Regioselective Ortho-Arylation of Polyhalo-Substituted (Hetero)Aryl Tosylates Using an Integrated Continuous Flow/Batch Protocol

Abstract

The regioselective ortho arylation of polyhalo-substituted (hetero)aryl tosylates has been investigated employing an integrated continuous flow/batch protocol. The regioselective ortho metalation of (hetero)aryl tosylates using n-BuLi and ZnCl2 was effectively achieved using continuous flow chemistry in a short residence time of 10.92 s, without removal of the tosyloxy group. The Pd-catalyzed Negishi coupling reactions of various (hetero)aryl iodides with the resulting arylzinc species proceeded readily at room temperature in 31% to 98% yields. Finally, the method was applied to the synthesis of perampanel in four linear steps, with an overall yield of 43%.