Pyrrole is one of the most important one-ring heterocycles. The ready availability of suitably substituted and functionalized pyrrole derivatives is essential for the progress of many branches of science, including biology and materials science. Access to this key heterocycle by multicomponent routes is particularly attractive in terms of synthetic efficiency, and also from the environmental point of view. We update here our previous review on this topic by describing the progress made in this area in the period between mid-2009 and the end of 2013.

Multicomponent reactions are one of the most interesting concepts in modern synthetic chemistry and, as shown in this critical review, they provide an attractive entry into pyrrole derivatives, which are very important heterocycles from many points of view including medicinal and pharmaceutical chemistry and materials science (97 references).

A sequential multicomponent process involving the high-speed vibration milling of ketones with N-iodosuccinimide and p-toluenesulfonic acid, followed by addition of a mixture of primary amines, β-dicarbonyl compounds, cerium(IV) ammonium nitrate and silver nitrate afforded polysubstituted, functionalized pyrroles. This one-pot, solid-state process can be considered as the coupling of an α-iodoketone preparation with a general version of the classical Hantzsch pyrrole synthesis.

The use of solvent-free, high-speed vibration milling conditions has allowed the development of ao ne-pot telescoped process for the synthesis of pyrroles starting from ketones, primary amines, and b-dicarbonyl compounds and comprising an initial a-iodination followed by an in situ three-component Hantzsch-type reaction. This methodw as compared with as olution-based protocol from a-iodoketones, primary amines,a nd b-dicarbonyl compounds. Although both protocols were far more general than previous Hantzsch-type pyrrole syntheses, the mechanochemical methodw as superior in that it afforded considerably higher yields in spite of comprising an additional step. The stereochemicali ntegrity of the pyrroles obtained from chiral aaminoesters wasm aintained. This solvent-free method was also used for the efficient preparationo fter-a nd quater-aryl/ heteroaryl frameworks containing two pyrrole units and avariety of fused pyrrole systems, including benzo[g]indoles, indeno[1,2-b]pyrroles, indoles,and homoindoles.

A Hantzsch-type multicomponent reaction under high-speed vibration milling conditions followed by acid treatment afforded atorvastatin lactone in 38% overall yield.