Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds

Once considered the 'holy grail' of organometallic chemistry, synthetically useful reactions employing C-H bond activation have increasingly been developed and applied to natural product and drug synthesis over the past decade. The ubiquity and relative low cost of hydrocarbons makes C-H bond functionalization an attractive alternative to classical C-C bond forming reactions such as cross-coupling, which require organohalides and organometallic reagents. In addition to providing an atom economical alternative to standard cross - coupling strategies, C-H bond functionalization also reduces the production of toxic by-products, thereby contributing to the growing field of reactions with decreased environmental impact. In the area of C-C bond forming reactions that proceed via a C-H activation mechanism, rhodium catalysts stand out for their functional group tolerance and wide range of synthetic utility. Over the course of the last decade, many Rh-catalyzed methods for heteroatom-directed C-H bond functionalization have been reported and will be the focus of this review. Material appearing in the literature prior to 2001 has been reviewed previously and will only be introduced as background when necessary. The synthesis of complex molecules from relatively simple precursors has long been a goal for many organic chemists. The ability to selectively functionalize a molecule with minimal pre-activation can streamline syntheses and expand the opportunities to explore the utility of complex molecules in areas ranging from the pharmaceutical industry to materials science. Indeed, the issue of selectivity is paramount in the development of all C-H bond functionalization methods. Several groups have developed elegant approaches towards achieving selectivity in molecules that possess many sterically and electronically similar C-H bonds. Many of these approaches are discussed in detail in the accompanying articles in this special issue of Chemical Reviews. One approach that has seen widespread success involves the use of a proximal heteroatom that serves as a directing group for the selective functionalization of a specific C-H bond. In a survey of examples of heteroatom-directed Rh catalysis, two mechanistically distinct reaction pathways are revealed. In one case, the heteroatom acts as a chelator to bind the Rh catalyst, facilitating reactivity at a proximal site. In this case, the formation of a five-membered metallacycle provides a favorable driving force in inducing reactivity at the desired location. In the other case, the heteroatom initially coordinates the Rh catalyst and then acts to stabilize the formation of a metal-carbon bond at a proximal site. A true test of the utility of a synthetic method is in its application to the synthesis of natural products or complex molecules. Several groups have demonstrated the applicability of C-H bond functionalization reactions towards complex molecule synthesis. Target-oriented synthesis provides a platform to test the effectiveness of a method in unique chemical and steric environments. In this respect, Rh-catalyzed methods for C-H bond functionalization stand out, with several syntheses being described in the literature that utilize C-H bond functionalization in a key step. These syntheses are highlighted following the discussion of the method they employ.

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Rhodium-Catalyzed C-C Bond Formation via Heteroatom-Directed C-H Bond Activation

N-Heterocyclic Carbenes in Late Transition Metal Catalysis

The area of transition-metal-catalyzed direct arylation through cleavage of CH bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with organometallic reagents In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners—including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations

Transition-metal-catalyzed direct arylation of (hetero)arenes by C-H bond cleavage.

Ruthenium(II)-Catalyzed C–H Bond Activation and Functionalization

Transition metal-catalyzed substitution of alcohols by N-nucleophiles (or N-alkylation of amines and related compounds with alcohols) avoids the use of alkylating agents by means of borrowing hydrogen (BH) activation of the alcohol substrates. Water is produced as the only by-product, which makes the “BH” processes atom-economic and environmentally benign. Diverse types of homogeneous organometallic and heterogeneous transition metal catalysts, and substrates such as N-nucleophiles including amines, amides, sulfonamides and ammonia, and various alcohols, can be used for this purpose, demonstrating the promising potential of “BH” processes to replace the procedures using traditional alkylating agents in pharmaceutical and chemical industries. Borrowing hydrogen activation of alcohols for C–N bond formation has recently been paid more and more attention, and a lot of new and novel procedures and examples have been documented. This critical review summarizes the recent advances in “BH” substitution of alcohols by N-nucleophiles since 2009. “Semi-BH” N-alkylation processes with or without an external hydrogen acceptor are also briefly presented. Suitable discussion of the “BH” strategy provides new principles for establishing green processes to replace the relevant traditional synthetic methods for C–N bond formation.

Substitution of alcohols by N-nucleophiles via transition metal-catalyzed dehydrogenation

C-S bond activation, cleavage and transformations by means of transition metal compounds have recently become more and more important in the petroleum industry and synthetic chemistry. Homogeneous transition metal compounds have been investigated in order to provide the fundamental insight into the C-S bond cleavage in problematic organosulfur compounds such as thiophene, benzo- and dibenzothiophene derivatives. Rendering transition-metal mediated reactions with organosulfur compounds catalytic may provide promising routes to deep hydrodesulfurization of petroleum feedstocks, and offer potentially useful synthetic protocols for cross-couplings and biomimetic organic synthesis. During the last few decades increasing work was documented on C-S bond activation and transformations by means of transition metal compounds. This review summarizes the recent advances in C-S bond cleavage via the insertion of transition metals into the inert C-S bonds of these problematic organosulfur compounds, and transition-metal mediated C-S bond transformations via C-S activation through cross-couplings of thioesters, ketene dithioacetals, sulfonyl chlorides, and other diverse organosulfur compounds.

Transition-metal mediated carbon–sulfur bond activation and transformations

Transition-metal-catalyzed C-alkylation of ketones and secondary alcohols, with alcohols, avoids use of organometallic or environmentally unfriendly alkylating agents by means of borrowing hydrogen (BH) or hydrogen autotransfer (HA) activation of the alcohol substrates. Water is formed as the only by-product, thus making the BH process atom-economical and environmentally benign. Diverse homogeneous and heterogeneous transition-metal catalysts, ketones, and alcohols can be used for this transformation, thus rendering the BH process promising for replacing those procedures that use traditional alkylating agents. This Minireview summarizes the advances during the last five years in transition-metal-catalyzed BH α-alkylation of ketones, and β-alkylation of secondary alcohols with alcohols. A discussion on the application of the BH strategy for C-C bond formation is included.

C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal-Catalyzed Dehydrogenation.

Asymmetric hydrogenation plays an important role in organic synthesis, but that of the challenging substrates such as N-unprotected imines, enamines, and N-heteroaromatic compounds (1H-indoles, 1H-pyrroles, pyridines, quinolines, and quinoxalines) has only received increased attention in the past three years. Considering the interaction modes of a Bronsted acid with a Lewis base, Bronsted acids may be used as the ideal activators of C=N bonds. This Minireview summarizes the recent advances in transition-metal-catalyzed, Bronsted acid activated asymmetric hydrogenation of these challenging substrates, thus offering a promising substrate activation strategy for transformations involving C=N bonds.

Brønsted acid activation strategy in transition-metal catalyzed asymmetric hydrogenation of N-unprotected imines, enamines, and N-heteroaromatic compounds.

Efficient rhodium(I)-catalyzed regioselective functionalization of aromatic C-H bonds has been realized with acid chlorides as the coupling partners via decarbonylation and C-H activation under phosphine-free conditions.

Zhengkun Yu

Papers

Substitution of alcohols by N-nucleophiles via transition metal-catalyzed dehydrogenation

Transition-metal mediated carbon–sulfur bond activation and transformations

C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal-Catalyzed Dehydrogenation.

Brønsted acid activation strategy in transition-metal catalyzed asymmetric hydrogenation of N-unprotected imines, enamines, and N-heteroaromatic compounds.

Rhodium-Catalyzed Regioselective C−H Functionalization via Decarbonylation of Acid Chlorides and C−H Bond Activation under Phosphine-Free Conditions