The thermal and boron-catalysed direct amide formation reactions: mechanistically understudied yet important processes

Abstract

Despite the amide formation reaction being one of the key cornerstone reactions in organic chemistry, the direct amide formation is both little used and little explored. Acceptance of the feasibility and general applicability of the reaction depends upon the ability of researchers to bring it into the mainstream by development of: (1) an understanding of the mechanism of the reaction; and (2) the design of catalysts which promote the reaction on a wide range of substrates and under ambient conditions. From the earliest report of the direct amide formation in the 19th century, there have been relatively few reports of mechanistic studies, though it is clear that there is not a simple relationship between ease of direct amide formation and the pK_a of the carboxylic acid and amine, or whether salt ammonium carboxylate formation is important. Consequently, direct amide formation has historically been run under higher temperature conditions. However, more recently, stoichiometric and catalytic boron compounds have been developed that considerably reduce the reaction temperatures under which direct amide formation will proceed. Limited attempts at mechanistic studies point to the formation of acyloxyborate or boronate species acting essentially as mixed anhydrides, though the exact order of these systems remains to be categorically determined.