Synthesis of Bi(hetero)aryls via Sequential Oxidation and Decarboxylation of Benzylamines in a Batch/Fully Automated Continuous Flow Process

Catalytic dehydrogenative cross-coupling of two C-H bonds represents a green strategy in view of the atom- and step-economy. However, the challenge is to discover a new innovative bond strategy, especially for the direct coupling between Csp(2)-H and benzylamines (BzAs). A series of biaryls and bi(hetero)aryls were prepared from commercially available substituted BzAs, AgNO3, cheap K2S2O8 as an oxidant, and benzene/pyridines as the coupling source in batch and flow processes. The batch reaction is somewhat problematic in terms of safety (peroxides, high temperature, high pressure, toxic pyridines), we have chosen an automated flow setup to perform the reaction in a controlled and safe manner in one pot for the synthesis of biaryls. The mechanistic studies revealed that the current protocol involves radical initiation, multi-step BzA oxidation, and subsequent decarboxylative coupling for the generation of biaryls.