A simple and efficient route for synthesis of 2-alkylbenzothiazoles

Introduction

Development of a straight forward method for synthesizing benzothiazoles and their derivatives is desired, since compounds containing benzothiazole moiety exhibit an array of biological activities, including, anticancer,¹ antimicrobial,² antituberculosis,³ antihypertensive,⁴ antiulcer,⁵ and also can be used as chemiluminescent agents⁶ and photosensitizers.⁷ Treatment of 2-aminothiophenol with aldehydes in the presence of catalysts such as RuCl₃,⁸ Pt/Al₂O₃,⁹ CdS nanosphere (CdSNS),¹⁰ cetyltrimethyl ammonium bromide (CTAB),¹¹ 3,6-di(pyridine-2-yl)-1,2,4,5-tetrazine (pytz),¹² bakers’ yeast¹³ and glucose oxidase (GOX)-chloroperoxidase (CPO)¹⁴ have been reported to give various 2-arylbenzothiazoles and some 2-alkylbenzothiazoles in satisfactory yields. In searching for an efficient catalyst-free synthesis of 2-substituted benzothiazoles, it was found that condensation of aromatic aldehydes with 2-aminothiophenol under melt reaction conditions afforded good to excellent yields of 2-arylbenzothiazoles under solvent-free conditions with no need of a catalyst. The reaction of aliphatic aldehydes, on the other hand, gave 2,3-dihydro-2-alkylbenzo[d]thiazoles as the sole products.¹⁵

We have examined the reaction of aliphatic aldehydes with 2-aminothiophenol and report herein our simple and efficient route to 2-alkylbenzothiazoles.

Experimental

Solvents were purified according to standard methods prior to use, while all other chemicals used were commercially available and used as received. Melting point was measured on a Sanyo Gallenkamp melting point apparatus and compared with that of known sample. IR spectra were recorded on a Perkin Elmer Spectrum One FT-IR Spectrometer. ¹H and ¹³C NMR spectra were recorded using a VARIAN MERCURY plus (400 MHz FT NMR).

General procedure for the preparation of 2-alkyl-2,3-dihydrobenzo[d]thiazoles

To a stirred solution of aliphatic aldehyde (7.5 mmol) in dichloromethane (7.5 ml) was added 4Å molecular sieves (5.0 g). 2-Aminothiophenol (1) (0.63 g, 5.0 mmol) was added dropwise to the mixture and stirred altogether at room temperature for 1.5 – 2 h. After completion of the reaction, the reaction mixture was filtered to remove the molecular sieves. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with 10% ethyl acetate/hexane as eluant to give the 2-alkyl-2,3-dihydrobenzo[d]thiazole.

2-Propyl-2,3-dihydrobenzo[d]thiazole (3a).

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3464, 3359, 3064, 2954, 2928, 1607, 1583, 1464, 1307, 1118, 736 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.09 (1H, d, J = 7.6 Hz, 4-H), 6.97 – 6.89 (1H, m, 6-H), 6.76 (1H, dt, J = 7.5 Hz, J = 0.9 Hz, 5-H), 6.64 (1H, d, J = 7.8 Hz, 7-H), 5.27 (1H, t, J = 6.5 Hz, 2-H), 4.12 (1H, brs, NH), 1.86 (2H,dt, J = 10.2 Hz, J = 6.9 Hz, 1′-H), 1.46 (2H, sex, J = 8.0 Hz, 2′-H), 0.98 (3H, t, J = 7.4 Hz, 3′-H); ¹³C NMR (CDCl₃) δ 146.7, 125.1, 122.0, 120.7, 110.8, 68.7, 40.7, 19.4, 13.8.

2-Methyl-2,3-dihydrobenzo[d]thiazole (3b)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3359, 2957, 2928, 2869, 1607, 1583, 1464, 1377, 1370, 736 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.08 (1H, d, J = 7.6 Hz, 4-H), 6.91 (1H, t, J = 7.6 Hz, 6-H), 6.76 (1H, t, J = 7.5 Hz, 5-H), 6.65 (1H, d, J = 8.3 Hz, 7-H), 5.39 (1H, q, J = 6.0 Hz, 2-H), 3.97 (1H, brs, NH), 1.60 (3H, d, J = 12.4, 6.0 Hz, 1′-H); ¹³CNMR (CDCl₃) d 146.4, 125.2, 122.0, 121.0, 111.1, 63.9, 63.8, 24.4.

2-Ethyl-2,3-dihydrobenzo[d]thiazole (3c)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3354, 3065, 2962, 1607, 1581, 1464, 1400, 1378, 1117, 736 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.08 (1H, d, J = 7.6 Hz, 4-H), 6.92 (1H, t, J = 7.6 Hz,6-H), 6.75 (1H, t, J = 7.5 Hz, 5-H), 6.63 (1H, t, J = 8.5 Hz, 7-H), 5.22 (1H, t, J = 6.3 Hz, 2-H), 4.13 (1H, brs, NH), 1.88 (2H, quint, J = 7.1 Hz, 1′-H), 1.02 (3H, t, J = 7.4 Hz, 2′-H); ¹³C NMR (CDCl₃) δ 146.7, 127.2, 125.1, 121.9, 120.6, 110.6, 70.2, 31.7, 10.2.

2-Isopropyl-2,3-dihydrobenzo[d]thiazole (3d)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3465, 3367, 3063, 2962, 2926, 1608, 1508, 1387, 1307, 1255, 745 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.08 (1H, d, J = 7.5 Hz, 4-H), 6.92 (1H, t, J = 7.6 Hz, 6-H), 6.73 (1H, t, J = 7.5 Hz, 5-H), 6.61 (1H, d, J = 7.8 Hz, 7-H), 5.16 (1H, d, J = 6.2 Hz, 2-H), 4.20 (1H, brs, NH), 2.06 – 1.95 (1H, m, 1′-H), 1.03 (6H, d, J = 6.7 Hz, 2′ and 3′-H); ¹³C NMR (CDCl₃) d 147.3, 127.1, 125.0, 121.6, 120.2, 109.9, 75.0, 35.8, 18.7,18.3.

2-Hexyl-2,3-dihydrobenzo[d]thiazole (3e)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3371, 3064, 2924, 2853, 1584, 1516, 1463, 1373, 756, 729 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.06 (1H, d, J = 7.6 Hz, 4-H), 6.90 (1H, t, J = 7.6 Hz, 6-H), 6.73 (1H, t, J = 7.5 Hz, 5-H), 6.64 (1H, d, J = 7.7 Hz,7-H), 5.26 (1H, t, J = 6.5 Hz, 2-H), 4.08 (1H, brs, NH), 1.94 – 1.80 (2H, m, 1′-H), 1.48 – 1.18 (8H, m, 2′, 3′, 4′, and 5′-H), 0.90 (3H, m, 6′-H); ¹³C NMR (CDCl₃) d 146.6, 125.8, 125.1, 121.9, 120.8, 110.8, 77.4, 77.1, 76.7, 68.9, 38.6, 31.7, 28.9, 26.1, 22.5, 14.0.

2-Benzyl-2,3-dihydrobenzo[d]thiazole (3f)

Yellow liquid; FTIR (neat, ν, cm^-1) n_max 3361, 3061, 3027, 2924, 1583, 1465, 1311, 1276, 755, 698 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.38 – 7.23 (6H, m, Ar-H), 7.09 (1H, d, J = 7.6 Hz, 4-H), 6.93 (1H, t, J = 7.6 Hz, 6-H), 6.76 (1H, t, J = 7.5 Hz, 5-H), 6.62 (1H, d, J = 7.7 Hz, 7-H), 5.41 (1H, dd, J = 7.7 Hz, J = 6.0 Hz, 2-H), 4.17 (1H, brs, NH), 3.18 (1H, dd, J = 13.4, J = 8.1 Hz, 1′-H), 3.09 (1H, dd, J = 13.4, J = 5.6 Hz, 1′-H); ¹³C NMR (CDCl₃) d 145.9, 137.0, 129.3, 128.8, 127.0, 125.3, 122.2, 120.6, 110.4, 77.3, 77.0, 76.7, 68.9, 45.0.

2-Phenylethyl-2,3-dihydrobenzo[d]thiazole (3g)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3357, 3060, 3025, 2920, 1581, 1466, 1400, 1223, 735, 694 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.34 – 7.27 (2H, m, 2′ and 6′-H), 7.22 (3H, t, J = 6.8 Hz, 3′, 4′ and 5′-H), 7.09 (1H, d, J = 7.5 Hz, 4-H), 6.91 (1H, t, J = 7.6 Hz, 6-H), 6.76 (1H, t, J = 7.5 Hz, 5-H), 6.64 (1H, d, J = 7.7 Hz, 7-H), 5.32 – 5.20 (1H, m, 2-H), 2.84 – 2.68 (2H, m, 1′-H), 2.20 (2H, dd, J = 14.5, 7.4 Hz, 2′-H); ¹³C NMR (CDCl₃) δ 146.44, 140.81, 129.03, 128.53, 128.43, 127.57, 126.14, 125.16, 121.99, 120.90, 110.99, 67.93, 40.19, 32.20.

Preparation of silica supported PCC

The solid supported PCC was prepared by a procedure reported in the literature.¹³ To a solution of PCC (23.5 g, 109 mmol) in acetone (109 ml) was added silica gel 70 – 230 mesh (109 g) and the mixture was stirred at room temperature for 3 h. After removal of the solvent under reduced pressure, the resulting solid was dried at 100 ^oC for 2 h.

General procedure for the preparation of 2-alkylbenzothiazoles

To a stirred suspension of PCC on silica gel (2.6 g, 2.2 mmol) in dichloromethane (10 ml) was added 2-alkyl-2,3-dihydrobenzothiazole (2.0 mmol) and the mixture was stirred at room temperature for 30 min. After completion of the reaction, the resulting mixture was filtered on a thin Celite pad. The filtrate was poured into water and extracted with ethyl acetate (3´20 ml). The organic layer was dried (anh.Na₂SO₄), filtered, concentrated, and purified by column chromatography on silica gel using 10% ethyl acetate/hexane to give the 2-alkylbenzothiazole.

2-Propylbenzothiazole (4a)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3062, 2962, 2930, 2871, 2361, 1739, 1592, 1517, 1455, 1434, 1378, 1310, 757 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.97 (1H, d, J = 8.1 Hz, 4-H), 7.83 (1H, d, J = 8.0 Hz, 7-H), 7.44 (1H,t, J= 8.0 Hz, 6-H), 7.34 (1H, t, J= 8.0 Hz, 5-H), 3.09 (2H, t, J = 7.6 Hz, 1′-H), 1.91 (2H, dd, J = 15.0 Hz, J = 7.5 Hz, 2′-H), 1.06 (3H, t, J = 7.4 Hz, 3′-H); ¹³C NMR (CDCl₃) δ 172.1, 153.3, 135.2, 125.8, 124.6, 122.5, 121.4, 36.2, 23.1, 13.7.

2-Methylbenzothiazole (4b)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3027, 2957, 2923, 2851, 1526, 1433, 1309, 1241, 1174, 759 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.95 (1H, d, J = 8.1 Hz, 4-H), 7.81 (1H, d, J = 8.0 Hz, 7-H), 7.44 (1H, t, J = 7.7 Hz, 6-H), 7.34 (1H, t, J = 7.6 Hz, 5-H), 2.83 (3H, s, CH₃); ¹³C NMR (CDCl₃) δ 166.9, 153.4, 135.6, 125.9, 124.7, 122.4, 121.3, 20.1.

2-Ethylbenzothiazole (4c)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3061, 2972, 2933, 1519, 1433, 1376, 1310, 1122, 756, 726 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.95 (1H, d, J = 8.2 Hz,4-H), 7.77 (1H, d, J= 8.0 Hz, 7-H), 7.39 (1H, t, J= 8.0 Hz, 6-H), 7.28 (1H, t, J= 8.0 Hz, 5-H), 3.10 (2H, m, 1′-H), 1.45 – 1.40 (3H, m, 2′-H); ¹³C NMR (CDCl₃) δ 173.4, 153.2, 135.0, 125.8, 124.5, 122.4, 121.4, 27.7, 13.7.

2-Isopropylbenzothiazole (4d)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3063, 2966, 2928, 2870, 1517, 1459, 1439, 1309, 1035, 1006, 759 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.98 (1H, d, J = 7.9 Hz, 4-H), 7.85 (1H, dd, J = 7.9 Hz, J = 0.5 Hz, 7-H), 7.44 (1H, t, J= 8.0 Hz, 6-H), 7.34 (1H, t, J= 8.0 Hz, 5-H), 3.43 (1H, hept, J = 6.9 Hz, 1′-H), 1.48 (6H, d, J = 6.9 Hz, 2′ and 3′-H); ¹³C NMR (CDCl₃) δ 178.6, 153.1, 134.7, 125.8, 124.5, 122.6, 121.5, 34.1, 22.8.

2-Hexylbenzothiazole (4e)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max3064, 2926, 2857, 1518, 1459, 1435, 1249, 1086, 1062, 758, 728 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.97 (1H, d, J = 8.1 Hz, 4-H), 7.83 (1H, d, J = 8.0 Hz, 7-H), 7.44 (1H, t, J = 7.7 Hz, 6-H), 7.34 (1H, t, J = 7.6 Hz, 5-H), 3.11 (2H, t, J = 7.7 Hz, 1′-H), 1.95 – 1.78 (2H, m, 2′-H), 1.47 – 1.07 (6H, m, 3′, 4′, and 5′-H), 0.89 (3H, t, J = 6.7 Hz, 6′-H); ¹³C NMR (CDCl₃) δ 172.4, 153.6, 135.1, 125.8, 124.6, 122.5, 121.4, 34.3, 31.5, 29.7, 28.8, 22.5, 14.0.

2-Benzylbenzothiazole (4f)

Yellow liquid; FTIR (neat, ν, cm^-1) v_max 3061, 3029, 2992, 2852, 1646, 1514, 1490, 1452, 1432, 757, 701 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 8.00 (1H, d, J = 8.2 Hz, 4-H), 7.79 (1H, d, J = 7.9 Hz, 7-H), 7.45 (1H, t, J = 7.5 Hz, 6-H), 7.41 – 7.27 (6H, m, ArH and 5-H), 4.44 (2H, s, 1′-H); ¹³C NMR (CDCl₃) δ 171.2, 153.2, 137.2, 131.3, 129.1, 128.8, 128.5, 127.3, 125.9, 124.8, 122.8, 121.5, 40.6.

2-Phenylethylbenzothiazole (4g)

Yellow solid; mp 60 – 62 ^oC (lit.¹⁶ 59-60 ^oC); FTIR (KBr, ν, cm^-1)v_max 3058, 3027, 2923, 2852, 1516, 1451, 1432, 1118, 752, 696 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 7.99 (1H, d, J = 8.1 Hz, 4-H), 7.84 (1H, d, J = 8.0 Hz, 7-H), 7.46 (1H, t, J = 7.7 Hz, 6-H), 7.40 – 7.16 (6H, m, ArH and 5-H), 3.47 – 3.34 (2H, m, 1′-H), 3.26 – 3.13 (2H, m, 2′-H); ^{13C NMR} (CDCl₃) δ 170.9, 153.2, 140.2, 135.1, 128.6, 128.4, 126.4, 125.9, 124.8, 122.6, 121.5, 36.0, 35.5.

Results and Discussion

We initially performed the reaction of 2-aminothiophenol (1) with butanal (2a) in the absence of solvent at room temperature for 24 h. As shown in Scheme 1, isolated products were 2-propyl-2,3-dihydrobenzo[d]thiazole (3a) and 2-propylbenzothiazole (4a) in 40 and 25% yields, respectively. Carrying out this reaction in CH₂Cl₂ in the presence of 4Å molecular sieves at room temperature for 2 h,¹⁷ on the other hand, provided 2-propyl-2,3-dihydrobenzo[d]thiazole (3a) in 96% yield as the sole product.

Scheme 1 Click here to View scheme

 

Treatment of 2-aminothiophenol (1) with aliphatic aldehydes 2b-g in CH₂Cl₂ in the presence of 4Å molecular sieves at room temperature for 1.5-2 h also gave excellent yields of the corresponding 2-alkyl-2,3-dihydrobenzo[d]thiazoles 3b-g, as illustrated in Table 1.

Table 1: Synthesis of 2-alkyl-2,3-dihydrobenzo[d]thiazoles 3b-g from the reaction of 2-aminothiophenol (1) with aliphatic aldehydes 2b-g in CH2Cl2 in the presence of 4Å molecular sieves  Click here to View table

 

Since pyridinium chlorochromate (PCC) supported on silica gel have been successfully used as an oxidant for the oxidative cyclization of thiophenolic Shiff’s bases in CH₂Cl₂,¹⁸ we therefore treated 2-alkyl-2,3-dihydrobenzo[d]thiazoles 3a-g with silica gel supported PCC in CH₂Cl₂ at room temperature. As shown in Scheme 3, this treatment afforded excellent yields of the corresponding 2-alkylbenzothiazoles 4a-g in 20 min.

Scheme 2  Click here to View scheme

 

Conclusion

The present two-step procedure involving condensation between 2-aminothiophenol and aliphatic aldehydes in the presence of 4Å molecular sieves followed by oxidation of the obtained 2-alkyl-2,3-dihydrobenzo[d]thiazoles using pyridinium chlorochromate (PCC) supported on silica gel as oxidizing agent provides a simple and efficient route to 2-alkylbenzothiazoles.

Acknowledgement

This work was financially supported by the Natural Products Research Unit, Department of Chemistry, Faculty of Science, Khon Kaen University, and the Center for Innovation in Chemistry (PERCH-CIC) and the Commission of Higher Education (CHE-RG), Ministry of Education.

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