Synthesis of highly substituted pyrroles using ultrasound in aqueous media

A two-step protocol for the synthesis of highly substituted pyrroles in aqueous media and without catalyst is described. The first step is the dimerization of a 1,3-dicarbonyl compound by ceric ammonium nitrate/ultrasound to produce a tetracarbonyl derivative. This derivative is then combined with an amine in the absence of any catalysts to obtain the pyrrole via a Paal–Knorr reaction. This route is an improvement when compared with classical methodologies toward Green Chemistry objectives.
Synthesis of highly substituted pyrroles using ultrasound in aqueous media
 Instituto de Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos, 149 – 21941-909 Rio de Janeiro, Rio de Janeiro, Brazil

Green Chemistry Letters and Reviews, 2012, 1-5

Pyrroles are heterocycles, which are present in natural molecules such as porphyrins and bilirubins 1–4 and many other compounds that possess antioxidant 5, antitumor 6–8, and anticancer 9 10 properties. The classic methods for the synthesis of pyrroles described in the literature are Knorr 11–14, Hantzsch 15, Paal–Knorr 16–20, and Barton–Zard21 22 reactions. The Paal–Knorr reaction, in which 1,4-dicarbonyl compounds react with primary amines under slightly acidic conditions, is a very attractive approach. Ranu et al. reported a process in aqueous media catalyzed by a water-tolerant Lewis acid that can lead to penta-substituted pyrroles 23.

In the literature, there is an effort to optimize this methodology leading to environmentally friendly processes. Current publications describe the use of solvent-free conditions with Lewis acid catalysts 24, microwave heating 25 26, ionic liquids 27, and ultrasound 28. Most of these processes lead to tri- and tetra-substituted pyrroles.
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