Synlett, Table of Contents Synlett 2019; 30(17): 2000-2003DOI: 10.1055/s-0039-1690183 letter © Georg Thieme Verlag Stuttgart · New YorkEfficient Halogenation of 2-Aminopyrazine Enric Lizano , Josep Grima , M. Dolors Pujol∗ Laboratori de Química Farmacèutica, Facultat de Farmàcia i Ciències de l’Alimentació, University of Barcelona, Campus Diagonal, Av. Joan XXIII, 27–31, 08028 Barcelona, Spain Email: mdpujol@ub.edu› Author AffiliationsRecommend Article Abstract Buy Article All articles of this category 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 Key words N-halosuccinimide - 2-aminopyrazine - nitrogen heterocycles - halogenation Full Text References References 1 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257 2a Trump DL, Payne H, Miller K, Bono JS, Stephenson J, Burris HA, Nathan F, Taboada M, Morris T, Hubner A. Prostate 2011; 71: 1264 2b Lida K, Itoh K, Kumagai Y, Oyasu R, Hattori K, Kawai K, Shimazui T, Akaza H, Yamamoto M. Cancer Res. 2004; 64: 6424 3 Revill P, Serradell N, Bolos J, Rosa E. Drugs Future 2007; 32: 788 4 Da Silva YK, Augusto CV, de Castro Barbosa ML, de Albuquerque melo GM, de Queiroz AC, de Lima Matos Freire Dias T, Junior WB, Barreiro EJ, Alezxandre-Moreira MS. Bioorg. Med. 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R.S.C. Adv. 2014; 4: 9885 17 Caldwell JJ, Veillard N, Collins I. Tetrahedron 2012; 68: 9713 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). Supplementary Material Supplementary Material Supporting Information