Synthesis of Pentasubstituted Pyrroles via Catalyst-Free Multicomponent Reactions

Abstract

A facile and versatile catalyst-free method for the preparation of a wide range of pentasubstituted pyrroles has been reported using four-component reactions of arylglyoxal monohydrate, β-keto esters, amines, and various cyclic 1,3-dicarbonyls under mild reaction conditions. Employing this methodology, pseudo seven-component reactions have also been achieved in the case of p-phenylenediamine to provide conjugated bispyrroles with arene spacers.

Key words

multicomponent reactions - β-keto esters - arylglyoxals - cyclic 1,3-dicarbonyls - pentasubstituted pyrroles

• References and Notes

• 1a Zhu J, Bienayme H. Multicomponent Reactions. Wiley-VCH; Weinheim: 2005
• 1b Tejedor D, Garcia-Tellado F. Chem. Soc. Rev. 2007; 36: 484
• 1c D’Souza DM, Mueller TJ. J. Chem. Soc. Rev. 2007; 36: 1095
• 1d Dömling A. Chem. Rev. 2006; 106: 17
• 1e Toure BB, Hall DG. Chem. Rev. 2009; 109: 4439
• 1f Ganem B. Acc. Chem. Res. 2009; 42: 463
• 1g Slobbe P, Ruijter E, Orru RV. A. Med. Chem. Commun. 2012; 3: 1189
• 1h Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
• 1i Kreye O, Tóth T, Meier MA. R. J. Am. Chem. Soc. 2011; 133: 1790
• 1j Murugavel G, Punniyamurthy T. Org. Lett. 2013; 15: 3828
• 2a Trost BM. Science 1991; 254: 1471
• 2b Clarke PA, Zaytsev AV, Morgan TW, Whitwood AC, Wilson C. Org. Lett. 2008; 10: 2877
• 2c Shen L, Cao S, Wu J, Zhang J, Li H, Liu N, Qian X. Green Chem. 2009; 11: 1414
• 2d Devi Bala B, Rajesh SM, Perumal S. Green Chem. 2012; 14: 2484
• 2e Kumar A, Sharma S. Green Chem. 2011; 13: 2017
• 2f Safaei HR, Shekouhy M, Rahmanpur S, Shirinfeshan A. Green Chem. 2012; 14: 1696
• 2g Ma N, Jiang B, Zhang G, Tu S.-J, Wever W, Li G. Green Chem. 2010; 12: 1357
• 2h Gu Y, De Sousa R, Frapper G, Bachmann C, Barrault J, Jerome F. Green Chem. 2009; 11: 1968
• 2i Tan J.-N, Li M, Gu Y. Green Chem. 2010; 12: 908
• 2j Yan S, Chen Y, Liu L, He N, Lin J. Green Chem. 2010; 12: 2043
• 2k Zhang Z.-H, Zhang X.-N, Mo L.-P, Li Y.-X, Ma F.-P. Green Chem. 2012; 14: 1502
• 2l Jain SL, Singhal S, Sain B. Green Chem. 2007; 9: 740
• 2m Zhang M, Jiang H, Liu H, Zhu Q. Org. Lett. 2007; 9: 4111
• 2n Wang X, Wang S.-Y, Ji S.-J. Org. Lett. 2013; 15: 1954
• 2o Fringuelli F, Girotti R, Piermatti O, Pizzo F, Vaccaro L. Org. Lett. 2006; 8: 5741
• 3a Huang Y, Yazbak A, Dömling A. Multicomponent Reactions . In Green Techniques for Organic Synthesis and Medicinal Chemistry . Zhang W, Cue BW. John Wiley and Sons; Chichester: 2012
• 3b Gu Y. Green Chem. 2012; 14: 2091
• 3c Isambert N, Duque MM. S, Plaquevent J.-C, Génisson Y, Rodriguez J, Constantieux T. Chem. Soc. Rev. 2011; 40: 1347
• 3d Garella D, Borretto E, Stilo AD, Martina K, Cravotto G, Cintas P. Med. Chem. Commun. 2013; 4: 1323
• 3e Singh MS, Chowdhury S. RSC Adv. 2012; 2: 4547
• 3f Jiang B, Yi M.-S, Shi F, Tu S.-J, Pindi S, McDowell P, Li G. Chem. Commun. 2012; 48: 808
• 3g Anastas P, Eghbali N. Chem. Soc. Rev. 2010; 39: 301
• 3h Martins MA. P, Frizzo CP, Moreira DN, Buriol L, Machado P. Chem. Rev. 2009; 109: 4140
• 4a Jones RA. Pyrroles: The Synthesis, Reactivity and Physical Properties of Substituted Pyrroles. Wiley; New York: 1992. Part II
• 4b Young IS, Thornton PD, Thompson A. Nat. Prod. Rep. 2010; 27: 1801
• 4c d’Ischia M, Napolitano A, Pezzella A. Pyrroles and their Benzo Derivatives: Applications . In Comprehensive Heterocyclic Chemistry III . Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Elsevier; Amsterdam: 2008
• 4d Walsh CT, Garneau-Tsodikova S, Howard-Jones AR. Nat. Prod. Rep. 2006; 23: 517
• 4e Falk H. The Chemistry of Linear Oligopyrroles and Bile Pigments. Springer; New York: 1989
• 4f Sundberg RJ. Pyrroles and their Benzoderivatives: Synthesis and Applications. In Comprehensive Heterocyclic Chemistry. Vol. 4. Katritzky AR, Rees CW. Pergamon; Oxford: 1984: 313-376
• 4g Fürstner A. Angew. Chem. Int. Ed. 2003; 42: 3582
• 5a Johnson DS, Sliskovic DR, Roth BD. Contemporary Drug Synthesis . John Wiley; Hoboken: 2004: 113-124
• 5b Zareba G. Drugs Today 2006; 42: 95
• 5c Procopiou PA, Draper CD, Hutson JL, Inglis GG. A, Ross BC, Watson NS. J. Med. Chem. 1993; 36: 3658
• 6a Boger DL, Boyce CW, Labroli MA, Sehon CA, Jin Q. J. Am. Chem. Soc. 1999; 121: 54
• 6b Palermo JA, Brasco MF. R, Seldes AM. Tetrahedron 1996; 52: 2727
• 7 Antonucci T, Warmus JS, Hodges JC, Nickell DG. Antivir. Chem. Chemother. 1995; 6: 98
• 8a Addor RW, Babcock TJ, Black BC, Brown DG, Diehl RE, Furch JA, Kameswaran V, Kamhi VM, Kremer KA, Kuhn DG, Lovell JB, Lowen GT, Miller TP, Peevey RM, Siddens JK, Treacy MF, Trotto SH, Wright DP. Jr. Insecticidal Pyrroles . In Synthesis and Chemistry of Agrochemicals III . American Chemical Society; Washington DC: 1992: 283-297
• 8b Meier GA, Silverman IR, Ray PS, Cullen TG, Ali SF, Marek FL, Webster CA. Agrochemicals III, ACS Symposium Series 504. Baker DR, Fenyes JG, Steffens JJ. American Chemical Society; Washington DC: 1992: 313-326
• 9a Loudet A, Burgess K. Chem. Rev. 2007; 107: 4891
• 9b Ziessel R, Goze C, Ulrich G. Synthesis 2007; 6: 936
• 10a Nalwa HS. Advanced Functional Molecules and Polymers: Electronic and Photonic Properties. CRC Press; New York: 2001
• 10b Gabriel S, Cécius M, Fleury-Frenette K, Cossement D, Hecq M, Ruth N, Jérôme R, Jérôme C. Chem. Mater. 2007; 19: 2364
• 10c Higgins SJ. Chem. Soc. Rev. 1997; 26: 247
• 10d Novák P, Müller K, Santhanam SV, Hass O. Chem. Rev. 1997; 97: 207
• 10e MacDiarmid AG. Synth. Met. 1997; 84: 27
• 11a Mal D, Shome B, Dinda BK. Pyrrole and its Derivatives . In Heterocycles in Natural Product Synthesis . Majumder KC, Chattopadhyay SK. Wiley-VCH; Weinheim: 2011: 187-220
• 11b Estevez V, Villacampa M, Menendez JC. Chem. Soc. Rev. 2010; 39: 4402
• 11c Jean A, Blanchet J, Rouden J, Maddaluno J, Paolis MD. Beilstein J. Org. Chem. 2013; 9: 1480
• 11d Winklhofer C, Terpin A, Peschko C, Steglich W. Synthesis 2006; 3043
• 11e Alizadeh A, Rezvanian A, Bijanzadeh HR. Synthesis 2008; 725
• 11f Anary-Abbasinejad M, Charkhati K, Anaraki-Ardakani H. Synlett 2009; 1115
• 11g Palmieri A, Gabrielli S, Cimarelli C, Ballini R. Green Chem. 2011; 13: 3333
• 11h Tamaddon F, Amirpoor F. Synlett 2013; 24: 1791
• 11i Guan Z.-H, Li L, Ren Z.-H, Li J, Zhao M.-N. Green Chem. 2011; 13: 1664
• 12a Knorr L. Ber. Dtsch. Chem. Ges. 1884; 17: 1635
• 12b Knorr L. Justus Liebigs Ann. Chem. 1886; 236: 290
• 13 Hantzsch A. Ber. Dtsch. Chem. Ges. 1890; 23: 147
• 14 Paal C. Ber. Dtsch. Chem. Ges. 1885; 18: 367
• 15a Ozdemir I, Gurbuz N, Kaloglu N, Dogan Ö, Kaloglu M, Bruneau C, Doucet H. Beilstein J. Org. Chem. 2013; 9: 303
• 15b Yoshida M, Al-Amin M, Shishido K. Synthesis 2009; 2454
• 15c Azizi N, Khajeh-Amiri A, Ghafuri H, Bolourtchian M, Saidi MR. Synlett 2009; 2245
• 16 Ke J, He ZC, Liu ZH, Li M, Lei A. Chem. Commun. 2013; 49: 7549
• 17 Hu Y, Wang C, Wang D, Wu F, Wan B. Org. Lett. 2013; 15: 3146
• 18 Zhang M, Neumann H, Beller M. Angew. Chem. 2013; 125: 625
• 19 Billedeau RJ, Klein KR, Kaplan D, Lou Y. Org. Lett. 2013; 15: 1421
• 20 Eftekhari-Sis B, Zirak M, Akbari A. Chem. Rev. 2013; 113: 2958
• 21a Fan W, Ye Q, Xu H.-W, Jiang B, Wang S.-L, Tu S.-J. Org. Lett. 2013; 15: 2258
• 21b Feng X, Wang Q, Lin W, Dou G.-L, Huang Z.-B, Shi D.-Q. Org. Lett. 2013; 15: 2542
• 21c Fu L.-P, Shi Q.-Q, Shi Y, Jiang B, Tu S.-J. ACS Comb. Sci. 2013; 15: 135
• 21d Wang H.-Y, Shi D.-Q. ACS Comb. Sci. 2013; 15: 261
• 21e Azuaje J, El Maatougui A, Pérez-Rubio JM, Coelho A, Fernández F, Sotelo E. J. Org. Chem. 2013; 78: 4402
• 21f Wang H, Liu X, Feng X, Huang Z, Shi D. Green Chem. 2013; 15: 3307
• 22a Gumńska M, Eckstein M. J. Med. Pharm. Chem. 1961; 3: 583
• 22b Ahadi S, Zolghadr M, Khavasi HR, Bazgir A. Org. Biomol. Chem. 2013; 11: 279
• 22c Shen S.-C, Sun X.-W, Lin G.-Q. Green Chem. 2013; 15: 896
• 22d Stanchev S, Momekov G, Jensen F, Manolov I. Eur. J. Med. Chem. 2008; 43: 694
• 22e Stanchev S, Hadjimitova V, Traykov T, Boyanov T, Manolov I. Eur. J. Med. Chem. 2009; 44: 3077
• 22f Rodríguez SA, Nazareno MA, Baumgartner MT. Bioorg. Med. Chem. 2011; 19: 6233
• 23a Karamthulla S, Pal S, Khan MN, Choudhury LH. RSC Adv. 2013; 3: 15576
• 23b Pal S, Khan MN, Karamthulla S, Choudhury LH. RSC Adv. 2013; 3: 15705
• 23c Pal S, Khan MN, Karamthulla S, Abbas SJ, Choudhury LH. Tetrahedron Lett. 2013; 54: 5434
• 23d Pal S, Singh V, Das P, Choudhury LH. Bioorg. Chem. 2013; 48: 8
• 23e Pal S, Choudhury LH, Parvin T. Mol. Diversity 2012; 16: 129
• 23f Khan MN, Pal S, Parvin T, Choudhury LH. RSC Adv. 2012; 2: 12305
• 24a Wang C, Dong H, Hu W, Liu Y, Zhu D. Chem. Rev. 2012; 112: 2208
• 24b Domingo VM, Alemán C, Brillas E, Juliá L. J. Org. Chem. 2001; 66: 4058
• 24c Hansford KA, Guarin SA. P, Skene WG, Lubell WD. J. Org. Chem. 2005; 70: 7996
• 24d Diaw AK. D, Yassar A, Gningue-Sall D, Aaron J.-J. ARKIVOC 2008; (xvii): 122
• 24e Just PE, Chane-Ching KI, Lacaze PC. Tetrahedron 2002; 58: 3467
• 25 Cheng Y.-J, Yang S.-H, Hsu C.-S. Chem. Rev. 2009; 109: 5868
• 26 Synthesis of Ethyl 4-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate (5a) – Typical Procedure A mixture of aniline (1 mmol) and ethyl acetoacetate (1 mmol) in EtOH (5 mL) was stirred for 1 h. To this solution 4-hydroxycoumarin (1 mmol) and phenylglyoxal monohydrate (1 mmol) were added, and the resultant mixture was stirred under reflux with progress of reaction being monitored by TLC. After completion of the reaction, the mixture was cooled to r.t., filtered, and the filtrate washed with cold EtOH. The resultant product was pure enough for characterization (88% yield); mp 146–148 °C. IR (KBr): 3161, 2977, 2366, 1694, 1616, 1559, 1538, 1500, 1458, 1370, 1299, 1198, 1174, 1134, 1092, 968, 759, 675, 588, 510 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.77 (br s, 1 H, OH), 7.78 (d, J = 8.0 Hz, 1 H, ArH), 7.58 (t, J = 7.5 Hz, 1 H, ArH), 7.42 (d, J = 8.0 Hz, 1 H, ArH), 7.37 (t, J = 7.0 Hz, 1 H, ArH), 7.33 (d, J = 8.5 Hz, 1 H, ArH), 7.31–7.26 (m, 2 H, ArH), 7.23 (t, J = 8.0 Hz, 2 H, ArH), 7.08–7.03 (m, 3 H, ArH), 6.99 (d, J = 7.5 Hz, 2 H, ArH), 4.02–3.97 (m, 2 H, OCH₂), 2.37 (s, 3 H, CH₃), 0.93 (t, J = 7.5 Hz, 3 H, CH₃). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 164.3, 161.9, 160.3, 152.2, 137.2, 136.8, 133.8, 131.7, 131.2, 129.5, 129.0, 128.2, 127.5, 127.0, 123.7, 123.3, 115.9, 115.8, 111.7, 111.6, 100.9, 58.5, 13.7, 12.6. Anal. Calcd for C₂₉H₂₃NO₅ (465.50): C, 74.83; H, 4.98; N, 3.01. Found: C, 74.80; H, 4.96; N, 3.07. Synthesis of Diethyl 1,1′-(1,4-Phenylene)bis[4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate] (8a) – Typical Procedure A mixture of p-phenylenediamnie (1 mmol) and ethyl acetoacetate (2 mmol) in EtOH (5 mL) was stirred for 1 h. To this solution 4-hydroxycoumarin (2 mmol) and phenyl-glyoxal monohydrate (2 mmol) were added, and the resultant mixture was stirred under reflux conditions, progress of reaction being monitored by TLC. After completion of the reaction, the mixture was cooled to r.t., filtered, and the residue washed with cold EtOH. The resultant product 8a, obtained in 72% yield was pure enough for characterization; mp 259–261 °C. IR (KBr): 3278, 2974, 2345, 1699, 1616, 1517, 1404, 1300, 1265, 1208, 1173, 1093, 1050, 968, 898, 869, 758, 710, 667, 571 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.75 (br s, 2 H, OH), 7.76 (d, J = 6.4 Hz, 2 H, ArH), 7.59–7.55 (m, 2 H, ArH), 734–7.29 (m, 8 H, ArH), 7.06–6.92 (m, 10 H, ArH), 3.99–3.98 (m, 4 H, OCH₂), 2.35 (s, 6 H, CH₃), 0.91 (t, J = 6.8 Hz, 6 H, CH₃). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 164.6, 162.4, 160.7, 152.4, 137.2, 133.9, 132.1, 130.9, 129.5, 127.9, 127.4, 124.0, 123.5, 116.1, 112.2, 111.9, 100.9, 58.9, 13.9, 12.7. Anal. Calcd for C₅₂H₄₀N₂O₁₀ (852.88): C, 73.23; H, 4.73; N, 3.28. Found: C, 73.25; H, 4.77; N, 3.26.