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Synlett 2023; 34(13): 1616-1620
DOI: 10.1055/a-2006-4703
letter

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

Gorle Simhachalam
a   Technology Development Centre, APSL, Dr. Reddy’s Laboratories Ltd., Hyderabad 560049, India
b   Department of Chemistry, GIS, GITAM (Deemed to be University), Visakhapatnam 530045, India
,
L. Vaikunta Rao
b   Department of Chemistry, GIS, GITAM (Deemed to be University), Visakhapatnam 530045, India
,
Dasi Samsonu
c   Department of Chemistry, Andhra University, Visakhapatnam 530003, India
,
Akula Raghunadh∗
a   Technology Development Centre, APSL, Dr. Reddy’s Laboratories Ltd., Hyderabad 560049, India
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2006-4703.
  • Supporting Information


Publication History

Received: 05 December 2022

Accepted after revision: 03 January 2023

Accepted Manuscript online:
03 January 2023

Article published online:
31 March 2023

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  • References and Notes

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  • 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.