Flow Synthesis of Capsaicin and Capsaicinoid Analogues 

Capsaicin and its derivatives are special alkaloids responsible for the pungency of spicy pepper fruits and are mainly used in the pharmaceutical, food, and cosmetic industries. Until now, only batch syntheses of capsaicin and some of its analogues have been described; the drawbacks, such as long reaction time, variable yields, and chemical waste emission, still challenge organic chemists to make progress in environmentally friendly synthesis. In this study, we have developed the first flow synthesis of capsaicin and its derivatives based on three reaction steps, such as the oxime formation of benzaldehydes, the reduction of oximes, and the N-acylation of benzylamines with carboxylic acids. Each of the continuous flow reaction steps was optimized by a model reaction, and after that, the reaction steps were coupled in a semicontinuous flow system. Our developed flow method is a safer, faster, more atom-efficient, and environmentally friendly process than the batch approaches described in the literature; furthermore, our method is in accordance with seven of the 12 principles of green chemistry. In addition, 3D printed flow reactors have also been developed and used for the flow synthesis of nonivamide to demonstrate an alternative and cheaper way of flow chemistry.