HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 11, 2011, pp. 2589-2596
Received, 21st July, 2011, Accepted, 30th August, 2011, Published online, 7th September, 2011.
DOI: 10.3987/COM-11-12311

■ One-Pot Synthesis of Benzothiazol-2-amines by Cyclization of the Adducts between 2-Iodophenyl Isothiocyanates and Amines under Metal-Free Conditions

Kazuhiro Kobayashi,* Akihiro Kobayashi, Kazuya Murahashi, and Shuhei Fukamachi

Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A convenient one-pot procedure for the preparation of N-substituted and N,N-disubstituted benzothiazol-2-amines under metal-free conditions has been developed, which employs the reaction of 2-iodophenyl isothiocyanates with primary and secondary amines followed by cyclization of the resulting thiourea precursors on treatment with triethylamine under relatively mild reaction conditions (< 70 ˚C). The reactions using diamines, such as ethylenediamines or trimethylenediamine, under similar conditions, albeit at higher temperature (130 ˚C), have proved to enable us to obtain N,N’-bis(benzothiazol-2-yl)ethane(or propane)diamines.

Benzothiazol-2-amine derivatives are an important class of heterocycles, because a number of molecules having this skeleton have been shown to exhibit a variety of biological activities.1 Therefore, there are many procedures available to prepare this type of compounds.2,3 The most facile method for the preparation of these derivatives is based on the substitution of 2-chlorobenzothiazole with amines.4 Recently, Batey’s group has demonstrated that the synthesis of N-substituted and N,N-disubstituted benzothiazol-2-amines can be achieved efficiently by using a transition metal [Pd(PPh3)4 or CuI] catalyzed intramolecular cyclization of 1-(di)alkylamino-3-(2-iodo(or bromo)phenyl)thioureas, prepared mainly by the addition of 2-iodo(or bromo)phenyl isothiocyanates with primary and secondary amines, at a relative higher temperature (80 ˚C).2a Later, one-pot preparation of N-arylbenzothiazol-2-amines by CuBr catalyzed cyclization of the adducts between 2-iodobenzenamines and aryl isothiocyanates has been reported Li et al.2d Now we wish to describe a convenient procedure for the synthesis of N-substituted and N,N-disubstituted benzothiazol-2-amines (3) from 2-iodophenyl isothiocyanates (1) and primary or secondary amines under metal-free5 and mild conditions.6 After completion of this work, we were aware of a report by Liu et al., which demonstrated that benzothiazol-2-amine derivatives could be obtained by treating N’-substituted-N-(2-halophenyl)thioureas with two equivalents of Cs2CO3 in dioxane at 130 ˚C.7 Our new procedure has been applied to one-pot preparation of N,N’-bis(benzothiazol-2-yl)ethane(or propane)diamines (5) by using ethylenediamines and trimethylenediamine. N,N’-Bis(benzothiazol-2-yl)ethanediamines have recently be prepared by the reaction of 2-chlorobenzothiazoles with ethylenediamines and some of these derivatives have been reported to exhibit high binding affinity to β-amiloyd fibrils.8

The starting 2-iodophenyl isothiocyanates (1) were readily available; 2-iodophenyl isothiocyanate (1a) was commercially available and 4-chloro- (1b) and 4-bromo-2-iodophenyl isothiocyanates (1c) could be prepared from the respective commercially available 2-iodoanilines in good yields utilizing previously reported procedures9-11 as described in EXPERIMENTAL. Conversion of 1 into the desired N-substituted and N,N-disubstituted benzothiazol-2-amines (3) was carried out according to the procedure illustrated in Scheme 1. Thus, compounds (1) were allowed to react with primary and secondary amines in DMF at room temperature to result in the immediate formation of the corresponding 1-(2-iodophenyl)thiourea derivatives (2). On treatment with an equimolar amount of Et3N and an additional stirring of the reaction mixture at the temperatures indicated in Table 1, these precursors cleanly underwent cyclization by intramolecular substitution of the sulfur atom of the thiourea moiety for the 2-iodo group to provide, after usual aqueous workup and the subsequent purification of the crude products by recrystallization or column chromatography on silica gel, the desired benzothiazol-2-amines (3) in generally good yields as summarized in Table 1. It indicates that the use of an aromatic amine, such as aniline, requires a rather extended reaction time (Entry 4). The ease of cyclization in the present method compared to other metal-free methods may be ascribed to the use of DMF as a solvent.

With the above-mentioned results in hand, the reaction of 2-iodophenyl isothiocyanates (1) with diamines, such as ethylenediamines and trimethylenediamine, was then explored in order to develop a procedure obtaining N,N’-bis(benzothiazol-2-yl)ethane(or propane)diamines (5). The initial experiment using 2-iodophenyl isothiocyanate (1a) (two molar amounts) and N,N’-dimethylethylenediamine was conducted under similar conditions as for the preparation of (3). Unfortunately, however, the cyclization of two thiazole rings producing the desired product (5a) could not be accomplished even by heating at 70˚, while the addition of the diamine to isothiocyanate giving the adduct 4a occurred immediately at room temperature. However, we were delighted to observe that, when the mixtures of 1 and diamines were heated at 130˚ as depicted in Scheme 2, the desired products (5) could be obtained in moderate to fair yields as summarized in Table 2. It should be noted that an attempted use of p-phenylenediamine as a diamine under similar conditions resulted in the formation of a complicated mixture of the products.
In conclusion, the results detailed herein demonstrate that N-substituted or N,N-disubstituted benzothiazol-2-amines (3) can be conveniently prepared in one pot from 2-iodophenyl isothiocyanates and primary or secondary amines. The present method may be of value in organic synthesis because of its advantages over previous similar methods: i) unnecessity of any metal catalysts, ii) mild reaction conditions, iii) use of a cheap organic base, iv) simplicity of the procedure, v) easy availability of the starting materials, and vi) applicability to the synthesis of N,N’-bis(benzothiazol-2-yl)alkane-1,ω- diamines.

EXPERIMENTAL
The melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were recorded with a Perkin-Elmer Spectrum65 FTIR spectrophotometer. The 1H NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz. The 13C NMR spectra were recorded using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz. Low-resolution MS spectra (EI, 70 eV) were measured by a JEOL JMS AX505 HA spectrometer. TLC was carried out on a Merck Kieselgel 60 PF254. Column chromatography was performed using WAKO GEL C-200E. All of the organic solvents used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. N-(4-Chloro-2-iodophenyl)formamide was prepared by the procedure reported previously by us.10 All other chemicals used in this study were commercially available.
N-(4-Bromo-2-iodophenyl)formamide. This compound was prepared by N-formylation of 4-bromo-2-iodoaniline with HCO2H under the conditions reported previously by us;10 yield: 73%; a pale-yellow solid; mp 158–160 ˚C (hexane–AcOEt); IR (KBr) 3229, 1654 cm–1; 1H NMR δ 7.08–8.64 (m, 5H). Anal. Calcd for C7H5BrINO: C, 25.80; H, 1.55; N, 4.30. Found: C, 25.50; H, 1.54; N 4.19.
1-Chloro-3-iodo-4-isothiocyanatobenzene (1b). N-(4-Chloro-2-iodophenyl)formamide (1.8 g, 6.5 mmol) was dissolved in THF (20 mL) and to this solution at 0 ˚C was added Et3N (4.6 g, 46 mmol) and POCl3 (1.4 g, 9.2 mmol) under stirring.11 After 5 min, saturated aqueous NaHCO3 (20 mL) was added and the mixture was extracted with Et2O (3 × 20 mL). The combined extracts were washed with saturated aqueous NaHCO3 (20 mL) and then brine (20 mL), and dried over anhydrous K2CO3. Evaporation of the solvent gave a crude 1-chloro-3-iodo-4-isocyanobenzene (1.5 g) as a yellow solid; mp 85–88 ˚C (decomp); IR (KBr) 2129 cm–1; 1H NMR δ 7.34 (d, J = 8.7 Hz, 1H), 7.37 (dd, J = 8.2, 1.8 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H). This isocyanide was used in the next step without any purification. Thus, a mixture of this isocyanide in THF (15 mL) containing Et3N (1.4 g, 14 mmol), sulfur (21 mg, 6.7 mmol), and selenium (13 mg, 0.17 mmol) was stirred for 2 h at rt.9 After concentration of the mixture by evaporation, the residue was subjected to column chromatography on silica gel (hexane) to give the crude product, which was purified by recrystallization to give pure 1b (1.4 g, 89%); colorless needles; mp 65–67 ˚C (pentane). IR (KBr) 2085 cm–1; 1H NMR δ 7.18 (d, J = 8.7 Hz, 1H), 7.31 (dd, J = 8.7, 2.3 Hz, 1 H), 7.80 (d, J = 2.3 Hz, 1H). Anal. Calcd for C7H3ClINS: C, 28.45; H, 1.02; N, 4.74. Found: C, 28.38; H, 1.08; N, 4.78.
1-Bromo-3-iodo-4-isothiocyanatobenzene (1c). This compound was prepared from N-(4-bromo-2- iodophenyl)formamide in a manner similar to that described for the preparation of 1b, via 1-bromo-3-iodo-4-isocyanobenzene [a pale-yellow solid; mp 90–95 ˚C; IR (KBr) 2128 cm–1; 1H NMR δ 7.28 (d, J = 8.2 Hz, 1H), 7.52 (dd, J = 8.2, 1.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H)], in 88% yield. A white solid; mp 81–84 ˚C (hexane); IR (KBr): 2083 cm–1; 1H NMR δ 7.12 (d, J = 8.2 Hz, 1H), 7.45 (dd, J = 8.2, 1.8 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H). Anal. Calcd for C7H3BrINS: C, 24.73; H, 0.89; N, 4.12. Found: C, 24.67; H, 0.92; N, 3.86.
General Procedure for the Preparation of Benzothiazol-2-amines (3). To a stirred solution of 1 (1.0 mmol) in DMF (5 mL) at rt was added an amine (1.0 mmol). After 5 min, Et3N (0.10 g, 1.0 mmol) was added and the mixture was then stirred under the conditions indicated in Table 1. Water (20 mL) was added and the mixture was extracted with AcOEt (3 × 10 mL). The combined extracts were washed with water (3 × 10 mL) and brine (10 mL), and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by recrystallization or column chromatography on silica gel to give 3.
N-Benzylbenzothiazol-2-amine (3a): A white solid; mp 165–167 ˚C (hexane–CH2Cl2) (lit.,12 mp 166–167 ˚C). The spectral (IR, 1H NMR, and 13C NMR) data were identical to those reported previously.4
2-(Pyrrolidin-1-yl)benzothiazole (3b): a white solid; mp 99–102 ˚C (hexane-CH2Cl2) (lit.,3a mp 101–103 ˚C). The 1H NMR data were identical to those reported previously.3a
N-Benzyl-N-isopropylbenzothiazol-2-amine (3c): a colorless oil. Rf 0.55 (THF–hexane 1:4); IR (neat) 1595, 1526 cm–1; 1H NMR δ 1.27 (d, J = 6.9 Hz, 6H), 4.65 (sept, J = 6.9, 1H), 4.71 (s, 2H), 7.04 (t, J = 7.3, 1H), 7.22–7.35 (m, 6H), 7.55 (dd, J = 8.2, 1.4 Hz, 2H); 13C-NMR (CDCl3) δ 20.38, 49.40, 52.33, 118.85, 120.49, 120.92, 125.80, 126.78, 127.10, 128.50, 130.64, 138.30, 152.80, 168.78; MS m/z 282 (47, M+), 239 (100). Anal. Calcd for C17H18N2S: C, 72.30; H, 6.42; N, 9.92. Found: C, 72.13; H, 6.47; N, 9.86.
6-Chloro-N-phenylbenzothiazol-2-amine (3d): a white solid; mp 196–198 ˚C (hexane–Et2O) (lit.,13 mp 198–200 ˚C); IR (KBr) 3237, 1624 1603, 1568 cm–1; 1H NMR δ 7.18 (t, J = 7.3 Hz, 1H), 7.29 (dd, J = 8.2, 1.8 Hz, 1H), 7.41 (dd, J = 8.2, 7.3 Hz, 2H), 7.48–7.50 (m, 3H), 7.59 (d, J = 1.8, Hz, 1H), 8.08 (br s, 1H).
2-[N-(6-Chlorobenzothiazol-2-yl)-N-methylamino]ethanol (3e): a white solid; mp 111–113 ˚C (hexane–Et2O); IR (KBr) 3374, 1597, 1541 cm–1; 1H NMR δ 3.22 (s, 3H), 3.63 (br s, 1H), 3.78 (t, J = 5.0 Hz, 2H), 3.92–3.95 (m, 2H), 7.24 (dd, J = 8.7, 1.8 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H); 13C-NMR (CDCl3) δ 40.21, 55.81, 61.46, 119.36, 120.31, 126.32, 126.49, 131.86, 151.02, 169.64; MS m/z 242 (100, M+). Anal. Calcd for C10H11ClN2OS: C, 49.48; H, 4.57; N, 11.54. Found: C, 49.31; H, 4.61; N, 11.32.
6-Bromo-N,N-diethylbenzothiazole-2-amine (3f): a pale-yellow solid; mp 43–44 ˚C (hexane); IR (KBr) 1595, 1539 cm–1; 1H NMR δ 1.28 (t, J = 7.3 Hz, 6H), 3.56 (q, J = 7.3 Hz, 4H), 7.35 (dd, J = 8.7, 1.8 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H); 13C NMR (CDCl3) δ 12.80, 45.46, 112.79, 119.59, 122.91, 128.92, 132.34, 152.31, 167.41; MS m/z 284 (33, M+), 255 (100). Anal. Calcd for C11H13BrN2S: C, 46.32; H, 4.59; N 9.82. Found: C, 46.46; H, 4.60; N 9.85.

6-Bromo-2-(morpholin-4-yl)benzothiazole (3g): a beige solid; mp 161–163 ˚C (hexane); IR (KBr) 1591, 1535 cm–1; 1H NMR δ 3.61 (t, J = 5.0 Hz, 4H); 3.83 (t, J = 5.0 Hz, 4H), 7.40 (s, 2H), 7.72 (s, 1H); 13C NMR (CDCl3) δ 48.42, 66.16, 113.95, 120.38, 123.23, 129.31, 132.23, 151.51, 168.99; MS m/z 298 (100, M+). Anal. Calcd for C11H11BrN2OS: C, 44.16; H, 3.71; N, 9.36. Found: C, 43.94; H, 3.71; N, 9.31.
General Procedure for the Preparation of N,N’-Bis(benzothiazol-2-yl)alkane-1,ω-diamines (5). To a stirred solution of 1 (1.0 mmol) in DMF (4 mL) was added a diamine (0.50 mmol) at rt. After 5 min, Et3N (0.11 g, 1.1 mmol) was added and the mixture was heated at 130 ˚C for the time indicated in Table 2 under stirring. Water (15 mL) was added and the mixture was extracted with AcOEt (3 × 10 mL). The combined extracts were washed with H2O (3 × 10 mL) and brine (10 mL), and dried over anhydrous Na2SO4. After evaporation of the solvent the residue was purified by recrystallization or column chromatography on silica gel to give 5.
N,N’-Bis(benzothiazol-2-yl)-N,N’-dimethylethane-1,2-diamines (5a): colorless needles; mp 173–175 ˚C (hexane–CH2Cl2). The 1H-NMR data for this product were identical to those reported previously.7
N,N’-Bis(benzothiazol-2-yl)propane-1,3-diamines (5b): a white solid; mp 188–190 ˚C (hexane–CHCl3); IR (KBr) 3225, 1610, 1574, 1433 cm­–1; 1H NMR δ 2.01 (quint, J = 6.0 Hz, 2H), 3.65 (t, J = 6.0 Hz, 4H), 6.22 (s, 2H), 7.09 (ddd, J = 7.8, 7.3, 1.4 Hz, 2H), 7.30 (ddd, J = 7.8, 7.3, 1.4 Hz, 2H), 7.57 (dd, J = 7.8, 1.4 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H); 13C NMR (CDCl3) δ 29.80, 41.64, 118.91, 120.77, 121.72, 125.97, 130.38, 152.32, 167.16; MS m/z 340 (38, M+), 191 (100). Anal. Calcd for C17H16N4S2: C, 59.97; H, 4.74; N, 16.46. Found: C, 59.86; H, 4.80; N, 16.32.
N,N’-Bis(6-chlorobenzothiazol-2-yl)-N-methylethane-1,2-diamines (5c): a pale-yellow solid; mp 201–204 ˚C (hexane–CH2Cl2); IR (KBr) 3223, 1614, 1597, 1449 cm­–1; 1H NMR δ 3.20 (s, 3H), 3.82 (br s, 2H), 3.96 (t, J = 5.5 Hz, 2H), 6.44 (br s, 1H), 7.23 (dd, J = 8.7, 2.3 Hz, 1H), 7.28 (dd, J = 8.7, 2.3 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H); 13C NMR (CDCl3) δ 39.66, 43.91, 51.72, 119.48, 119.62, 120.45 (two overlapped C’s), 126.35, 126.53, 126.65, 126.86, 131.80, 132.02, 151.16, 151.19, 166.59, 169.43; MS m/z 408 (37, M+), 224 (100). Anal. Calcd for C17H14Cl2N4S2: C, 49.88; H, 3.45; N, 13.69. Found: C, 49.80; H, 3.40; N, 13.79.
N,N’-Bis(6-chlorobenzothiazol-2-yl)-N,N’-diethylethane-1,2-diamines (5d): A beige solid; mp 157–158 ˚C (hexane–CHCl3); IR (KBr) 1597, 1541, 1442 cm­–1; 1H NMR δ 1.29 (t, J = 7.3 Hz, 6H), 3.54 (q, J = 7.3 Hz, 4H), 3.87 (s, 4H), 7.24 (dd, J = 8.7, 2.3 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 2.3 Hz, 2H); 13C-NMR (CDCl3) δ 12.77, 47.68, 47.84, 119.43, 120.30, 126.10, 126.32, 131.98, 151.77, 167.35; MS m/z 450 (27, M+), 252 (100). Anal. Calcd for C20H20Cl2N4S2: C, 53.21; H, 4.47; N, 12.41. Found: C, 53.14; H, 4.62; N, 12.37.
N,N’-Bis(6-chlorobenzothiazol-2-yl)propane-1,3-diamines (5e): a pale-yellow solid; mp 219–220 ˚C (hexane–CHCl3); IR (KBr: 3215, 1605, 1556, 1430 cm­–1; 1H NMR δ 2.01 (quint, J = 6.0 Hz, 2H), 3.65 (br s, 4H), 6.14 (br s, 2H), 7.26 (dd, J = 8.2, 2.3 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 2.3 Hz, 2H); 13CNMR (DMSO-d6) δ 28.26, 41.64, 118.77, 120.58, 124.56, 125.63, 131.92, 151.46, 166.67; MS m/z 408 (79, M+), 238 (100). Anal. Calcd for C17H14Cl2N4S2: C, 49.88; H, 3.45; N, 13.69. Found: C, 49.60; H, 3.43; N, 13.62.
N,N’-Bis(6-bromobenzothiazol-2-yl)-N,N’-diethylethane-1,2-diamines (5f): a beige solid; mp 155–157 ˚C (hexane–CHCl3); IR (KBr) 1593, 1541, 1441 cm­–1; 1H NMR δ 1.29 (t, J = 7.3 Hz, 6H), 3.53 (q, J = 7.3 Hz, 4H), 3.87 (s, 4H), 7.38 (d, J = 0.9 Hz, 4H), 7.69 (t, J = 0.9 Hz, 2H); 13C NMR (CDCl3) δ 12.76, 47.70, 47.84, 113.26, 119.91, 123.09, 129.08, 132.48, 152.12, 167.35; MS m/z 538 (67, M+), 283 (100). Anal. Calcd for C20H20Br2N4S2: C, 44.46; H, 3.73; N, 10.37. Found: C, 44.39; H, 3.94; N, 10.10.

ACKNOWLEDGEMENT
This work was partially supported by a Grant-in-Aid for Scientific Research (C) 22550035 from Japan Society for the Promotion of Science. We thank Mrs. Miyuki Tanmatsu of this university for recording mass spectra and performing combustion analyses.

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