Pyrroles multicomponent reactions

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. 

Heterocycles with a l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine core are also available through this multicomponent reaction. Compounds with a related structure are of high interest either for synthetic applications or for biological purposes. For the first time we were able to propose a one-pot access to pyrrolopiperazine and azasteroide-type scaffolds, illustrating the potential of this ecocompatible sequence to create molecular complexity and diversity from simple and readily available substrates (Scheme 60) [164]. In this case, the primary amine partner bears a pyrrole nucleophile, which neutralizes the transient iminium intermediate to form a new C-C bond via an intramolecular Pictet-Spengler-type cyclization. 

Odom and coworkers have developed titanium pyrrole derivatives as highly efficient catalysts for multicomponent reactions. The processes involve the reaction between an alltyne, an isonitrile and a primary amine, giving rise to di-imine intermediates, which react in situ with either... 

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). 

Multicomponent reactions continue to be a popular way to achieve rapid construction of polysubstituted pyrrole skeletons. Cyanopyrrole 59 was synthesized in moderate to good yields from gem-dicyano olefin 56, piperidine (57), and tert-butyl isocyanide (58) without the need for a catalyst. Although the reaction is limited to cyanopyrroles, the nitrile moiety is a useful handle for further chemical transformations (130L4246). 

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. 

FIGURE 6.15 Selected pyrrole structures synthesized through a multicomponent reaction 327 [104], 328 [105], and 329 [106]. 

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... 

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... 

Keywords Phencyl bromides, amines, diethyl/dimethyl acetylenedicarboxylate, [bmim]BF4, room temperature, one-pot multicomponent reaction, functionalized pyrroles... 

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. 

SCHEME 29 Construction of pyrroles (52) using multicomponent reaction in aqueous PEG. 

SCHEME 30 Annulation of pyrrole ring using multicomponent reaction in PEG. 

Multicomponent reactions Pyrroles Pyrrolidinones Tetramic acids... 

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... 

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. 

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]. 

In Scheme 1.8.5.4, three versions of the Hantzsch multicomponent one-pot reaction are shown leading to thiazoles, pyrroles and dihydropyridines.3 ... 

---