Abstract
An efficient, green and environmentally friendly grindstone method for the synthesis of 2-arylbenzothiazole derivatives in the presence of urea nitrate as the catalyst under solvent-free conditions was developed. All products were characterized by elemental analysis and spectral methods.
Introduction
Benzothiazole is a versatile pharmacophore, possessing a wide spectrum of biological activities [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. Accordingly, efficient approaches to the synthesis of benzothiazole derivatives, including green chemistry, are of interest. The important characteristics of green chemistry are the recovery of the catalyst after the catalytic reaction and minimization of waste. In this report a green synthesis of 2-arylbenzothiazoles using fine grinding of substituted 2-aminobenzenethiol and substituted aldehyde using a mortar and pestle under solvent-free conditions in the presence of urea nitrate catalyst is described. Urea nitrate is easily prepared in the laboratory and has been used previously to catalyze various organic transformations including the imino Diels-Alder reaction [14], regioselective nitration [15], [16], aromatization of 1,4-dihydropyridines [17] and cleavage of oximes under microwave irradiation [18] among other transformations. CAUTION:Urea nitrate is unstable and even at room temperature (rt) slowly releases nitric acid. As it is a powerful explosive [19] it must be handled with care [20], [21]. Urea nitrate can easily be neutralized by treatment with water.
Results and discussion
In continuation of our research, an attempt was made to synthesize some derivatives of 2-arylbenzothiazole derivatives from 2-aminobenzenethiol under environmental benign conditions using urea nitrate as a catalyst via the grindstone method. The compounds 3a–f were synthesized by performing organic transformations under solvent-free conditions. The reaction has previously been performed under different conditions (Table 1) using ZnO NPs [22], ZnO NPs (ball milling strategy) [23], tetrabutylammonium bromide (TBAB) [24], TiO2 [25], glycerol [26], tungstophosphoric acid impregnated zirconium phosphate [27], sulfonated porous carbon (SPC) [28], calcined eggshell [29] and liquid-assisted hand grinding [30], among other methods. Most of the synthetic approaches reported in the literature are characterized by high yields and short reaction times but the catalysts used are impractical and hazardous solvents are used along with tedious isolation procedures. By contrast, the synthesis of urea nitrate is simple, economical and the products 3a–f are obtained without using solvents and avoiding tedious isolation procedures. Bearing in mind the importance of urea nitrate as a catalyst, we made efforts to develop an environment friendly method using the grindstone technique. Our method involves grinding substituted 2-aminobenzenethiol and various aldehydes with a mortar and pestle using urea nitrate as a catalyst and the product is obtained in a few seconds, visualized by a dramatic color change. Excellent yields are obtained without a tedious purification process of column chromatography. The reaction is carried out at rt in the absence of any solvent with different substituted thiols 1 and aromatic aldehydes 2 in the presence of urea nitrate and produces compounds 3a–f (Scheme 1). Compounds 3d,e and 3f have been synthesized previously using different methods [31], [32] but the yields and reaction times have not been satisfactory. In this work, these compounds were resynthesized using urea nitrate as a catalyst via the grinding procedure. It was found that the rate of reaction increased continuously with the increase in the catalyst concentration up to 15 mol%, which was found to be the optimal concentration. The optimum reaction time (grinding) was 30 s. The reaction was also attempted in the presence of HNO3 and urea alone under otherwise similar conditions but the product was obtained in a lower yield along with a longer reaction time. The structures of all synthesized compounds were confirmed by analysis of IR and NMR spectra.
Comparative study of various catalysts.
| Entry | Catalyst | Reaction condition | Time | Yield (%) |
|---|---|---|---|---|
| 1 | Urea nitrate (15 mol%)a | Grinding, solvent free, rt | 30 s | 98 |
| 2 | ZnO NPs (5 mg) [22] | Solvent free or ethanol, rt | 2–8 min | 95 |
| 3 | ZnO NPs [23] | Ball milling, 600 rpm, rt | 30 min | 87 |
| 4 | Tetrabutylammonium bromide (TBAB) (15 mol%) [24] | Reflux at 60°C | 30 min | 90 |
| 5 | TiO2 P25 (0.1)/H2O2 [25] | Ambient-light conditions at 50°C | 5 min | 96 |
| 6 | Glycerol (2 mL) [26] | Microwave irradiation at 100°C | 4 min | 92 |
| 7 | Tungstophosphoric acid impregnated zirconium phosphate (5 mol%) [27] | Microwave irradiation at 100°C | 15 min | 95 |
| 8 | Sulfonated porous carbon (SPC) (0.1 g) [28] | Microwave irradiation in water | 6 min | 93 |
| 9 | Calcined egg shell [29] | Grinding, solvent free, rt | 16 min | 92 |
aPresent work.
Conclusion
An efficient and green procedure for the synthesis of 2-arylbenzothiazoles from substituted 2-aminobenzenethiol was developed. The work is highly advantageous because of easy workup, solvent-free conditions, high yields, no waste generation and the ease of product isolation and purification.
Experimental
All chemicals were commercially procured from Sigma-Aldrich and Hi-Media and used without further purification. An agate mortar and pestle was used for the synthesis. Melting points were determined in open capillary tubes and are uncorrected. The IR spectra were recorded in KBr pellets on a Bruker FT-IR spectrometer. The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were scanned on a Bruker Avance II 400 spectrometer using tetramethylsilane (TMS) as an internal standard and CDCl3 as a solvent. The mass spectra were recorded on a Waters Xevo G2-S QT spectrometer. The purity of synthesized compounds was checked by thin layer chromatography (TLC) using silica gel G as an adsorbent and eluting with hexanes/ethyl acetate; visualization was accomplished by UV irradiation or exposure to iodine. The starting material 2-amino-4,6-dimethyl-benzenethiol was synthesized as previously reported [33].
Synthesis of urea nitrate catalyst
Urea (3 g) in a 100-mL beaker was treated dropwise by stirring with HNO3 (10 mL). A clear solution was formed upon heating. The solution was cooled to rt and the resultant bright shiny crystals of urea nitrate were filtered, dried and stored in air tight vials. The catalyst is unstable in the presence of water.
General procedure for synthesis of 2-phenylbenzothiazoles 3a–f
An aromatic aldehyde (1 mol), o-aminothiophenol (1 mmol) and urea nitrate (15 mol%) were grounded together using a mortar and pestle at rt for few seconds giving rise to a dramatic color change as the reaction progressed. The resultant solid mass was treated with ice-cold water and the mixture was stirred for 30 min to remove urea. After filtration, the solid residue of 6a–f was crystallized from ethanol.
4-(5,7-Dimethyl-benzothiazol-2-yl)-benzonitrile (3a)
Yield 96%; dark yellow crystals; mp 212–215°C; IR: 3051 (C-H stretching, Ar), 2965 (C-H stretching, CH3), 2213 (-CN, stretching) 1470 cm−1 (aromatic C=C); 1H NMR: δ 2.19 (s, 3H, CH3), 2.21 (s, 3H, CH3), 7.26–7.79 (m, 6H, Ar-H and BT-H); 13C NMR: δ 20.3, 21.6, 115.9, 117.0, 124.4, 127.1, 127.5, 129.9, 132.3, 132.9, 134.5, 136.4, 137.3, 139.0, 153.1, 166.2; MS (EI): m/z 264.89 [M+]. Anal. Calcd for C16H12N2S; C, 72.70; H, 4.58; N, 10.60. Found: C, 72.53; H, 4.52; N, 10.65.
2-(3,4-Dimethoxy-phenyl)-5,7-dimethyl-benzothiazole (3b)
Yield 95%; red orange crystals; mp 174–177°C; IR: 3110 (C-H stretching, Ar), 2973 (C-H stretching, CH3), 1452 cm−1 (aromatic C=C); 1H NMR: δ 2.26 (s, 3H, CH3), 2.30 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.95–7.87 (m, 5H, Ar-H and BT-H); 13C NMR: δ 20.5, 21.8, 56.2, 57.4, 111.0, 112.2, 123.4, 128.8, 130.3, 131.5, 131.9, 138.5, 138.9, 148.3, 149.1, 152.6, 166.5; MS (EI): m/z 299.47 [M+]. Anal. Calcd for C17H17NO2S; C, 68.20; H, 5.72; N, 4.68. Found: C, 65.30; H, 5.82; N, 4.71.
2-Furan-2-yl-5,7-dimethyl-benzothiazole (3c)
Yield 98%; dark purple crystals; mp 182–185°C; I: 3085 (C–H stretching, Ar), 2943 (C-H stretching, CH3), 1473 cm−1 (aromatic C=C); 1H NMR: δ 2.32 (s, 3H, CH3), 2.38 (s, 3H, CH3), 6.63 (dd, 1H, J=3.4, 1.8 Hz), 7.08 (d, 2H, BT-H), 7.17 (dd, 1H, J=3.4, 0.8 Hz), 7.87 (dd, 1H, J=1.8, 0.8 Hz); 13C NMR: δ 20.9, 21.4, 108.8, 112.3, 122.7, 129.7, 131.0, 137.0, 138.4, 144.1, 149.1, 151.1, 156.6; MS (EI): m/z 229.74 [M+]. Anal. Calcd for C13H11NOS; C, 68.09; H, 4.84; N, 6.11. Found: C, 68.11; H, 4.93; N, 6.23.
2-(3,4-Dimethoxy-phenyl)-benzothiazole (3d)
Yield 98%; dark yellow crystals; mp 136–139°C; IR: 3120 (C-H stretching, Ar), 3053 (C-H stretching, CH3), 1465 cm−1 (aromatic C=C); 1H NMR: δ 3.68 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 6.94–7.46 (m, 7H, Ar-H and BT-H); 13C NMR: δ 56.1, 57.3, 111.6, 113.2, 122.4, 122.8, 124.9, 126.4, 128.4, 131.0, 134.1, 148.5, 149.1, 153.4, 163.5; MS (EI): m/z 271.82 [M+]. Anal. Calcd for C15H13NO2S; C, 66.40; H, 4.83; N, 5.16. Found: C, 66.57; H, 4.93; N, 5.26.
2-(4-Ethoxy-phenyl)-benzothiazole (3e)
Yield 95%; gray crystals; mp 117–120°C; IR: 3152 (C-H stretching, Ar), 3087 (C-H stretching, CH3), 2925 (CH2, C-H stretching), 1460 cm−1 (aromatic C=C); 1H NMR: δ 1.27 (t, 3H, CH3, J=7.0 Hz), 4.14 (q, 2H, CH2, J=7.0 Hz), 7.12–7.97 (m, 8H, Ar-H and BT-H); 13C NMR: δ 14.7, 63.6, 114.5, 114.7, 122.7, 124.1, 125.2, 126.9, 127.3, 128.1, 128.5, 135.4, 154.3, 161.0, 167.1; MS (EI): m/z 255.68 [M+]. Anal. Calcd for C15H13NOS: C, 70.56; H, 5.13; N, 5.49. Found: C, 70.68; H, 5.19; N, 5.55.
2-Furan-2-yl-benzothiazole (3f)
Yield 97%; dark purple crystals; mp 105–108°C; IR: 3080 (C-H stretching, Ar), 1458 cm−1 (aromatic C=C); 1H NMR: δ 6.70 (1H, dd, J=3.4, 1.8 Hz), 7.19 (1H, dd, J=3.4, 0.9 Hz), 7.30–8.09 (m, 4H, BT-H), 7.98 (1H, dd, J=1.8 Hz and 0.9 Hz); 13C NMR: δ 108.8, 112.3, 122.6, 124.6, 124.8, 126.3, 133.8, 144.1, 149.1, 153.1, 156.6; MS (EI): m/z 201.59 [M+]. Anal. Calcd for C11H7NOS: C, 65.65; H, 3.51; N, 6.96. Found: C, 65.76; H, 3.58; N, 6.93.
Acknowledgment
The authors are grateful to Department of Chemistry, MLSU for providing laboratory facilities. Analytical facilities by SAIF Chandigarh are duly acknowledged.
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