Iodine-Mediated One-Pot Synthesis of 2-(Piperazin-1-yl)pyrazine Derivatives from N-Alkyl Piperazines

Abstract

An iodine-mediated one-pot reaction of N-alkyl piperazines is described for the first time. This transformation provides a straightforward and facile pathway to the synthesis of 2-(piperazin-1-yl)pyrazine derivatives with the corresponding N-alkyl piperazines as single material. Based on a series of control experiments, a plausible reaction mechanism has been proposed.

Key words

iodine - sodium acetate - one-pot reaction - 2-(piperazin-1-yl)pyrazine - N-alkyl piperazine

• References and Notes

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• 18 Experimental Procedures and Characterization Data; General Procedure for the Synthesis of Compound 2: To a solution of substrate 1 (10 mmol) in MeCN (20 mL), iodine (5.1 g, 20 mmol) and NaOAc (3.3g, 40 mmol) were carefully added. The reaction mixture was stirred at 70 °C and monitored by TLC. After completion of the reaction, the mixture was cooled and concentrated to provide the crude product which was purified by recrystallization from EtOH or by column chromatography using basic alumina. 2-(4-Benzylpiperazin-1-yl)pyrazine (2a): the product was obtained by recrystallization from EtOH as a white solid (1.13 g). Yield: 89%; mp 85–87 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.30 (d, J = 1.5 Hz, 1 H), 8.07 (dd, J = 2.7, 1.5 Hz, 1 H), 7.83 (d, J = 2.6 Hz, 1 H), 7.32–7.39 (m, 4 H), 7.23–7.29 (m, 1 H), 3.53–3.58 (m, 4 H), 3.52 (s, 2 H), 2.43–2.48 (m, 4 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 155.13, 141.90, 138.38, 132.88, 131.77, 129.37, 128.68, 127.48, 62.49, 52.60, 44.43. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₉N₄: 255.1604; found: 255.1614.