Site‐Selective Electrochemical Benzylic C−H Amination

Abstract

C−H/N‐H cross‐coupling is an ideal strategy to synthesize various amines but remains challenging owing to the requirement for sacrificial chemical oxidants and the difficulty in controlling the regio‐ and chemo‐selectivity. Herein we report a site‐selective electrochemical amination reaction that can convert benzylic C−H bonds into C‐N linkages via H2 evolution without need for external oxidants or metal catalysts. The synthetic strategy involves anodic cleavage of benzylic C−H to form a carbocation intermediate, which is then trapped with an amine nucleophile leading to C−N bond formation. Key to the success is to include HFIP as a co‐solvent to modulate the oxidation potentials of the alkylbenzene substrate and the aminated product to avoid overoxidation of the latter.

Cross‐Coupling of C−H and N−H Bonds: A Hydrogen Evolution Strategy for the Construction of C−N Bonds

“…Continuing their interest in C−N bond formation via electrochemical C−H amination reactions, [195] Xu′s research group recently developed a metal‐ and external oxidant‐free method to construct a C−N bond from site‐selective electrochemical benzylic C−H bond amination reaction (Scheme 95). [196] …”

A General Strategy for C(sp3)–H Functionalization with Nucleophiles Using Methyl Radical as a Hydrogen Atom Abstractor

“…While access to carbocation intermediates may be accomplished electrochemically, contemporary methodologies are largely limited by the high overpotential required for reactivity, thereby restricting the scope of amenable C(sp 3 )-H and nucleophile coupling partners. 32,33 Whereas C(sp 3 )-H functionalization via HAT-ORPC has been proposed in a recent study from Liu and Chen, the method uses a strong, stoichiometric oxidant and solvent quantities of nucleophile. 7 Here we report a HAT-ORPC platform for C(sp 3 )-H functionalization using a mild, commercially available N-acyloxyphthalimide as HAT precursor.…”

“…Notably, 4-pyridyl diphenylmethane underwent fluorination in 63% yield, demonstrating tolerance to a valuable Nheterocycle scaffold (31). 52 Other heterocycles such as thiophenes, furans, and thiazoles were also tolerated under the reaction conditions (32)(33)(34)(35). Since many bioactive compounds contain heterocyclic fragments, this observation prompted us to evaluate the method for the late-stage derivatization of various pharmaceuticals and complex molecules.…”

Electro-oxidative Intermolecular Allylic C(sp3)–H Aminations

“…More recently, Xu reported on the electro-catalyzed benzylic C−H amination. 60 Within our program on sustainable C−H activation, 35−37 we have now devised the first electrochemical oxidative intermolecular allylic C(sp 3 )−H aminations (Scheme 1c). Salient features of our findings include the following: (1) transition-metal-free conditions, (2) absence of chemical oxidants, (3) electric current as the sole oxidant, and (4) a user-friendly undivided cell setup.…”