A Photoredox-Catalyzed Approach for Formal Hydride Abstraction to Enable Csp3–H Functionalization with Nucleophilic Partners

Abstract

While a great number of C–H functionalization methods have been developed in recent years, new mechanistic paradigms to deconstruct such bonds have been comparatively rare. Amongst possible strategies for breaking a C<i><sub>sp</sub><sup>3</sup></i>–H bond are deprotonation, oxidative addition with a metal catalyst, direct insertion via a nitrene intermediate, hydrogen atom transfer (HAT) with both organic and metal-based abstractors, and lastly, hydride abstraction. The latter is a relatively unexplored approach due to the unfavorable thermodynamics of such an event, and thus has not been developed as a general way to target both activated and unactivated C<i><sub>sp</sub><sup>3</sup></i>–H bonds on hydrocarbon substrates. Herein, we report our successful efforts in establishing a catalytic C–H functionalization manifold for accessing an intermediate carbocation by formally abstracting hydride from unactivated C<i><sub>sp</sub><sup>3</sup></i>–H bonds. The novel catalytic design relies on a stepwise strategy driven by visible light photoredox catalysis and is demonstrated in the context of a C–H fluorination employing nucleophilic fluorine sources. Difluorination of methylene groups is also demonstrated, and represents the first C–H difluorination with nucleophilic fluoride. Additionally, the formal hydride abstraction is shown to be amenable to several other classes of nucleophiles, allowing for the construction of C–C or C–heteroatom bonds.

Photoredox-Catalyzed Benzylic Esterification via Radical-Polar Crossover

“…During the course of our study, we disclosed that the benzylic C–H bond could be converted to a C–O bond − under similar reaction conditions via hydrogen atom transfer . The treatment of 4-phenyltoluene ( 5a ) with PIDA in CH 2 Cl 2 in the presence of PC4 (for the structure, see Table ) as the catalyst under blue light irradiation afforded 6a in a 51% yield.…”

Photocatalytic Late-Stage C–H Functionalization

“…111,112,126−128 Based upon the same HAT/oxidative radical-to-polar crossover concept, Musacchio and co-workers tamed O-centered radicals, generated from the single-electron reduction of peroxide species (TBPI), and developed an allylic and benzylic C−H functionalization platform (Scheme 140C). 559 As in the work by Stahl and co-workers (Scheme 96B), 386 tert-butoxy radicals are efficient hydrogen-atom abstractors that can generate resonance-stabilized radical. These intermediates can undergo oxidative radical-to-polar crossover and nucleophilic attack.…”

“…Modest conversions to the desired C−H fluorinated products of adamantane and leucine (<20%) were observed, similarly to the work of Doyle and co-workers. 559 Calcium antagonist diltiazem underwent benzylic fluorination over available α-oxy and α-amino positions, without the need for nitrogen protection. Aromatase inhibitor letrozole, among the elective drugs for breast and ovarian malignancies, delivered its fluorinated analogue.…”