Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer

• Published in: Journal of the American Chemical Society Vol. 142; no. 1; pp. 468 - 478
• Main Authors: Lehnherr, Dan, Lam, Yu-hong, Nicastri, Michael C, Liu, Jinchu, Newman, Justin A, Regalado, Erik L, DiRocco, Daniel A, Rovis, Tomislav
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.01.2020; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; FUNCTIONALIZATION; C-H ARYLATION; RECEPTOR ANTAGONISTS; HETEROCYCLES; FUKUI FUNCTIONS; CONVERSION; CHEMISTRY; PHOTOCHEMICALLY INDUCED REACTIONS; KETIMINES; MOLECULAR-ORBITAL THEORY
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.9b10870

Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochemical method to access such hindered amines starting from benchtop-stable iminium salts and cyano­heteroarenes. A wide variety of substituted heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those substituted with a halide, trifluoromethyl, ester, amide, or ether group, a heterocycle, or an unprotected alcohol or alkyne. Mechanistic insight based on DFT data, as well as cyclic voltammetry and NMR spectroscopy, suggests that a proton-coupled electron-transfer mechanism is operational as part of a hetero-biradical cross-coupling of α-amino radicals and radicals derived from cyano­heteroarenes.