Synthetic chemists aspire both to develop novel chemical reactions and to improve reaction conditions to maximize resource efficiency, energy efficiency, product selectivity, operational simplicity, and environmental health and safety. Carbon−carbon bond formation is a central part of many chemical syntheses, and innovations in these types of reactions will profoundly improve overall synthetic efficiency. This Account describes our work over the past several years to form carbon−carbon bonds directly from two different C−H bonds under oxidative conditions, cross-dehydrogenative coupling (CDC). We have focused most of our efforts on carbon−carbon bonds formed via the functionalization of sp3 C−H bonds with other C−H bonds. In the presence of simple and cheap catalysts such as copper and iron salts and oxidants such as hydrogen peroxide, dioxygen, tert-butylhydroperoxide, and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), we can directly functionalize various sp3 C−H bonds by other C−H bonds without requiring ...

Cross-dehydrogenative coupling (CDC): exploring C-C bond formations beyond functional group transformations.

Functionalizing traditionally inert carbon–hydrogen bonds represents a powerful transformation in organic synthesis, providing new entries to valuable structural motifs and improving the overall synthetic efficiency. C–H bond activation, however, often necessitates harsh reaction conditions that result in functional group incompatibilities and limited substrate scope. An understanding of the reaction mechanism and rational design of experimental conditions have led to significant improvement in both selectivity and applicability. This critical review summarizes and discusses endeavours towards the development of mild C–H activation methods and wishes to trigger more research towards this goal. In addition, we examine select examples in complex natural product synthesis to demonstrate the synthetic utility of mild C–H functionalization (84 references).

Towards mild metal-catalyzed C–H bond activation

Direct C-H transformation via iron catalysis.

Dehydrogenation as a substrate-activating strategy in homogeneous transition-metal catalysis.

The selective oxidation of C-H bonds and the use of O(2) as a stoichiometric oxidant represent two prominent challenges in organic chemistry. Copper(II) is a versatile oxidant, capable of promoting a wide range of oxidative coupling reactions initiated by single-electron transfer (SET) from electron-rich organic molecules. Many of these reactions can be rendered catalytic in Cu by employing molecular oxygen as a stoichiometric oxidant to regenerate the active copper(II) catalyst. Meanwhile, numerous other recently reported Cu-catalyzed C-H oxidation reactions feature substrates that are electron-deficient or appear unlikely to undergo single-electron transfer to copper(II). In some of these cases, evidence has been obtained for the involvement of organocopper(III) intermediates in the reaction mechanism. Organometallic C-H oxidation reactions of this type represent important new opportunities for the field of Cu-catalyzed aerobic oxidations.

Copper-Catalyzed Aerobic Oxidative C ? H Functionalizations: Trends and Mechanistic Insights

Catalytic reactions which involve the cleavage of an sp3 C−H bond adjacent to a nitrogen atom in N-2-pyridynyl alkylamines are described. The use of Ru3(CO)12 as the catalyst results in the addition of the sp3 C−H bond across the alkene bond to give the coupling products. A variety of alkenes, including terminal, internal, and cyclic alkenes, can be used for the coupling reaction. The presence of directing groups, such as pyridine, pyrimidine, and an oxazoline ring, on the nitrogen of the amine is critical for a successful reaction. This result indicates the importance of the coordination of the nitrogen atom to the ruthenium catalyst. In addition, the nature of the substituents on the pyridine ring has a significant effect on the efficiency of the reaction. Thus, the substitution of an electron-withdrawing group on the pyridine ring as well as a substitution adjacent to the sp2 nitrogen in the pyridine ring dramatically retards the reaction. Cyclic amines are more reactive than acyclic ones. The choice o...

and Fumitoshi Kakiuchi

Papers

Ru3(CO)12-Catalyzed Coupling Reaction of sp3 C−H Bonds Adjacent to a Nitrogen Atom in Alkylamines with Alkenes