An Efficient One Pot Synthesis of Substituted Derivatives of Pyrimido Benzothiazole

 

Vijay N Bhosale1*, Sambhaji P Vartale1, Sarla N Kalyankar1, Jagannath S Jadhav2 and Sharad V Kuberkar1

1P. G. Department of Organic Chemistry, Yeshwant Mahavidyalaya, Nanded- 431602,India

2Department of Organic Chemistry, N.S.B. College, Nanded-431605,India.

*Corresponding Author E-mail:  bhosalevn@rediffmail.com

 

ABSTRACT

8-Chloro–3- cyano – 2 - methylthio – 4 - oxo - 4[H] - pyrimido - [2,1-b] [1,3] benzothiazole has been prepared by the reaction of 6-Chloro-2-amino benzothiazole with ethyl-2-cyano-3,3-bismethylthioacrylate in the presence of diemethyl formamide and anhydrous potassium carbonate. Suspectibility of compound towards condensation with different reagents like aryl amines, heteryl amines, phenols and compound containing active methylene group has been investigated.

 

KEYWORDS: 8-Chloro–3- cyano – 2 - methylthio – 4 - oxo - 4[H] - pyrimido - [2, 1-b] [1, 3] benzothiazole, ethyl-2-cyano-3, 3-bismethylthioacrylate.

 

 

INTRODUCTION:

Biological activities and various applications of benzothiazole compounds1-3 and compounds containing pyrimidine ring4-5 have stimulated considerable interest to explore the synthesis of new potential compounds in which pyrimidine ring is fused with another biological active nucleus such as benzothiazole through nitrogen atom.

 

The literature survey revels that very few references are available on the synthesis of pyrimido benzothiazole compound.6-10 Wade et. al.7-8 reported synthesis of acidic derivatives of 4H-pyrimido [2,1-b][1,3] benzothiazole –4-ones by the condensation of 2-amino-benzothiazole, 2-amino benzoxazole and 2-amino-1-methyl-benzimidazole independently with 2-amino fumarate and diethyl ethoxy methylene malonate and their antiallergic activity. Methods of preparation of these compounds, reported by this group7-8 are cumbersome, since these methods require the presence of steam of nitrogen gas and gave either 2 or 3 substituted derivatives.

 

Hence, it was considered approprite to devise a convinient route to synthesis 2, 3 – disubstituted 8-Chloro-3-cyano-4-oxo-4[H]-pyrimido [2,1-b] [1,3] benzothiazole. It is surmised that pyrimido benzothiazole and its 2, 3-disubstituted derivatives would exhibits intersting pharmacological applications.

 

RESULTS AND DISCUSSION:

In continuation of our studies in present work, we report one pot synthesis of 8-chloro-3-cyano-2-methylthio-4-oxo-4[H]-pyridimo-[2,1-b] [1,3] benzothiazole and preparation of its 2-substituted derivatives. This compound 3 was prepared by refluxing 6-chloro-2-amino-benzothiazole 1 with ethyl-2-cyano-3,3-bismethyl thioacrylate 2 in the presence of dimethyl formamide and anhydrous potassium carbonate. Since parent compound 3 possesses replaceable active thiomethyl group of 2-position, the suspectibiblity of it towards condensation with different reagents like aryl amines, heteryl amines, phenols and compound containing active methylene group has been investigated. These reaction results in the formation of 2,3-disubstituted derivatives of 8-chloro-3-cyano-2-methylthio-4-oxo-4[H]-pyridimo-[2,1-b] [1,3] benzothiazole.

 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

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Mechanism: Scheme-1

 

The compound 3 on reaction with dimethyl amine in the presence of dimethyl formamide and anhydrous postassium carbonate afforted 8-chloro-3-cyano – 2 – dimethyl amino – 4 – oxo – 4 [H] – pyridimo - [2,1-b] [1,3] benzothiazole 4a. Similarly other aryl amino derivatives were prepared by the reaction of compound 3 independently with p-nitro aniline, p-chloro aniline, p-toludine and p-anisidine to yeild compound 4b-e. Compound 3 on treatment with o-methyl phenol, p- cresol, p-chloro phenol, o-nitro phenol afforded corrosponding 2-aryloxy derivatives i.e. 8-chloro-3-cyano-2-(o-methyl phenoxy/p-methyl phenoxy/p-chloro phenoxy/o-nitro phenoxy/p-nitro phenoxy)-4-oxo-4[H]-pyrimido [2,1-b] [1,3] benzothiazole 5a-e.

 

8-chloro-3-cyano-2-pyrrolidino 6a / 2-morpholino 6b/ 2-piperidino 6c / -4-oxo-4[H]-pyridimo-[2,1-b] [1,3] benzothiazole has been prepared by condensing the cyclic secondary amines independently with compound 3 in presence of dimethyl formamide and anhydrous potassium carbonate.

 

Another type of 2-substituted derivatives of compound 3 were also investigated by reacting compound 3 independently with compounds containing active methylene group viz. ethylacetoacetate, ethyl cyano acetate, diethyl malonate and malonitrile in presence of dimethyl foramide and anhydrous potassium carbonate to form compound 7a-d.

 

The structures of these newly synthesized compounds were confirmed by elemental analysis, IR, 1H-NMR and mass spectral data.

 

EXPERIMENTAL:

All melting points were determined in capillary tube and uncorrected. IR spectra were recorded in KBr pellets on a Bomen, MB 104 FT infrared spectrophotometer. The 1H-NMR were obtained on a FT Gemino 60 (60 MHz) spectrometer with tetramethyl silane as an internal standard. Mass specta were recorded on a FT VG-7070 H mass spectrophotometer using EI technique of 70 ev. Microanalysis was performed on a Heraeus CHN-O rapid analyzer. All the reaction was monitored by thin layer chromatography carried out on 0.2 mm silica gel-G plate using iodine vapour for detection.

8–chloro–3 – cyano – 2 – methylthio – 4 – oxo – 4 [H] – pyrimido - [2,1-b] [1,3] benzothiazole (3 ). A mixture of 6-Chloro-2-amino-benzothiazole (1.84 g, 0.01 m mole) and ethyl 2-cyano-3, 3 –bismethyl thioacrylate (2.12 g, 0.01 m mole) was refluxed in the presence of dimethyl formamide (20-25 ml) and anhydrous potassium carbonate (0.5 g) for 4 h. The reaction mixture was cooled to room temperature and poured on ice cold water. The solid seperated was filtered, washed with water and recrystallised from DMF-ethanol mixture to give 3.

 

1.56 g (51%) m.p. 2550C; EI-MS (m/z - RA%): 309 (M+2, 3), 307(M+, 10), 260, 232, 206, 168, 142; IR (cm-1, KBr) 3210, 2209, 1678; 1H-NMR (DMSO-d6) : d2.6 (s, 3H, SCH3), d 7.1-7.8 (m, 3H, Ar-H) : Found : C, 46.85; H, 1.93; N, 13.65. C12H6N3OS2Cl requires C, 46.90; H, 1.95; N, 13.68.

 

8 – Chloro – 3 - cyano – 2 - (dimethyl amino / p-nitroanilino / p-chloroanilino / p-toludino / p-anisidino) -  4 – oxo – 4[H] – pyrimido [2, 1-b] [1,3] benzothiazole  (4a-e). A mixture of 3 (1 g, 0.001 m mole) and (dimthyl amine / p-nitro aniline / p-chloro aniline / p-toludine / p-anisidine) (1 g, 0.001 m mole) was refluxed in the presence of 30 ml of diemthyl formamide and anhydrous potassium carbonate (0.5g) for 4 h. The reaction mixture was cooled at room tempertaure and poured in ice cold water. The seperated solid product was filtered, washed with water and recrystallised from ethanol to give 4a-e.

 

4a 0.75 g (78%), m.p. 3100C; EI-MS (m/z - RA%): 306 (M+2, 33), 304(M+, 100); IR (cm-1, KBr) 2199, 1661; 1H-NMR (DMSO-d6) : d 1.1 (s, 3H, CH3), d 7.5-8.8 (m, 8H, Ar-H), d 9.2(s, 1H, -NH, exchange with D2O) : Found : C, 51.29; H, 2.92; N, 18.39. C13H9N4OSCl requires C, 51.31; H, 2.96; N, 18.42.

 

4b 0.66 g (65%), m.p. 2700C; EI-MS (m/z - RA%): 399 (M+2, 3), 397(M+, 10); IR (cm-1, KBr) 3250, 2212, 1736; Found : C, 58.97; H, 2.95; N, 15.30. C18H11N4OSCl requires C, 59.01; H, 3.00; N, 15.33.

 

4c 0.64 g (64%), m.p. 2800C; EI-MS (m/z - RA%): 404 (M+2, 15), 402(M+, 45); IR (cm-1, KBr) 3265, 2190, 1680;

 

Found : C, 50.70; H, 1.95; N, 13.90. C17H8N4OSCl requires C, 50.74; H, 1.99; N, 13.93.

 

4d 0.68 g (68%), m.p. 2650C; EI-MS (m/z - RA%): 368 (M+2, 25), 366(M+, 75); IR (cm-1, KBr) 1677, 2215, 3280; Found : C, 58.97; H, 2.95; N, 15.30. C18H11N4OSCl requires C, 59.01; H, 3.00; N, 15.33.

 

4e 0.69g (68%),m.p.302oc;EI-MS(m/z-RA):384 (M+2;20%), 382 (M+;60%) ;IR(cm-1, KBr) 1708cm,1 2210cm,1 3275cm,1 ;Found: C,56.50;H,2.82; N,14.62. C18H11N4O2SCl. Requires C,56.54;h,2.87;N,14.65.

 

8-Chloro-3-cyano-2-(o-methyl phenoxy / p-methyl phenoxy / p-chloro phenoxy / o-nitro phenoxy / p-nitro phenoxy)-4-oxo-4[H]-pyrimido [2, 1-b] [1,3] benzothiazole (5a-e). A mixture of 3 (1 g, 0.001 M mole) and (o-methyl phenol / p-methyl phenol / p-chloro phenol / o-nitro phenol / p-nitro phenol) (1g, 0.001 M mole) was refluxed in the presence of 25 ml of dimethyl formamide and anhydrous potassium carbonate (0.5 g) for 4 h. After cooling the reaction mixture kept over night and poured in ice cold water. The seperated solid product was filtered, washed with water and recrystallised from ethaol to give 5a-e.

 

5a 0.54 g (54%), m.p. 3300C; EI-MS (m/z - RA%): 367 (M+2, 10), 365(M+, 30); IR (cm-1, KBr) 1716, 2219; Found : C, 59.14; H, 2.68; N, 19.14. C18H10N5O3SCl requires C, 59.17; H, 2.73; N, 19.17.

 

5b 0.44 g (44%), m.p. 3100C; EI-MS (m/z - RA%): 367 (M+2, 20), 365(M+, 60); IR (cm-1, KBr) 1705, 2200; Found : C, 59.14; H, 2.69; N, 19.13. C18H10N5O3SCl requires C, 59.17; H, 2.73; N, 19.17.

 

5c 0.33 g (32%), m.p. 3030C; EI-MS (m/z - RA%): 405 (M+2, 30), 403(M+, 90); IR (cm-1, KBr) 1685, 2195; Found : C, 50.58; H, 1.69; N, 10.39. C17H7N3O2SCl2 requires C, 50.62; H, 1.73; N, 10.42.

 

5d 0.34 g (35%), m.p. 3050C; EI-MS (m/z - RA%): 400 (M+2, 25), 398(M+, 75); IR (cm-1, KBr) 1678, 2192; Found : C, 51.20; H, 1.73; N, 14.04. C17H7N4O4SCl requires C, 51.25; H, 1.75; N, 14.07.

 

5e 0.41 g (40%), M.P. 3080C; EI-MS (m/z - RA%): 400 (M+2, 30), 398(M+, 90); IR (cm-1, KBr) 1680, 2195; Found : C, 51.21; H, 1.73; N, 14.02. C17H7N4O4SCl requires C, 51.25; H, 1.75; N, 14.07.

 

8-Chloro-3-cyano-2-pyrrolidino / morpholino / piperidino – 4 – oxo-4[H]-pyrimido [2,1-b] [1,3] benzothiazole (6a-c). A mixture of 3 (1 g, 0.001 M mole) and appropriate cyclic secondary amine (pyrrolidine / morpholine / piperidine) was refluxed in presence of 30 ml dimethyl formamide and (0.5 g) anhydrous potassium carbonate for 3 h. After cooling the contents were poured into ice-cold water and kept over night. The separated solid was filtered, washed with water and recrystallised from ethanol to give 6a-e.

 

6a 0.66 g (66%), m.p. 3060C; EI-MS (m/z - RA%): 332 (M+2, 33), 330(M+, 100); IR (cm-1, KBr) 1668, 2220; Found : C, 54.50; H, 3.30; N, 16.91, C15H11N4OSCl requires C, 54.54; H, 3.33; N, 16.96.

 

6b 0.61 g (61%), m.p. 3110C; EI-MS (m/z - RA%): 348 (M+2, 15), 346(M+, 45); IR (cm-1, KBr) 1709, 2220; 1H-NMR (CDCl3) : d 3.8 (t, 4H, two-N-CH2), d 4.1 (t, 4H, two-OCH2), d 7.2-7.7(m, 3H, Ar-H) : Found : C, 51.97; H, 3.15; N, 16.15, C15H11N4O2SCl requires C, 52.02; H, 3.17; N, 16.18.

 

6c 0.64 g (64%), m.p. 3210C; EI-MS (m/z - RA%): 346 (M+2, 25), 344 (M+, 75); IR (cm-1, KBr) 1690, 2190, 1270; Found : C, 55.78; H, 3.74; N, 16.25, C16H13N4OSCl requires C, 55.81; H, 3.77; N, 16.27.

 

8-Chloro-3-cyano-2-(ethyl acetoacetyl / ethyl cyano acetyl / diethyl malonyl / malonitrile)-4-oxo-4[H]-pyrimido-[2,1-b] [1,3] benzothiazole (7a-d) . A mixture of 3 (1 g, 0.001 M mole) and (ethyl aceto acetate / ethyl cyano acetate / diethyl malonate / malononitrile) (1 g, 0.001 m mole) was refluxed in presence of 30 ml DMF and anhydrous potassium carbonate (0.5g) for 4 h. The reaction mixture was cooled at room temperature and poured in ice-cold water and kept over night. The separated solid was filtered, washed with water and recrystallised from ethanol to give 7a-d.

 

7a 0.49 g (49%), m.p. 2050C; EI-MS (m/z - RA%): 391 (M+2, 23); IR (cm-1, KBr) 1747, 1697, 2224, 1248; Found : C, 52.40; H, 3.04; N, 10.77, C17H12N3O4SCl requires C, 52.44; H, 3.08; N, 10.79.

 

7b 0.62 g (61%), m.p. 3150C; EI-MS (m/z - RA%): 360 (M+2, 10); 358(M+, 30), IR (cm-1, KBr) 1744, 1695, 2227, 1248; Found : C, 53.60; H, 2.48; N, 15.60, C16H9N4O3SCl requires C, 53.63; H, 2.51; N, 15.64.

 

 

7c 0.57 g (57%), m.p. 3170C; EI-MS (m/z - RA%): 421 (M+2, 20), 419(M+, 60); IR (cm-1, KBr) 1747, 1697, 2224, 1250; Found : C, 51.51; H, 3.32; N, 10.00, C18H14N3O5SCl requires C, 51.55; H, 3.34; N, 10.02.

 

7d 0.62 g (62%), m.p. 3010C; EI-MS (m/z - RA%): 327 (M+2, 17), 325(M+, 51); IR (cm-1, KBr) 1680, 2210; Found : C, 51.65; H, 1.20; N, 21.50, C14H4N5O-SCl requires C, 51.69; H, 1.23; N, 21.53

 

CONCLUSION:

A convenient route for the synthesis of 8-Chloro–3- cyano – 2 - methylthio – 4 - oxo - 4[H] - pyrimido - [2,1-b] [1,3] benzothiazole has been prepared.

 

A simple route for the preparation of 2,3 – disubstitute derivatives of  8-Chloro–3- cyano – 2 - methylthio – 4 - oxo - 4[H] - pyrimido - [2,1-b] [1,3] benzothiazole is also reported.

 

ACKNOWLEDGEMENT:

Authors are grateful to Dr. N.V. Kalyankar, Principal, Yeshwant College, Nanded for providing laboratory facilities , Director, Indian Institute of Chemical Technology, Hyderabad, for providing spectra  and Department of Science and Technology for sanctioning a Major Research Project (SR/FTP/CS-111/2007).

 

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Received on 23.10.2009        Modified on 19.11.2009

Accepted on 17.12.2009        © AJRC All right reserved

Asian J. Research Chem. 3(1):Jan.-Mar. 2010  page 161-165