The C-C bond is a basic building block in chemistry, and its formation is often the first step towards building more complex molecules. The direct generation of C-C bonds from C-H by cross-dehydrogenative-coupling (CDC) reactions in 2003 has presented a paradigm shift towards more efficient synthetic design, and over the last decade this has become a hot topic in Green Chemistry.
This edited book presents a summary of the latest developments in the formation of C-C bonds direct from two different C-H bonds via oxidative dehydrogenative couplings. The editor, (CJ Li, McGill University) has pioneered various copper and organo-catalyzed CDC reactions within his Green Chemistry and Organic Synthesis group, and has brought together expertise from across the world to present the various CDC reactions being used today. Practicing synthetic chemists seeking to improve the efficiency of their reactions will benefit from this approach, while students and those wishing to adopt these reactions will gain a thorough understanding of the field. The conclusions presented at the end of the book will inspire all readers to the future opportunities in the field.
The C-C bond is a basic building block in chemistry, and its formation is often the first step towards building more complex molecules. The direct generation of C-C bonds from C-H by cross-dehydrogenative-coupling (CDC) reactions in 2003 has presented a paradigm shift towards more efficient synthetic design, and over the last decade this has become a hot topic in Green Chemistry.
This edited book presents a summary of the latest developments in the formation of C-C bonds direct from two different C-H bonds via oxidative dehydrogenative couplings. The editor, (CJ Li, McGill University) has pioneered various copper and organo-catalyzed CDC reactions within his Green Chemistry and Organic Synthesis group, and has brought together expertise from across the world to present the various CDC reactions being used today. Practicing synthetic chemists seeking to improve the efficiency of their reactions will benefit from this approach, while students and those wishing to adopt these reactions will gain a thorough understanding of the field. The conclusions presented at the end of the book will inspire all readers to the future opportunities in the field.
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Overview
The C-C bond is a basic building block in chemistry, and its formation is often the first step towards building more complex molecules. The direct generation of C-C bonds from C-H by cross-dehydrogenative-coupling (CDC) reactions in 2003 has presented a paradigm shift towards more efficient synthetic design, and over the last decade this has become a hot topic in Green Chemistry.
This edited book presents a summary of the latest developments in the formation of C-C bonds direct from two different C-H bonds via oxidative dehydrogenative couplings. The editor, (CJ Li, McGill University) has pioneered various copper and organo-catalyzed CDC reactions within his Green Chemistry and Organic Synthesis group, and has brought together expertise from across the world to present the various CDC reactions being used today. Practicing synthetic chemists seeking to improve the efficiency of their reactions will benefit from this approach, while students and those wishing to adopt these reactions will gain a thorough understanding of the field. The conclusions presented at the end of the book will inspire all readers to the future opportunities in the field.
About the Author
Chao-Jun Li received his B.S. at Zhengzhou University (1983), M.S. at the Chinese Academy of Sciences in Beijing (1988) and Ph.D. at McGill University (1992, with T. H. Chan and D. N. Harpp). After an NSERC Postdoctoral research term with B. M. Trost at Stanford University, he became Assistant Professor (1994), Associate Professor (1998), and Full Professor (2000-2003) at Tulane University. In 2003, he became a Canada Research Chair (Tier I) in Organic/Green Chemistry and a Professor of Chemistry at McGill University in Canada. Currently, he serves as the Co-Chair (with Bernard West) of the Canadian Green Chemistry and Engineering Network. His current research efforts are focused on developing innovative and fundamentally new organic reactions that will defy conventional reactivities and have high synthetic efficiency. Professor Li is currently US Associate editor of the RSC Journal Green Chemistry
Full Professor at Warsaw University of Technology, Poland, former Chair of Process Intensification at Delft University of Technology, the Netherlands, and former Director of TU Delft Process Technology Institute. With more than 40 years of industrial and academic research experience he is author of numerous scientific publications on process intensification, chemical reaction engineering and industrial catalysis. He is principal author and co-editor of the world’s first book on Process Intensification. Prof. Stankiewicz is Editor-in-Chief of Chemical and Process Engineering: New Frontiers (Polish Academy of Sciences) and Series Editor of the Green Chemistry Books Series (Royal Society of Chemistry). He was founder and first Chairman of the Working Party on Process Intensification at the European Federation of Chemical Engineering. He was also founder and Chairman the Board of the European Process Intensification Centre (EUROPIC). Current research interests of Prof. Stankiewicz focus on intensification of catalytic processes using renewable electricity-based energy fields. The research in that area has brought him prestigious Advanced Investigator Grant from the European Research Council.
Peter Rudolf Seidl - Professor, Graduate Program on Technology of Chemical and Biochemical Processes, EQ/UFRJ (TPQB/EQ/UFRJ), and responsible for the establishment of the Brazilian Green Chemical School (EBQV). Thesis advisor and project coordinator in physical organic chemistry applied to chemical process areas such as petroleum, pharmaceuticals, mineral technology, etc., publishing widely in these areas and holding an international patent on the use of cashew wastes as a raw material. Former President of the Brazilian Chemical Association (ABQ) and active in the organization of meetings and workshops, such as the 1st International Conference on Chemistry of the Amazon (held shortly after Rio 92) and, more recently, the 1st Workshop on Asphaltenes Characterization and Properties held in 2009 and Biorefineries 2010 Recent Advances and New Challenges, held last November.
Read an Excerpt
From C-H to C-C Bonds
Cross-Dehydrogenative-Coupling
By Chao-Jun Li
The Royal Society of Chemistry
Copyright © 2015 The Royal Society of ChemistryAll rights reserved.
ISBN: 978-1-78262-008-2
CHAPTER 1
The Evolution of the Concept of Cross-Dehydrogenative-Coupling Reactions
SIMON A. GIRARD, THOMAS KNAUBER AND CHAO-JUN LI
1.1 Introduction
Among the countless reactions developed throughout the history of organic chemistry, carbon-carbon bond formation reactions are very special, as such reactions create the framework for organic molecules to build on and for functional groups to be attached to. Thus, the development of methods for forming C–C bonds plays a central role in the design and synthesis of organic matter: molecules and materials. Historically, nucleophilic additions, substitutions, and Friedel-Crafts type reactions formed the pillars of methods to connect two simpler molecules via the formation of a C–C bond in acyclic structures. The development of pericyclic reactions laid the foundation for synthesizing cyclic structures. Over the past four decades, transition metal catalyses via cross-coupling and metathesis have overcome some limitations of the classical reactions, e.g., nucleophilic substitutions involving sp carbon centers, and have greatly increased the efficiency of C–C bond formations, especially those involving arenes and alkenes, in modern organic chemistry. Their importance is attested by the awarding of Nobel Prizes in both 2005 and 2010.
However, in spite of the great success of both classical C–C bond formation methods and the modern extraordinary achievements of transition metal catalysis, state-of-the-art C–C bond formation reactions must use pre-functionalized starting materials, which require extra steps (sometimes multiple steps) to synthesize. In many cases, during the core C–C bond formation processes, the pre-formed functional groups are simultaneously 'lost'. The necessity of these repetitive pre-functionalization and defunctionalization steps plus the associated isolations and purifications, ultimately diminishes the overall material efficiency in the synthesis of complex organic molecules and increases chemical waste. The reduction in efficiency is aggravated with an increase in the complexity of molecules, as exemplified by the E-factor of Sheldon. To reduce the number of steps involved and increase the efficiency in synthetic chemistry, we must explore new frontiers of chemical reactions, in which various chemical bonds in widely available natural resources, petroleum, natural gas, biomass, N2, CO2, O2, water, and others can be selectively transformed directly without affecting other bonds and without the need for excessive pre-activations. As part of this effort, the transition metal catalyzed C–H bond activation and subsequent C–H bond formations have, thus, attracted much interest in recent years. Outstanding achievements have been made in this area and many complex compounds can be made much more rapidly. However, these reactions still require at least one functionalized partner in order to generate the desired C–C bond formation products.
Historically, the copper-mediated oxidative homodimerization of alkynes (the Eglinton reaction), an first reported over a century ago, represents the earliest success of directly generating a C–C bond from two C–H bonds. The reaction requires a stoichiometric quantity of Cu(OAc)2 as both mediator and oxidant. The Glaser-Hay coupling modified such oxidative homodimerization of alkynes by using a catalytic Cu(I) catalyst with oxygen as the terminal oxidant. On the other hand, the oxidative homodimerization of electron-rich arenes has also become highly successful in generating arene dimers and polymers for a wide range of applications: from fine chemicals and pharmaceuticals to electronic materials. Both types of reaction, however, are limited to homodimerizations and are beyond the present book.
In synthetic chemistry, what is very challenging and highly desirable is the selective formation of two different C–H bonds from two completely different compounds (or two chemically different sites within a molecule). As C–H bonds are generally relatively inert, compared to all other bonds in organic molecules, such cross-oxidative couplings involving only C–H bonds in the presence of, and without affecting other more reactive bonds, would be unthinkable within classical chemical knowledge.
Prior to the concept of cross-dehydrogenative-coupling (CDC), Moritani and Fujiwara developed the oxidative formation of Heck-type reaction products directly from arenes and alkenes, instead of aryl halides and alkenes, by using palladium as the catalyst. This type of reaction is now referred to as the 'Moritani-Fujiwara reaction'. Although one can argue that an alkene is still a functional group, this is an early example of formal generation of a C–C bond from two different C–H bonds by removing two hydrogen atoms oxidatively. Since Chapter 2 is devoted entirely to this type of reaction, this chapter will only touch on them briefly.
Developing green chemistry methods for chemical syntheses has been an objective of our laboratory over the past two decades. Over the years, we have explored various unconventional chemical reactions that could potentially simplify syntheses, decrease overall waste and maximize resource utilization. In our early studies, we focused on developing Grignard-type reactions in aqueous media in order to simplify protection-deprotection processes involved in organic synthesis, especially carbohydrates. This led to the success of virtually all types of Barbier-Grignard reactions in water, as well as the synthesis of various natural products, both by us and many others. Since water is analogous to protonic functional groups such as hydroxyls, acids, and amines, these water-tolerant reactions allow a drastic reduction in the number of transformations in those syntheses by eliminating the protection and deprotection steps. Nevertheless, the pre-generation of organic halides and the requirement of stoichiometric quantities of metal will still lead to stoichiometric waste.
As an aspirational endeavor, we then shifted our attention to explore Barbier-Grignard type and other nucleophilic addition reactions by using C–H bonds as surrogates for organometallic reagents, to simplify the halogenation-dehalogenation process and to avoid the utilization of a stoichiometric amount of metal for such reactions. Furthermore, we would like to explore such reactions in water, combining the advantages of both simplifying the protection-deprotection processes as well as avoiding halogenation-dehalogenation processes. Our efforts have been highly fruitful. Among them, our laboratory has pioneered a wide range of direct catalytic additions of terminal alkynes to various electrophiles in water and the most well-known one is the so-called 'aldehyde-alkyne-amine coupling', often in water.
The success of the above encouraged us to explore the ultimate question in 2003: can we generate C–C bonds selectively from two different C–H bonds of any type without having to convert either one into a pre-synthesized functional group in the first place, possibly even in water? The success of such reactions could potentially lead to chemical transformations beyond functional group-based transformations — a potential tool for the next generation of synthetic chemists. A general scheme for such a process would involve two different types of C–H bonds in any setting, and would form a C–C bond at the specific desirable sites by an overall formal loss of H either in the form of an H molecule or through the use of an oxidant (Scheme 1.1). To help our understanding, we termed these reactions CDCs. Despite the use of "dehydrogenative" in the name, the term is not limited to the generation of H molecules. The CDC reaction has become one of the most active areas of research and extensive progress has been made in all aspects of such reactions. This introductory chapter will only discuss briefly the early evolution of such reactions.
1.2 CDC Reactions Involving sp3 C–H Bonds and sp C–H Bonds
1.2.1 Reaction of sp3 C–H Bonds Adjacent to Nitrogen
As a starting point, we chose the formation of C–C bonds from α-sp3 C–H bonds of nitrogen in amines, and alkynyl sp C–H bonds to generate pro-pargylic amines. This choice was based on three reasons: (1) propargylic amines are of great pharmaceutical interest and are synthetic intermediates for various nitrogen compounds; (2) the sp3 C–H bond a to nitrogen in amines can be readily activated to generate iminium ions via single-electron-transfer (SET) processes, or by transition metals as described by Leonardand Murahashi; and (3) the aldehyde-alkyne-amine coupling (A) reactions to afford propargyl amines described earlier, proceed via the formation of the same intermediate (Scheme 1.2). We reasoned that the CDC of the sp3 C–H α to nitrogen with a terminal alkyne should thus occur readily under oxidative conditions.
In the early 1990s, Miura observed the formation of a small amount of the alkynylation product in a complex product mixture when reacting amines with alkynes in the presence of CuCl2 and oxygen; no further investigation was made. As a prototype for the concept of the selective CDC reaction, we found that the desired CDC reaction product was obtained in good yield and high selectivity with the combination of a copper catalyst and tert-butyl hydroperoxide (TBHP) as the terminal oxidant. Various copper salts such as CuBr, CuBr2, CuCl, and CuCl2 were all effective for this transformation. Various alkynes were reacted with dimethylaniline derivatives to give the alkynylation products in 12–82% yields (Scheme 1.3) and aromatic alkynes often provided better yields than aliphatic alkynes. The reactions tolerated various functional groups such as alcohols and esters.
As a potential synthetic application of CDCs, we found that various p-methoxyphenyl glycine amides could be directly alkynylated with pheny-lacetylene readily at room temperature (Scheme 1.4). By hydrogenating the alkyne and removal of PMP, this methodology provides a versatile method for synthesizing homophenylalanine derivatives, an important synthon in many angiotensin-converting enzyme inhibitors. A series of direct and site-selective peptide functionalizations was also realized by using CDC reactions (Scheme 1.5).
1.2.2 Asymmetric Reaction of sp C–H Bonds Adjacent to Nitrogen
The asymmetric synthesis of organic compounds is another major effort in modern organic chemistry. With our earlier high success it was intriguing to see if it is possible to achieve enantioselective C–C bond formations based on the direct reaction of prochiral CH2 groups via CDC. Indeed, asymmetric alkynylation of tetrahydroisoquinolines (THIQs) to generate optically active C1-substituted derivatives was realized by using a copper salt together with pybox 1, among others (Figure 1.1), as the chiral ligand. Both Cu(I) and Cu(II) were found to be effective catalysts, although slightly higher enan-tioselectivities were observed with Cu(I) catalysts (Scheme 1.6). The catalytic asymmetric CDC alkynylation also proceeded in water and without a solvent, however both the yields and the enantioselectivities were decreased.
1.2.3 Reaction of sp3 C–H Bonds Adjacent to Oxygen
Compared with the sp3 C–H bond adjacent to nitrogen, the sp3 C–H bond adjacent to oxygen is much less reactive. In our initial attempt to effect such CDC reactions, only the addition of an sp3 C–H bond across an alkyne was observed, and this was via a radical process. Subsequently, we found that a silver-catalyzed oxidative coupling of terminal alkynes and benzylic ethers using 2.5 mol% silver triflate, and 1.5 equiv. of 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) in a mixture of 4:1 toluene:chlorobenzene at 120 °C successfully provided the alkynylation of benzylic ether derivatives via the CDC process (Scheme 1.7). However, poor yields were obtained with acyclic methyl benzyl ether.
1.2.4 Reaction of Benzylic sp3 C–H Bonds
More recently, we demonstrated the first alkynylation of benzylic C–H bonds not adjacent to a heteroatom with 1 mol% of a CuOTf-toluene complex in the presence of 1.5 equiv. of DDQ. Various alkynes were successfully coupled with diphenylmethane derivatives (Scheme 1.8). Aromatic alkynes were smoothly converted and the use of electron-rich derivatives resulted in a slightly improved yield, rationalized by the nucleophilicity of the substrates. However, aliphatic alkynes (i.e., n-hexyne) did not give the corresponding CDC product under standard conditions. The mechanism was proposed to proceed via the generation of radical intermediates, which were converted into a benzylic cation in the presence of DDQ through two successive SET steps. The resulting hydroquinone subsequently then abstracted the acidic proton from the alkyne to form the copper acetylide, which added to the benzylic cation to afford the desired product.
1.3 CDC Reactions Involving sp3 C–H Bonds and sp2 C–H Bonds
1.3.1 Reaction of sp3 C–H Bonds Adjacent to Nitrogen
The proposed iminium intermediate in the CDC-type alkynylation implies that other C–H based pronucleophiles, besides terminal alkynes, can also couple with an α-sp3 C–H bond of a nitrogen in amines via the same process. Thus, we examined electron-rich arenes as one such nucleophile via a cross-dehydrogenative Friedel-Crafts type arylation. Indole derivatives were coupled with N-aryl-THIQs under the CuBr/TBHP system to produce the desired CDC reaction product in good-to-excellent yields (Scheme 1.9). It is worth noting that the reaction was not sensitive to moisture or air, and that the desired product was obtained in reasonable yield even when the reaction was carried out in water under an atmosphere of air. The reactions selectively occurred at the C3-position of the indoles, if both the C2- and C3-positions of the indoles were unoccupied, and the C2-substituted products were obtained when the C3-position of the indoles was substituted.
2-Naphthol is another electron-rich aromatic compound which can also lead to sp3-sp2 CDC-type products. Thus, a new type of Betti base was formed via the CDC reaction of N-phenyl-THIQ with 2-naphthol derivatives under our CuBr/TBHP system with a small amount of homocoupled 2,2-binaphthol (BINOL) (Scheme 1.10). Subsequently, the scope of cross-dehydrogenative Friedel-Crafts type arylations was significantly improved by the development of highly efficient catalyst systems, and an intramolecular Cu-catalyzed aerobic synthesis of functionalized cinnolines via a Friedel-Crafts-type CDC arylation was reported by Zhang et al.
We then investigated the CDC reaction between a-sp C–H bonds of nitrogen in THIQs and sp2 C–H bonds of electron-deficient alkenes. The reaction generated the Morita-Baylis-Hillman (MBH) reaction product by using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst (Scheme 1.11). Another common MBH catalyst, triphenylphosphine, was found to be nearly ineffective due to the generation of triphenylphosphine oxide during the reaction.
1.3.2 Reaction of sp3 C–H Bonds Adjacent to Oxygen
In addition to the sp3 C–H bond adjacent to nitrogen, sp3 C–H/sp2 C–H CDC reactions have also been successful adjacent to oxygen. We discovered a palladium-catalyzed coupling of N-heterocycles with simple alcohols initiated by dicumyl peroxide (Scheme 1.12).
Subsequently, the radical coupling of benzothiazoles, benzoxazoles and benzimidazoles with alcohols or ethers in the presence of excess TBHP was reported by He et al.
1.3.3 Reaction of Benzylic and Allylic sp3 C–H Bonds
Allylic compounds as well as diphenylmethanes have also been disclosed as substrate classes for CDC-type arylations. A PdCl2-catalyzed cross-dehydrogenative allylation reaction of indole derivatives was introduced by the group of Bao in 2009 using DDQ as the stoichiometric oxidant (Scheme 1.13). Shi also reported a FeCl2-catalyzed benzylation reaction of electron-rich arenes with diphenylmethanes (Scheme 1.14).
(Continues...)
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Table of Contents
Introduction;
Oxidative Heck-Type Reaction: The Fujiwara-Moritani Reaction;
Copper-Catalyzed CDC Reactions;
Iron Catalyzed CDC Reactions;
Light-Assisted CDC Reactions;
Aryl-Aryl Coupling via CDC Reactions;
Asymmetric CDC Reactions;
CDC Reactions without Metal;
Intramolecular CDC Reactions;
Synthetic Applications of CDC Reactions;
Conclusions