Ultra-fast and sustainable formal [3 + 3] cycloadditions enabled by mixed variable optimization on an automated micromole scale flow platform

Abstract

Herein, we report a simple and comprehensive mixed variable optimization strategy which enabled the development of ultra-fast formal [3 + 3]-cycloadditions of 1,3-dicarbonyl equivalents with enals in flow. Our approach, which includes sequential sampling, statistical filtering, and black box optimization, is coupled with an automated micromole scale flow platform to perform complex optimizations with limited chemical expense and minimal human intervention. The efficiency of the sampling, filtering and optimization (SFO) strategy was demonstrated with the development of ultra-fast, sustainable and mild formal cycloadditions [3 + 3] that usually require in batch prolonged reaction times and/or high temperatures. Successful scaling experiments demonstrated the transferability from the micromole scale flow platform to a standard flow chemistry reactor.