Regioselective Synthesis of Fully Substituted Fused Pyrroles through an Oxidant-Free Multicomponent Reaction

Abstract

The synthesis of fully substituted fused pyrroles through a multicomponent reaction between a thioamide, an aldehyde, and ammonium acetate is described. This process improves on a route commonly employed in the patent literature by avoiding the use of potentially hazardous oxidants, which cause the formation of side products and require a stringent process of derisking to be utilized on scale. The reaction proceeds under mild conditions, displays excellent functional group tolerance, and facilitates diversification through multiple vectors.N ovel methods for the rapid production of highly substituted heterocycles are of interest to organic chemists due to their application as pharmaceutical and agrochemical agents. 1 Fully substituted pyrroles are of particular value, as demonstrated by Pfizer's blockbuster statin, Lipitor. 2 Recently, compounds containing the fused 3-amino-2-aryltetrahydropyrrolopyridinone core have received attention in the oncology therapeutic area as inhibitors of EGFR, 3 HER2, 4 MAPKAP-K2, 5 BRAF, 6 Casein kinase, 7 and other significant targets for the treatment of cancer (Scheme 1a).The existing syntheses of this motif proceed through an intramolecular oxidative cyclization reaction of a thioamide, such as 1, with oxidizing agents such as H 2 O 2 or mCPBA (Scheme 1b). 8,3a The mechanism of this cyclization is reported to proceed through the generation of cyclic intermediate 2, which undergoes a base-promoted or spontaneous elimination of S 0 to produce fused pyrrole 3. 9 Although this process has been used successfully to support medicinal chemistry campaigns, it suffers from drawbacks that limit its applicability for scale-up; specifically, lengthy linear routes to access starting materials, difficult-to-separate side products resulting from overoxidation of the lactam ring, and the use of oxidizing agents with thermal liabilities that require a stringent process of derisking to ensure process safety requirements are satisfied. 10 We envisaged that these issues would be overcome by employing reagents at the oxidation level required for cyclization. Specifically, a multicomponent reaction between enol 4, an ammonia source, and an aldehyde would directly generate cyclic intermediate 2 without the need for additional oxidants (Scheme 1c). Extrusion of S 0 would then generate the desired compounds. This procedure would also reduce the

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“…10 These reactions are characterized by convergence, ease of execution, efficiency, reducing waste, high yields, and atom economy. 11,12 With the rising interest in generating heterocyclic compound libraries, exploring fresh multicomponent and synthetic reactions for academic and industrial research is an engaging research endeavor.…”