Indole is an important component of natural products, a “privileged pharmacophore” in medicinal chemistry and a key constituent of various pigments and materials. The synthesis and functionalization of indole scaffolds has thus been a major focus over the last century. Flow chemistry has been considered an enabling technology, due in part to enhanced mixing that may accelerate reaction rates. However, few applications of flow processes in indole synthesis have been reported, mostly focused on the Fisher indole synthesis. The Heumann indole process was originally developed for the synthesis of indigo and featured fusion of N-phenylglycine-o-carboxylic acid into indoxylic acid, by treatment with acetic anhydride. Employment of o-amino-aryl ketones in the Heumann indole process has also provided a few substituted indoles typically in moderate yield. Studying the Heumann indole process to prepare 3-substituted indoles, we have found that flow chemistry offers advantages compared to batch chemistry. Significantly better yields, shorter reaction times and cleaner products were obtained by employing flow technology in three steps in succession from the o-amino-aryl ketone to the N-acetyl-indole products. Our presentation will describe this flow indole synthesis method and its application in the preparation of novel 3-substituted indoles.

Renaissance of the Heumann indigo process

2019 Spring National Meeting

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