Biology (CECB)
Universitetsparken 5
Copenhagen
Denmark
Véronique Michelet
PSL Research University
Chimie ParisTech - CNRS
Institut de Recherche de Chimie Paris
rue P. et M. Curie
Paris Cedex 05
France
Carmen Nájera
University of Alicante
Department of Organic Chemistry
Faculty of Sciences and Institute of Organic Synthesis
ctra San Vicente s/n
Alicante
Spain
George A. O'Doherty
Northeastern University
Department of Chemistry and Chemical Biology
Hurtig Hall
Huntington Ave
Boston
MA 02115
USA
Raphael Rodriguez
Institut de Chimie des Substances Naturelles
CNRS-UPR 2301
1, avenue de la Terrasse-Bât.27
Gif/Yvette Cedex
France
Sanne Schoffelen
University of Copenhagen
Department of Chemistry
Center for Evolutionary Chemical Biology (CECB)
Universitetsparken 5
Copenhagen
Denmark
Masakatsu Shibasaki
Institute of Microbial Chemistry (Bikaken)
Laboratory of Synthetic Organic Chemistry
3-14-23 Kamiosaki
Shinagawa-ku
Tokyo 141-0021
Japan
Patrick Y. Toullec
PSL Research University
Chimie ParisTech - CNRS
Institut de Recherche de Chimie Paris
rue P. et M. Curie
Paris Cedex 05
France
Barry M. Trost
Stanford University
Department of Chemistry
Roth Way
Stanford
CA 94305-5080
USA
Fiona R. Truscott
Institut de Chimie des Substances Naturelles
CNRS-UPR 2301
1, avenue de la Terrasse-Bât.27
Gif/Yvette Cedex
France
Nick Uhlig
McGill University
Department of Chemistry
Sherbrook Street West
Room 322
Montreal
Quebec H3A 2K6
Canada
Woo-Jin Yoo
McGill University
Department of Chemistry
Sherbrook Street West
Room 322
Montreal
Quebec H3A 2K6
Canada
Liang Zhao
McGill University
Department of Chemistry
Sherbrook Street West
Room 322
Montreal
Quebec H3A 2K6
Canada
Preface
Alkyne is a basic functionality with “relatively low thermodynamic reactivities” in the classical text of organic chemistry. These classical alkyne reactions often require stoichiometric reagents, which result in low efficiency in chemical syntheses, and “harsh” reaction conditions that cannot tolerate the presence of the various “more reactive functional groups”. The pursuit of synthetic efficiency combined with the recent emphasis of “future sustainability and Green Chemistry,” and the pressing desire for new chemical tools in synthetic biology inspire chemists to uncover new reactions that are catalytic in nature (rather than consuming stoichiometric reagents), occur under ambient conditions (including milder temperature and aqueous media), can tolerate various functional groups, and render “dial-up” reactivity when needed. Alkynes provide the most ideal candidate for such features. While being relatively inert under “classical” conditions, alkynes can be readily “activated” selectively, in the presence of other functional groups and under mild conditions, via transition-metal catalysis through either selective alkyne carbon-carbon triple bond reactions or terminal alkyne C-H bond reactions. Such a unique reactivity allow alkynes to be embedded and be “dialed-up” whenever needed. For the past few decades, modern alkyne chemistry has thus been developed rapidly to feature these characteristics. These developments further focus on atom-economic transformations where minimal or no theoretical by-products are formed. Furthermore, many of these catalytic transformations are orthogonal to biological conditions. These modern catalytic alkyne reactions are much more resource-, time-, and manpower-efficient, and provide an alternative to classical stoichiometric alkyne chemistry. This book comprises a collection of contributions from leading experts and covers various modern catalytic reactions of alkynes. We hope that this focused book will be very helpful not only to students and researchers in chemistry but also to those in material and biological studies and will provide them with tools and opportunities unavailable with classical alkyne chemistry.
Stanford
Montreal
August 2014
Barry M. Trost
Chao-Jun Li
1Introduction
Chao-Jun Li and Barry M. Trost
1.1 History of Alkynes
Alkyne is one of the fundamental functional groups that established the foundation of organic chemistry [1]. The smallest member of this family, acetylene, was first discovered in 1836 by Edmund Davy [2]. It was rediscovered and named “acetylene” by Marcellin Berthelot in 1860 by passing vapors of organic compounds through a red-hot tube or sparking electricity through a mixture of cyanogen and hydrogen gas. Acetylene is a moderately common chemical in the universe [3], often in the atmosphere of gas giants. In 1862, Friedrich Wöhler discovered the generation of acetylene from the hydrolysis of calcium carbide (Equation 1.1). Acetylene produced by this reaction was the main source of organic chemicals in the coal-based chemical industry era. When petroleum replaced coal as the chief source of carbon in the 1950s, partial combustion of methane (Equation 1.2) or formation as a side product of hydrocarbon cracking became the prevalent industrial manufacturing processes for acetylene. The next member of the family, propyne, is also mainly prepared by the thermal cracking of hydrocarbons. The first naturally occurring acetylic compound, dehydromatricaria ester (1), was isolated in 1826 [4] from an Artemisia species. Well over 1000 alkyne-containing natural products have been isolated since then, among which many are polyyne-containing natural products isolated from plants, fungi, bacteria, marine sponges, and corals [5].
The higher members of alkynes are generally derived from the smaller homologs via alkyne homologation processes of the terminal alkynes (see Equation 1.8, below), while some alkynes are generated through elimination reactions with organic halides under basic conditions (Equation 1.3) [1]. A search in Sci Finder shows that >70 000 terminal alkynes and >10 000 internal alkynes are now commercially available from various sources.
1.2 Structure and Properties of Alkynes
Alkynes contain a tripe bond, composed of a σ-covalent bond formed from two sp-hybridized carbons and two π-bonds resulted from the overlapping of two orthogonal unhybridized p-orbitals on each carbon (2) [1]. Consequently, alkynes are generally rod-like. Cyclic alkynes are less common with benzyne as an important reactive intermediate in organic chemistry [6]. Acetylene is linear and intrinsically unstable under pressure due to its high compressibility as well as its propensity to undergo exothermic self addition reactions. Consequently, acetylene itself can explode violently at high pressure and the safe limit for acetylene is 103 kPa. Thus, acetylene is generally shipped in acetone or dimethyl formamide (DMF) solutions or contained in a gas cylinder with porous filling [7]. Acetylene has been used as a burning fuel and for illumination purposes in the late nineteenth century and early twentieth century [8]. In modern times, alkynes have found a wide range of applications ranging from organic electronic materials, metal-organic frame works (MOF), pharmaceutical agents, and others [9]. The linearity of the alkyne creates strain when an alkyne is part of a ring [10]. In spite of this fact, cyclopentyne, cyclohexyne, and cycloheptyne can be generated at least fleetingly, their existence being confirmed by in situ trapping, notably by 1,3-dipolar cycloadditions [11]. Cyclooctyne is still highly strained but has sufficient stability to be isolated and used in click chemistry to study biological processes [12].
1.3 Classical Reactions of Alkynes
The higher degree of unsaturation of alkynes compared to alkenes increases their reactivity toward addition to both alkenes and alkynes. In particular, virtually all additions of HX and RX to alkynes are exothermic. Consequently, these stoichiometric addition reactions have been the basis of most reactions in the classical alkyne chemistry (Equation 1.4) [1]. These classical alkyne addition reactions include the additions of hydrogen, halogens, water, hydrogen halides, halohydrins, hydroborations, and others. With a stoichiometric amount of a strong oxidizing reagent such as KMnO4, the addition may be followed by C–C cleavage to give the corresponding acids (Equation 1.5). Less reactive reagents can also be added through the use of a transition-metal catalyst. The unique electronic character of alkynes wherein their HOMO–LUMO gap is rather small makes them especially effective as coordinators to transition metals. Thus, they function as chemoselective functional groups for catalytic transformations. For example, catalytic addition of dihydrogen to alkynes can proceed to either alkenes or alkanes depending on the choice of the catalysts (Equation 1.6) [13]. Further, the hydroalumination [14], hydrosilylation [15], hydrostannylation [16], as well as carboalumination [17] represent important modern advances of the alkyne addition reactions.
A second class of reactions pertains to terminal alkynes. Due to the increased s-character, the alkynyl C–H bonds (pKa = 25) are much more acidic than the corresponding alkenyl C–H bonds (pKa = 43) and alkyl C–H bonds (pKa > 50) [18]. Thus, base-promoted additions of terminal alkynes to carbonyl compounds can occur under different basic conditions, a process discovered over a century ago (Equation 1.7). Treatment of terminal alkynes with bases such as lithium amide, butyllithium, or Grignard or zinc reagents generates metal acetylides stoichiometrically, which can then react with different carbon-based electrophiles to produce various higher alkyne homologs in the classical synthetic chemistry (Equation 1.8) [1]. Such processes can be catalyzed to permit deprotonation with much weaker bases as in the coupling with aryl halides under Pd/Cu catalysis (Sonogashira reaction, see Equation 1.13).
1.4 Modern Reactions
Although the classical stoichiometric addition reactions, alkyne cleavage reactions, and homologation reactions have established the foundation of alkyne chemistry, a rebirth of interest derives from recent concerns regarding societal and ecological sustainability under the mantra of Green Chemistry [19], which emphasizes chemical transformations that are more atom economic [20] and chemoselective, thereby minimizing the use of protecting groups [21]. Furthermore, rapid developments in the field of chemical biology demand chemical transformations that are orthogonal to biological conditions and functionalities in bioorganisms and which can work efficiently under both in vitro and in vivo biological conditions [22]. Alkynes, being both good π-donors and π-acceptors for transition metals as well as being energy rich, can be effectively activated by a catalyst thereby lowering the energy barrier to proceed to the more stable products while being unreactive toward various biological elements. At the same time, they can be chemoselectively activated in the presence of most typical functional groups (e.g., hydroxyl and carbonyl groups as well as alkenes) and in protic solvents including water [23]. Such triggered reactivities are orthogonal to the classical reactivities and can be tuned to target specific desired reaction sites while maintaining tolerance toward other functionalities through the discrete choice of catalyst, which will greatly simplify the syntheses of complex compounds and allow direct modifications of biomolecules in their native states and ambient environment. Modern developments, in view of atom economy, can be represented by three major classes: (i) catalytic cyclization reactions, (ii) catalytic homologations of terminal alkynes, and (iii) catalytic isomerization reactions of alkyne.
Although alkyne oligomerization was known at a high temperature since the late nineteenth century [2], various cyclization reactions of alkynes catalyzed by transition metals are among the most important developments in modern alkyne chemistry. The most well-known examples include the transition-metal-catalyzed [2 + 2 + 2] cycloaddition reactions (Equation 1.9) [24], the Pauson–Khand-type reaction of alkyne–alkene–carbon monoxide (Equation 1.10) [25], the enyne cyclization reactions (Equation 1.11) [26], and the 1,3-dipolar cycloaddition such as that with azides (the archetypical Click reaction) (Equation 1.12) [27].
The second major class of modern alkyne reactions is the catalytic transformation of terminal alkyne C–H bonds. Although homologation of terminal alkynes through the reactions of metal acetylides with organic halide is a classical alkyne reaction, such a reaction cannot be applied to aryl and vinyl halides due to their inert nature in nucleophilic substitution reactions. The development of catalytic coupling of terminal alkynes with aryl and vinyl halides (the Sonogashira reaction) has overcome this classical challenge and opened up a new reactivity mode in alkyne homologation (Equation 1.13) [28]. Complimentary to the classical Favorskii reaction (Equation 1.7), the modern development of catalytic direct addition of terminal alkynes to aldehydes provides great opportunities in generating optically active propargyl alcohols (Equation 1.14) [29]. The catalytic direct additions of terminal alkynes to imines (and derivatives) (Equation 1.15) [30] and conjugate addition to unsaturated carbonyl compounds (Equation 1.16) [31] represent other major achievements in modern alkyne reactions. On the other hand, the catalytic oxidative dimerization (Glaser–Hay coupling) [32] and simple alkyne dimerization (Equation 1.17) [33] which date from the late 1800s have become increasingly important in modern synthetic chemistry.
Two additional processes that have much unrealized potential in synthetic chemistry are the alkyne disproportionation (metathesis) and the alkyne redox isomerization reactions. Like the alkene metathesis, the catalytic alkyne–alkyne metathesis reaction retains all functionalities by switching the groups attached to the alkynes (Equation 1.18) [34]. Another unique atom-economic reaction of alkynes that is currently under-utilized but will have a great potential for future development is the “alkyne-zipper reaction” (Equation 1.19) [35]. Such reactions shift readily accessible internal alkyne triple bond to terminal positions for further homologations. A different type of “retaining functionality is found in the redox isomerization of propargyl alcohols to generate conjugated ketones” (Equation 1.20) [36].
1.5 Conclusion
With the recent emphasis on sustainability and the ever increasing needs in synthetic efficiency, alkynes provide a truly unique functionality that is orthogonal to other functional groups, biological conditions, and ambient environment, yet can be selectively triggered to occur in a specific reaction mode with the absence of protecting groups or anhydrous conditions. Such reactions will have great potential to simplify synthetic chemistry and will find wide applications in chemical biology and organic materials. This book, comprising experts on related subjects, provides an overview of developments of modern alkyne reactions. Due to the limit of space, many other important developments in modern alkyne chemistry such as various catalytic conversions of alkyne triple bonds [37] and alkyne polymerizations [38] have not been covered in this book.
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Part ICatalytic Isomerization of Alkynes
2Redox Isomerization of Propargyl Alcohols to Enones
Barry M. Trost
2.1 Introduction
The synthesis of enones has classically relied upon aldol condensation (Figure 2.1) [1]. Its strength lies in the ready availability of the substrates and its high atom economy. It suffers from issues of chemo- and regioselectivity. Self-condensation of the aldehyde and the ability to form two regioisomeric enone products has led to numerous variations to minimize such issues. One solution employs olefination protocols which suffer from poor atom economy. A particularly interesting strategy recognizes that propargyl alcohols are isomeric with enones as shown in Scheme 2.1. The availability of propargyl alcohols by a simple addition of a terminal acetylene to an aldehyde then can make enones readily available by an atom economic sequence of simple addition followed by isomerization. In 1922, Meyer and Schuster [2] described the rearrangement of the oxidation pattern of propargyl alcohols wherein the hydroxyl group undergoes the equivalent of a 1,3-shift to form the rearranged enone after tautomerization (Scheme 2.1, path a). The Meyer–Schuster rearrangement has been well reviewed and will not be a subject of this chapter.
Figure 2.1 Enone synthesis via aldol condensation.
Scheme 2.1 Redox neutral processes for enone synthesis.
An alternative which maintains the positional integrity of the hydroxyl group involves the shift of two hydrogens (Scheme 2.1, path b) which may be referred to as a redox isomerization. Mechanistically, such a rearrangement of hydrogens is not straightforward. Classically, this transformation typically was performed by a stoichiometric reduction of the triple bond followed by stoichiometric oxidation of the alcohol (or vice versa). While early strides revealed base catalysis could be effective for a certain very limited type of structure, the importance of making synthesis more environmentally benign stimulated efforts to broaden the generality of the process, especially to include nonactivated types of propargyl alcohols. In this chapter, an overview of redox isomerization is presented organized along the line of catalysts.
2.2 Base Catalysis
In 1949, Ninaham and Raphael [3] reported the isomerization of a γ-hydroxybutynoate to an E-γ-ketobutenoate in the presence of triethylamine. In 1954, Vaitiekunas and Nord [4] extended this isomerization of a γ-hydroxybutynoate (1) to an E-γ-ketobutenoate (3) under similar conditions (Equation 2.1) in 85% yield when
Ar = 2-thienyl. The facility of the process derives from the stability of the supposed enolate intermediate 2. Studies in 2007 revealed that the Z-enoate 4 (Ar = Ph or 2-furyl) can result from such a process, depending upon choice of base. Using bicarbonate in dimethylsulfoxide (DMSO) gives the Z isomers, presumably resulting from a kinetic protonation which occurs from the least hindered face to deliver the Z-alkene 4 (Ar = Ph or 2-furyl) [5]. On the other hand, 1,4-diazabicyclo[2.2.2.]octane (DABCO) in DMSO gives the E-isomer 4 (Ar = Ph or 2-furyl) [6]. It is possible that a tertiary amine base isomerizes the initial isomer to the thermodynamically more stable E isomer. The electron-withdrawing group can be an electron-deficient heterocycle as in 5 (Equation 2.2) [7]. The electron-withdrawing group that enhances the activity of the propargylic proton need not be directly attached to the alkyne. Thus, the alkyne 6 undergoes redox isomerization with triethylamine (Equation 2.3) [8]. Since such substrates can be produced by the Sonogashira coupling in the presence of
triethylamine, the intermediate propargyl alcohol may undergo redox isomerization during the coupling step although some role for the Pd in the redox isomerization cannot be ruled out [8].
An alternative strategy places the anion stabilizing group at the propargylic center. Thus, a substrate bearing a 2-pyridyl substituent at this position as in 7 requires both acid and base catalysis to effect isomerization as shown in Equation (2.4) [9].
Using an inductively strong electron-withdrawing group such as polyfluoro alkyl as in 8 also allows base catalyzed isomerization. While a simple tertiary amine suffices (Equation 2.5) [10], the isomerization also proceeds under
Mitsunobu conditions via a mechanism that is obscure at best (see below) [11]. Diyne carbinols 9 wherein a second alkyne serves as an adequate anion stabilizing group (Equation 2.6) also isomerizes with a somewhat stronger base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at an elevated temperature (Equation (2.6)) [12]. Surprisingly, 1,3-diarylpropargyl alcohol suffices. In one such case,
the juxtaposition of a γ-hydroxyl group as in 10 led to trapping the intermediate enone 11 to form a benzodihydrofuran 12 under the reaction conditions (Equation 2.7) [13]. The most useful variant is employing an o-aminophenyl group as the alkyne-bound aryl group [14]. Again, since the Sonogashira coupling proceeds under basic conditions, both redox isomerization and cyclization to a quinolone 13 may occur to provide a reasonably efficient atom economic reaction wherein only 1 equiv of hydroxide base and 2 equiv of water
result along with an iodide salt (Equation 2.8) [15]. Most recently, even only one aryl ring at the propargylic carbinol was sufficient to promote base-catalyzed redox isomerization. The ability of the enone products to serve as Michael acceptors allows an atom and step economic approach to β-substituted ketones such as pyrazole adduct 14 (Equation 2.9) [16].
2.3 Ru Catalyzed
The first example of a transition-metal-catalyzed isomerization of primary propargyl alcohols to enals was reported by Ma and Lu [[17] in 1989 using a Ru complex 15 which required long reaction times at high temperatures. The reaction was envisioned to proceed by hydrometallation–dehydrometallation to form an allenol
which tautomerized to the enone (Equation 2.10). An improvement was reported in 1995 using η5-indenyl-bis-(triphenylphosphine) ruthenium chloride (16) as catalyst and indium trichloride as a cocatalyst [18]. Subsequently,
a significant further improvement used indium triflate as catalyst wherein 1–3 mol% of Ru and In complexes sufficed and reactions occurred in 0.5–3 h [18]. Both primary (Equation 2.11) and secondary (Equation 2.12) alcohols participate. The excellent chemoselectivity is illustrated by the examples of propargyl alcohols 17–19 (Equations (2.12) [18], (2.13) [18], (2.14) [19]).
The dienal 20 served as a key intermediate in the synthesis of a leukotriene. Particularly noteworthy is the chemoselective bis redox isomerization of 19 to bis dienal 21 on the way to the polyacetylenic natural product adociacetylene. The chemoselectivity demonstrated in these examples is inconsistent with a hydrometallation–dehydrometallation mechanism. The ready availability of butynediol as a building block is further enhanced by its chemoselective redox isomerization. Indeed, the accessibility of the functional crotonaldehyde 22 via
Ru-catalyzed isomerization (Equation 2.15) allowed it to provide easy access to the sphingofungins. In this case, a more coordinatively unsaturated indenyl ruthenium complex was employed as depicted in Equation (2.14). Such cycloocta-1,5-diene (COD) ligands bound to Ru have been shown to be reacted off by a [2 + 2 + 2] cycloaddition with an alkyne to free two open coordination sites [18].
Deuterium labeling studies revealed that a 1,2-hydride shift occurred generating a Ru carbenoid intermediate 23 (Scheme 2.2) [18]. Further evidence for this mechanism was the interception of the Ru carbenoid by intramolecular cyclopropanation of a tethered olefin (e.g., 24) as shown in Equation (2.16) [20]. This reaction was a key step in
a concise synthesis of echinopine A, 25 (Equation 2.17) [21]. A C–C bond rather than H can migrate when a cyclopropyl ring is annealed to the propargyl carbon. Depending upon the nature of the substituent on the alkyne terminus,
either a 1,2 shift occurs to give the alkylidenecyclobutanone 26 (Equation 2.18) or a 1,3 shift occurs to form
cyclopentenone 27 (Equation 2.19) [22]. This selectivity may result from the preference to coordinate the alkyne with the hydroxyl group in the former but with the cyclopropyl C–C bond in the latter.
Scheme 2.2 Hydride shift mechanism for the Ru-catalyzed redox isomerization.
The in situ formation of a Michael acceptor via redox isomerization sets the stage for a cascade. Thus, juxtaposition of a suitable oxygen as in 28 (Equation 2.20) [23], nitrogen as in 29 (Equation 2.21) [24], or even carbon as in 30 (Equation 2.22) [25] nucleophiles provide easy access to the corresponding heterocycles 31 and 32 or carbocycle 34. In the first two cases, cyclization to the heterocycles occurred in tandem with the redox isomerization. On the other hand, under
the acidic conditions of the redox isomerization, cyclization of the carbon pronucleophile 33 did not occur. Thus, upon completion of the redox isomerization, a chiral organocatalyst was added to effect the asymmetric cyclization of 33 to give 34 in high ee. Switching from the exo type of cyclization as in Equation (2.21) to an endo geometry slowed the rate of cyclization too. Thus, in the case of the nitrogen Michael donor, redox isomerization of the sulfonamide 35 (Equation 2.23) was not accompanied by cyclization via Michael addition [24]. For completion of the
cascade, simple addition of potassium carbonate in methanol to the initial reaction mixture allowed Michael addition to form the piperidinone 36.
The vinyl ketones are also electrophilic enough in the presence of the redox catalyst system, notably the presence of the In Lewis acid, that electrophilic aromatic substitution can occur as shown in Equation (2.24) [26]. A similar
reaction was effected using a cyclopentadienone Ru complex 37 although higher temperatures were required (Equation 2.25) [27]. The chemoselectivity of the Michael addition to the divinyl ketone intermediate is also noteworthy. A
dinuclear Ru complex 38 has also been reported to be effective under milder conditions (10% NH4PF6, 1,2-dichloroethane (DCE), 60°) although the yields were considerably lower [28].
While a hydride shift mechanism appears to account for the above examples, a hydrometallation–dehydrometallation mechanism is more likely in the case of (Ph3P)3Ru(H2)CO (39) as the catalyst [29]. Using complex 39, a 1,4-dihydroxy-2-alkyne 40 can be initially isomerized to a γ-hydroxyenone which can undergo a second redox isomerization of the remaining allyl alcohol to a 1,4-diketone (Equation 2.26). At the high temperature of the reaction in the presence of acid, cyclodehydration occurs to generate the aromatic 2,5-disubstituted furan. If the redox isomerization is performed under neutral conditions, the reaction stops at the 1,4-diketone. Such
1,4-diketones are precursors to pyrroles by simple addition of a primary amine (Equation 2.27) [29]. Alternatively, base treatment can provide cyclopentenone.
2.4 Rh Catalysis
In 1995, Sarah and Pellicciari [30], motivated by the synthesis of peptide isosteres (Equation 2.41), examined the use of Wilkinson's complex for the redox isomerization of γ-hydroxy-α,β-acetylenic esters such as 39 (Equation 2.28) using a substrate derived from phenyl alanine. While the mechanism of this process has not been established, a
reasonable possibility is depicted in Equation (2.28). It invokes a coordinatively unsaturated Rh complex bound to oxygen undergoing a β-hydrogen elimination forming a rhodium hydride. Hydrometallation of the alkyne followed by protonation would complete the catalytic cycle.
Evidence for such a mechanism derives from the development of a more active catalyst as shown in Equation (2.29) [31]. This catalyst works well for aryl- and vinyl- substituted propargyl alcohols as illustrated with the
cyclohexenyl substituent as in 41 in Equation (2.29). This catalyst also proved effective to convert 2-butyne-1,4-diols 42 to 1,4-diketones 43 (Equation 2.30) even with saturated alkyl groups. Interestingly, the monomethyl ether delivered the
furan 44, presumably because the intermediate γ-keto-α,β-unsaturated enone preferably eliminated methanol to aromatize (Equation 2.31). An interesting application of this process is its use to effect a kinetic resolution of propargylic alcohols (Equation 2.33) [32]. While the desired product is the unchanged alcohol enantioenriched, it does show a different dimension of the process.
2.5 Palladium Catalysis
A major mechanism for Pd-catalyzed processes involves hydropalladation and dehydropalladation such as in the migration of double bonds. In 1988, this mechanism was used to effect a redox isomerization as shown
in Equation (2.33) [33]. In this case, formate serves as the hydride source to generate the [Pd–H] species. Lu and coworkers [34] reported the use of a similar mechanism for the redox isomerization of 2-butyne-1,4-diol-type compounds, 45, wherein the [Pd–H] species presumably derives by protonation of a Pd(0) by the diol (Equation 2.34). This example
highlights the chemoselectivity of the process given the highly reactive nature of a bis-enone as a product. It should be noted that these conditions failed with a mono-propargyl alcohol. Using a stronger acid for such a bis-isomerization served not only as a source for the Pd–H by protonation of Pd(0) but also effected tandem cyclodehydration to form furans (Equation 2.35) [35]. By using an external diol to generate the [PdH] species, the scope of
the reaction now allowed it to proceed with a simpler propargyl alcohol (Equation 2.36) [36]. Unfortunately, equilibration occurred under the reaction conditions to give a mixture of α,β- and β,γ-unsaturated enones. The advantage of a
bidentate phosphine, dppe, was noted in the synthesis of prostaglandin analogs [37]. The redox isomerization provided access to the flavor and perfume ingredient damascene 46 (Equation 2.37) [38]. A particularly effective way to generate an active form of the [Pd–H] species is by exposing a typical heterogeneous palladium hydrogenation
catalyst to hydrogen gas. For example, employment of Pearlman's catalyst pretreated with a small amount of hydrogen effected redox isomerization at room temperature (Equation 2.38) [39] in work directed toward the synthesis of the amphidinolides.
2.6 Miscellaneous
Lu and coworkers [40] established the effectiveness of an Ir complex to effect redox isomerization via a hydrometallation–dehydrometallation mechanism. This catalyst was equally effective for redox isomerization of a simple propargyl alcohol (Equation 2.39) as well as a 2-butyne-1,4-diol system (Equation 2.40). Unfortunately,
isomerization of the conjugated double bond to the β,γ position accompanied the redox isomerization.
While Pt complexes have not been described to perform a redox isomerization of the type discussed herein, there is a silyl version (Equation (2.41)) [41]. The reaction appears to be initiated by a facile 1,2-silyl shift promoted
by coordination of the alkyne by the coordinatively unsaturated platinum. The utility of the resultant vinylsilane to access geometrically defined trisubstituted olefins makes this version of the redox isomerization a useful variation.
The most unusual set of conditions for the redox isomerization of the propargyl alcohol 47 is the use of
the conditions of the Mitsunobu reaction (Equation 2.42) [11]. Mechanistically how this process proceeds is not defined nor even apparent.
2.7 Conclusions
While the field of redox isomerization is just emerging, its potential in improving both atom and step economy is already apparent. At this stage, Ru complexes have progressed the most as appropriate catalysts. Indeed, reasonably mild conditions give promise for good chemoselectivity. At the same time, prospecting for other catalysts has barely begun. Equally exciting is the merging of redox isomerizations with other addition reactions leading to tandem or cascade events. The combined prospects for future development are immense. At this time, redox isomerization is a great complement to the Meyer–Schuster rearrangement and thus we can tune the regioselectivity of the resultant oxidation pattern from the same precursor by just a simple change in catalyst.
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