Zinc and Trimethylsilyl Chloride Mediated Synthesis of 2,3,5-Trisubstituted Pyrrole Diesters from Nitriles and Ethyl Bromoacetate

Abstract

An efficient, zinc-mediated, single-pot and CN+3C type pseudo-four-component synthesis of 2,3,5-trisubstituted pyrrole diesters was achieved from readily available aromatic/benzylic/aliphatic nitriles and ethyl bromoacetate under trimethylsilyl chloride catalysis.

Key words

Blaise reaction - pyrroles - tandem processes - pseudo four component

• References and Notes

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• 26 Synthesis of Ethyl 5-(2-Ethoxy-2-oxoethyl)-2-phenyl-1H-pyrrole-3-carboxylate (2a); Typical Procedure: To a slurry of zinc powder (0.96 g, 9.94 mmol) in anhydrous THF (6 mL) under a nitrogen atmosphere, TMSCl (0.26 g, 50 mol% in 1 mL THF) was added and the resulting suspension was heated to reflux for 20 min. To this refluxing slurry of activated zinc, benzonitrile 1a (0.51 g, 4.97 mmol in 1 mL THF) and ethyl bromoacetate (2.51 g, 17.91 mmol) were added simultaneously by using two syringes. Soon after initial addition of the two reactants the reaction mixture became dark green and finally red. The reaction mixture was heated to reflux for 6 h to achieve completion (TLC; EtOAc–hexanes, 20%; R_f = 0.3). The THF was removed under reduced pressure and the resulting mixture was subjected to silica gel column chromatography (EtOAc–hexanes, 20%) to afford 2a (1.35 g, 91%) as a pale-yellow viscous liquid. IR (KBr): 3334, 2930, 2858, 1738, 1702, 1675, 1223, 781 cm^–1. ¹H NMR [400 MHz, CDCl₃ + CCl₄ (1:1)]: δ = 9.48 (s, 1 H), 7.50–7.52 (m, 2 H), 7.26–7.30 (m, 3 H), 6.46–6.46 (d, J = 2 Hz, 1 H), 4.08–4.14 (m, 4 H), 3.55 (s, 2 H), 1.19–1.27 (m, 6 H). ¹³C NMR [100 MHz, CCl₄ + CDCl₃ (1:1)]: δ = 170.7 (C), 164.9 (C), 137.1 (C), 129.1 (2CH), 127.8 (2CH), 123.5 (C), 111.9 (C), 111.1 (CH), 61.1 (CH₂), 59.4 (CH₂), 32.7 (CH₂), 14.2 (CH₃), 14.1 (CH₃). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₄N₂O₃Na: 305.0902; found: 305.0900.