Organocatalytic Mannich/cyclization/aromatization sequence: direct synthesis of substituted pyrrole-3-carboxaldehydes{{ Indresh Kumar,* ab Nisar A. Mir, a Panduga Ramaraju a and Basant P. Wakhloo c Received 22nd June 2012, Accepted 8th August 2012 DOI: 10.1039/c2ra21258g A robust method for the synthesis of substituted pyrrole-3- carboxaldehydes from N-PMP aldimines and succinaldehyde is reported. This reaction involves an organocatalytic direct Mannich reaction, and an acid catalyzed cyclization and oxidative aromatization sequence with high yields (up to 82%). Pyrroles 1 are well-known heterocycles that are present in numerous biologically active natural as well as synthetic compounds. 2 These show many biological activities, such as antibacterial, 3a antiviral, 3b antitumor, 3c anti-oxidative, 3d anti-inflammatory 3e activity as well as multiple applications in materials science. 4 The Paal–Knorr con- densation is one of the classical methods for the synthesis of pyrroles, where the 1,4-dicarbonyl unit provides four carbon atoms of the ring and an amine group provides the nitrogen atom with the N-substituent (eqn (1), Fig. 1). 5 However, the problems and limitations, such as the harsh cyclization conditions, 5g associated with the Paal–Knorr method have driven the development of other methods, which mainly rely on cycloaddition, 6 multi-component, 7 and metal-mediated reactions. 8 Although there are a few indirect routes, 9a–c none of the methods offer direct access to substituted pyrrole-3-carboxaldehyde, 9d even though these compounds are important synthetic intermediates. 10a–c Direct substitution at the C-3 position of pyrrole, 10d, e particularly, direct formylation at C-3, remains a challenge because electrophilic substitutions mainly occur at the C-2 position. Therefore, a general strategy to synthesize pyrrole-3-carboxaldehydes from simple build- ing blocks with a minimal number of overall synthetic steps is highly desirable. Additionally, it is also motivating to develop a new method with variation, where 1,4-dicarbonyl compounds serve as the source of the three ring atoms and the other two atoms of the pyrrole moiety could be obtained from imines (eqn (2), Fig. 1). Organocatalytic cascade reactions involving two or more selective transformations using single/multiple catalysis, serve as powerful tools to conserve energy and minimize the number of synthetic operations. 11 With the idea of cascade synthesis for pyrroles in mind, we reasoned that a simple catalytic route for substituted pyrrole-3- carboxaldehydes could be developed from succinaldehyde and imines. Although, imines have been used earlier to synthesize pyrroles, 12 to the best of our knowledge, this is the first report to employ such building blocks: aldimines and succinaldehyde. Herein, we report an entirely new synthetic method for the synthesis of substituted pyrrole-3-carboxyaldehdyes, which consists of the following steps viz. a direct Mannich reaction, followed by acid catalyzed cyclization and oxidative aromatization, as a two-step sequence. As part of our recent interest in the development of synthetic methods for heterocyclic compounds, 13 we anticipated that an aqueous solution of succinaldehyde 3, 14 a synthetically useful 1,4- dicarbonyl unit, might participate in a cascade sequence similar to aqueous glutaraldehyde used by Hayashi and co-workers for other reactions. 15 The optimization study for this direct approach to synthesize pyrrole-3-carboxaldehdye were conducted using N-PMP aldimine 2a pre-formed from p-nitrobenzaldehyde as shown in Table 1. During the initial experimental studies, we found that proline 1 catalyzed the direct Mannich reaction of aqueous succinaldehyde 3 with imine 2a, followed by acid catalyzed cyclization and DDQ mediated aromatization as a two-step sequence to afford substituted pyrrole 3-carboxaldehyde 4a in high yield (entry 8, Table 1). The amount of water present alters the course of the reaction (entry 6–8 and 10, Table 1), similar to that discussed earlier by Barbas and others for direct organocatalytic Mannich reactions. 16 Additionally, we also examined other solvent combinations (entry 1–6, Table 1) a Department of Chemistry, Birla Institute of Technology & Science, Pilani 333 031, Rajasthan, India. E-mail: indresh.chemistry@gmail.com; indresh.kumar@bits-pilani.ac.in; Fax: +91 1596 244183; Tel: +91 1596 245073 Ext. 276 b School of Biology & Chemistry, College of Science, Shri Mata Vaishno Devi University, Katra 182 320, India c Instrumentional Division, IIIM-CSIR Lab, Jammu 180 001, India { Electronic Supplementary Information (ESI) available: For experimental procedures and characterization data of new compounds. See DOI: 10.1039/ c2ra21258g { This article is dedicated to Prof. H. Ila for her contribution to heterocyclic chemistry. Fig. 1 Direct approaches to substituted pyrroles from 1,4-dicarbonyls. RSC Advances Dynamic Article Links Cite this: RSC Advances, 2012, 2, 8922–8925 www.rsc.org/advances COMMUNICATION 8922 | RSC Adv., 2012, 2, 8922–8925 This journal is ß The Royal Society of Chemistry 2012 Downloaded on 18 September 2012 Published on 08 August 2012 on http://pubs.rsc.org | doi:10.1039/C2RA21258G View Online / Journal Homepage / Table of Contents for this issue