Benzylic C–H bond functionalization through photo-mediated mesyloxy radical formation

Abstract

Herein, we report a photo-mediated methodology for the benzylic C‒H bond oxygenation. Our approach employs in-situ generated (methylsulfonyloxy)-pyridinium mesylate salts to produce mesyloxy radicals apt for benzylic C‒H bond cleavage through hydrogen atom transfer (HAT). Subsequent oxidation of the benzylic radical yields a carbocation, functionalized by the mesylate counterion through oxidative radical-polar crossover (ORPC). The reactive benzylic mesylates are converted to stable benzylic alcohols via a straightforward protocol. Reaction optimization utilized modern design of experiment techniques (DoE) for facile setup and rapid reaction. Our proposed mechanistic paradigm is supported by comprehensive investigations, including fluorescence quenching studies, cyclic voltametric measurements, and determination of kinetic isotope effects (KIE). Density functional theory (DFT) calculations elucidate the divergent performance between (methylsulfonyloxy)-pyridinium salts and (trifluoromethylsulfonyloxy)-pyridinium salts. The functionalization of unactivated C–H bonds represents a versatile strategy for the diversification of drug intermediates in synthetic organic chemistry.1, 2 Besides transition metal catalysis, electrosynthesis or biocatalysis, the utilization of radical-species for C–H bond functionalization has been rapidly gaining attention.3-8 In the past, radicals were frequently generated under harsh reaction conditions, restricting compatibility with functional groups. However, the advent of photoredox catalysis has facilitated the generation of radicals under mild conditions.9,10 In this context, redox-active pyridinium salts have served as unique radical precursors, generating reactive species after single-electron reduction by an appropriate photoredox catalyst.11-15 Electronic effects have a significant impact on the generation and reactivity of radical species.16 For instance, the electronic properties of both the exocyclic and heteroarene substituents in redox-active pyridinium salts play a crucial role in dictating the formation of N-centered versus X-centered radicals through dissociative electron transfer (DET) (Figure 1).17 Strongly electron withdrawing N-substituents X (e.g. TfO‒ and F‒) favour heterolytic bond cleavage generating N-centered pyridinium radicals py•+ and less electron-withdrawing N-substituents (e.g. F3CO‒, RO‒) favour homolytic bond-cleavage generating an X-centered radical X•. It has been demonstrated that the resulting radicals can undergo a variety of chemical transformations, which were applied in both C(sp2)‒H and C(sp3)‒H bond functionalisations.18