Visible-Light-Promoted Continuous-Flow Iodination of Primary C(sp3)-H Bonds: An Undirected and Regioselective Approach.

Selective functionalization of primary C(sp3)-H bonds without directing group assistance is notoriously difficult because of their high bond dissociation energies and the inherent instability of primary radical intermediates. Here, we report a practical continuous-flow protocol for the regioselective iodination of primary C(sp3)-H bonds in alkanes, employing inexpensive, readily available iodine, NaNO2 and aqueous HCl in carbon tetrachloride solvent under visible-light irradiation. Significantly, this method selectively functionalizes primary C(sp3)-H bonds over typically more reactive secondary, tertiary, or even benzylic sites. A broad range of linear, branched, and complex alkanes, including drugs and natural products, is efficiently converted into the corresponding primary alkyl iodides with excellent functional-group compatibility. These resulting alkyl iodides serve as versatile intermediates for late-stage transformations, thereby providing indirect access to otherwise difficult C(sp3)-H functionalization. Mechanistic investigations indicate that the reaction proceeds through a reversible and nonselective C-H activation to generate a mixture of alkyl radicals, followed by a kinetically controlled iodination that selectively traps the primary radical species.