Catalyst-free activation of N–C(O) Amide bonds – efficient cascade synthesis of N-acyl thiocarbamides in batch and continuous-flow

Abstract

The amide bond stands as a crucial functional group in chemistry and biology, integral to various processes aiding the creation of essential pharmaceutical and industrial compounds. Developing efficient transformations through metal-free, environmentally friendly, and sustainable methods for breaking N–C bonds in amides poses a noteworthy synthetic challenge. Herein, we present a green method to activate the N–C amide bond in N-acyl saccharin, employing ammonium thiocyanate in sustainable 2-MeTHF as the solvent medium. This approach facilitates the efficient and divergent synthesis of N-carbamothioylbenzamides and O-alkyl thiocarbamides. Additionally, it features a bench-stable and recyclable core of reagents, a low E-factor, high atom efficiency, simple and mild conditions, excellent functional group tolerance, and a broad substrate scope. Moreover, we accomplished the synthesis of N-carbamothioylbenzamides through a continuous-flow method in a short reaction time (17 min), highlighting that our novel approach is versatile for synthetic and industrial use and applicable in both batch and flow conditions. This method demonstrates the practicality of gram-scale reactions and showcases its efficacy in synthesizing valuable heterocyclic compounds like thiazoles and triazole through successful synthetic transformations.