Copper-Promoted Regioselective Synthesis of Polysubstituted Pyrroles from Aldehydes, Amines, and Nitroalkenes via 1,2-Phenyl/Alkyl Migration

Abstract

The facile copper-catalyzed synthesis of polysubstituted pyrroles from aldehydes, amines, and β-nitroalkenes is reported. Remarkably, the use of α-methyl-substituted aldehydes provides efficient access to a series of tetra- and pentasubstituted pyrroles via an overwhelming 1,2-phenyl/alkyl migration. The present methodology is also accessible to non α-substituted aldehydes, yielding the corresponding trisubstituted pyrroles. On the contrary, the use of ketones, in place of aldehydes, does not promote the organic transformation, signifying the necessity of α-substituted aldehydes. The reaction proceeds under mild catalytic conditions with low catalyst loading (0.3-1 mol %), a broad scope, very good functional-group tolerance, and high yields and can be easily scaled up to more than 3 mmol of product, thus highlighting a useful synthetic application of the present catalytic protocol. Based on formal kinetic studies, a possible radical pathway is proposed that involves the formation of an allylic nitrogen radical intermediate, which in turn reacts with the nitroalkene to yield the desired pyrrole framework via a radical 1,2-phenyl or alkyl migration.

Recent Advancements in Pyrrole Synthesis

“…Lykakis and Kostakis reported a facile copper(II)-catalyzed reaction between aldehydes, amines, and -nitroalkenes 252 to yield polysubstituted pyrroles 253 (Scheme 29). 122 In this chemistry, the pyrrole framework is proposed to be formed via a radical mechanism involving allylic nitrogen radical intermediate 254, which subsequently adds to nitroalkene 252 at the -carbon. The resulting aldimine species 255 then undergoes deprotonation, 1,2-migration, cyclization, and aromatization to afford pyrrole 253.…”

Application of β‐Nitrostyrene in Multicomponent Reactions for the Synthesis of Pyrrole Derivatives

“…The results shown the best yield was obtained by [Cu(II)(L) 2 (OTf) 2 ] ( Cu – 4 ) (Scheme ). The plausible mechanism for this reaction is demonstrated in (Scheme ) …”

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

“…Accordingly, numerous synthetic methods to construct pyrrole skeletons were reported, including the classical Hantzsch [7,8] and the Paal-Knorr pyrrole syntheses [ [9][10][11], which have been developed to harvest the pyrrole frameworks. In the past few years, the interest in developing new methods to synthesize this heterocyclic motif has rapidly grown; transition metal-catalyzed cyclization [12][13][14] and multicomponent reactions [15][16][17][18] are some of the commonly used approaches for the construction of pyrrole scaffolds. Additionally, the biocatalytic synthesis of substituted pyrroles was also developed [19].…”