INTRODUCTION:

Benzothiazole contains a benzene ring fused to a thiazole ring. Benzothiazoles comprise a novel class of therapeutic compounds¹. 2-Arylbenzothiazoles are an important class of compounds owing to their potent utility as antitumor agent², antituberculotics³, antiparasitics⁴, calcium channel antagonists^5,6, chemiluminescent agents⁷, anticonvulsant⁸and also as photo sensitizes. So, we planned one pot synthesis of substituted benzothiazoles by using green synthetic tools.

The green synthetic tools used were microwave oven, use of ecofriendly catalyst zirconyl chloride in solvent free conditions⁹.

The microwave-assisted synthesis is one of the important tools of Green Synthesis. This is an eco friendly technology and helps to prevent pollution. We were, therefore, interested in developing a rapid, microwave-assisted protocol of various substituted benzothiazoles¹⁰ and screen them for anti-inflammatory activity.

RESULTS AND DISCUSSION:

The synthetic route for obtaining 2-aryl/heteryl benzothiazole 3a from 2-aminothiophenol and substituted aldehydes is presented in Scheme I.

Microwave assisted technology has been adopted to achieve remarkable rate enhancement and dramatic reduction in reaction times, better yields and cleaner reactions. Facile, one pot synthesis of 2-arylbenzothiazole by condensation of 2-aminothiophenol with aromatic/heterocyclic aldehydes, in and solvent free condition under microwave irradiation using eco friendly catalyst is reported here. Zirconium oxychloride is used as an ecofriendly catalyst, which is an efficient Lewis acid catalyst used in various transformations. This catalyst is cheaper cost wise, soluble in water and it has been used for cyclo condensation reactions .The reaction proceeds efficiently and was completed within 3-6min, yields were better than conventional method, which requires refluxing of 6-8 hrs in solvent. The physical observations for synthesis of 2-aryl/ heteryl benzothiazole are presented in Table I.

The synthesized compounds were identified on the basis of IR, Mass and PMR spectral analysis. All the newly synthesized compounds were evaluated for their anti inflammatory activity and have shown promising activity.

SCHEME I

Catalyst = Zirconium oxy chloride

Table 1 -Physical data of the synthesized compounds 3a (1-8)

Comp.no.3a

Molecular formula

Molecular weight

Time (min.)

Yield (%)

M.P (⁰C)

C₁₄H₁₁NOS

241

110

C₁₃H₉NS

211

2.5

C₁₃H₈NSCl

245

1.5

C₁₃H₉NOS

227

C₁₂H₈N₂S

212

3.5

C₁₁H₇NS₂

217

C₁₃H₈N₂O₂S

256

1.5

C₁₄H₁₁NSO₂

257

160

MATERIALS AND METHODS:

All the chemicals used were of Merck make. The reactions were carried out in synthetic microwave oven CATA R with temperature probe. Melting points were determined in open capillaries using melting point apparatus and are uncorrected. IR spectra were recorded on FT IR JASCO 4000 in KBr powder.¹H NMR were recorded on Brucker advance II 400 NMR spectrophotometer in CDCl₃. Mass spectra were recorded on TOS MS +484 Spectrophotometer Physical data of the synthesized compounds is presented in Table 1. Compounds were synthesized in solvent free conditions using eco friendly catalyst under microwave irradiation.

General procedure for the preparation of 2-aryl benzothiazoles, 3a (1-8)

In this method 2-amino thiophenol (0.01mol), substituted aldehyde (0.01mol) and a pinch of catalyst zirconium oxy chloriode were triturated, transferred to 50 ml borosil beaker and irradiated in synthetic microwave oven at 700 H watt. The temperatures of the reaction were measured with the help of temperature probe. All the reactions were carried out at 70°C- 85°C. The completion of reactions was monitored by the TLC. The time required for the completion of reactions was recorded. At the end of the reaction, the reaction mixture was washed with cold water to remove catalyst³. The product was filtered, dried and recrystallized from ethanol. All the compounds 3a (1-8) were prepared following this general method and were recrystallized from ethanol.

The structures of the compounds were confirmed by elemental and spectral analysis. The spectral data of compounds 3a (1-8) is given below:

1. 2-(4’-Methoxyphenyl)-benzothiazole, 3a 1

Yellowish-green solid. IR (KBr, cm^-1): 3097, 2928, 2334, 1693, 608; ¹HNMR(CDCl₃, δ ppm) : 3.73(s,1H, CH3), 6.8-8.3 (m, 8H, Ar-H); m/e 241, (M-C₇H₇O)135, (M-C₇H₄NS)108

Compound Code	Paw Edema (in ml) (Mean±SE)
Compound Code	0hr	1hr	2hr	4hr
Control	3.71±0.023	4.62±0.075	5.01±0.21	4.58±0.23
Std. Indomethacin	3.78±0.143	3.82±0.183	3.73±0.17	3.70±0.26**
1	3.54±0.03	4.12±0.09	3.58±0.24	3.64±0.78*
2	3.48±0.15	4.72±0.32	3.38±0.52**	3.49±0.04**
3	3.61±0.17	4.76±0.29	4.42±0.14	3.58±0.07
4	3.46±0.09	4.12±0.52	4.38±0.17	3.50±0.07
5	3.83±0.12	4.64±0.37	4.28±0.12	3.63±0.28
6	3.75±0.17	4.78±0.21	3.62±0.09**	3.58±0.05**
7	3.77±0.16	4.66±0.23	3.54±0.12**	3.50±0.14**
8	3.63±0.19	4.48±0.37	3.78±0.25*	3.48±0.39**

Std: Indomethacin; Dose: 10mg/kg; **P < 0.01, *P < 0.05

2. 2-Phenyl-benzothiazole 3a 2

Yellow solid. IR (KBr,cm^-1) 3097 ,2900, 2335,1693, 608;

¹HNMR (CDCl₃, δ ppm): 7.3-8.3 (m, 9H, Ar-H); m/e 211, (M-C₇H₄NS) 77, (M-C₆H₅)136.

3. 2-(4’-Chlorophenyl)-benzothiazole, 3a3

Yellow solid. IR (KBr, cm^-1): 3097, 2800, 2334, 1693, 725, 600; ¹HNMR(CDCl₃, δ ppm): 7.33-8.3(m, 8H, Ar-H); m/e 245, (M-C₇H₄NS) 111.5, (M-C₆H₄Cl) 135.

4. 2-(2’-Hydroxyphenyl)-benzothiazole, 3a 4

Yellow solid .IR (KBr, cm^-1): 3756, 3097, 2340,693 602; ¹HNMR(CDCl₃, δ ppm): 5.0 (s, 1H, Ar-OH), 6.79-8.23 (m, 8H, Ar-H); m/e 227, (M-C₇H₄NS) 93, (M-C₆H₅O) 134.

1. 2-(Pyridine-2-yl)-benzothiazole, 3a 5

Brown solid. IR (KBr, cm^-1) 3097,2928, 2335,1693, 610; ¹HNMR(CDCl₃, δ ppm) : 7.55-8.33 (m,8H,Ar-H); m/e 212, (M-C₇H₄NS) 78,(M-C₅H₄N) 136.

6. 2-(4’-Thiophene)-benzothiazole, 3a 6

Brown solid .IR (KBr, cm^-1): 3097,2900, 2334,1693, 631; ¹HNMR(CDCl₃, δ ppm): 7.0(d, 1H, =CH of thiophene ring), 7.1(d, 1H, =CH of thiophene ring)), 7.2 (d,1H, =CH of thiophene ring), 7.55-8.23 (m,4H,Ar-H), m/e 217, (M-C₇H₄NS) 83, (M-C₄H₃S) 134

7. 2-(4’-Nitrophenyl)-benzothiazole 3a7

Yellowish -green solid .IR (KBr, cm^-1): 3097,2900,2335, 611; ¹HNMR(CDCl₃, δ ppm ) : 7.33-8.3(m,8H,Ar-H ); m/e 256, (M-C₇H₄NS) 122,(M-C₆H₄NO₂) 133.

8. 2-(4’-hydroxy-3’-methoxyphenyl) benzothiazole 3a 8

Yellowish -green solid. IR (KBr, cm^-1): 3097, 2900, 2334, 1693, 664; ¹HNMR(CDCl₃, δ ppm): 3.73(s, 1H, OMe), 5.0 (s, 1H, -OH), 6.8-8.23 (m, 7H, Ar-H); m/e 257, (M-C₇H₇O₂) 123,(M-C₇H₄NS) 134.

PHARMACOLOGY:

Anti-inflammatory activity¹²

Among the many methods used for screening of anti-inflammatory drugs, one of the most commonly employed techniques is based upon the ability of such agents to inhibit the edema produced in the hind paw of the rat after injection of a phlogistic agent. Many phlogistic agents (irritants) have been used such as brewer’s yeast, formaldehyde etc. the effect can be measured in several ways. Many methods have been described to measure the paw volume by simple and less accurate and by more sophisticated electronically devised methods. In the present investigation Carageenan-induced Rat Paw oedema method was employed to study anti-inflammatory activity.

Male or female Wistar Albino rats with body weight 100 – 200gm were selected. The animals were starved overnight before start of the study. The animals dosed with 10mg/kg body weight of the test drugs and control received the same volume of water. After 30min. 0.05ml of 1% solution of carrageenan was injected into the plantar side of the left hind paw. The paw was marked with ink at the level of lateral malleolus and immersed in mercury up to the mark to determine the paw volume. Similarly after 30min., 1hr, 2hr, 4hr the paw volume was measured.

Evaluation The volumes are obtained in ml and the average (mean) values are obtained by the statistical analysis. The statistical analysis is performed by using one-way ANOVA followed by Tukey’s test. (Table 2)

CONCLUSION:

In conclusion, we have demonstrated a facile, efficient one pot green synthesis of 2-aryl/heteryl benzothiazole from various aryl and heteryl aldehydes and 2-aminothiophenol in solvent- free conditions under microwave irradiation. The use of ecofriendly catalyst zirconium oxy chloride provided the product 2-aryl/heteryl benzothiazoles 3a (1-8) in excellent yields. All the compounds were evaluated for anti-inflammatory activity and have shown promising anti-inflammatory activity. This approach allows for the synthesis of diverse range of 2-aryl/heteryl benzthiazoles.

ACKNOWLEDGEMENT:

Authors are grateful to the Chairman Mrs. Fatma Rafiq Zakaria, The Chairman, of the Maulana Azad Education Trust for providing necessary research activities. The authors are also thankful to Principal Dr. M.H Dehghan for encouragement and support. We are also thankful to Prof. Shashikant Pattan for his cooperation in conducting the pharmacological screening of the compounds.

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Received on 31.03.2010 Modified on 02.05.2010

Asian J. Research Chem. 3(4): Oct. - Dec. 2010; Page 872-875