Versatile Methods for the Synthesis of 2-Amino-6-trifluoromethoxy-(nitro)benzothiazoles

References

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• Domino , E. F. , Una , K. U. and Kerwin , J. 1952 . J Pharmacol. Exp. Ther. , 105 : 486 P. E. Todesco, Sci. Fac. Chim. Ind. Bologna, 23(2–3), 107. Recently antihypoxic and anticonvulsant activities of (+/−)-N-methyl-N-{1-[3-(4-fluoro phenoxy)-2-hydroxypropyl]piperidin-4-yl}benzothiazol-amine (sabeluzole) were reported: G. H. C. Clinke, L. Tritsmans, Psychopharmacology, 1988, 96(3), 486, Drugs of The Future 1988, 13(6), 529 and references cited therein
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• Commercially available from ALFA Products
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• 2-Nitro-4-trifluoromethoxy-benzenethiourea 5 (yellow crystals, m. p. 110°C) was synthesized in low yield (10%) by nitration of 4-trifluoromethoxy-benzenethiourea 14 (cream-coloured solid, m. p. 140°C). The latter was obtained by a two-step Synthesis from 4-trifluorometho-xy-aniline 13 (commercially available from ALDRICH) in 58% overall yield.(a) NH4SCN, C6H5COCl, acetone, rt, 12 hours(b) NaoH(50%), 80°C, 12hours(c) Conc. H2SO4-conc. HNO3, 10°C,10hours51H-NMR (DMSO-d6, 200MHz) δ: 9.8 (m, 1H, NHCS), 8.4–7.6 (m, 2H, NH2), 8.0 (dt, J=2Hz, 1H, H6), 7.7 (ddt, J=8.5 and 2Hz, 1H, H4), 7.9 (dt, J=8.5Hz, 1H, H3). MS (EI) m/z(%): 281(5, M±), 235(100, M-NO2), 176(10), 149(10), 69(10, CF,3+). IR (KBr)v max: 3370,3300 and 3200 (NH), 1650 and 1625 (aromatic benzothiazole ring and NH2), 1525 (NO2), 1355 (NO2), 1325–1125 (C-F and C-O) cm-1
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• Hugerschoff , T. 1903 . Chem. Ber. , 36 : 3121 C. E. Dalgliesh, F. G. Mann, J. Chem. Soc 1945, 893, H. Erlenmeyer, H. Ueberwasser, Helv. Chem. Acta. 1942, 25, 515
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• To our knowledge, few examples were described in the literature: a 2-amino-5-nitro-benzothiazole was prepared in high yields by cyclization of 2,4-dinitrochlorobenzene or 2,4-dinitrophenyl thiocyanate with thiourea in pyridine or ammonium thiocyanate in sulpholane. R. Hamprech, U. S. Patent. 4,808,723, 1989 (Chem. Abstr. 101 211131).b. 2-amino-4-nitro-benzothiazole was prepared by cyclization of 2-nitro-phenylthiourea with sulphur dichloride (S. Claude, R. Tabacchi, L. Duc, J-F. Marrel, Helv. Chem. Acta, 1981, 64(5), 1545) or lead(IV)-phosphate complexe (S. A. Von Mahmoud, S.A. Mohamed, J. Prakt. Chem., 1974, 316(1), 154.c. 2-amino-6-nitro-benzothiazole was prepared by cyclisation of 4-nitro-phenylthiourea with lead(IV)-phosphate complexe (S. A. Von Mahmoud, S. A. Mohamed, J. Prakt. Chem., 1974, 316(1), 154), by reduction of 2.4-dinitro-phenylthiocyanate (J. Schulze, H. Tannerberg, H. Matschiner, Z. Chem., 1980, 20(12), 436) or by direct nitration of 2-benzothiazolamine (See reference 5)
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• Yagupolskii , L. M. and Troitsskaya , V. I. 1961 . J. Gen. Chem. USSR, Engl. Transl. , 31 : 845 W. A. Sheppard, J. Am. Chem. Soc. 1963, 1314
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• The treatment of silylated riluzole 7 with conc.HNO3-conc.H2SO4 at low temperature (O°C, 1 hour) produced a mixture of 2-amino-4,5-dinitro-6-trifluoromethoxy-benzothiazole and 2-amino-4,7-dinitro-6-trifluoromethoxy-benzothiazole with 72% overall yield
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• Colvin , E. W. 1981 . Silicon in Organic Synthesis , 125 – 133 . London : Butterworths . W. P. Weber, “Silicon Reagents for Organic Synthesis”, Springer-Verlag, Berlin, 1983, pp. 114–128, H. Isibashi, H. Sakashita, S. Morita, S. Mitani, Chemistry Letters, 1989,603, G. Felix, J. Dunogues, R. Calas, Angew. Chem. Int. Ed. Engl., 1979, 18(5), 402
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• Another example of a regioselective-ipso-electrophilic-substitution reaction on compound 7, is the action of bromine (glacial acetic acid, 70°C, 3 hours) which produces specifically 2-amino-4-bromo-6-trifluoromethoxy-benzothiazole 6 with 64% yield.
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• a. Hydrolysis of the dilithiated species 8 with dilute HCl produced riluzole quantitatively. b. Under similar conditions (2.5 equivalents of n-butyllithium, -78°C, THF), the metalation of 2-amino-6-bromo-benzothiazole followed by the addition of trimethylchlorosilane afforded 2-amino-6-trimethysilyl-benzothiazole in very low yield (6%, white crystals, m.p. 140°C)
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• In addition, 1% of 2-chloro-5-nitro-6-trifluoromethoxy-benzothiazole was isolated after flash-chromathography [yellow solid, m.p. 125°C, Rf=03 in chloroform-cyclohexane mixture as eluent 35/65, 1H-NMR (CDCl3, 400MHz) δ: 7.9 (q, 5J(H-F) = 1 Hz, 1H, H7), 8.6(s, 1H, H4)]
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• Sheppard , W. 1963 . J. Am. Chem. Soc. , 85 : 1314 This nucleophilic aromatic substitution of the trifluoromethoxy group (which acts as an halogen, see, was activated by the presence of a nitro group in ortho position. The anionic intermediate termed Meisenheimer complex (T. J. Broxton, R. P. T. Chung, J. Org. Chem 1990, 55, 3886 and references cited therein) was stabilized by conjugaison in the benzothiazole ring
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• Barnett , C. Ger. Offen. Patent. DE 2,350,875 . 1974 . (Chem. Abstr. 81 13492)
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• Papenfuhs , T. Ger. Offen. Patent. DE 3,023, 227 . 1980 . (Chem. Abstr. 96 104229)
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• Yagupolskii , L. M. and Ganel'smann , L. Z. 1963 . J. Gen. Chem. USSR, Engl. Transl. , 33 : 2301
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• To prepare the free base, a solution of 6.(HBr) in dichloromethane was treated with 10 equivalents of sodium hydroxide, the free base was obtained after normal work up
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