Direct Superacid‐Promoted Difluoroethylation of Aromatics

• Published in: Chemistry : a European journal Vol. 28; no. 6; pp. e202103926 - n/a
• Main Authors: Artault, Maxime, Vitse, Kassandra, Martin‐Mingot, Agnès, Thibaudeau, Sébastien
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 27.01.2022; Wiley Subscription Services, Inc; Wiley-VCH Verlag
• Subjects: Amines; Aromatic compounds; bioisostere; Chemical Sciences; Chemistry; Chemistry, Multidisciplinary; difluoroethylation; Intermediates; late-stage functionalization; Low temperature; NMR; Nuclear magnetic resonance; Organic chemistry; Physical Sciences; Science & Technology; Substrates; superacid; superelectrophile; difluoroethylation; CYTOCHROME-P450; O-DEMETHYLATION; REGIOSELECTIVE ELECTROPHILIC TRIFLUOROMETHYLATION; CLEAVAGE; bioisostere; BIOMIMETIC POLYENE CYCLIZATIONS; CATION-STABILIZING AUXILIARIES; FLUORINE ATOM; late-stage functionalization; CYP2D6; superacid; INHIBITORS; DERIVATIVES; superelectrophile
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202103926

Under superacid conditions, aromatic amines are directly and regioselectively 1,1‐difluoroethylated. Low temperature in situ NMR studies confirmed the presence of benzylic α‐fluoronium and α‐chloronium ions as key intermediates in the reaction. This method has a wide substrate scope and can be applied to the late‐stage functionalization of natural alkaloids and active pharmaceutical ingredients. Through an original superelectrophile‐promoted difluoroethylation in superacid, CF2‐Me aromatic amines can be synthesized directly and regioselectivity. Applied to simple substrates, natural alkaloids and active pharmaceutical ingredients, this method offers an alternative for the late‐stage synthesis of aryl methyl ethers bioisosters.