Multicomponent Pyrrole Syntheses

In the last years, only some examples of multicomponent pyrrole syntheses have been published, but those are highly interesting in terms of reaction conditions and substitution patterns of the obtained pyrroles. One example is the conversion of a-iodoketones 594 in a Hantzsch pyrrole synthesis under high-speed vibration milling conditions (HSVM) and CAN catalysis, with silver nitrate as scavenger for the produced hydroiodic acid (Scheme 13.149) [269]. 

Braun RU, Muller TJJ (2004) Coupling-isomerization-stetter and coupling-isomerization-stetter-paal-knorr sequences - a multicomponent approach to furans and pyrroles. Synthesis 2391-2406... 

R. Dhawan, S. A. Amdtsen, J. Am. Chem. Soc. 2004, 126, 468 69. Palladium-catalyzed multicomponent coupling of aUcynes, imines, and acid chlorides a direct and modular approach to pyrrole synthesis. 

A family of interesting polycychc systems 106 related to pyrrolidines was obtained in a one-pot double intermolecular 1,3-dipolar cycloaddition, irradiating derivatives of o-allyl-sahcylaldehydes with microwaves in toluene for 10 min in presence of the TEA salt of glycine esters [71]. A very similar approach was previously proposed by Bashiardes and co-workers to obtain a one-pot multicomponent synthesis of benzopyrano-pyrrolidines 107 and pyrrole products 108 (Scheme 37). The latter cycloadducts were obtained when o-propargylic benzaldehydes were utihzed instead of o-allyhc benzalde-hydes, followed by in situ oxidation [72]. 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

In an extension of traditional Stetter methodology, Miiller and co-workers have used the Stetter reaction in a one-pot multicomponent reaction for the synthesis of furans and pyrroles (Scheme 19) [85,86], The ot,P-unsaturated ketone XXVI is formed in situ and undergoes a Stetter reaction followed by a Paal-Knorr condensation. 

Catalytic multicomponent synthesis of highly substituted pyrroles has been described. A one-pot reaction uses DBU with the commercially available thiazolium salt 513 to produce the necessary nucleophilic zwitterionic catalyst in situ, which promotes a conjugate addition of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. Subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired polysubstituted pyrrole compounds in a one-pot process in moderate to high yields (Scheme 129) <2004OL2465>. Microwave heating dramatically reduced the reaction time (from 16 h to 30 min), but offered no improvement in yields. 

Bharadwaj, A. R., Scheldt, K. A. Catalytic Multicomponent Synthesis of Highly Substituted Pyrroles Utilizing a One-Pot Sila-Stetter/Paal-Knorr Strategy. Org. Lett. 2004, 6, 2465-2468. 

Multicomponent condensations such as the Ugi reaction [44] and the Big-inelli condensation [45] are especially useful for the creation of diverse chemical libraries on the solid phase. Four-component condensations have been reviewed by Mjalli and Toyonaga [46] for the synthesis on the solid phase of small-ring heterocycles [47]. For example, the one-pot condensation of an amine (derived from amino acids) and an aldehyde, followed by the addition of an isocyanide and a carboxylic acid, provides a dipeptidomimetic iV-alky 1-A-acyl- a-amino amide 10 that can serve as a useful starting point for the synthesis of imidazoles 11 and pyrroles 12, which are pharmaceutically useful compounds (Fig. 4). 

The synthesis of pentasubstituted pyrroles has been reported by Mjalli and Toyonaga [46] using a multicomponent condensation. The treatment of the intermediate 10 with neat acetic anhydride or isobutylchloroformate and tri-ethylamine in toluene, followed by the addition of a series of acetylenic esters, provided the polymer-bound pentasubstituted pyrroles 12 (Fig. 4). The reaction proceeded by in situ cyclization of the intermediate via [3+2]... 

Pyrroles are the core unit of a wide variety of natural products [76]. Although many methods are available for the synthesis of these species, most are multi-step procedures resulting in low yields [77, 78]. However, Hantzsch made another important contribution to the progress of multicomponent chemistry. In his procedure pyrroles were successfully prepared from primary amines, j8-ketoesters, and a-halo-genated j5-ketoesters [79]. Only a few other one-step procedures have been reported for pyrroles but, because of to long reaction times and insufficient scope of substitution at the ring, these are not very satisfactory [80, 81]. 

An interesting variant is the multicomponent synthesis of pyrroles from carbonyl compounds, primary amines, and nitroalkanes first described by Ishii et al. 

Approaches to the synthesis and medicinal importance of pyrroles have been reviewed. The synthesis of pyrroles using multicomponent reactions was reviewed and advances in this area from mid-2009 to the end of 2013 are covered (14CSR4633). Another review covered the synthesis of pyrroles using the Paal-Knorr reaction (14AHC95).The synthetic approaches and biosynthetic hypotheses of pyrrole—imidazole alkaloids were discussed in another report (14CC8628). Synthesis of pyrrole-based heterocyclic molecules through metal triflate-catalyzed addition reactions of pyrrole to C—C and C-N bonds was reviewed (14PAC925). 

M. Zhang, X. Fang, H. Neumann, M. Beher, J. Am. Chem. Soc. 2013, 135, 11384-11388. General and regioselective synthesis of pyrroles via ruthenium-catalyzed multicomponent reactions. 

A. R. Bharadwaj, K. A. ScheidL Org. Lett. 2001, 3, 2465-2468. Catalytic multicomponent synthesis of highly substituted pyrroles utilizing a one-pot sila-Stetter/Paal-Knorr strategy. 

S. Shamim, I. R. Siddiqui, J. Heterocyclic Chem. 2013, 50, E111-E115. Ionic liquid promoted multicomponent reaction a good strategy for the eco-compatible synthesis of functionalized pyrroles, (f) B. M. Babu, G. S. Kumar, P. B. Thakur, V. M. Bangade, H. M. Meshram, Tetrahedron Lett. 2013, 54, 2296-2302. Catalyst-free four-component protocol for the synthesis of substituted pyrroles under reusable reaction media, (g) C. Martm-Santos, C. Jarava-Barrera, A. Parra, F. Esteban, C. Navarro-Ranninger, J. Alemin, ChemCatChem... 

For other example of catalyst free multicomponent synthesis of pyrroles, see X. Wang, X.-P. Xu, S.-Y. Wang, W. Zhou, S.-J. Ji, Org. Lett. 2013, 15, 4246- 249. Highly efficient chemoselective synthesis of polysubstituted pyrroles via isocyanide-based multicomponent domino reaction. 

P. Fontaine, G. Masson, J. Zhu, Org. Lett. 2009,11,1555-1558. Synthesis of pyrroles hy consecutive multicomponent reaction/ [4+1] cycloaddition of a-iminonitriles with isocyanides. 

Estevez V, Villacampa M, Menendez JC (2010) Multicomponent reactions for the synthesis of pyrroles. Chem Soc Rev 39 4402—4421... 

Khalili B, Jajarmi P, Efiekhari-Sis B, Hashemi MH (2008) Novel one-pot, three-component synthesis of new 2-alkyl-5-aryl-(fH)-pyrrole-4-ol in water. J Org Chem 73 2090-2095 Murthy SN, Madhav B, Kumar AV, Rao KR, Nageswar YVD (2009) Multicomponent approach towards the synthesis of substituted pyrroles under supramolecular catalysis using P-cyclodextrin as a catalyst in water under neutral conditions. Helv Chim Acta 92 2118-2124 Pan L, Bi X, Liu Q (2013) Recent developments of ketene dithioacetal chemistry. Chem Soc Rev 42 1251-1286... 

Alizadeh A, Zarei A, Rezvanian A (2011) A novel and one-pot multicomponent approach to the synthesis of dihyroindeno[l,2-6]pyrroles and indeno[2, l 4,5]pyrrolo[l,2-a]-fused 1,3-diazaheterocycles. Synthesis 2011 497-501... 

Siddiqui, I. R., Kumar, D., and Shamim, S. (2013). Ionic liquid promoted multicomponent reaction a good strategy for the eco-compatible synthesis of functionalized pyrroles. J. Heterocyclic Chem., 50, El 11-El 15. 

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