UC Santa Barbara

Flow chemistry is one of the most efficient ways of practicing chemistry. The development of reliable flow chemistry methods is of great significance from an industrial perspective since safety and ease in scaling up processes are this technology's key advantages. Herein we discuss the development of novel flow methodologies for making azacycles and amides.Azacycles are an essential class of pharmaceutically active compounds whose synthesis is generally conducted in batch by methods involving highly functionalized reagents and a homogeneous catalyst with or without a promoter. A more direct route to azacycles, for example, from ethers, would enable more streamlined, efficient, and sustainable processes. This work synthesized a wide range of N-substituted pyrrolidines, piperidines, and pyrroles by the direct reaction of cyclic ethers or furans with primary amines. Amorphous silica-alumina, a simple and readily available solid acid, catalyzes the cyclocondensation reaction for both aromatic and aliphatic amines and allows the reaction to be conducted continuously in a packed-bed reactor. When the reactant is a simple ether that can also serve as the solvent, N-substituted azacycles are obtained in high yield by simple solvent removal without further workup. The solid acid-catalyzed reaction in flow provides a simple and efficient route to N-substituted azacycles. Amide bond formation is a crucial transformation in pharmaceutical manufacturing. Conventional protocols involve harsh conditions or the stoichiometric usage of toxic coupling agents such as HATU or EDC. Amidation of esters is a promising strategy because it requires cheap, stable, and readily available methyl or ethyl esters and produces volatile alcohol as the only byproduct. In this project, we have developed an efficient continuous flow protocol with short residence times using amorphous silica-alumina as the catalyst.