An Efficient One-Pot, Three-Component Synthesis of Tetrasubstituted Pyrroles under Catalyst- and Solvent-Free Conditions

Gnanaoli Karthiyayini; Deepan Babu Rajkumar; Subbiah Nagarajan; Vellaisamy Sridharan; C. Uma Maheswari

doi:10.1055/a-2113-2981

Synlett, Table of Contents

Synlett 2023; 34(16): 1930-1938
DOI: 10.1055/a-2113-2981

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An Efficient One-Pot, Three-Component Synthesis of Tetrasubstituted Pyrroles under Catalyst- and Solvent-Free Conditions

Gnanaoli Karthiyayini

^aDepartment of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur-613401, India

,

Deepan Babu Rajkumar

^aDepartment of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur-613401, India

,

Subbiah Nagarajan

^bDepartment of Chemistry, National Institute of Technology-Warangal, Warangal-506004, India

,

Vellaisamy Sridharan

^cDepartment of Chemistry and Chemical Sciences, Central University of Jammu, Rahya-Suchani (Bagla), District-Samba, Jammu-181143, J&K, India

,

C. Uma Maheswari∗

^aDepartment of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur-613401, India

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Abstract

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Abstract

An environmentally benign, catalyst- and solvent-free, three-component synthesis of tetrasubstituted pyrroles was established. The reaction proceeds via a nucleophilic attack of primary amine on dialkyl acetylenedicarboxylate followed by Michael addition with β-nitrostyrene and successive intramolecular cyclization and aromatization to yield 1,2,3,4-tetrasubstituted pyrroles in good to excellent yields. A wide range of primary amines including aromatic amines and benzylamines were coupled with differently substituted β-nitrostyrenes and dialkyl acetylenedicarboxylate. Furthermore, compared to previous reported methods, the present study is highly atom economical and environmentally benign and can be scaled up.

Key words

pyrrole - multicomponent reaction - solvent- free - catalyst-free - green synthesis

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References

References and Notes

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21e Santhini PV, Babu SA, Akhil KR, Suresh E, John J. Org. Lett. 2017; 19: 2458 General Procedure for the Synthesis of Tetrasubstituted Pyrrole A mixture of amine (1.2 mmol), dialkyl acetylenedicarboxylate (1.2 mmol), and β-nitro alkene (1.0 mmol) was taken in a reaction vial and stirred at 120 °C for 4–6 h. Progress of the reaction was monitored by TLC. After the completion of the reaction, water was added to the mixture and extracted with ethyl acetate. The extract was washed with brine solution and dried over anhydrous Na₂SO₄. Removal of the solvent under vacuum afforded the crude product, which was purified by column chromatography using hexane/ethyl acetate mixture (90:10). Diethyl 1-(4-Methoxyphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate (4a) Isolated yield 86%, 338 mg, brownish oily liquid. ¹H NMR (600 MHz, CDCl₃): δ = 7.44 (dd, J = 4.2, 0.6 Hz, 2 H), 7.35 (dd, J = 4.2, 3.4 Hz, 2 H), 7.28–7.25 (m, 2 H), 6.94 (d, J = 1.1 Hz, 2 H), 6.93 (s, 1 H), 4.30 (q, J = 3.6 Hz, 2 H), 4.16 (q, J = 3.6 Hz, 2 H), 1.27 (t, J = 3.6 Hz, 2 H), 1.17 (t, J = 3.5 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 166.43, 160.02, 159.57, 133.40, 132.58, 128.56, 127.82, 127.52, 127.10, 126.14, 124.53, 123.47, 121.85, 114.01, 61.38, 60.85, 55.60, 14.13, 14.03. HRMS (ESI): m/z calcd for C₂₃H₂₃NO₅ [M + H]: 393.1576; found: 394.1653. Diethyl 1-Phenethyl-4-phenyl-1H-pyrrole-2,3-dicarboxylate (4u) Isolated yield 51%, 119 mg, white solid; mp 66–68 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.34–7.28 (m, 6 H), 7.25–7.22 (m, 2 H), 7.20–7.16 (m, 2 H), 6.70 (s, 1 H), 4.56–4.47 (m, 2 H), 4.33 (q, J = 3.3 Hz, 2 H), 4.29 (q, J = 3.3 Hz, 2 H), 3.08 (q, J = 3.6 Hz, 2 H), 1.35 (t, J = 3.3 Hz, 3 H), 1.28 (t, J = 3.6 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 166.95, 160.25, 137.98, 133.46, 128.90, 128.62, 128.46, 127.39, 126.77, 126.73, 125.59, 123.27, 122.65, 120.18, 61.26, 60.65, 51.17, 38.17, 14.15, 14.06. HRMS (ESI): m/z calcd for C₂₄H₂₅NO₄ [M + H]⁺: 391.1784; found: 392.1861. Ethyl 2-(4-Methoxyphenyl)-4-oxo-2,4-dihydrochromeno[3,4-c]pyrrole-3-carboxylate (4am′) Isolated yield 68%, 246.8 mg, yellow solid; mp 77–79 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.66 (dt, J = 3.8, 0.4 Hz, 1 H), 7.36–7.33 (m, 3 H), 7.32 (d, J = 4.4 Hz, 2 H), 7.22 (ddd, J = 3.9, 2.7, 1.6 Hz, 1 H), 6.99 (d, J = 4.4 Hz, 2 H), 4.29 (q, J = 3.6 Hz, 2 H), 3.87 (s, 1 H), 1.21 (t, J = 3.6 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 160.09, 159.98, 151.45, 131.97, 128.29, 126.99, 126.70, 124.06, 122.61, 122.27, 118.47, 117.42, 115.68, 114.34, 110.74, 61.93, 55.60, 13.77. HRMS (ESI): m/z calcd for C₂₁H₁₇NO₅ [M + H]⁺: 363.1107; found: 364.1181.

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