General strategies for the rapid construction of chemical complexity are critical to the advancement of synthetic organic chemistry. In recent years, photoredox catalysis has enabled the broad and diverse construction of chemical bonds by providing mild, direct access to carbon-centered radical intermediates. However, many opportunities in this context remain to be explored. For example, the photocatalytic functionalization of carbon-centered radicals is predominately explored in the context of direct functionalization by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating interest in developing mild, general functionalization strategies with nucleophiles through the enabling paradigm offered by photocatalysis. Furthermore, most methodologies leveraging the carbon-centered radical have yet to display a generality that would allow for the construction of vastly different chemical architectures from a single methodology and a common set of readily accessible starting materials. To address these challenges, we have leveraged photocatalysis to access the highly versatile carbocation intermediate as a gateway to diverse bond formations. First, we describe the development of a photocatalytic C(sp3)–H functionalization strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover, effecting formal hydride abstraction in the absence of a strong Lewis acid or strong oxidant. The resulting carbocation is functionalized by halides, water, alcohols, thiols, an electron-rich arene, and an azide, affecting a diverse array of bond formations. Reaction development is demonstrated in the context of nucleophilic fluorination, which is gratifyingly applicable to the late-stage diversification of several bioactive molecules. Mechanistic studies indicate that HAT is mediated by methyl radical, a HAT agent previously unexplored and with differing polarity to many of those used in photoredox catalysis. Accordingly, in the fluorination of ibuprofen ethyl ester, this methodology delivers new site-selectivity for late-stage C(sp3)–H functionalization. Our groups also report the utility of this oxidative radical-polar crossover approach to the development of a general annulation strategy for the streamlined construction of diverse saturated heterocycles from nucleophiles and olefins.

Harnessing the carbocation: Photocatalytic methodologies revealing versatile carbocation intermediates for methyl radical guided nucleophilic C(sp3)–H functionalization and the general synthesis of saturated heterocycles

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ACS Fall 2022

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