Microdroplet Chemistry Accelerating a Three-Component Passerini Reaction for α-Acyloxy Carboxamide Synthesis

α-Acyloxy carboxamides are important multifunctional natural products that show bioactive and pharmacological activities. Traditional three-component Passerini reactions among isocyanates, aldehydes/ketones, and carboxylic acids for affording α-acyloxy carboxamides suffer from several drawbacks such as long reaction time, high reaction temperature, special reaction devices, etc. Herein, we developed a high-efficiency microdroplet method for accelerating the Passerini reactions by 3 orders of magnitude by comparing with the rate constants in bulk, achieving high-yield and gram-scale (scaling up to 1.91 g for 1 h collection) synthesis of α-acyloxy carboxamides at near room temperature. The Passerini microdroplet method shows a wide scope for a variety of benzoic acids, aryl aldehydes, and isocyanates. Moreover, the Passerini reaction was poorly conducted in aqueous microdroplets but well accelerated in acetonitrile microdroplets with at least 230 times efficiency than on-water Passerini reactions. All results proved it an attractive alternative to classic organic synthesis for the construction of α-acyloxy carboxamides and derivatives.