Microwave Assisted Synthesis, Characterization and Antimicrobial Activity of Some Schiff Bases of 2- Amino (4- Chloro Phenyl) Thiazoles

 

Kavitha P.N.*, S. Mohan, J. Saravanan and Subhajit Dutta

Department of Pharmaceutical Chemistry, PES College of Pharmacy, Bangalore-50, Karnataka, India.

*Corresponding Author E-mail: pnkavi@gmail.com

ABSTRACT:

2- amino (4- chloro phenyl)thiazoles were synthesized by brominating p-chloroaceto phenone to give p-chloro phenacyl bromide which was then reacted with thiourea in microwave synthesizer to give 2- amino (4- chloro phenyl) thiazoles(II). Later the compound II were treated with ten different substituted aryl aldehydes to yield ten new Schiff bases (III). The compounds were characterized by IR, ¹H NMR and Mass spectral data. Investigation on the antimicrobial activity of these compounds was determined by cup plate method against bacteria and fungi. Among the compounds tested, five compounds exhibited significant antimicrobial activity

 

 

INTRODUCTION:

In the past few years, microwave irradiation has been found to be a convenient source of energy in chemical laboratories. Microwave assisted organic synthesis (MAOS) offers a simple, non-conventional technique for the synthesis of a wide variety of compounds having medicinal, pharmaceutical and commercial importance¹. This technology makes use of principles of Green Chemistry. The use of microwave ovens for rapid organic synthesis for the first time described the utilization and advantages of microwave irradiation for organic synthesis^2,3. Microwave-induced organic reaction enhancement (MORE) is a simple, fast, economic, environment friendly non-traditional method of organic synthesis. The spectacular results viz. shorter reaction time, experimental simplicity, selectivity of products and easy work up etc were obtained giving clear indication on the potentialities of this technique over conventional heating^4,5.

 

Among the heterocyclic compounds, sulphur and nitrogen containing moieties have attracted maximum attention, as they are full of useful ramifications especially in the biological and industrial fields. Thiazole nucleus in particular is the centre of attraction in developing various essential moieties in pharmaceutical industries. A simple sulphonamide antibiotic derived from 2-aminothiazole, sulphathiazole was one of the first commercial synthetic drugs containing thiazole⁶.

 

Substituted thiazoles and benzothiazoles have been reported to possess an array of biological activities like anti-microbial^7,8, anti-inflammatory⁹, antimalarial ¹⁰ antipsychotic¹¹,antioxidant¹² and antitubercular activities¹³ . The above reports encouraged us to carry out the synthesis of novel thiazoles. The synthesized compounds were evaluated for their anti-microbial activity.

 

MATERIAL AND METHODS:

Chemicals:

p-chloroacetophenone, bromine, 4-methoxy benzaldehyde, 3,4,5-trimethoxy benzaldehyde, 2-chlorobenzaldehyde, 2-hydroxy benzaldehyde, 4-chloro benzaldehyde, 4-hydroxy benzaldehyde and 3-methoxy-4-hydroxy, 3,4-dimethyl amino benzaldehyde were procured from Merck India Ltd, Mumbai. Thiourea was procured from Ranbaxy laboratories, Delhi. Sodium carbonate was procured from CDH laboratory reagents, 3-nitro benzaldehyde and 4-nitro benzaldehyde was procured from S. D. Fine Chem. Ltd, Bilaspur.

 

Preparation of p-chlorophenacyl bromide:

To a solution of p-chloro acetophenone (0.1M) in acetic acid (20 ml), bromine (0.1M) in acetic acid (15 ml) was added drop wise with stirring at 0-10⁰C for one hour. It was further stirred for 2 hours at room temperature and poured into crushed ice (100g). The solid was separated by filtration, washed with water and dried. The crude p-chlorophenacyl bromide was purified by recrystallization twice with methanol to obtain colorless crystals. (66%)  M.P-94-96⁰C.

 

 

Table 1: Physical data of 2- amino (4- chloro phenyl) thiazole (SMK-II)

Comp. Code	Mol. Formula	M.W(g)	Recrystallization Solvent	M.P (0C)	% Yield	TLC Solvent System	Rf Value
SMK-II	C9H7ClN2S	210.68	Benzene	145	92	CHCl3:EA (8:2)	0.57

 

Table 2: Physical data of 2-[(substituted benzylidene) amino]-4-(4- chloro phenyl) thiazoles (SMK-II a-j)

Comp. Code	R	Mol. formula	M.W (g)	M.P (0C)	% Yield	TLC Solvent System	Rf Value
SMK-IIa	4-dimethyl amino	C18H16ClN3S	341.86	210	95	CHCl3:EtOH (8:2)	0.66
SMK-IIb	3,4,5-trimethoxy	C19H17ClN2 O3S	388.87	198	65	CHCl3:EtOH (8:2)	0.69
SMK-IIc	3-nitro	C16H10ClN3O2S	343.79	185	68	CHCl3:EtOH (8:2)	0.54
SMK-IId	4-methoxy	C17H13ClN2OS	328.04	195	63	CHCl3:EtOH (8:2)	0.62
SMK-IIe	4-hydroxy	C16H11ClN2OS	314.79	166	72	CHCl3:EtOH (8:2)	0.72
SMK-IIf	4-chloro	C16H10Cl2N2S	333.24	176	91	CHCl3:EtOH (8:2)	0.65
SMK-IIg	2-chloro	C16H10Cl2N2S	333.24	174	65	CHCl3:EtOH (8:2)	0.73
SMK-IIh	2-hydroxy	C16H11ClN2OS	314.79	168	58	CHCl3:EtOH (8:2)	0.55
SMK-IIi	3-methoxy-4-hydroxy	C17H13ClN2O2S	344.82	155	89	CHCl3:EtOH (8:2)	0.64
SMK-IIj	2-nitro	C16H10ClN3O2S	343.79	183	78	CHCl3:EtOH (8:2)	0.74

 

 

Preparation of 2- amino (4- chloro phenyl) thiazoles:

A mixture of p-chloromphenacyl bromide (1.1g, 5 mM), thiourea (0.38g, 5 mM) in ethanol (10 ml) was irradiated in an unmodified microwave oven for 1 min. with an on-off cycle. The reaction was monitored on TLC using n-hexane/EtOAc (7:3 v/v) as a solvent system. On completion of the reaction the reaction mixture was cooled to room temperature and triturated with sodium carbonate solution. The triturated mixture was allowed to stand for 15 min to complete the separation of the product and then filtered. The solid was washed with water, dried and crystallized from benzene to yield pure thiazole. The thiazole were further treated with different substituted aromatic aldehydes to give schiff bases of 2-amino(4-chloro phenyl)thiazoles.

All the products were subjected to analysis by different spectral methods like, IR, NMR and mass and the structural interpretation was carried out.

Antimicrobial studies:

All the synthesized compounds were screened for their antibacterial and antifungal activity by agar diffusion method¹⁴ at a concentration of 50µg/ml against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Klebsiella pneumonia, Aspergillus niger and Candida albicans. After 24h of drug addition, zone of inhibition was measured in mm and recorded. Ampicillin, Norfloxacin and Mecanazole nitrate at 50 µg/ml were used as standards in the experiment.

 

Table 3: Spectral data of 2- amino (4- chloro phenyl) thiazole (SMK-II)

Comp. Code	Λmax.(nm)	IR(KBr)(cm-1)	1H NMR(DMSO)(δ)
SMK-II	240	738.66(C-Cl); 1571.47 (ArC=C); 3140.27(ArC-H); 1306.64(C-N); 3403.03 and 1514.14(NH2);	5.00 (br,2H, NH2); 7.25 (s,1H, Thiazole-H); 7.55 (d,2H, Ar-H); 7.74 (d,2H, Ar-H)

 

Table 4: Physical data of 2-[(substituted benzylidene) amino]-4-(4- chloro phenyl)  thiazoles (SMK-II a-j)

Comp. Code	R	Λ max. (nm)	IR(KBr)(cm-1)	1H NMR (DMSO)(δ)	MASS M+
SMK-IIa	4-dimethyl amino	280	744.96(C-Cl); 1308.32 (C-N);1615.53(N=CH); 1532.01 and1468.60 (ArC=C);3120.44 (ArC-H)	3.06(s,6H,2CH3);6.80(d,2H, Ar-H);7.50(d,2H,Ar-H);7.85 (d,2H,Ar-H);7.95(t,3H,Ar-H and Thiazole-H);8.89(s,1H,-N=CH);	[146]+
SMK-IIb	3,4,5-trimethoxy	282	727.27(C-Cl); 2850.80 (OCH3);1640.53 (N=CH); 1516.08 and 1475.68(ArC=C); 3050.57(ArC-H)	----	----
SMK-IIc	3-nitro	268	833.46(C-Cl); 1665.04(N=CH);  1600 and 1475.56 (ArC=C); 2925.23(ArC-H);1530.64 and 1350.66(NO2)	----	----
SMK-IId	4-methoxy	277	730.27(C-Cl); 2865.63 (OCH3);  1633.77(N=CH);  1599.08 and 1475.68 (ArC=C); 3025.15(ArC-H)	----	----
SMK-IIe	4-hydroxy	272	773.35(C-Cl); 1623.87(N=CH);  1530.94 and 1485.86 (ArC=C); 3128.08 (ArC-H); 1267.49 (C-O); 3431.07 (OH)	----	----
SMK-IIf	4-chloro	261	726.47(C-Cl); 1673.83(N=CH);  1620.17 and 1486.57 (ArC=C); 3120.56 (ArC-H)	7.20(d,2H,Ar-H);7.50 (d,2H,Ar-H);7.85 (d,2H,Ar-H);7.95 (t,3H,Ar-H and Thiazole-H); 8.89(s,1H,        -N=CH);	----
SMK-IIg	2-chloro	260	765.55(C-Cl); 1644.87(N=CH);  1567.94 and 1454.57 (ArC=C); 3155.56 (ArC-H)	----	----
SMK-IIh	2-hydroxy	270	736.35(C-Cl); 1655.69(N=CH);  1600.94 and 1470.86 (ArC=C); 3125.55 (ArC-H); 1339.55 (C-O); 3455.76(OH)	----	----
SMK-IIi	3-methoxy-4-hydroxy	278	727.72(C-Cl); 1673.82 (N=CH);  1589.56 and 1475.96(ArC=C); 3150.98 (ArC-H); 2865.63 (OCH3); 1344.45 (C-O); 3498.86 (OH)	----	----
SMK-IIj	2-nitro	267	745.46(C-Cl);1689.54 (N=CH);  1608.56 and 1476.96(ArC=C); 3120.50 (ArC-H); 1550.04 and 1350.88(NO2)	----	----

 

Table 5: Antimicrobial activity of 2- amino (4- chloro phenyl) thiazole (SMK-II)

Comp. Code	Zone of Inhibition in mm.
	S. aureus	B. subtilus	E. coli	K. pneumonia	A. niger	C. albicans
SMK-II	14	13	12	12	15	--
Ampicillin	24	19	23	18	--	--
Norfloxacin	34	27	25	27	--	--
Miconazole	--	--	--	--	30	27

 

Table 6:Antimicrobial activity of 2-[(substituted benzylidene) amino]-4-(4- chloro phenyl) thiazoles (SMK-II a-j)

Comp. Code	Zone of Inhibition in mm.
	S.aureus	B.subtilus	E.coli	K.pneumonia	A. niger	C. albicans
SMK-IIa	16	12	14	--	15	--
SMK-IIb	18	14	--	14	13	--
SMK-IIc	14	12	--	12	12	--
SMK-IId	15	15	14	10	13	--
SMK-IIe	20	17	15	14	18	--
SMK-IIf	22	18	20	17	19	--
SMK-IIg	20	17	17	16	18	--
SMK-IIh	20	15	16	14	17	--
SMK-IIi	20	15	19	15	17	--
SMK-IIj	13	12	11	10	12	--
Ampicillin	24	19	23	18	--	--
Norfloxacin	34	27	25	27	--	--
Miconazole	--	--	--	--	30	27

 

 

RESULTS:

Among the drugs tested for antimicrobial activities, SMK-IIe, SMK-IIf, SMK-IIg, SMK-IIh and SMK-IIi exhibited potent activity by showing zone of inhibition ranging from 14 to 22 mm. All these drugs showed potent activity against staphylococcus aureus with high zone of inhibition. All other drugs showed moderate inhibitory properties against the test organisms. Against Candida albicans, none of the test drugs showed inhibitory activity. Standard drugs, Ampicillin, Norfloxacin and Mecanazole nitrate exhibited potent inhibitory properties against all the test organisms.

 

DISCUSSION:

From the IR, ¹H NMR and Mass spectra obtained, characterization of data has been done and given in table 1, 2, 3 and 4. The IR spectrum of 2- amino (4- chloro phenyl) thiazole shows the –NH_­2 ­ peak at 3403.0 cm-¹. The NMR spectrum shows a broad peak at δ = 5 of –NH_­2 ­ and also a sharp singlet peak at δ = 7.25 of thiazole-H along with the doublet peaks of the Ar-Hs.

 

The IR spectra of all the Schiff bases show the disappearance of –NH_­2 ­ peak and the appearance of –N=CH (Imine) peak at a range of 1690-1640 cm-¹, which clearly suggest the formation of the expected compounds. The NMR spectra of the compounds 2-[(4-dimethylamino benzylidene) amino]-4-(4-chloro phenyl) thiazole (SMK-IIa) and 2-[(4-chloro benzylidene) amino]-4-(4- chloro phenyl) thiazoles (SMK-IIf), show sharp singlet peak at δ = 8.9 of –N=CH (Imine-H) which also further confirm the formation of the compounds of the series. The compound SMK IIa was also confirmed by Mass spectrum. The spectrum shows exact mass as 341 and molecular ion peak (M⁺) at 146.

 

Acknowledgements:

The authors are thankful to Management, PES College of Pharmacy for providing necessary facilities and AICTE, New Delhi for grant under Research promotion scheme.

 

REFERENCES:

1.       Subarna Ganguli. An overview of microwave synthesis.  Pharma times, 2006; 38(12), 24-25

2.       Gedye R.et al .The use of microwave ovens for rapid organic synthesis. Tetrahedron Lett., 1986, 27, 279-282.

3.       Gedye, R. N et al .Synthesis of Organic compounds in microwave ovens. Can. J. Chem. 1988, 66, 17-26.

4.       Caddick S, Microwave assisted synthesis of 2-aminoquinolines.Tetrahedron, 1995, 51, 10403.

5.       D. Stuerga et al. Microwave heating as a new way to induce localized enhancements of reaction rate. Non-isothermal and heterogeneous kinetics. Tetrahedron, 1996, 52, 5505-5510.

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6.       Metger JV.Chemistry of Heterocyclic compounds.Vol.6, Pergamon press.1984; 328.

7.       Sahu SK et al Synthesis and antibacterial activity of 2-(2,4-dinitrophenyl)-3,5- diphenyl(substituted)-6-aryl-3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d]thiazoles.Indian journal of pharmaceutical sciences, 2006; 68(3): 377-380

8.       Trapani G et al Synthesis and antimicrobial activity of some N-alkenyl-2 acyl alkylidene-2,3-dihydro-1,3-benzothiazoles. Arzneimittel-forschung, 1994; 44(8): 969-971.

9.       Palagiano et al .Synthesis and SAR study of some imidazo{2,1-b]thiazole carboxylic and acetic acids with anti-inflammatory and analgesic activities.Eur J Med Chem 1995;30(11):901-909.

10.     Hout S et al .Activity of benzothiazoles and chemical derivatives on Plasmodium falciparum.Parasitology, 2004; 129: 525-542.

11.     Takamori et al. Antipsychotic profile of 5-{2-[4-(6-fluoro-1H-indole-3-yl)piperidin-1- yl]ethyl}-4-(4-fluorophenyl) thiazole-2-carboxylic acid amide(NRA0562) in rats. Life Sciences 2002;71(8):947-52.

12.     Mohan S et al.Microwave assisted synthesis of a series of Ethyl 2- arylamino-4-aryl/ heteroarylthiazole-5-acetates and their antioxidant property. Asian Journal of Chemistry, 2005; 17(2):991-995.

13.     Andreani A et al. Synthesis and antitubercular activity of  imidazo[2,1-b] thiazoles. European journal of medicinal chemistry, 2001; 36(9): 743-746.

14.     Barry A L, Antimicrobial susceptibility test, principle and practices (Illus lea and fehinger, Philedephia USA) 1976, pp 93-108.

 

 

Received on 19.04.2010        Modified on 08.05.2010

Accepted on 24.05.2010        © AJRC All right reserved