Route to Benzimidazol-2-ones via Decarbonylative Ring Contraction of Quinoxalinediones: Application to the Synthesis of Flibanserin, A Drug for Treating Hypoactive Sexual Desire Disorder in Women and Marine Natural Product Hunanamycin Analogue

Abstract

A simple and practical method to access a variety of benzimidazol-2-ones is reported here. A series of N-alkyl-substituted benzimidazol-2-ones were synthesized by decarbonylative ring contraction starting from corresponding quinoxalinediones for the first time. The utility of the method has been demonstrated by synthesizing recently approved controversial drug flibanserin (Addyi) and a urea analogue of marine antibiotic natural product hunanamycin-A.

Synthesis of imidazolocoumarins by the amide-directed oxidative cyclisation of enol-Ugi derivatives

“…An alternative reaction mechanism could involve an intramolecular transamination of 10 to give a chromenopiperazine (19), followed by ring contraction to form the imidazole ring. 36 To study the feasibility of this transformation, amine 10e was thermally cyclised to chromenopiperazine 19e 34 and this was then subjected to the oxidation with PIDA (Scheme 5). In these conditions no reaction was observed and the starting 19e was the only recovered product.…”

The methodology for preparing domperidone: strategies, routes and reaction processes

“…More convenient methods, benzimidazolone could be synthesized via the Curtius reactions of phthalic anhydrides 5 or anthranilic acid 6 and azide. 15 Interestingly, Shingare et al 22 proposed a mild protocol for the synthesis of benzimidazolone through decarbonylation of quinoxalinediones 7. Among them, the cyclization reaction of o -phenylenediamine and carbonyl reagents is the main method to synthesize benzimidazolone.…”

Continuous one-flow multi-step synthesis of active pharmaceutical ingredients

“…In literature several batch syntheses have been described with yields ranging from 32-51%. [47][48][49] Greiner and co-workers developed an interrupted one-flow system for the synthesis of flibanserin (44) with a minimal number of manual unit operations. 50 Previous existing batch protocols to flibanserin included protecting group introduction and removal as separate steps which was not considered feasible.…”

“…49 Alternatively, reported N-alkylations were challenging and required forcing reaction conditions with insoluble bases. 47 The authors therefore devised a novel synthetic route for the synthesis of flibanserin in flow (Fig. 13).…”