Catalyst-Free Tandem Ring-Opening/Click Reaction of Acetylene-Bearing Donor–Acceptor Cyclopropanes

Abstract

Cyclopropane-1,1-hemimalonates bearing a 2-(2-alkynylphenyl) moiety underwent ring opening by an azide nucleophile, generating an alkyl azide that, in turn, underwent [3+2]-dipolar cycloaddition with the alkyne. The products are novel linearly fused tricyclic 1,2,3-triazoles.

Key words

heterocycles - cycloaddition - cyclopropanes - triazole - click chemistry

• References and Notes


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• 11 Synthesis of Triazoles 8a–h; General Procedure: Cyclopropane hemimalonate 18a–h (1 equiv) was dissolved in a solution of 2-methoxyethanol–H₂O (10:1) and then NaN₃ (1.2 equiv) and NH₄Cl (1.4 equiv) were added. The mixture was heated to reflux and the reaction was monitored by TLC analysis until completion (1.5–2 h). The reaction mixture was then cooled to room temperature, and H₂O was added. The reaction was extracted three times with Et₂O. The organic layers were combined and dried with MgSO₄, filtered, and the solvent was removed. The residue was purified by flash column chromatography (EtOAc–hexanes) to yield the desired triazole 8a–h.Methyl 3-(8H-[1,2,3]Triazolo[5,1-a]isoindol-8-yl)-propanoate (8a): Synthesized from 2-(2-ethynylphenyl)-1-(methoxycarbonyl)cyclopropanecarboxylic acid (18a; 0.080 g, 0.328 mmol), NaN₃ (0.026 g, 0.394 mmol), NH₄Cl (0.025 g, 0.459 mmol), 2-methoxyethanol–H₂O. Yield: 0.064 g (0.263 mmol, 80%); clear oil; R_f = 0.12 (EtOAc–hexanes, 30%). IR (thin film): 3136, 3057, 2998, 2951, 2850, 1734, 1624, 1471, 1437, 1416, 1379, 1245, 1205, 1094 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 7.82 (s, 1 H), 7.63 (d, J = 7.0 Hz, 1 H), 7.50–7.40 (m, 3 H), 5.54 (dd, J = 7.8, 3.9 Hz, 1 H), 3.64 (s, 3 H), 2.81–2.73 (m, 1 H), 2.60–2.52 (m, 1 H), 2.47–2.40 (m, 1 H), 2.29–2.20 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.8, 144.8, 129.1, 128.6, 127.1, 124.3, 123.8, 121.7, 61.9, 51.8, 28.8, 28.5. HRMS (EI): m/z calcd for C₁₃H₁₃N₃O₂: 243.1008; found: 243.1006.