HETEROCYCLES

Note | Regular issue | Vol. 81, No. 12, 2010, pp. 2841-2847
Received, 21st August, 2010, Accepted, 1st October, 2010, Published online, 4th October, 2010.
DOI: 10.3987/COM-10-12051

■ Iron-Catalyzed One-Pot Synthesis of 2-Aminobenzothiazoles from 2-Aminobenzenethiols and Isothiocyanates under Ligand-Free Conditions in Water

Wenying Wang, Wenying Zhong, Runxia Zhou, Jinsheng Yu, Juan Dai, Qiuping Ding,* and Yiyuan Peng*

College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China

Abstract

A practical and efficient method for the synthesis of 2-aminobenzothiazoles has been developed via an iron-catalyzed one-pot tandem reaction. Various 2-aminobenzothiazoles were conveniently synthesized in moderate to excellent yields. It is highlighted that the reaction is conducted under ligand-free conditions in water.

2-Aminobenzothiazole derivatives are an important class of common heterocyclic compounds that exhibit a wide range of biological activities and medicinal properties. Some 2-aminobenzothiazoles are potential drugs for tuberculosis,1 epilepsy,2 diabetes,3 antitumor (e.g. R116010),4 and glutamate (e.g. Riluzole).5 Due to the importance of 2-aminobenzothiazoles, many synthetic methods have been reported over the last decade. The transition metal-catalyzed intramolecular cyclization of 2-bromophenylthioureas is one of the most efficient methods. 6 One-pot strategies for the synthesis of various useful heterocyclic compounds have been received much attention because of their more convenient manipulations and good efficiencies during the past decade. Recently, 2-aminobenzothiazoles as a significant N- and S-heterocyclic compounds have been reported via one-pot strategies.7 Among the strategies, we described a novel and efficient via Cu(I)-catalyzed one-pot tandem intermolecular addition-intramolecular cyclization reactions to prepare 2-aminobenzothiazole derivatives.7a Subsequently, FeF3 or CuBr-catalyzed one-pot tandem methods were reported by Li and co-workers.7b and 7c Although powerful methods to prepare 2-aminobenzothiazoles have been emerged, the transition metal combined with a ligand and using organic solvent were essential to obtain good result.6,7 From environmental points of view, the development of a cheap and efficient catalyst under ligand-free conditions in aqueous medium is still desirable. As a part of our continuing interest in the use of transition metal-catalyzed one-pot multicomponent tandem cyclization for benz-fused heterocycle synthesis,8 herein we report the successful realization the synthesis of 2-aminobenzothiazoles using ligand-free iron-catalyzed one-pot tandem strategy in water. To the best of our knowledge, there is no report about the formation of 2-aminobenzothiazoles via one-pot iron-catalyzed coupling process under ligand-free conditions in water. Although we recently reported a very efficient method for the synthesis of such compounds via FeCl3-catalyzed tandem reaction of 2-iodoaniline with isothiocyanate in water, 1,10-phenanthroline as ligand was essential to obtain a good result. 8a
Preliminary studies were performed by treatment of 2-aminobenzenethiol 1a and phenyl isothiocyanate 2a in water in the presence of a catalytic amount of various Fe or Cu catalysts (Table 1). To our delight, we found that the desired product 3a could be afforded in 70% yield when Fe2(SO4)3·H2O (10 mol%) was utilized as catalyst under ligand- and base-free conditions (Table 1, entry 1). Blank experiment showed that Fe2(SO4)3·H2O was essential to obtain good result (Table 1, entry 2), although Pazdera reported the similar reaction in organic solvent without catalyst in moderate to good yield.9 The yield (86%) was greatly enhanced in the presence of Na2CO3 (Table 1, entry 3). Several other bases were examined meanwhile, and Na2CO3 showed as the best one. Subsequently, five other Fe salts [Fe(NO3)3·9H2O, FeSO4·7H2O, Fe(NH4)2(SO4)2·H2O, FeCl3 and FeS] and four Cu salts (CuI, CuCl, CuBr, CuO) catalysts were evaluated, and the results showed that Fe(NO3)3·9H2O was the best choice (Table 1, entry 9). Further investigation showed that sodium dodecylbenzenesulfonate (SDBS) as an additive (phase-transfer catalysts) can improve the yield (96%) of product to some extent (Table 1, entry 18). Therefore, the optimized conditions were to use a combination of Fe(NO3)3·9H2O (10 mol%) and SDBS (20 mol%) in the presence of Na2CO3 as base in water at 80 °C.

The scope of the process was studied under the optimized reaction conditions. From Table 2, for most cases, the transformation proceeded smoothly with a wide range of isothiocyanates and 2-aminobenzenethiols leading to the corresponding products 3 in moderate to good yields. As expected, the reaction of 2-aminobenzenethiol 1a and 4-nitrophenyl isothiocyanate 2b gave rise to the desired product 3b in 84% yield (Table 2, entry 2). Similar or better yield was generated when 4-fluorophenyl isothiocyanate 2c or 4-chlorophenyl isothiocyanate 2d was used as a partner in the reaction (Table 2, entries 3 and 4). 4-Methylphenyl isothiocyanate 2e also furnished the corresponding product in good yield using 2-aminobenzethiol 1a (Table 2, entry 5). To our delight, alkyl isothiocyanate was also good substrate for this one-pot tandem reaction in moderate yield (Table 2, entry 6). Methoxy-, bromo- or iodo-substituted 2-aminobenzenethiols 1b, 1c and 1d were examined meanwhile, and the desired products were obtained in moderate to excellent yields (Table 2, entries 7-12).

In conclusion, we have described a practical and efficient route for generation of diverse 2-aminobenzothiazoles via Fe(NO3)3·9H2O-catalyzed one-pot tandem addition/cyclization reaction of 2-aminobenzenethiol and isothiocyanate. It is noteworthy that the reaction is conducted under ligand-free conditions in water. We believe that this methodology may become a very useful tool in organic synthesis.

EXPERIMENTAL
General procedure for Fe(NO3)3·9H2O-catalyzed one-pot tandem reaction of 2-aminobenzenethiol 1 with isothiocyanate 2: A mixture of 2-aminobenzenethiol 1 (0.30 mmol), isothiocyanate 2 (0.36 mmol, 1.2 equiv.), Na2CO3 (0.6 mmol, 2.0 equiv.), Fe(NO3)3·9H2O (0.03 mmol, 10 mol%), SDBS (0.06 mmol, 20 mol%) was stirred in water (3.0 mL) at 80 °C under air. After completion of the reaction as indicated by TLC, the reaction mixture was cooled in ice bath. The solid was filtered off and washed with saturated brine, then washed with water, and dried under vacuum. Then the solid was washed with petroleum ether, and the product 3 was obtained in almost pure form (except for 3b needing to pass through a small plug of silica).
N-Phenylbenzo[d]thiazol-2-amine (3a),7a white solid, mp 158-160 oC; 1H NMR (400 MHz, CDCl3) δ 7.13-7.19 (m, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 8.0 HZ, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1Hz), 9.0 (br, 1H); 13 C NMR (100 MHz, CDCl3) δ 118.7, 119.9, 120.3, 121.9, 123.9, 125.6, 129.1, 129.3, 129.5, 150.7, 164.5.
N-(4-Nitrophenyl)benzo[d]thiazol-2-amine (3b),7a yellow solid, mp 230-231 oC; 1H NMR (400 MHz, DMSO-d6) δ 7.24 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 9.2 Hz, 2H), 8.27 (d, J = 9.2 Hz, 2H), 11.2 (br, 1H); 13C NMR (100 MHz, DMSO-d6) δ 117.6, 120.5, 121.9, 123.7, 125.9, 126.7, 130.8, 141.4, 146.9, 152.0, 161.2. N-(4-Fluorophenyl)benzo[d]thiazol-2-amine (3c),8a white solid, mp 216-217 oC; 1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 8.8 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.77-7.82 (m, 3H), 10.52 (br, 1H); 13C NMR (100 MHz, DMSO-d6) δ 116.0 (d, 2J CF = 22 Hz), 119.7 (d, 2J CF = 18 Hz), 119.8, 121.5, 122.8, 126.3, 130.3, 137.4, 152.4, 157.9 (d, 1J CF = 237 Hz), 162.0.
N-(4-Chlorophenyl)benzo[d]thiazol-2-amine (3d),8a white solid, mp 208-209 oC; 1H NMR (400 MHz, DMSO-d6) δ 7.19 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 119.1, 119.3, 121.0, 122.4, 125.4, 125.9, 128.8, 129.9, 139.5, 151.9, 162.2.
N-p-Tolylbenzo[d]thiazol-2-amine (3e),8a white solid, mp 178-179 oC; 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 7.13 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.9, 119.1, 120.8, 121.2, 122.1, 126.0, 129.8, 130.1, 134.6, 137.4, 151.5, 165.9.
N-Cyclohexylbenzo[d]thiazol-2-amine (3f) 1H NMR (400 MHz, CDCl3) δ 1.18-1.45 (m, 5H), 1.61-1.77 (m, 3H), 2.11-2.13 (m, 3H), 3.5 (br, 1H), 5.79 (br, 1H), 7.05 (t, J = 7.2 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.8, 25.4, 33.2, 54.6, 118.6, 120.7, 121.2, 125.8, 130.3, 152.4, 166.9; HRMS Calcd for C13H17N2S [M+H]+: 233.1112. Found: 233.19.
6-Methoxy-N-phenylbenzo[d]thiazol-2-amine (3g) white solid, mp 131-132 oC; 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 6.91 (dd, J = 2.4, 8.8 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.35 ( t, J = 8.0 Hz, 2H), 7.44 (s, 1H), 7.47 (t, J = 8.8 Hz, 2H), 8.40 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 55.9, 105.3, 114.0, 119.9,120.0, 123.9, 129.4, 131.1, 140.2, 145.8, 155.9, 162.6; HRMS Calcd for C14H13N2OS [M+H]+: 257.0749. Found: 257.0739.
6-Methoxy-N-p-tolylbenzo[d]thiazol-2-amine (3h) white solid, mp 164-165 oC; 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 3.80 (s, 3H), 6.90 (dd, J = 2.4, 8.8 Hz, 1H), 7.12 (d, J = 2.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.33 ( d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 8.35 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 20.2, 55.4, 104.8, 113.3, 119.2, 120.1, 129.5, 130.6, 133.5, 137.1, 145.4, 155.2, 162.9; HRMS Calcd for C15H15N2OS [M+H]+: 271.0905. Found: 271.0909.
N-(4-Chlorophenyl)-6-methoxybenzo[d]thiazol-2-amine (3i) white solid, mp 179-181 oC; 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 6.95 (dd, J = 2.4, 8.8 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.45 ( d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 56.0, 105.3, 114.2, 120.5, 120.6, 128.7, 129.5, 131.4, 138.7, 146.0, 156.3, 161.9; HRMS Calcd for C14H12ClN2OS [M+H]+: 291.0359. Found: 291.0375.
6-Bromo-N-p-tolylbenzo[d]thiazol-2-amine (3j) yellow solid, mp 202-203 oC; 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.40 ( s, 2H), 7.70 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.9, 114.6, 120.3, 121.0, 123.3, 129.3, 130.2, 131.7, 134.9, 136.8, 150.6, 165.5; HRMS Calcd for C14H12BrN2S [M+H]+: m/z 318.9905. Found: 318.9917.
6-Iodo-N-phenylbenzo[d]thiazol-2-amine (3k) white solid, mp 184-186 oC; 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 1.6, 8.4 Hz, 1H), 7.89 ( s, 1H), 8.50 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 120.3, 121.1, 124.7, 129.1, 129.5, 129.6, 135.1, 139.4, 151.8; HRMS Calcd for C13H10IN2S [M+H]+: 352.9609. Found: 352.9615.
N-(4-Chlorophenyl)-6-iodobenzo[d]thiazol-2-amine (3l) white solid, mp 214-215 oC; 1H NMR (400 MHz, DMSO-d6) δ 7.35-7.38 (m, 3H), 7.59 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 10.67 (br, 1H); 13C NMR (100 MHz, DMSO-d6) δ 85.2, 119.3, 121.2, 125.7, 128.8, 129.0, 132.5, 134.5, 139.0, 151.4, 161.6; HRMS Calcd for C13H9ClIN2S [M+H]+: 386.9220. Found: m/z 386.9230.

ACKNOWLEDGEMENTS
Financial supported from National Natural Science Foundation of China (21002042), Natural Science Foundation of Jiangxi Educational Committee (GJJ10387), Jiangxi Province of China (2009GQH0054), and Startup Foundation for Doctors of Jiangxi Normal University (200900266) is gratefully acknowledged.

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