Synthesis, evaluation and application of novel bifunctional N,N-di-isopropylbenzylamineboronic acid catalysts for direct amide formation between carboxylic acids and amines

Three new derivatives of N,N-di-isopropylbenzylamine-2-boronic acid have been prepared by directed metallation-borylation methods, to derive the 3-fluoro, 3-methoxy and 5-trifluoromethyl systems. The addition of an electron withdrawing group does increase the reactivity of such systems to act as improved direct amide formation catalysts under the most ambient conditions employed to date. In contrast, an electron donating group does result in considerable lowering of catalyst reactivity. DoE studies have been used to identify the ideal reaction conditions under which these types of catalysts should be used, typified by the parent system N,N-di-isopropylbenzylamine-2-boronic acid. This shows best performance at a 5 mol% loading and under higher dilution conditions, which most likely reflect the drying capacity of the solvent.