Selectivity in the Addition of Electron‐Deficient Radicals to the C2 Position of Indoles. Issue 36 (11th September 2020)

• Record Type: Journal Article
• Authors: Li, Yi; Vaz, Roy J.; Olson, Steven H.; Munson, Mark; Paras, Nick A.; Conrad, Jay
• Is Part Of: European journal of organic chemistry. Issue 36(2020)
• Page Start: 5828
• Page End: 5832
• Publication Date: 2020-09-11
• Subjects: Density functional calculations -- Indoles -- Radical reactions -- Photocatalysis; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201901784
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract : 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. Abstract : Computational methods are used to model the addition of electron deficient radicals (· CH2 CN or · CF3 ) at 2 or 3‐positon of indoles. Lower reaction barriers are found for the reaction at C2 rather than C3 . The resulting C2 ‐substituted indole radical intermediate is also lower in energy leading to the experimentally observed C2 selectivity. This is in contrast to the long established C3 selectivity for indole reactions with electrophiles.