Highly Efficient Synthesis of Polysubstituted 2-Aminopyrroles via a Multicomponent Domino Reaction

Abstract

A highly efficient approach to polysubstituted 2-amino­pyrroles containing a coumarin derivative unit at the 5-position of the pyrrole ring was developed via a novel multicomponent domino reaction of glyoxal monohydrate derivatives, anilines, coumarin derivatives, and malononitrile. This transformation proceeded via an α-amino­ketone as the key intermediate.

Key words

2-aminopyrroles - domino reaction - multicomponent reaction - coumarin derivatives - heterocycles

• References and Notes

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• 12 General Procedure of 2a–y A mixture of glyoxal monohydrate derivative (0.5 mmol, 1.0 equiv), coumarin derivative (0.5 mmol, 1.0 equiv), and amine (0.5 mmol, 1.0 equiv) were stirred in DCE (3 mL) at rt for 15 min. Then, malononitrile (0.5 mmol, 1.0 equiv) and Et₃N (0.5 mmol, 1.0 equiv) were added to the mixture and the reaction was stirred for another 8 h under N₂. After the reaction was complete, the mixture was diluted with DCM (10 mL). The mixture was then washed with H₂O (5 mL). The organic extracts were collected and concentrated. Purification of the crude product was carried out by chromatography (silica gel, MeOH/DCM = 1:30) to afford 2a–y as the desired products. 2-Amino-5-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1-isobutyl-4-(p-tolyl)-1H-pyrrole-3-carbonitrile (2a) Pale yellow solid, 164 mg, 79% yield; mp 231.7–233.4 °C. ¹H NMR (500 MHz, CD₃OD): δ = 7.87 (dd, J = 8.0, 1.3 Hz, 1 H), 7.68–7.60 (m, 1 H), 7.39–7.31 (m, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 3.45 (qd, J = 14.8, 7.6 Hz, 2 H), 2.23 (s, 3 H), 1.91 (dt, J = 13.7, 7.0 Hz, 1 H), 0.86 (d, J = 6.7 Hz, 3 H), 0.81 (d, J = 6.7 Hz, 3 H). ¹³C NMR (125 MHz, CD₃OD): δ = 165.68, 163.96, 153.27, 149.26, 136.23, 132.97, 130.61, 128.50, 127.47, 124.99, 124.16, 123.86, 118.11, 116.20, 115.44, 111.76, 96.18, 72.19, 50.48, 28.70, 19.77, 18.93, 18.78. HRMS (ESI): m/z calcd for C₂₅H₂₄N₃O₃[M + H]⁺: 414.1812; found: 414.1812.