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Synthesis and charcterization some substituted benzothiazole derivaties.

4-Thiazolidinones exhibit pharmacological activities such as anti inflammatory [1], antitubercular [2], antitumor [3], antibacterial [4,5] and antifungal [6] activities. Moreover, benzothiazole derivatives are associated with anti inflammatory, anticonvulsant, antibacterial [9] and anti-HIV [10] activities. In the light of these findings synthesis of some new 4-thiazolidinones derivatives having benzothiazole nucleus has been undertaken in order to assess their pharmacological profile. Therefore, we have prepared 5-(4-Substituted benzylidene)-3-(6-Substituted benzo[d]thiazol-2-yl)-2-(4-Substituted phenyl) thiazolidin-4-one from substituted aniline.

Experimental

Melting points were determined in open capillary tubes with LAB-INDIA MS-VIS Visual melting point apparatus and uncorrected. T.L.C was run on silica gel G plates using toluene: ethyl acetate: formic acid (5:4:1) as developing solvent for the purity of the compounds. IR spectra were obtained on FT-IR 8300 (shimadzu) spectrometer by pressed-pellet technique. [sup.1]HNMR spectra were determined on AVANCE 300 MHz instrument. Chemical shifts are given in o values down field from TMS as internal standard. Mass spectra were recorded on SHIMADZU QP2010 PLUS. All compounds showed appropriate IR, [sup.1]HNMR and Mass spectra. Elemental analyses were carried out with a VARIO EL III, CHNS Elimentar analyzer and results were within [+ or -] 0.6% of theoretical values.

[FIGURE 1 OMITTED]

Synthesis of 6-Substituted-1, 3-benzothiazol-2-amine (I)

A mixture of aniline (0.01 M) and potassium thiocyanate (0.01 M) in glacial acetic acid (20 mL) was cooled and stirred. To this solution bromine (0.01 M) was added from dropping funnel at such a rate that the temperature does not rise beyond 0[degrees]C. After all the bromine has been added, the solution was stirred for an additional 2h at 0[degrees]C. It was allowed to stand for overnight during which period an orange precipitate settled at the bottom, water (6 mL) was added quickly slurry was heated at 85[degrees]C on steam bath and filtered hot. The orange residue was placed in a reaction flask and treated with 10 mL of glacial acetic acid, heated again to 85[degrees]C and filtered in hot. The combined filtrate was cooled and neutralized with concentrated ammonia solution to pH 6 when dark yellow precipitate was appeared. Recrystallized from benzene to obtain the 6-substituted-1, 3-benzothiazol-2-amine [11].

6-Chloro-2-aminobenzothiazole: yield 75%; m.p. 210-215[degrees]C; IR (KBR) 3430, 3010, 1350, 712 [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]) [delta] 7.10 (s,1H, Ar), 7.56 (s, 1H, Ar), 4.00(s, 2H, N[H.sub.2]); MS m/z 183([M.sup.+]), 184([M.sup.+1]), 185([M.sup.+2]) 74(base).

6-Floro-2-aminobenzothiazole: yield 31%; m.p. 192-196[degrees]C; IR (KBR) 3430, 3010, 1350, 1215 [cm.sup.-1]; [supp.1]H NMR (CD[Cl.sub.3]) [delta] 7.21 (s, 1H, Ar), 8.12 (s, 1H, Ar), 6.68(s, 2H, N[H.sub.2]); MS m/z 168([M.sup.+]), 169([M.sup.+1]), 170([M.sup.+2]) 100(base).

6-Nitro-aminobenzothiazole: yield 74%; m.p. 162-165[degrees]C; IR (KBR) 3430, 3010, 1558, 1350 [cm.sup.-1]; [sup.1]H NMR (CD[O.sub.3]) [delta] 8.48 (s, 1H, Ar), 9.05(s, 1H, Ar), 5.14(s, 2H, N[H.sub.2]); MS m/z 195([M.sup.+]), 197([M.sup.+2]) 74(base).

6-Methoxy-aminobenzothiazole: yield 69.4%; m.p. 262-265[degrees]C; IR (KBR) 3360, 3300, 1640 [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]) [delta] 3.90 (s, 3H, Ar), 7.16 (s, 1H, Ar), 5.32(s, 2H, N[H.sub.2]); MS m/z 180([M.sup.+]), 182([M.sup.+2]) 45(base).

Synthesis of 4-substituted benzylidene)-6-substituted benzo[d]thiazol-2-amine (II)

A mixture of compound (I) (0.01M) and substituted benzaldehyde (0.02 M) and 2-3 drops of glacial acetic acid in methanol (20 mL) was refluxed on a water bath for about 5 h. The solid was separated and recrystallized from ethanol [12].

4-Chlorobenzylidene)-6-chlorobenzo[d]thiazol-2-amine: yield 45%; m.p.216-218[degrees]C; IR(KBR) 1555,707 [cm.sup.-1]; [sup.1]HH NMR (DMSO) [delta] 7.56 (s, 1H, Ar), 7.6 (s, 1H, Ar), 7.75(s, 1H, N = CH); MS m/z 305([M.sup.+]), 306([M.sup.+1]).

4-Methoxybenzylidene)-6-chlorobenzo[d]thiazol-2-amine: yield 45%; m.p. 264-268[degrees]C; IR (KBR) 1575,1029,760 [cm.sup.-1]; [sup.1]H NMR ((DMSO) [delta] 7.13 (s, 1H, Ar), 8.17 (s, 1H, Ar), 3.73 (s, 3H, Ar), 7.73(s, 1H, N = CH); MS m/z 302([M.sup.+]), 303([M.sup.+1]), 304([M.sup.+2]).

4-Chlorobenzylidene)-6-florobenzo[d]thiazol-2-amine: yield 38%; m.p. 254-256[degrees]C; IR (KBr) 1576, 1215, 770 [cm.sup.-1]; [sup.1]H + NMR ((DMSO) [delta] 7.19(s, 1H, Ar), 7.31 (s, 1H, Ar), 7.75(s, 1H, N = CH); MS m/z 290([M.sup.+]).

4-Methoxybenzylidene)-6-florobenzo[d]thiazol-2-amine: yield 49%; m.p.221-224[degrees]C; IR(KBR) 1640, 1252, 1030, 760 [cm.sup.-1]; [sup.1]H NMR ((DMSO) [delta] 7.18 (s, 1H, Ar), 7.74 + (s, 1H, Ar), 3.42(s, 3H, Ar), 7.76 (s, 1H, N = CH); MS m/z 286([M.sup.+]), 287([M.sup.+1]), 288([M.sup.+2]).

4-Chlorobenzylidene)-6-nitrobenzo[d]thiazol-2-amine: yield 51%; m.p. 196-198[degrees]C; IR (KBR) 1571, 1560, 780 [cm.sup.-1]; [sup.1]H NMR ((DMSO) [delta] 7.19(s, 1H, Ar), 7.31 (s, 1H, Ar), 7.75(s, 1H, N = CH); MS m/z 317([M.sup.+]), 318([M.sup.+1]).

4-Methoxybenzylidene)-6-nitrobenzo[d]thiazol-2-amine: yield62%; m.p.221-224[degrees]C;

IR(KBR) 1576, 1558, 1027, 760 [cm.sup.-1]; [sup.1]H NMR ((DMSO) [delta] 7.18 (s, 1H, Ar), 7.76 (s, 1H, Ar), 3.45(s, 3H, Ar), 7.72 (s, 1H, N = CH); MS m/z 313([M.sup.+]), 315([M.sup.+2]).

4-Chlorobenzylidene)-6-methoxybenzo[d]thiazol-2-amine: yield 55%; m.p. 201-205[degrees]C; IR (KBR) 1575, 1029, 780 [cm.sup.-1]; [sup.1]H NMR ((DMSO) [delta] 7.3(s,1H, Ar), 7.6(s, 1H, Ar), 3.73(s, 3H, Ar), 7.75(s, 1H, N = CH); MS m/z 302([M.sup.+]), 303([M.sup.+1]).

4-Methoxybenzylidene)-6-methoxybenzo[d]thiazol-2-amine: yield 62%; m.p. 221-224[degrees]C; IR (KBR) 1576,1558,1027, 760 [cm.sup.-1]; [sup.1]H NMR ((DMSO) [delta] 7.18 (s, 1H, Ar), 7.76 (s, 1H, Ar), 3.45(s, 3H, Ar), 7.72 (s, 1H, N = CH); MS m/z 298([M.sup.+]), 300([M.sup.+2]).

Synthesis of 3-(6-substituted benzo[d]thiazol-2-yl)-2-(4-substituted phenyl) thiazolidin-4-one (III)

A mixture of compound (0.01M) (II) in ethanol (50 mL) and mercaptoacetic acid (0.01 M) with pinch of Zn[Cl.sub.2] was refluxed on a water bath for 8 h. The solid was recrystallized from methanol & chloroform (1:1) mixture to give compound [12].

3-(6-Chloro benzo[d]thiazol-2-yl)-2-(4-chloro phenyl) thiazolidin-4-one: yield 59%; m.p. 169-172[degrees]C; IR (KBR) 2815, 1649, 1555, 1531, 707 [cm.sup.-1]; [sup.1]H NMR (DMSO) [delta] 7.56 (s, 1H, Ar), 7.6 (s, 1H, Ar), 5.21(s, 1H, HC-Ar), 3.91(s, 2H, SC[H.sub.2]); MS m/z 381([M.sup.+]), 382([M.sup.+1]).

3-(6-Chloro benzo[d]thiazol-2-yl)-2-(4-methoxy phenyl) thiazolidin-4-one: yield 62%; m.p. 212-214[degrees]C; IR (KBR) 2837, 1732, 1531, 1029, 699 [cm.sup.-1]; [sup.1]H NMR (DMSO) [delta] 7.14 (s, 1H, Ar), 7.77 (s, 1H, Ar), 5.21(s, 1H, HC-Ar); 3.91(s, 2H, SC[H.sub.2]), 3.73 (s, 3H, Ar); MS m/z 376([M.sup.+]), 377([M.sup.+1]).

2-(4-Chloro phenyl)-3-(6-fluoro benzo[d]thiazol-2-yl) thiazolidin-4-one: yield 32%; m.p. 195-197 [degrees]C; IR (KBR) 2814, 1716, 1262,770 [cm.sup.-1]; [sup.1]H NMR (DMSO) [delta] 7.14 (s, 1H, Ar), 7.65 (s, 1H, Ar), 5.16(s, 1H, HC-Ar); 3.89(s, 2H, SC[H.sub.2]), 3.73 (s, 3H, Ar); MS m/z 363([M.sup.+]), 364([M.sup.+1]).

3-(6-Fluoro benzo[d]thiazol-2-yl)-2-(4-methoxy phenyl) thiazolidin-4-one: yield 49%; m.p. 175-179 [degrees]C; IR (KBR) 2817, 1649, 1262, 1026 [cm.sup.-1]; [sup.1]H NMR (DMSO) [delta] 7.14 (s, 1H, Ar), 7.77 (s, 1H, Ar), 5.21(s, 1H, HC-Ar); 3.91(s, 2H, SC[H.sub.2]), 3.73 (s, 3H, Ar); MS m/z 360([M.sup.+]).

2-(4-Chloro phenyl)-3-(6-nitro benzo[d]thiazol-2-yl) thiazolidin-4-one: yield 61%; m.p. 246-249 [degrees]C; IR (KBR) 3090, 1724, 1558,1535, 780 [cm.sup.-1]; [sup.1]H NMR (DMSO) [delta] 8.14 (s, 1H, Ar), 9.05 (s, 1H, Ar), 5.92(s, 1H, HC-Ar); 3.38(s, 2H, SC[H.sub.2]), 3.28 (s, 3H, Ar); MS m/z 390([M.sup.+]).

2-(4-Methoxy phenyl)-3-(6-nitro benzo[d]thiazol-2-yl) thiazolidin-4-one: yield 70%; m.p. 156-158 [degrees]C; IR (KBR) 3026, 1743, 1565, 1027 [cm.sup.-1]; [sup.1]H NMR (DMSO) [delta] 8.48 (s, 1H, Ar), 9.05 (s, 1H, Ar), 5.76(s, 1H, HC-Ar); 3.38(s, 2H, SC[H.sub.2]), 3.73 (s, 3H, Ar); MS m/z 387([M.sup.+]) 389([M.sup.+2]).

2-(4-Chloro phenyl)-3-(6-methoxy benzo[d]thiazol-2-yl) thiazolidin-4-one: yield 62%; m.p. 269-271 [degrees]C; IR (KBR) 2837, 1732, 1531, 1029, 699 [cm.sup.-1]; [sup.1]H NMR (DMSO) o 7.14 (s, 1H, Ar), 7.77 (s, 1H, Ar), 5.21(s, 1H, HC-Ar); 3.91(s, 2H, SC[H.sub.2]), 3.73 (s, 3H, Ar); MS m/z 376([M.sup.+]), 377([M.sup.+1]).

3-(6-Methoxybenzo[d]thiazol-2-yl)-2-(4-methoxyphenyl) thiazolidin-4-one: yield 58%; m.p. 269-271 [degrees]C; IR (KBR) 2830, 1742, 1525, 1024, 641 [cm.sup.-1]; [sup.1]H NMR (DMSO) [delta] 7.14 (s, 1H, Ar), 7.77 (s, 1H, Ar), 5.21(s, 1H, HC-Ar); 3.91(s, 2H, SC[H.sub.2]), 3.73 (s, 3H, Ar); MS m/z 372([M.sup.+]).

Synthesis of 5-(4-Substituted benzylidene)-3-(6-substituted benzo[d]thiazol-2-yl) 2-(4-substituted phenyl) thiazolidin-4-one (IV)

Equimolar solution of (III) (0.02 M) and substituted benzaldehyde (0.02 M) in 1,4-dioxan (30 mL) in the presence of sodium ethoxide was refluxed for about 5h on water bath and solvent was removed in vacuo. The resulting solid was recrystallized from methanol [12].

DS1: IR (KBR) 3542, 2815, 1649, 1555,707 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.18(s, 1H, N-CH), 5.17(s, 1H, C=C-Ar), 7.56 (s, 1H, Ar), 8.13(s, 1H, Ar); MS m/z 503([M.sup.+]), 501.

DS2: IR (KBR) 3545, 2837, 1732, 1575, 1029, 760 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.18(s, 1H, N-CH), 3.73 (s, 3H, Ar), 5.17(s, 1H, C=C-Ar), 7.56 (s,1H, Ar), 8.13(s,1H, Ar); MS m/z 498([M.sup.+]), 500([M.sup.+2]).

DS3: IR (KBR) 3537, 2672, 1730, 1571, 1024,751 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.18(s, 1H, N-CH), 3.73 (s, 3H, Ar), 5.17(s, 1H, C=C-Ar), 7.56 (s, 1H, Ar), 8.13(s, 1H, Ar); MS m/z 495([M.sup.+]), 496([M.sup.+1]).

DS4: IR (KBR) 3586, 2814, 1576, 1265, 770 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.18(s, 1H, N-CH), 5.17(s, 1H, C=C-Ar), 7.26 (s, 1H, Ar), 7.83(s, 1H, Ar); MS m/z 485([M.sup.+]), 487([M.sup.+2]).

DS5: IR (KBR) 3439, 2721, 1541, 1248, 1026, 770 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.12(s, 1H, N-CH), 3.61 (s, 3H, Ar), 5.17(s, 1H, C=C-Ar), 7.15 (s, 1H, Ar), 7.83(s, 1H, Ar); MS m/z 482([M.sup.+]), 484([M.sup.+2]).

DS6: IR (KBR) 3539, 2921, 1541, 1248, 1026 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.12(s, 1H, N-CH), 3.61 (s, 3H, Ar), 3.73 (s, 3H, Ar), 5.17(s, 1H, C=C-Ar), 7.15 (s, 1H, Ar), 7.83(s, 1H, Ar); MS m/z 478([M.sup.+]), 479([M.sup.+1]).

DS7: IR (KBR) 3586, 2920, 1560, 770 [cm.sup.-1]; [sup.1]H NMR (DMSO) ; 1H NMR (DMSO) 3.18(s, 1H, N-CH), 5.17(s, 1H, C=C-Ar), 7.26 (s, 1H, Ar), 7.83(s, 1H, Ar); MS m/z 512([M.sup.+]), 514([M.sup.+2]).

DS8: IR (KBR) 3577, 2721, 1602, 1027, 680 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.12(s, 1H, N-CH), 3.61 (s, 3H, Ar), 5.17(s, 1H, C=C-Ar), 7.15 (s, 1H, Ar), 7.83(s, 1H, Ar); MS m/z 509([M.sup.+]), 511([M.sup.+2]).

DS9: IR (KBR) 3539, 2921, 1565, 1026 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.12(s, 1H, NCH), 3.61 (s, 3H, Ar), 3.73 (s, 3H+1 Ar), 5.17(s, 1H, C=C-Ar), 7.15 (s, 1H, Ar), 7.3(s, 1H, Ar); MS m/z 505([M.sup.+]), 506([M.sup.+1]).

DS10: IR (KBR) 3573, 2921, 1576, 1026, 743[cm.sup.-1]; [sup.1]H NMR (DMSO) 3.12(s, 1H, N-CH), 3.61 (s, 3H, Ar), 3.73 (s, 3H, Ar), 5.17(s, 1H, C=C-Ar), 7.12 (s, 1H, Ar), 7.53(s, 1H, Ar); MS m/z 498([M.sup.+]), 500([M.sup.+2]).

DS11: IR (KBR) 3573, 2921, 1576, 1026,761 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.12(s, 1H, N-CH), 3.61 (s, 3H, Ar), 3.73 (s, 3H, Ar), 5.17(s, 1H, C=C-Ar), 7.15 (s, 1H, Ar), 7.83(s, 1H, Ar); MS m/z 494([M.sup.+]), 496([M.sup.+2]).

DS12: IR (KBR) 3573, 2921, 1576, 1026 [cm.sup.-1]; [sup.1]H NMR (DMSO) 3.12(s, 1H, NCH), 3.61 (s, 3H, Ar), 3.73 (s, 3H, Ar), 5.17(s, 1H, C=C-Ar), 7.06 (s, 1H, Ar), 7.63(s, 1H, Ar); MS m/z 474([M.sup.+]), 475([M.sup.+1]).

Results and discussion

The target compounds were synthesized by standard protocol. During the synthesis, all intermediates compounds were identified and the completion of reaction was ensured by TLC with suitable solvent system and purified by eluting solvent systems, toluene: Ethylacetate: Formic acid (5: 4: 1). The crystals were collected and then used for characteristic of IR, NMR, and Mass and Melting point determination and pharmacological evaluations.

Acknowledgement

The authors are thankful to our beloved chairman Sri P.Balraj, S.S.R College of Pharmacy, Mahabubnagar and A.P.

References

[1] Goel, B., Ram, R., Tyagi, E., Bansal, A., Kumar, D., Mukherjee, D and Sinha, J.N., Eur. J. Med Chem., 1999, 34, 265.

[2] Joshi, D.G., Oza H.B and Parekh, H.H., Indian J. Heterocyclic. Chem., 2001, 11, 145.

[3] Singh, S.P., Ansari, W.H., Lemiere, G., Jonckers, T and Rogers, D., Eur. J. Med Chem., 2002, 37, 63.

[4] Patel, H.D., Misty, B.D and Desai, K.R., Indian J. Heterocyclic. Chem., 2002, 11, 233.

[5] Dobaria, A.V., Patel, J.R., Padalia, J.V and Parekh, H.H., Indian J. Heterocyclic. Chem., 2001, 11, 115.

[6] Daulatabad, C.D and Bhat, G.G., Indian J. Heterocyclic. Chem., 199, 9, 157.

[7] Sharma, P.K., Sawhay, S.N., Gupta, A., Singh, G.B and Bani., Indian J. Chem., 1998, 37B, 376.

[8] Yogeeswari, P., Sriram, D., Ramamoorthy, L., Sunil, J.J., Satish, K.S and Stables, J.P., Eur. J. Med Chem., 2002, 37, 231.

[9] Bhusari, K.P., Khedekar, P.B., Umathe, S.N., Bahekar, R.H and Rao, R.R.A., Indian J. Heterocyclic. Chem., 2001, 10, 231.

[10] Racane, L., Tralic, K.V., Fiser, J.L., Boykin, D.W., Karminski, Z.G., Heterocycles., 2001, 55, 2085.

[11] Siddiqui, N., Rana, A., Khan, S.A., Mashooq, A. B., Eur. J. Med Chem., 2008, 43, 1114-1122.

[12] Singh, S., Smriti singh., Praveen singh., Indian J. Heterocyclic. Chem., 2006, 15, 263-266.

D. Shashank *, E. Naveen kumar (1), V. Sri Ram (2), V. Balasubramaniam (3), V. Padmini (4), T. Lathamry (5) and R. Suthakaran (6)

* (1,2,3,6) Smt.Sarojini Ramulamma College of Pharmacy, Mahabubnagar-509 001. (5) J.K.K.Nataraja College of Pharmacy, Komarapalyam-638 183.

E-mail-shashank050301@gmail.com
Table 1: Physico chemical properties of DS1-DS12.

Compound   X             Y             Z
ID

DS1        Cl            Cl            Cl
DS2        Cl            Cl            OC[H.sub.3]
DS3        Cl            OC[H.sub.3]   OC[H.sub.3]
DS4        F             Cl            Cl
DS5        F             Cl            OC[H.sub.3]
DS6        F             OC[H.sub.3]   OC[H.sub.3]
DS7        N[O.sub.2]    Cl            Cl
DS8        N[O.sub.2]    Cl            OC[H.sub.3]
DS9        N[O.sub.2]    OC[H.sub.3]   OC[H.sub.3]
DS10       OC[H.sub.3]   Cl            Cl
DS11       OC[H.sub.3]   Cl            OC[H.sub.3]
DS12       OC[H.sub.3]   OC[H.sub.3]   OC[H.sub.3]

Compound   Melting        Yield
ID         point          (%)
           ([degrees]C)

DS1        195            72
DS2        221            65
DS3        172            81
DS4        188            49
DS5        170            53
DS6        216            52
DS7        160            72
DS8        196            74
DS9        215            61
DS10       224            53
DS11       210            59
DS12       188            67
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Author:Shashank, D.; Kumar, E. Naveen; Ram, V. Sri; Balasubramaniam, V.; Padmini, V.; Lathamry, T.; Suthaka
Publication:International Journal of Applied Chemistry
Article Type:Report
Geographic Code:9INDI
Date:May 1, 2010
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