From Flask to Mill: Reductive Functionalization of Fluoroacetamides as a Case Study for Transferring Solvent-Based Reactions to the Solid State

Abstract

The development of sustainable methods is a central focus of modern organic synthesis and has applications in various areas of the chemical industry. Mechanochemistry is a highly desirable green synthetic method as it departs from traditional solution-based reactions and their concurrent generation of waste solvent. Here, we report results of the adaptation of a solution-based method for the reductive functionalization of fluoroacetamides to a mechanochemical protocol as a case study. This greener solid-state, one-pot strategy is based on the partial reduction of amides by an in situ mechanochemically generated zirconocene chloride hydride (Schwartz’s reagent) and tandem nucleophilic addition of indole to afford high-value functionalized fluorinated amines in moderate to good yields. In addition to it being the first time this reductant has been mechanochemically generated, the sustainable approach was complemented by operationally simple purification by an acidic resin. Significant improvements in green metrics (E factor and EcoScale) were observed by this adaptation of the methodology.