Synthesis of arylethylamines via C(sp3)–C(sp3) palladium-catalyzed cross-coupling

Lippa, Rhys A. and Battersby, David J. and Murphy, John A. and Barrett, Tim N. (2021) Synthesis of arylethylamines via C(sp3)–C(sp3) palladium-catalyzed cross-coupling. Journal of Organic Chemistry, 86 (4). 3583–3604. ISSN 0022-3263

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    Substituted arylethylamines represent a key structural motif in natural, pharmaceutical, and agrochemical compounds. Access to such scaffolds has been the subject of long-standing synthetic interest. Herein, we report the synthesis of such scaffolds via a palladium-catalyzed C(sp3)-C(sp3) coupling between (chloromethyl)aryls and air-/moisture-stable N,N-dialkylaminomethyltrifluoroborate salts. Rapid hit identification was achieved using microscale high-throughput experimentation and was followed by millimolar-scale reaction parameter optimization. A range of structurally and electronically varied arylethylamine products were obtained in moderate to excellent yields (27-96%, >60 examples). The reaction mechanism is proposed to proceed via formation of a trialkylbenzylammonium species prior to oxidative addition.