Synthesis of 3-Substituted Indoles by Yonemitsu Three-Component Reactions Accelerated in Microdroplet/Thin Film

Abstract

3-Substituted indoles are an important framework of many drugs, agricultural chemicals, functional materials, and bioactive compounds. Malononitrile-based three-component Yonemitsu reactions are attractive choices for the synthesis of 3substituted indole derivatives but suffered from long reaction time and harsh conditions (e.g., elevated temperature and special catalysts/solvents) in conventional conversions. In this study, we developed a metal-free, efficient, mild, and wide microdroplet/thinfilm method to construct 18 3-substituted indoles from various substituted aromatic aldehydes and indoles with good reaction yields (42−69%) and fantastic reaction acceleration (1.32 × 10 3 rate acceleration factor relative to the bulk reaction). By spraying 0.8 mol L −1 reactants at 300 μL min −1 , the rate of the microdroplet/thin film product was scaled up to 1.72 g h −1 . Overall, the microdroplet/thin-film method offered several advantages including high efficiency, mild conditions, wide scope, and gram-scale ability, making it attractive for synthesizing 3-substituted indoles under the requirements of sustainable chemistry.