Iodine-Catalyzed [3+2]-Cyclization of Substituted Benzylidenemalononitriles and Ethyl Glycinate Hydrochloride: Direct Access to 5-Amino-1H-pyrrole-2-carboxylates

Abstract

An iodine-catalyzed [3+2]-cycloaddition reaction of substituted benzylidenemalononitriles and ethyl glycinate hydrochloride in DMF has been developed for the synthesis of 5-amino-1H-pyrrole-2-carboxylates. This efficient method provides access to a variety of structurally diverse pyrrole-2-carboxylate derivatives. The structure of a typical product was confirmed by X-ray crystallography.

Key words

[3+2]-cycloaddition - ethyl glycinate hydrochloride - benzylidenemalononitrile - aminopyrrolecarboxylates - aromatization

• References and Notes

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• 28 Ethyl 5-Amino-3-aryl-4-cyano-1H-pyrrole-2-carboxylates 3a–t; General Procedure A mixture of the appropriate benzylidenemalononitrile 1 (1.0 mmol) and I₂ (51 mg, 0.2 mmol) in DMF (25 mL) was heated to 120 °C, and ethyl glycinate hydrochloride (2a; 349 mg, 2.5 mmol) was added. The resulting mixture was stirred at 120 °C for 18–28 h until full conversion of the benzylidenemalononitrile was achieved (TLC; hexanes–EtOAc, 1:1). The mixture was then diluted with H₂O (60 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with H₂O (25 mL) and brine (25 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give a crude product that was purified by column chromatography [silica gel, EtOAc–hexanes (1:1.5)]. Ethyl 5-Amino-4-cyano-3-phenyl-1H-pyrrole-2-carboxylate (3a) Yellow solid; yield: 184 mg (72%); mp 223.2–223.5 °C (PE–EtOAc). IR (KBr): 3690, 3456, 3280, 2977, 2209, 1653, 1596, 1511, 1419, 1362, 1307, 1189, 1155, 1025, 760, 700 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.87 (s, 1 H), 7.45–7.30 (m, 5 H), 6.14 (s, 2 H), 4.06 (q, J = 7.0 Hz, 2 H), 1.11 (t, J = 7.0 Hz, 3 H). ¹³C{¹H} NMR (100 MHz, DMSO-d ₆): δ = 159.8, 149.8, 133.3, 132.7, 130.2, 129.9, 128.0, 116.8, 110.3, 75.8, 59.8, 14.5. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₃N₃NaO₂: 278.0905; found: 278.0899.
• 29 CCDC 1944944 contains the supplementary crystallographic data for compound 3s. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.