Preparation of Functionalized Aryl, Heteroaryl, and Benzylic Potassium Organometallics Using Potassium Diisopropylamide in Continuous Flow

Abstract

We report the preparation of lithium-salt-free KDA (potassium diisopropylamide; 0.6 m in hexane) complexed with TMEDA (N,N,N',N'-tetramethylethylenediamine) and its use for the flow-metalation of (hetero)arenes between -78 °C and 25 °C with reaction times between 0.2 s and 24 s and a combined flow rate of 10 mL min^-1 using a commercial flow setup. The resulting potassium organometallics react instantaneously with various electrophiles, such as ketones, aldehydes, alkyl and allylic halides, disulfides, Weinreb amides, and Me₃ SiCl, affording functionalized (hetero)arenes in high yields. This flow procedure is successfully extended to the lateral metalation of methyl-substituted arenes and heteroaromatics, resulting in the formation of various benzylic potassium organometallics. A metalation scale-up was possible without further optimization.