Photocatalytic Activation of Less Reactive Bonds and Their Functionalization via Hydrogen-Evolution Cross-Couplings

Abstract

Conspectus Cross-coupling reactions have been established as potential tools for manufacture of complex molecular frameworks of diversified interests by connecting two simple molecules through the formation of a carbon–carbon (C–C) or a carbon–heteroatom (C–X) bond. Conventional cross-couplings are transition metal-catalyzed reactions between electrophiles and nucleophiles. Generally, the electrophilic partner is an aryl or alkenyl halide, the nucleophile is an organometallic reagent, and both are obtained from prefunctionalization of their corresponding hydrocarbons. During the past decade, transition metal-catalyzed dehydrogenative cross-couplings between two carbon–hydrogen (C–H) bonds and between one C–H bond and one heteroatom–hydrogen (X–H) bond, which build a C–C and a C–X linkage respectively, have emerged as an attractive strategy in synthetic chemistry. Such straightforward couplings allow use of less functionalized reagents, thus reducing the number of steps to the target molecule and minimizing waste production. However, such reactions involve the use of stoichiometric amounts of sacrificial oxidants such as peroxides, high-valent metals, and iodine(III) oxidants. This leads to low atom economy and possible generation of toxic wastes. Recently, visible light photocatalytic dehydrogenative cross-coupling reactions have received much attention due to their potential in utilizing sunlight as a source of energy making the process appealing. In this approach, metal complexes, organic dyes, or semiconductor quantum dots that absorb visible light are employed as photocatalysts. Upon irradiation, photocatalyst initiates single electron transfer with substrate(s) to generate a radical cation or radical anion of the substrate, which undergoes the desired reaction of interest. In this case, molecular oxygen is utilized as the oxidant with the formation of hydrogen peroxide as the only byproduct. These aspects make the process much greener than the corresponding transition metal-catalyzed dehydrogenative cross-coupling reactions. Research efforts from our group have led to the development of an environmentally benign strategy to construct a C–C bond from two different C–H bonds and to construct a C–X bond from one C–H bond and one X–H bond by visible light photocatalysis. Our approach, photocatalytic hydrogen-evolution cross-coupling reactions, combines a photocatalyst with a proton reduction cocatalyst to create a dual catalyst system. The former catalyst uses light energy as the driving force for the cross-coupling, while the latter catalyst may capture electrons from the substrates or reaction intermediates to reduce the protons eliminated from the reactive scaffolds (C–H/C–H or C–H/X–H bonds) into molecular hydrogen (H 2 ). Thus, without use of any sacrificial oxidant and under mild conditions, our dual catalyst system affords cross-coupling products with excellent yields with generation of an equimolar amount of H 2 as the sole byproduct. The photocatalytic hydrogen-evolution cross-coupling is highly step and atom economical and particularly useful for reactions that involve species sensitive to oxidative conditions. This Account highlights the findings from our laboratories on photocatalytic hydrogen-evolution cross-coupling reactions featuring activation and functionalization of C(sp 3 )–H bonds adjacent to amino groups and to oxygen atoms in ethers, aromatic C(sp 2 )–H bonds, and several types of X–H bonds. We expect that this strategy for combining photocatalytic activation of C–H and X–H bonds with proton reduction holds significant potential for development of atom economical and environmentally benign transformations.