INTRODUCTION:

Thiazole and its derivatives play a vital role in nature. For example, the thiazolium ring present in vitamin B1 serves as an electron sink and its coenzyme form is important for the decarboxylation of α-ketoacids. This heterocyclic system has found broad applications in drug development for the treatment of allergies, inflammation, hypertension, schizophrenia, bacterial and HIV infections [1]. A tetrahydrothiazole also appears in the skeleton of penicillin which is one of the first and most important broad spectrum antibiotics.


Fentiazac		Tiabendazole

Amiphenazole	Abafungin

Aminothiazoles are known to be ligands of estrogen receptors as well as a novel class of adenosine receptor antagonists [2]. Other analogues are used as fungicides, inhibiting invivo growth of Xanthomonas, as an ingredient of herbicides or as schistosomicidal and anthelmintic drugs. Recently, thiazole derivatives have been utilized for the treatment of pain, as fibrinogen receptor anta-gonists with antithrombotic activity and as inhibitors of bacterial DNA gyrase-B [3]. In view of the emerging importance of thiazoles and their derivatives, several methods for their synthesis were developed using various catalysts [4], conditions [5] and strategies [6]. However, many of the reported methods suffer from drawbacks such as harsh reaction conditions, unsatisfactory yields, prolonged reaction time, tedious workup procedures and use of expensive catalysts. Therefore, the development of an efficient chemical processes is a major challenge for chemists in organic synthesis. As part of our on going program to develop a novel methodologies, herein we report a simple and efficient protocol for the synthesis of thiazole derivatives under mild reaction conditions.

RESULTS AND DISCUSSIONS:

In a typical experiment, an equimolar amount of 2-bromo-1-phenylethanone (1) and thiourea (2a) were reacted in presence of cadmium chloride at room temperature to afford the corresponding product, 4- phenylthiazol-2-amine (3a) in excellent yields, as shown in the scheme 1 and the reaction was completed within 1 hour. The reaction was carried out in acetonitrile.

At room temperature to afford the corresponding derivative, 4-(naphthalene-2-yl)-thiazol-2-amine (3k) in excellent yields and the reaction was completed within 1 hour. This reaction was successfully applied to various substituted thiourea compounds such as 1-methylthiourea (2l), with excellent yields. In general, all the reactions were carried out in presence of cadmium chloride as catalyst, at room temperature in acetonitrile. In general, all the reactions were completed within 1-2 hours of reaction time, with excellent yields and the details were mentioned in the table 1. All the products were confirmed by their 1H NMR, IR and Mass spectroscopy data.

CONCLUSION:

In summary, we have described a simple and novel methodology for the synthesis of thiazole In a similar manner, 2-bromo-1-phenylethanone (1) was reacted smoothly with 1-methyl thiourea (2b), 1-phenyl thiourea (2c), ethanethioamide (2d) and benzothioamide (2e) successfully. Encouraged by the results obtained with the above experiments, we have extended this methodology to various bromocarbonyl compounds, as well as different substituted thiourea compounds. In another model experiment, 2-bromo- 1-(4-bromo phenyl)-ethanone was subjected to condensation reaction with thiourea in acetonitrile. at room temperature to afford the corresponding product, 4-(4-bromophenyl)-thiozol-2-amine (3f) in excellent yields. The reaction was carried out in presence of a catalytic (10% mol) amount of Cadmium chloride and the reaction was completed within 1 hour. This reaction was demonstrated successfully with various substituted thiourea compounds such as 1-methylthiourea (2g), 1-phenyl thiourea (2h), ethane thioamide (2i) and benzothioamide (2j) with excellent yields. In another typical experiment, 2-bromo-1-(naphthalen-2-yl)-ethanone was treated with thiourea in acetonitrile derivatives by the coupling of 2-bromo ketones and thiourea compounds. The present method offers significant advantages such as mild reaction conditions, high conversions, short reaction offers significant advantages such as mild reaction conditions, high conversions, short reaction times, cleaner reaction profiles and excellent yields.

EXPERIMENTAL SECTION:

General methods.

Melting points were recorded on Buchi R-535 apparatus. IR spectra were recorded on a Perkin-Elmer FT-IR 240-c spectrophotometer using KBr disk. 1H NMR-Spectra were recorded on Gemini-200 spectrometer in CDCl₂ using TMS as internal standard. Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at 70 eV.

General procedure:

A mixture of 2-bromo carbonyl compound (2 mmol) and thiaurea (2 mmol) was stirred in presence of CdCl₂ (10% mol) in acetonitrile (10 mL) at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (2x10 mL). The combined filtrates were washed with brine solution, dried over Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel 60-120 mesh. All the pure products were identified by their spectroscopy data

Table 1: Efficient synthesis of thiazoles in presence of CdCl₂.

Entry	Bromo compound(1)	Thiurea(2)	Product(3)	Reaction (time)	Yield (%)
a				1.0	90
b				1.0	88
C				1.5	83
D				2.0	89
E				2.0	88
F				2.0	85
g				1.0	90
H				1.5	88
I				2.0	83
J				1.5	82
K				2.0	86
L				2.0	87

The reaction may proceed via initial formation of an imine followed by sulfur or oxygen insertion resulting in the formation of 2-aminothiozole derivatives as shown in the scheme 2.

Mechanism

Scheme 2. Probable reaction mechanism

Spectral data for all the compounds:

4-Phenylthiazol-2-amine (3a): White solid. Mp 134-136 0C; IR (KBr): υ 3434, 3253, 3155, 2924, 2855, 1599, 1520, 1482, 1440 1336, 1216, 1071, 910, 846, 773 cm.-1; 1H N MR (CDCl3): δ4.97 (brs, 2H), 6.69 (s, 1H), 7.25-7.39 (m, 3H), 7.70-7.75 (m, 2H). EIMS m/z (%): 177 (m+1100), 149 (10), 134 (90), 104 (15), 89 (30), 77 (15), 63 (10), 42 (15).

N-Methyl-4-phenylthiazol-2-amine (3b): Yellow solid. Mp 118-120 0C; IR (KBr): υ 3221, 3115, 3001, 2922, 1586, 1481, 1402, 1329, 1155, 1055, 919, 841, 775, 671 cm.-1; 1HNMR (CDCl3): δ2.99 (s, 3H), 6.40 (brs, 1H), 6.62 (s, 1H), 7.22-7.40 (m, 3H), 7.74 (d, 2H, J = 6.6 Hz). EIMS m/z (%). 190 (m+ 35), 162 (30), 134 (90), 121 (10), 102 (25), 89 (22), 77 (20), 65 (20), 47 (100).

N-4-Diphenyloxazol-2-amine (3c): Yellow solid. Mp 110-112 0C; IR (KBr): υ 3186, 2923, 2853, 1564, 1498, 1461, 1424, 1309, 1067, 915, 842, 749, 695 cm.-1 1HNMR (CDCl3): δ6.75 (s, 1H), 6.99-7.08 (m, 1H), 7.25-7.40 (m, 8H), 7.77 (d, 2H, J = 6.8 Hz). EIMS m/z (%): 253 (m+1 100), 190 (10), 142 (10), 102 (10), 98 (10), 60 (10).

2-Methyl-4-phenylthiazole (3d): White solid. Mp 66-68 0C; IR (KBr): υ 3423, 3103, 3058, 2924, 2853, 1597, 1496, 1322, 1265, 1168, 1023, 976, 849, 740, 672 cm.-1 1H N MR (CDCl3): δ2.80 (s, 3H), 7.24- 7.40 (m, 4H), 7.84 (d, 2H, J = 7.0 Hz). EIMS m/z (%): 175 (m+ 75), 149 (10), 134 (100), 108 (10), 89 (25), 63 (10), 45 (10).

2,4-Diphenylthiazole (3e): White solid. Mp 118-120 0C; IR (KBr): υ 3447, 3114, 2924, 2855, 1505, 1466, 1392, 1233, 1102, 1050, 974, 851, 762, 687 cm.-1 1HNMR (CDCl3): δ7.41-7.48 (m, 6H), 7.51 (d, 2H, J = 10.5 Hz), 7.86 (d, 2H, J = 10.5 Hz), 7.99-8.05 (m, 1H). EIMS m/z (%): 238 (m+1 100), 134 (55), 103 (15), 90 (30).

4-(4-Bromophenyl)-Thiazol-2-amine (3f): Brown solid. Mp 164-166 0C; IR (KBr): υ 3426, 3280, 3108, 2925, 1532, 1468, 1391, 1334, 1067, 1035, 1004, 822, 727, 669 cm.-1 1HNMR (CDCl3):δ4.96 (brs, 2H, NH2), 6.70 (s, 1H), 7.47 (d, 2H, J = 8.0 Hz), 7.62 (d, 2H, J = 8.0 Hz).; EIMS m/z (%): 257 (m+2 100), 255 (m+ 90), 225 (10), 149 (10).

4-(4-Bromophenyl)-N-Methylthiazol-2-amine (3g): Yellow solid. Mp 138-140 0C; IR (KBr): υ 3259, 3109, 2924, 1574, 1450, 1392, 1104, 1048, 827, 723, 665 cm.-1; 1HNMR (CDCl3): δ3.00 (s, 1H), 5.75 (brs, 1H), 6.67 (s, 1H), 7.47 (d, 2H, J = 8.0 Hz), 7.64 (d, 2H, J = 8.0 Hz).; EIMS m/z (%). 271 (m+2 100), 269 (m+ 90), 220 (10), 115 (10), 91 (10).

4-(4-Bromophenyl)-N-Phenyloxazol-2-amine (3h): Yellow solid. Mp 112-114 0C; IR (KBr): υ 3250, 3186, 2923, 2853, 1564, 1498, 1461, 1424, 1309, 1067, 915, 842, 749, 695 cm.-1;1H NMR (CDCl3): δ 6.76 (s, 1H), 7.02-7.12 (m, 1H), 6.37 (d, 4H, J = 7.0 Hz), 7.43-7.55 (m, 2H), 7.61-7.64 (m, 2H).

4-(4-Bromophenyl)-2-Methylthiazole (3i): White solid. Mp 130-132 0C; IR (KBr): υ 3113, 2921, 1504, 1462, 1397, 1170, 1065, 980, 848, 742, 658 cm.-1 1HNMR (CDCl3): δ2.79 (s, 3H), 7.27 (s, 1H), 7.51 (d, 2H, J = 7.0 Hz), 7.75 (d, 2H, J = 7.0 Hz).; EIMS m/z (%): 257 (m+2 100), 255 (m+1 97), 231 (10), 178 (10), 102 (10), 91 (10), 77 (10).

4-(4-Bromophenyl)-2-Phenylthiazole (3j): White solid. Mp 122-124 0C; IR (KBr): υ 3114, 2924, 2855, 1505, 1466, 1392, 1233, 1102, 1050, 974, 851, 762, 686 cm.-1 1HNMR (CDCl3): δ7.40-7.50 (m, 5H) 7.55 (d, 2H, J = 7.0 Hz), 7.87 (d, 2H, J = 7.0 Hz), 8.02 (d, 1H, J = 7.0 Hz). EIMS m/z (%): 318 (m+2 50), 316 (m+ 48), 237 (100), 225 (10), 133 (48).

4-(Naphthalen-2-yl)-Thiazol-2-amine (3k): Brown solid. Mp 140-142 0C; IR (KBr): υ 3436, 3169, 3057, 2927, 1530, 1392, 1220, 1111, 1038, 857, 749, 706 cm.-1 1HNMR (CDCl3): δ5.05 (brs, 2H), 6.82 (s, 1H), 7.40-7.48 (m, 2H), 7.78-7.88 (m, 4H), 8.28 (s, 1H). EIMS m/z (%): 227 (m+1 100), 115 (10).

N-Methyl-4-(naphthalen-2-yl)-thiazol-2-amine (3l): Light yellow solid. Mp 116-118 0C; IR (KBr): υ 3244, 3114, 3052, 2918, 1584, 1449, 1399, 1127, 1050, 949, 862, 741 cm.-1 1HN MR (CDCl3): δ 3.00 (s, 3H), 6.45 (brs, 1H, NH), 6.80 (s, 1H), 7.39-7.48 (m, 2H), 7.74-7.86 (m, 4H), 8.27 (s, 1H). EIMS m/z (%): 241 (m+1 100), 122 (10), 98 (10).

ACKNOWLEDGEMENTS:

The authors acknowledge the Osmania University for providing the research facility and UGC, the direct contributions for the staff of Department of Chemistry and Analytical team.

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Received on 08.11.2014 Modified on 20.12.2014

Asian J. Research Chem 8(1): January 2015; Page 46-50

DOI: 10.5958/0974-4150.2015.00010.3