Iodine-Catalyzed One-Pot Multicomponent Synthesis of Pyrrolo/indolo[1,2-a]quinoxalines Substituted with ortho-Carbonyl Alkyl Benzoates/Benzoic Acids via Spirocyclic Ring Opening

Abstract

An efficient iodine-catalyzed cascade coupling protocol was developed for the synthesis of tetracyclic and pentacyclic pyrrolo[1,2-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives via the iodine-mediated oxidative Pictet–Spengler reaction of 2-(1H-pyrrol-1-yl)aniline or 2-(1H-indol-1-yl)aniline with ninhydrin followed by spirocyclic ring opening with alcohol/water. The target compounds were obtained in good-to-excellent yields with a broad substrate scope.

Key words

Pictet–Spengler reaction - spirocyclic ring opening - quinoxalines - cascade coupling - multicomponent synthesis

Publication History

Received: 05 December 2022

Accepted after revision: 03 January 2023

Accepted Manuscript online:
03 January 2023

Article published online:
31 March 2023

• References and Notes

• 1a Guillon J, Mouray E, Moreau S, Mullie C, Forfar I, Desplat V, Belisle-Fabre S, Pinaud N, Ravanello F, Le-Naour A, Leger JM, Gosmann G, Jarry C, Deleris G, Sonnet P, Grellier P. Eur. J. Med. Chem. 2011; 46: 2310
• 1b Guillon J, Le Borgne M, Rimbault C, Moreau S, Savrimoutou S, Pinaud N, Baratin S, Marchivie M, Roche S, Bollacke A, Pecci A, Alvarez L, Desplat V, Jose J. Eur. J. Med. Chem. 2013; 65: 205
• 2a Desplat V, Geneste A, Begorre MA, Fabre SB, Brajot S, Massip S, Thiolat D, Mossalayi D, Jarry C, Guillon J. J. Enzyme Inhib. Med. Chem. 2008; 23: 648
• 2b Desplat V, Moreau S, Gay A, Fabre SB, Thiolat D, Massip S, Macky G, Godde F, Mossalayi D, Jarry C, Guillon J. J. Enzyme Inhib. Med. Chem. 2010; 25: 204
• 2c Guillon J, Grellier P, Labaied M, Sonnet P, Leger JM, Deprez-Poulain R, Forfar-Bares I, Dallemagne P, Lemaitre N, Pehourcq F, Rochette J, Sergheraert C, Jarry C. J. Med. Chem. 2004; 47; 1997
• 2d Maga G, Gemma S, Fattorusso C, Locatelli GA, Butini S, Persico M, Kukreja G, Romano MP, Chiasserini L, Savini L, Novellino E, Nacci V, Spadari S, Campiani G. Biochemistry 2005; 44: 9637
• 3a Tekuri C, Singh DK, Nath M. Dyes and Pigm. 2016; 132: 194
• 3b Carbas BB, Kivrak A, Zora M, Onal AM. Electroanal. Chem. 2012; 677–680: 9
• 3c Carbas BB, Kivrak A, Zora M, Onal AM. React. Funct. Polym. 2011; 71: 579
• 4a Pardeshi SD, Patil BN, Patil P, Chaskar AC. Tetrahedron Lett. 2019; 60: 151250
• 4b Wang X, Liu H, Xie C, Zhou F, Ma C. New J. Chem. 2020; 44: 2465
• 4c Patil BN, Lade JJ, Pardeshi SD, Patil P, Chaskar AC. ChemistrySelect 2019; 4: 11362
• 4d Ni J, Jiang Y, Qi Z, Yan R. Chem. Asian J. 2019; 14: 2898
• 5a Huo HR, Tang XY, Gong YF. Synthesis 2018; 50: 2727
• 5b Liu H, Zhou F, Luo W, Chen Y, Zhang C, Ma C. Org. Biomol. Chem. 2017; 15: 7157
• 5c Lade JJ, Patil BN, Vhatkar MV, Vadagaonkar KS, Chaskar AC. Asian J. Org. Chem. 2017; 6: 1579
• 5d Dai C, Deng S, Zhu Q, Tang X. RSC Adv. 2017; 7: 44132
• 5e An Z, Zhao L, Wu M, Ni J, Qi Z, Yu G, Yan R. Chem. Commun. 2017; 53: 11572
• 6a Kamal A, Babu KS, Kovvuri J, Manasa V, Ravikumar A, Alari A. Tetrahedron Lett. 2015; 56: 7012
• 6b Zhang Z, Xie C, Tan X, Song G, Wen L, Gao H, Ma C. Org. Chem. Front. 2015; 2: 942
• 6c Preetam A, Nath M. RSC Adv. 2015; 5: 21843
• 6d Allan PN. M, Ostrowska MI, Patel B. Synlett 2019; 30: 2148
• 6e Verma AK, Jha RR, Sankar VK, Aggarwal T, Singh RP, Chandra R. Eur. J. Org. Chem. 2011; 2011: 6998
• 7a Yi CS, Yun SY. J. Am. Chem. Soc. 2005; 127: 17000
• 7b Li J, Zhang J, Yang H, Gao Z, Jiang G. J. Org. Chem. 2017; 82: 765
• 7c Rubio-Presa R, Pedrosa MA, Fernández-Rodríguez RM. A, Arnáiz FJ, Sanz R. Org. Lett. 2017; 19: 5470
• 7d Uraguchi D, Sasaki H, Kimura Y, Ito T, Ooi T. J. Am. Chem. Soc. 2018; 140: 2765
• 8a Davies J, Sheikh NS, Leonori D. Angew. Chem. Int. Ed. 2017; 56: 13361
• 8b Xie C, Feng L, Li W, Ma X, Ma X, Liu Y, Ma C. Org. Biomol. Chem. 2016; 14: 8529
• 8c Cai Y, Jalan A, Kubosumi AR, Castle SL. Org. Lett. 2015; 17: 488
• 8d Kulinkovich OG. Chem. Rev. 2003; 103: 2597
• 8e Seiser T, Saget T, Tran DN, Cramer N. Angew. Chem. Int. Ed. 2011; 50: 7740
• 8f Marek I, Masarwa A, Delaye PO, Leibeling M. Angew. Chem. Int. Ed. 2015; 54: 414
• 8g Yao S, Zhang K, Zhou QQ, Zhao Y, Shi DQ, Xiao W. Chem. Commun. 2018; 54: 8096
• 8h Davies J, Sheikh NS, Leonori D. Angew. Chem. Int. Ed. 2017; 56: 13361
• 8i Jiang H, Studer A. Angew. Chem. Int. Ed. 2017; 56: 12273
• 9a Madhubabu MV, Shankar R, More SS, Basaveswara Rao MV, Syam Kumar UK, Raghunadh A. RSC Adv. 2016; 6, 36599
• 9b Raghavendra RK, Ramamohan M, Raghunadh A, Suresh Babu M, Praveen Kumar S, Kalita D, Laxminarayana E, Prasad B, Pal M. RSC Adv. 2015; 5: 61575
• 9c Murthy VN, Nikumbh SP, Praveen Kumar S, Vaikunta Rao L, Raghunadh A. Tetrahedron Lett. 2015; 56: 5767
• 9d Murthy VN, Nikumbh SP, Praveen Kumar S, Chiranjeevi Y, Vaikunta Rao L, Raghunadh A. Synlett 2016; 27: 2362
• 9e Raghunadh A, Krishnaji T, Suresh Babu M, Murthy VN, Vaikunta Rao L, Syam Kumar UK. SynOpen 2020; 4, 55
• 10a Madhava Reddy L, Veerabadra Reddy V, Chandra Shekar P, Vallabhareddy S, Krishna Reddy C, Subba Reddy BV. ChemistrySelect 2018; 3: 9881
• 10b Mandal S, Pramanik A. J. Org. Chem. 2021; 86: 5047
• 11 General procedure for the synthesis of alkyl 2-(pyrrolo/indolo[1,2-a]quinoxaline-4/6 -carbonyl)benzoate derivatives (11/12): To a stirred solution of 1-(2-aminophenyl)pyrrole (3.16 mmol, 1.0 equiv) (7) or 2-(1H-indol-1-yl)aniline (3.16 mmol, 1.0 equiv) (9) in an alcohol (10 mL) was added ninhydrin (3.32 mmol, 1.05 equiv) (8) followed by iodine (10 mol %) at room temperature. The reaction mixture was heated under air to the reflux temperature and then stirred for 5–8 h. After completion of the reaction, the reaction mixture was cooled to room temperature and excess iodine was quenched with saturated aqueous Na₂S₂O₃ solution. The product was extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous Na₂SO₄, and filtered. The solvent was evaporated under vacuum to obtain the crude product, which was further purified by silica gel (60–120 mesh) column chromatography by using a 10–30% ethyl acetate in hexane solvent system to afford the desired compounds. Compound 11b: Yellow solid; yield: 90%; mp 143–145 °C; ¹H NMR (400 MHz, CDCl₃): δ = 8.01–8.00 (m, 2 H), 7.93–7.92 (m, 1 H), 7.83–7.81 (m, 2 H), 7.66–7.57 (m, 4 H), 7.40–7.36 (m, 1 H), 7.04–7.03 (m, 1 H), 3.84 (q, J = 7.2 Hz, 2 H), 0.85 (t, J = 7.2, 6.8 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 195.8, 166.6, 147.9, 140.2, 134.5, 132.0, 131.5, 131.4, 130.0, 129.9, 128.8 (2 C), 127.9, 125.1, 123.5, 115.3, 114.2, 113.6, 109.8, 61.2, 13.5; HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₇N₂O₃: 345.1239; found: 345.1217. Compound 12e: Dark brown solid; yield: 95%; mp 137–139 °C; ¹H NMR (400 MHz, CDCl₃): δ = 8.50–8.44 (m, 2 H), 8.19 (s, 1 H), 8.07 (d, J = 7.6 Hz, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 7.82–7.79 (m, 1 H), 7.70–7.57 (m, 5 H), 7.50–7.46 (m, 1 H), 7.36–7.32 (m, 1 H), 3.84 (t, J = 6.8 Hz, 2 H), 1.26–1.19 (m, 2 H), 1.11–1.03 (m, 2 H), 0.58 (t, J = 7.2 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 195.6, 166.6, 149.7, 140.5, 132.1, 131.9, 131.2, 130.8, 130.1, 130.0, 128.9, 128.8, 124.5, 123.9, 123.4, 122.8, 114.6, 114.3, 103.5, 65.2, 30.2, 18.8, 13.3; HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₃N₂O₃: 423.1709; found: 423.1689.
• 12 General procedure for the synthesis of 2-(pyrrolo/indolo[1,2-a]quinoxaline-4/6-carbonyl)benzoic acid derivatives (14/15): To a stirred solution of 1-(2-aminophenyl)pyrrole (3.16 mmol, 1.0 equiv) (7) or 2-(1H-indol-1-yl)aniline (3.16 mmol, 1.0 equiv) (9) in water (10 mL) was added ninhydrin (3.32 mmol, 1.05 equiv) (8) followed by iodine (10 mol%) at room temperature. The reaction mixture was heated under air to the reflux temperature (100 °C) and then stirred for 4–8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and excess iodine was quenched with saturated aqueous Na₂S₂O₃ solution. The product was extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous Na₂SO₄, and filtered. The solvent was evaporated under vacuum to obtain the crude product, which was further purified by silica gel (60–120 mesh) column chromatography by using a 20–30% ethyl acetate in hexane solvent system to afford the desired products (14a,b and 15a,b) in good yield and purity. Compound 14a: Yellow solid; yield: 80%; mp 213–215 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 13.04 (br s, 1 H), 8.60–8.59 (m, 1 H), 8.36 (d, J = 8.0 Hz, 1 H), 7.95–7.92 (m, 1 H), 7.76–7.64 (m, 4 H), 7.61–7.60 (m, 2 H), 7.49–7.43 (m, 1 H), 7.11–7.09 (m, 1 H); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 195.8, 167.6, 147.9, 140.6, 133.8, 132.1, 131.7, 130.5, 130.3, 130.2, 128.6 (2 C), 127.7, 125.7, 122.8, 116.1, 115.2, 114.9, 109.2; IR (KBr): 3748, 3133, 2920, 1770, 1697, 1675, 1477, 1377, 1276, 1146, 1071, 898, 738, 709, 666 cm^–1; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₃N₂O₃: 317.0926; found: 317.0905.