Brønsted acid-enhanced direct hydrogen atom transfer photocatalysis for selective functionalization of unactivated C(sp3)–H bonds

The manipulation of unactivated aliphatic C–H bonds remains one of the most challenging tasks in synthetic chemistry. Direct hydrogen atom transfer (HAT) photocatalysis is an appealing approach to this goal. However, many methods are constrained due to low catalytic efficiency. Here we report the use of a Brønsted acid to enhance the efficiency of an inexpensive organic HAT photocatalyst, eosin Y. This strategy enables valuable transformations, including alkylation, heteroarylation and fluorination, of a wide array of unactivated C(sp3)–H bonds, using the alkane substrate as the limiting reagent. The process has been applied to the late-stage functionalization of natural products and pharmaceuticals to selectively form C–H-functionalized analogues. Experimental and computational mechanistic studies show that the HAT reactivity is significantly enhanced when the sp3 oxygen atoms on eosin Y are protonated. The method has been shown to be general across different types of direct HAT photocatalysts, demonstrating its potential in native C–H bond functionalization.