Direct amidation is a classical transformation in which a carboxylic acid condenses directly with an amine to afford an amide. Statistically, amidation reactions account for 15‒20% of all reactions routinely performed in pharmaceutical industry. Approximately a quarter of all marketed drugs and two-thirds of all published drug candidates bear at least one amide bond. A conventional direct amidation requires a stoichiometric coupling reagent that creates negative environmental impacts. Therefore, the catalytic version of this transformation was elected by the ACS GCI Pharmaceutical Roundtable to be one of the objectives with top priority. However, it has been a long-standing challenge in terms of the diminished reactivity in the absence of coupling reagents. The few reported precedents have not been widely applied due to the harsh conditions and narrow substrate scopes.
Recently, a Comment entitled “Challenges and Outlook for Catalytic Direct Amidation Reactions” featuring the works of Prof. Xiao Wang’s group has been published in Nature Catalysis (Nat. Catal. 2019, 2, 98‒102; https://www.nature.com/articles/s41929-018-0215-1). This forward-looking article introduces seven categories of possible new solutions to the challenges in catalytic direct amidation based on preliminary results in the pilot studies done by Prof. Wang’s lab, in the hope of providing insights for future breakthroughs in this important yet underdeveloped area. The new strategies include the use of bifunctional boronates as frustrated Lewis pairs, biomimetic MOF catalysis, thiourea-amine catalysts, photo-regenerable coupling reagents, ester-mediated condensation, catalytic formation of preactivated synthons, catalytic solid-phase peptide synthesis, and in particular, catalytic amidation in continuous-flow facilitated by microreactors. This article also discussed the prebiotic formation of life-related primordial molecules such as peptides, and the inspiration for modern chemical synthesis. Prof. Wang’s group is interested in continuous-flow chemistry, microreactors and green catalysis.
