Efficient Halogenation of 2-Aminopyrazine

Abstract

2-Aminopyrazine was halogenated with NIS, NCS, and NBS under different reaction conditions. Chlorination and bromination were achieved with good yields by using acetonitrile as the solvent. However, iodination was only obtained in poor yields. Undoubtedly, the best conditions for both mono- and dihalogenation were the use of NBS, acetonitrile, and microwave assistance for short periods. 3,5-Dibromo-2-aminopyrazine is an excellent functionalized starting material for the synthesis of nitrogen heterocycles.

Key words

N-halosuccinimide - 2-aminopyrazine - nitrogen heterocycles - halogenation

• References

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• 18 Halogenation; General ProcedureTo a solution of pyrazine-2-amine (1.0 mmol) in methanol, acetonitrile, dimethylformamide, or lithium diisopropylethylamine (5–10 mL) was added N-iodosuccinimide (NIS) (procedure A) (1.1–3.0 mmol) or I₂ (1.1 mmol) or N-chlorosuccinimide (NCS) (procedure B) or N-bromosuccinimide (NBS) (procedure C) [in the reaction with I₂ also LDA (1.5 mmol) was added]. The reaction mixture was stirred until no starting material could be detected by thin-layer chromatography. Then, the solvent was removed under reduced pressure to give the crude product, which was purified by silica gel column chromatography.Reaction under Microwave Irradiation; General ProcedureTo a solution of the pyrazine-2-amine (1.0 mmol) in acetonitrile (5 mL) in a glass tube (10 mL) sealed with a silicon septum was added N-iodosuccinimide (NIS) (procedure A) (1.1–3.0 mmol) or I₂ (1.1 mmol) or N-chlorosuccinimide (NCS) (procedure B) or N-bromosuccinimide (NBS) (procedure C) (1.1–2.2 mmol) containing magnetic stirring. The tube was introduced to the microwave oven, heated to 100 °C, and subjected to a variable MW power until 300 W (an IR sensor measured the temperature of the glass tube surface) until no starting material could be detected by thin-layer chromatography. Then, the solvent was removed under reduced pressure to give the crude product, which was purified by silica gel column chromatography. Alternatively, the crude reaction mixture can be extracted with diethyl ether/water (3×15 mL), dried with sodium sulfate, filtered, and the solvent can be removed to dryness. Representative product:2-Amino-3,5-dibromopyrazine ¹H NMR (400 MHz, CDCl₃): δ = 5.18 (br s, 2 H, NH₂), 8.04 (s, 1 H, H-6). ¹³C NMR (100.6 MHz, CDCl₃): δ = 123.6 (C3), 124.0 (C5), 143.1 (CH, C6), 151.9 (C2). Mp: 118–120 °C (Lit.^16amp 117–118 °C).