A Novel Synthesis of Tetrasubstituted Pyrroles via Tandem Benzylic Oxidative Cyclization

Abstract

A new method for the synthesis of tetrasubstituted pyrroles from a domino reaction between primary benzylamines and dialkyl acetylenedicarboxylates, in the presence of potassium cyanide without using a metal or oxidant, is described.

Key words

pyrrole - acetylenic ester - primary benzylamine - potassium cyanide

• References and Notes

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• 34 General Procedure for the Synthesis of Compounds 3 To a stirred solution of amine 1 (1 mmol) and acetylenic ester 2 (2 mmol) in MeCN (5 mL) was added KCN (1 mmol) at r.t. After completion of the reaction [about 24 h; TLC (EtOAc–hexane, 1:5) monitoring], the solvent was evaporated, and the residue was purified by column chromatography [silica gel (230–400 mesh; Merck); EtOAc–hexane, 1:5] to give pure product. Trimethyl 5-Phenyl-1H-pyrrole-2,3,4-tricarboxylate (3a) Pale yellow oil; yield 0.19 g (61%). IR (KBr): 3421, 3000, 1728, 1610 cm^–1. ¹H NMR (500.1 MHz, CDCl₃): δ = 3.76, 3.79, 4.04 (9 H, s, 3 MeO), 7.45–7.47 (3 H, m, CH), 7.06 (2 H, d, ³ J = 7.8 Hz, CH), 9.24 (1 H, br s, NH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 51.5, 52.3, 52.7 (3 MeO), 122.4 (C), 126.3 (C), 128.3 (2 CH), 128.6 (C), 129.9 (2 CH), 129.6 (CH), 131.9 (C), 142.6 (C), 161.7 (C=O), 164.9 (C=O), 167.8 (C=O) ppm. MS (EI): m/z (%) = 317 (3) [M⁺], 302 (4), 258 (23), 91 (14), 77 (6), 59 (7). Anal. Calcd for C₁₆H₁₅NO₆ (317.29): C, 60.57; H, 4.56; N, 4.41. Found: C, 60. 75; H, 4.52; N, 4.47. General Procedure for the Synthesis of Compounds 5 To a stirred solution of 4-methylbenzylamine (1b, 1 mmol), DMAD (1 mmol), and methyl propiolate (4a, 1 mmol) in MeCN (5 mL) was added KCN (1 mmol) at r.t. After completion of the reaction [about 24 h; TLC (EtOAc–hexane, 1:5) monitoring], the solvent was evaporated, and the residue was purified by column chromatography [silica gel (230–400 mesh; Merck); EtOAc–hexane, 1:5] to give pure product. Dimethyl 2-{[(E)-3-Methoxy-3-oxoprop-1-enyl](4-methylbenzyl)amino}maleate (5a) Pale yellow powder; mp 94–96 °C; yield 0.22 g (63%). IR (KBr): 3415, 2952, 1712, 1590 cm^–1. ¹H NMR (500.1 MHz, CDCl₃): δ = 2.36 (3 H, s, Me), 3.62, 3.67, 4.02 (9 H, s, MeO), 4.83 (2 H, s, CH₂N), 5.17 (1 H, d, ³ J = 13.3 Hz, CH), 5.24 (1 H, s, CH), 7.03 (2 H, d, ³ J = 7.8 Hz, CH), 7.16 (2 H, t, ³ J = 7.8 Hz, CH), 7.59 (2 H, t, ³ J = 13.3 Hz, CH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 21.0 (Me), 51.1 (CH₂N), 51.5, 51.6, 53.4 (3 MeO), 97.1 (CH), 98.8 (CH), 125.7 (2 CH), 129.8 (2 CH), 130.0 (C), 137.7 (C), 143.4 (CH), 150.1 (C), 164.4 (C=O), 166.2 (C=O), 167.5 (C=O) ppm. MS (EI): m/z (%) = 347 (3) [M⁺], 332 (8), 288 (11), 105 (25), 77 (13), 59 (7). Anal. Calcd for C₁₈H₂₁NO₆ (347.36): C, 62.24; H, 6.09; N, 4.03. Found: C, 62.51; H, 6.14; N, 4.08.
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