Chemodivergent photoinitiated radical-polar crossover α- and α,β-C–H bond functionalisation of cyclic amine and ether scaffolds

Saturated heterocycles bearing acetal, N,O-acetal, or aminal motifs are prominent in many complex molecules and are of high value in synthetic and medicinal chemistry. Their assembly has often relied on Shono-type α-C(sp3)–H bond oxidations to give the cationic species that is trapped by the solvent or nucleophile. However, the development of a single Shono-type oxidative method that can enable both α-functionalisation and α,β-difunctionalisation has remained challenging. Here, we present a photoinitiated chemodivergent radical-polar crossover protocol mediated by dichloramine-T that enables selective α-functionalisation with C-, N-, O-, or S-based nucleophiles, or concomitant with β-chlorination, of a saturated N- or O-heterocycle. The method combines previously separate and distinct oxidative strategies for α-functionalisation and α,β-difunctionalisation into a single unified approach. The utility of the chemodivergent protocol was exemplified by its applicability to twelve classes of the cyclic amine and ether compound family and late-stage functionalisation of several natural product and drug molecule derivatives. Saturated heterocycles with acetal motifs are crucial in synthetic and medicinal chemistry, yet their efficient α- and α,β-functionalisation remains challenging. Here, the authors introduce a photoinitiated chemodivergent radical-polar crossover method using dichloramine-T, enabling selective α-functionalisation and β-chlorination.