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

Abstract

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 αacyloxy 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.

Is Reaction Acceleration of Microdroplet Chemistry Favorable to Controlling the Enantioselectivity?

“…As shown in Figure b, a yield of 55% was obtained for the microdroplet Passerini reaction upon 20 min collection, whereas the bulk Passerini reaction provided 8% amide product ( 9 ) for 20 min reaction and 32% yield for 48 h reaction. Although the Passerini reaction has been reported to be accelerated by 1 order of magnitude on water, our recent study demonstrated that addition of water led to sharply decreased reaction yields or even no Passerini reactions by microdroplet chemistry upon addition of 80% v/v water . Therefore, the addition of water was not considered here.…”

“…Although the Passerini reaction has been reported to be accelerated by 1 order of magnitude on water, 69 our recent study demonstrated that addition of water led to sharply decreased reaction yields or even no Passerini reactions by microdroplet chemistry upon addition of 80% v/v water. 70 Therefore, the addition of water was not considered here. This comparison demonstrated again the acceleration capability of microdroplet chemistry (2 orders of magnitude by roughly comparing the reaction time in the two reactors at similar reaction yields).…”