Selectivity in the Addition of Electron‐Deficient Radicals to the C2 Position of Indoles

The addition of electron‐deficient radicals to the C2 position of indoles has been described in the literature as opposed to electrophilic addition at the C 3 position. Density functional theory calculations were used to understand the switch in regioselectivity from C3 to C2 for indole to undergo radical additions. Electron deficient radicals have a lower barrier for the reaction at C 2 and a lower energy radical intermediate that benefits from benzylic radical stabilization. Trifluoromethyl radical addition has a lower energy barrier than acetonitrile radical, and the C 3 addition transition state is just 0.8 kcal/mol higher than C2 . This is supported by experimental observations.