Pyrrole four-component synthesis

Scheme 49 Four-component synthesis of 4,5-dthydro-l//-pyrrol-3-carboxamide derivatives...

Scheme 52 Cl-Stetter addition-Paal-Knorr four-component synthesis of 1,2,3,5-tetrasubstituted and 2,3,5-trisubstituted pyrroles 97...

Arndtsen and coworkers [154] described the first Pd-catalyzed synthesis of miinchnones 6/1-318 from an imine 6/1-316, a carboxylic acid chloride 6/1-317 and CO. The formed 1,3-dipol 6/1-318 can react with an alkyne 6/1-319 present in the reaction mixture to give pyrroles 6/1-321 via 6/1-320, in good yields. The best results in this four-component domino process were obtained with the preformed catalyst 6/1-322 (Scheme 6/1.83). 

Mjalli AMM, Sarshar S, Baiga TJ (1996) Solid phase synthesis of pyrroles derived from a four component condensation. Tetrahedron Lett 37 2943-2946... 

Alizadeh A, Rezvanian A, Zhu LG (2008) One-pot synthesis of 4,5-dihydro-lH-pyrrol-3-carboxamide derivatives via a four-component reaction. Tetrahedron 64 351-355... 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

Scheme 5.22 Retrosynthetic concept for a three-component furan and four-component pyrrole synthesis.

This straightforward three-component approach to 1,4-diketones can readily expanded to a CIR-Stetter-Paal-Knorr synthesis of furans 24 and pyrroles 25 in the sense of a consecutive three-component or four-component reaction in a one-pot fashion. 

Shabbani et al. found that a similar reaction sequence occurred using tetronic acid, leading to 4H-furo[3,4-b]pyrans [72]. The same group also developed an alternative synthesis of the pyrrole 119 using succinimide or maleimide having an acidic NH group as reaction partner [73]. The reaction is a pseudo-four-component process since 2 equiv. of isocyanides are consumed and incorporated into the final adduct (Scheme 5.35). 

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). 

In a series of papers, Armstrong and co-workers " employed the elegant Ugi four-component condensation to construct munchnone precursors and, following deprotonation, munchnones. The overall sequence, which has been adapted to the solid-phase synthesis of pyrroles by Armstrong and co-workers " and, independently, by MjaUi and co-workers, is illustrated in Scheme 4.4 for the synthesis of pyrrole 38. A Rink or Wang resin can be used as a precursor to 35. The Ugi condensation leads directly to 36 and munchnone 37 formation is induced with acid. Trapping of 37 with DMAD and cleavage from the resin yields 38. 

A dual catalyst system piperidine-iodine was used in the synthesis of 3-substituted coumarins through a one-pot three-component reaction of salicylaldehyde derivatives, P-keto esters, and l-(2-aminophenyl)pyrrole in DMF at room temperature (14T2048) and through a four-component reaction of salicylaldehyde derivatives, P-keto esters, ammonium acetate, and isatoic anhydride in DMF at 60°C (Scheme 55) (14SL1596). 

Expanding upon these early results, the Odom group [322] showed that using a preformed diyne is not required but rather a four-component coupling reaction could be exploited to generate pentasubstituted pyrroles in up to 82% isolated yield (Table 15.27). In this case, the Ti(indolyl) complexes have been used to advantage to reahze this efficient synthesis. 

Table 15.27 Synthesis of pyrroles through a four-component coupling reaction.

SCHEME 3.72 Four-component iron(IIl)-catalyzed synthesis of pyrroles. 

S. Maiti, S. Biswas, U. Jana, J. Org. Chem. 2010, 75, 1674— 1683. Iron(in)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes and nitroal-kanes a simple and direct synthesis of functionalized pyrroles. 

SCHEME 6.51 FeCl -catalyzed four-component coupling synthesis of functionalized pyrroles 348. 

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... 

Bromodimethylsulfonium bromide (BDMS)-catalyzed synthesis of substituted pyrroles through a one-pot four-component reaction. 

M. Lai, P. R. Bagdi, R. S. Basha, P. Saravanan, S. Patra, A. T. Khan, Tetrahedron Lett. 2012, 53, 4145 150. Synthesis of tetra-substituted pyrroles, a potential phosphodiesterase 4B inhibitor, through nickel(It) chloride hexahydrate catalyzed one-pot four-component reaction. 

Pal et al. [26] reported an iodine-catalyzed four-component reaction of 1,3-dicar-bonyl compounds, amines, aldehydes, and nitroalkanes affording polysubstituted pyrroles 3 under a metal-free condition. This is the first example of Grob and Ca-menisch s pyrrole synthesis [27] catalyzed by iodine via one-pot four-component reaction (Scheme 10.2). 

Das et al. [29] developed a simple, efficient, cost-effective, and metal-free four-component coupling reaction of aldehydes, amines, dialkyl acetylenedicaiboxyl-ates, and nitromethane for the synthesis of corresponding 1,2,3,4-tetra-substituted pyrroles 6 using molecular iodine as a catalyst (Scheme 10.4). 

Bandyopadhyay D, Cruz J, Yadav RN, Banik BK (2012) An expeditious iodine-catalyzed synthesis of 3-pyrrole-substituted 2-azetidinones. Molecules 17 11570-11584 Reddy GR, Reddy TR, Joseph SC, Reddy KS, Pal M (2012) Iodine catalyzed four-component reaction a straightforward one-pot synthesis of functionalized pyrroles under metal-free conditions. RSCAdv 2 3387 3395... 

Das B, Bhunia N, Lingaiah MA (2011) Simple and elficient metal-free synthesis of tetra-substituted pyrroles by iodine-catalyzed four-component coupling reaction of aldehydes, amines, dialkyl acetylenedicarboxylates, and nitromethane. Synthesis 2011 3471-3474 Khan AT, Ghosh A, Khan MM (2012) One-pot four-component domino reaction for the synthesis of substituted dihydro-2-oxypyrrole catalyzed by molecular iodine. Tetrahedron Lett 53 2622-2626... 

Solid-phase synthesis of pyrroles was reported by Mjalli et al. " Pyrroles were prepared via Rink resin-bound mesoionic munchnones (Scheme 11.12). Munchnones behave as azomethine ylides in 1,3-dipolar cycloaddition. Cycloadditions with alkynes give pyrroles after aromatization and spontaneous release of carbon dioxide. A set of compounds was obtained from simple starting materials, aldehyde, amine, carboxylic acid, and isocyanide via the Ugi four-component condensation. Trifluoroacetic acid released highly substituted pyrroles as amides from the Rink resin in high overall yield and purity. A related method via the miinchnone pathway was reported by Strocker et al., and two pyrroles were obtained in 4% and 17% yields. 

One-pot Synthesis of Pyrrolo[3,2-(7]pyridazines and Pyrrole-2,3-diones via Zirconocene-mediated Four-component Coupling of Si-tethered Diyne, Nitriles and Azide. 

One-Pot Synthesis of Pyrrolo[3,2-d]pyridazines and Pyrrole-2,3-Diones via Zirconocene-Mediated Four-Component Coupling of Bis(alkynyl)silane,... 

Zhang S, Zhao J, Zhang WX et al (2011) One-pot synthesis of pyrrolo [3,2-rf] p5oidazines and pyrrole-2,3-diones via zirconocene-mediated four-component couphng of Si-tethered di5me, nitriles and azide. Org Lett 13 1626-1629... 

Malt S, Biswas S, Jana U (2010) lron(lII)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes a simple and direct synthesis of functionalized pyrroles. J Org Chem 75 1674—1683. doi 10.1021/jo902661y Makosza M, Jagusztyn-Grochowska M, Ludwikow M, Jawdosiuk M (1974) Reactions of organic anions— L reactions of phenylacetonitrile derivatives with aromatic nitrocompounds in basic media. Tetrahedron 30(20) 3723-3735. doi 10.1016/S0040-4020(01)90658-l Mamedov VA, Levin YA (1996) Unexpected reaction of o-phenylenediamine with... 

Radha Krishna Murthi [53] accessed to a faster and efficient metal-free synthesis of polysubstituted pyrroles (23) in good yields under ultrasoxmd assistance. Starting materials were p-keto esters (19), benzylamines (20), aromatic aldehydes (21), and nitromethane (22) in the presence of amberlyst-15 as a reusable catalyst via a four-component reaction (Scheme 7). 

Mjal996 Mjalli, A.M.M., Sarshar, S. and Baiga, T.J., Solid Phase Synthesis of Pyrroles Derived From a Four Component Condensation, Tetrahedron Lett., 37 (1996) 2943-2946. 

In designing a porphyrin synthesis, or indeed in making the decision about exactly which published approach to use, substituent symmetry considerations are of the utmost importance. Clearly, if all of the substituents on the pyrrole positions, or on the meso positions are identical, then tetramerization of a single monopyrrole is the method of choice. Porphyrins, per se, are comprised of a cyclic array or four pyrrole subunits linked by four methine carbons one therefore needs to assemble four pyrroles and four linking (meso) carbons into one macrocycle. Thus, the origin and type of meso-carbon to be employed is also an essential component to be considered. Likewise, whether or not the future meso-carbons should be attached to the pyrrole component or added into the reaction mixture separately is an issue to consider. 

Maiti and cowoilcers have recently reported an excellent work about the synthesis of pentasubstituted pyrroles starting from three, four, and seven components of common precursors under very mild reaction conditions using CeCl3-7HjO as activator (Scheme 6.48) [108]. 

---