Three-component Hantzsch pyrrole synthesis

Reproduced from Estdvez V, Villacampa M, Menpndez JC. Three-component access to pyrroles promoted by the CAN-silver nitrate system under high-speed vibration milling conditions a generalization of the hantzsch pyrrole synthesis. Chem Common 2013 49 591-3, with permission from the Royal Society of Chemistry. 

The traditional Hantzsch pyrrole synthesis consists of a one-pot reaction between P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones. This process, known as the three-component (3CP) Hantzsch pyrrole synthesis, has been largely replaced by a two component (2CP) Hantzsch synthesis using preformed enamines. Preformed enamines help provide better control over the regioselectivity of the reaction. In addition, the use of preformed enamines helps reduce the side products produced from the self condensation of P-ketoesters. 

T. A. Moss, T. Nowak, Tetrahedron Lett. 2012, 53, 3056-3060. Synthesis of 2,3-dicarbonylated pyrroles and furans via the three-component Hantzsch reaction. 

In a three-component cyclocondensation, a-halocarbonyl compounds react with P-ketoesters (or P-diketones) and ammonia or primary amines to give pyrrole-3-carboxylates (or 3-acyIpyrroIes), which are substituted either in 1,2,4- or in 1,2,5-position, for example, 43/45 (Hantzsch synthesis) ... 

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