Reductive Fischer-Type Indole Synthesis Employing Carboxylic Acids as Surrogates of Aldehydes

Abstract

To tackle some shortcomings of the classic Fischer indole synthesis employing aldehydes as starting materials, we report herein a reductive Fischer-type indole synthesis based on carboxylic acids. This method comprises a tandem sequence involving B(C₆F₅)₃-catalyzed hydrosilylation of carboxylic acids with Et₃SiH to generate the corresponding O,O-disilyl acetals, p-TsOH-mediated transamination with arylhydrazines to form hydrazones, and a late-stage Fischer indole cyclization. In this manner, carboxylic acids act as surrogates of aldehydes. Using this one-pot protocol, a series of 3-substituted indoles, including 3,4-, 3,5-, and 3,6-disubstituted indole derivatives have been synthesized. The utility of this protocol is demonstrated by the efficient synthesis of the versatile natural product 3-methylindole, the key intermediate in the commercial production of the antidepressant drug Vilazodone (Viibryd), and the core scaffold of one of the most frequently prescribed agents for the treatment of hypercholesterolemia—all from inexpensive, commercially available carboxylic acids and arylhydrazines. The one-pot reaction tolerates several functional groups such as halogen (F, Cl, Br, I), MeO, CN, and CF₃, which are either key moieties for the development of medicinal and agrochemical agents, or can be used as a handle for the further elaboration of the indole products, as demonstrated by the two-step synthesis of a tetracyclic indole derivative.

Keywords

Carboxylic acids / Fischer indole synthesis / Reductive transformation / Boron catalysis / Hydrosilylation / N-Heterocycles / Methodology and reactions / Synthetic methods

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