Synthesis of Fused Heterocyclic Rings Incorporating Pyrrolo[2,1-b]benzothiazole Moiety

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1 Article International Journal of Modern Organic Chemistry, 2012, 1(3): International Journal of Modern Organic Chemistry Journal homepage: Synthesis of Fused Heterocyclic Rings Incorporating Pyrrolo[2,1-b]benzothiazole Moiety ISSN: Florida, USA A. A. Fadda 1,*, Kh. S. Mohamed 2, Amera El-Farargy 1 1 Department of Chemistry, Faculty of Science, Mansoura University, ET Mansoura, Egypt 2 Engineering Chemistry Department, Higher institute for engineering and Technology New Damietta, Egypt * Author to whom correspondence should be addressed; afadda50@yahoo.com; Tel.: Fax: ; Article history: Received 19 September 2012, Received in revised form 26 October 2012, Accepted 28 October 2012, Published 29 October Abstract: A variety of new fused heterocyclic rings incorporating pyrrolo[2,1- b]benzothiazole moiety were synthesized by reaction of 2-oxo-1,2- dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3-carbonitrile (2) with hydrazine, guanidine hydrochloride, thiourea, benzaldehyde, benzylidene maolnonitrile, and ethylene diamine. The structures of the newly synthesized compounds are established on the basis of chemical and spectroscopic evidence. Keywords: Benzothiazole; pyrimidine; pyrrolo[2,1-b]benzothiazole. 1. Introduction The twentieth century has been characterized both by a drastic reduction in the mortality caused by infectious diseases and by a rise in the control of neoplastic pathologies. Nevertheless, microorganism and viruses, on the one hand, and tumors, on the other, still represent a dreadful menace to men s health and therefore, for a more efficient control, require the steady development of novel and more powerful drugs. To this end, as a continuation of our research program for synthesis of new benzothiazole derivatives [1-4] and for the biological interest of benzothiazole derivatives [5-12], we synthesized new compounds containing aza heterocycles fused with benzothiazole.

2 Experimental 2.1. Instruments All melting points are (uncorrected) in degree centigrade and were determined on Gallenkamp electric melting point apparatus. Elemental analysis was carried out at the Microanalytical Unit Faculty of Science, Cairo University, Egypt. The IR spectra expressed in cm -1 and recorded in KBr pellets on a Pye Unicam SP The 1 H NMR spectra were determined on Varian Gemini 200 MHz NMR spectrometers using TMS as an internal standard with δ= 0 ppm. Mass spectra were determined on a GC-MS.QP-100 EX Schimadzye (Japan). Elemental analyses (C, H, N and S) were carried out at the Microanalytical Center of Cairo University, Giza, Egypt Synthesis Synthesis of 2-oxo-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3-carbonitrile (2) Compounds 1 (2.5g, 0.01 mol), and alcoholic solution of potassium hydroxide (3 ml, 15%) was refluxed in dimethylformamide for 4 h. The reaction mixture was left to cool at room temperature, and poured onto ice- water (100 ml) to yield precipitates, which were filtered, dried, and recrystallized from DMF-ethanol to give compound 2. Pale brown crystals; yield (91%); mp 285 o C; IR (KBr) (cm -1 ): 1668 (C=O), 2220 (CN); 1 H NMR (DMSO-d 6 ), δ 4.71 (s, 2H, CH 2 ), (m, 4H, aromatic protons); MS: m/z 214 (M + ). Analytical calculated for C 11 H 6 N 2 OS: C, 61.67; H, 2.82; N, 13.08; S, Found: C, 61.65; H, 2.79; N, 13.10; S, Synthesis of 1H-benzo[d]pyrazolo[4',3':3,4]pyrrolo[2,1-b]thiazol-3-amine (3) A mixture of compound 2 (2.14 g, 0.01 mol) and hydrazine hydrate (0.5 g, 0.01 mol) was refluxed in dimethylformamide for 3 h. The reaction mixture was then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from ethanol-dmf to give 3. Brown crystals; yield (64%); mp > 300 o C; IR (KBr) (cm -1 ): 3401, 3388 (NH 2 ), 3211 (NH), 1610 (C=N); 1 H NMR (DMSO-d 6 ), δ 6.44 (s, 1H, CH), (m,6h, aromatic protons + NH 2 ) and (s, 1H, NH); MS: m/z 228 (M + ). Analytical calculated for C 11 H 8 N 4 S: C, 57.88; H, 3.53; N, 24.54; S, 14.05, 8.85%. Found: C, 57.85; H, 3.51; N, 24.49; S, 14.01%. 1-Benzylidene-2-oxo-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3-carbonitrile (4) A mixture of 2 (2.14 g, 0.01 mol), and benzaldehyde (1.06 g, 0.01 mol), was refluxed in dimethylformamide containing a catalytic amount of triethylamine for 2 h (TLC controlled). The reaction mixture was then left to cool at room temperature, and poured onto ice cold water (100 ml).

3 195 The solid product was collected by filtration and recrystallized from DMF-ethanol to give compounds 4. Yellow crystals; yield (92%); mp 168 o C; IR (KBr) (cm -1 ): 2223 (CN), 1643 (C=O); 1 H NMR (DMSO-d 6 ), δ 6.47 (s, 1H, CH), (m, 9H, aromatic protons); MS: m/z 302 (M + ). Analytical calculated for C 18 H 10 N 2 OS: C, 71.50; H, 3.33; N, 9.27; S, 10.61%. Found: C, 71.54; H, 3.34; N, 9.29; S, 10.58%. 3-Phenyl-3,3a-dihydro-2H-benzo[d]pyrazolo[3',4':4,5]pyrrolo[2,1-b]thiazole-10-carbonitrile (5) A mixture of compound 4 (3.02 g, 0.01 mol) and hydrazine hydrate (0.01 mol) was refluxed in dimethylformamide for 3 h. The reaction mixture was then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from ethanol-dmf to give 5. Brown crystals; yield (79%); mp 183 o C; IR (KBr) (cm -1 ): 3287 (NH), 2199 (CN); 1 H NMR (DMSO-d 6 ), δ 3.80 (d, 1H, CH), 4.20 (d, 1H, CH), ( (m, 9H, aromatic protons), (s, 1H, NH); MS: m/z 316 (M + ). Analytical calculated for C 18 H 12 N 4 S: C, 68.33; H, 3.82; N, 17.71; S, 10.13%. Found: C, 68.35; H, 3.87; N, 17.74; S, 10.11%. 1-(2-(4-Nitrophenyl)hydrazono)-2-oxo-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3-carbonitrile (6) In an ice bath to a solution of 2 (2.14 g, 0.01 mol) in pyridine (10 ml), 4-nitrophenyl diazonium chloride (1.85 g, 0.01 mol) was added. The reaction mixture was stirred for 4 h in ice bath. The obtained solid product was collected by filtration and recrystallized from DMF to afford compound 6. Brown crystals; yield (84%); mp 233 o C; IR (KBr) (cm -1 ): 3289 (NH), 2178 (CN), 1644(C=O); 1 H NMR (DMSO-d 6 ), δ (m, 8H, aromatic protons), 9.10 (s, 1H, NH); MS: m/z 363 (M + ). Analytical calculated for C 17 H 9 N 5 O 3 S: C, 56.19; H, 2.50; N, 19.27; S, 8.82%. Found: C, 56.21; H, 2.53; N, 19.25; S, 8.80%. Synthesis of 2-amino-4-phenyl-4H-enzo[d]pyrano[2',3':4,5]pyrrolo[2,1-b]thiazole-3,11- dicarbonitrile (9) Method A. A mixture of 4 (3.02 g, 0.01 mol), and malononitrile (0.06 g, 0.01 mol), was refluxed in dimethylformamide containing a catalytic amount of triethylamine for 5 h. The reaction mixture was then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from DMF-ethanol to give compound 9. Method B. A mixture of 2 (2.14 g, 0.01 mol), and benzylidenemalononitrile (11) (1.54 g, 0.01 mol), was refluxed in dimethylformamide containing a catalytic amount of triethylamine for 4 h (TLC controlled), then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from DMF-ethanol to give compound 9. Brown

4 196 crystals; yield (77%); mp > 300 o C; IR (KBr) (cm -1 ): 3411, 3378 (NH 2 ), 2214, 2189 (two CN); 1 H NMR (DMSO-d 6 ), δ 4.89 (s, 1H, CH), (m,9h, aromatic protons), 9.20 (s, 2H, NH 2 ); MS: m/z 368 (M + ). Anal. calcd. for C 21 H 12 N 4 OS: C, 68.46; H, 3.28; N, 15.21; S, 8.70%. Found: C, 68.46; H, 3.28; N, 15.21; S, 8.70%. Synthesis of 2-amino-4-phenylbenzo[4',5']thiazolo[3',2':1,5]pyrrolo[3,2-b]pyridine-3,11- dicarbonitrile (10) Method A. A mixture of 4 (3.02 g, 0.01 mol), and malononitrile (0.06 g, 0.01 mol) and ammonium acetate (0.77 g, 0.01 mol), was refluxed in dimethylformamide for 6 h. The reaction mixture was then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from DMF/ethanol to give compound 10. Method B. A mixture of 2 (2.14 g, 0.01 mol), and benzylidenemalononitrile (11) (1.54 g, 0.01 mol) and ammonium acetate (0.77 g, 0.01 mol) was refluxed in dimethylformamide for 6 h, then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from DMF-ethanol to give compound 10. Brown crystals; yield (75%); mp 210 o C; IR (KBr) (cm -1 ): 3411, 3369 (NH 2 ), (two CN); 1 H NMR (DMSO-d 6 ), δ (m, 11H, aromatic protons + NH 2 ); MS: m/z 365 (M + ). Analytical calculated for C 21 H 11 N 5 S: C, 69.03; H, 3.03; N, 19.17; S, 8.78%. Found: C, 69.04; H, 3.06; N, 19.16; S, 8.74%. Synthesis of benzo[4',5']thiazolo[3',2':1,5]pyrrolo[3,4-d]pyrimidine-2,4-diamine (12a) A mixture of 2 (2.14 g, 0.01 mol), and guanidine hydrochloride (0.95 g, 0.01 mol) and a catalytic amount of fused sodium acetate (1 g) was refluxed in dimethylformamide for 8 h. The reaction mixture was then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from DMF-ethanol to give compounds 12a. Yellow crystals; yield (71%); mp 220 o C; IR (KBr) (cm -1 ): 3416, 3401, 3385, 3373 (2NH 2 ); 1 H NMR (DMSO-d 6 ), δ 6.49 (s, 1H, CH), 6.96 (br, s, 2H, NH 2 ), (m, 4H, aromatic protons + NH 2 ); MS: m/z 255 (M + ). Analytical calculated for C 12 H 9 N 5 S: C, 56.45; H, 3.55; N, 27.43; S, 12.56%. Found: C, 56.43; H, 3.57; N, 27.40; S, 12.53%. Synthesis of 4-aminobenzo[4',5']thiazolo[3',2':1,5]pyrrolo[3,4-d]pyrimidine-2-thiol (12b) A mixture of 2 (2.14 g, 0.01 mol), and thiourea (0.76 g, 0.01 mol) was refluxed in dimethylformamide containing a catalytic amount of triethylamine for 10 h. The reaction mixture was then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from DMF-ethanol to give compound 12b. Brown crystals; yield (63%); mp 208 o C; IR (KBr) (cm -1 ): 3405, 3375, 3278 (NH 2 + NH); 1 H NMR (DMSO-d 6 ), δ 5.44

5 197 (s, 1H, SH), 6.71 (s, 1H, CH), (m, 6H, aromatic protons + NH 2 ); MS: m/z 272 (M + ). Anal. calcd. for C 12 H 8 N 4 S 2 : C, 52.92; H, 2.96; N, 20.57; S, 23.55%. Found: C, 52.89; H, 2.94; N, 20.56; S, 23.53%. Synthesis of 2,3-dihydro-1H-benzo[4',5']thiazolo[3',2':1,5]pyrrolo[3,4-e][1,4]diazepin-5-amine (13) A mixture of 2 (2.14 g, 0.01 mol), and ethylene diamine (0.60 g, 0.01 mol) was refluxed in dimethylformamide containing catalytic amount of triethylamine for 10 hours, then left to cool at room temperature, and poured onto ice cold water (100 ml). The solid product was collected by filtration and recrystallized from DMF-ethanol to give compound 13. Brown crystals; yield (83%); mp > 300 o C; IR (KBr) (cm -1 ): 3411, 3369 (NH 2 ), 3189 (NH); 1 H NMR (DMSO-d 6 ), δ 1.8 (t, 2H, CH 2 ), 3.2 (t, 2H, CH 2 ), 6.44 (s, 1H, CH), (m, 6H, aromatic protons + NH 2 ), 8.2 (s, 1H, NH); MS: m/z 256 (M +, 23%). Analytical calculated for C 13 H 12 N 4 S: C, 60.91; H, 4.72; N, 21.86; S, 12.51%. Found: C, 60.89; H, 4.74; N, 21.90; S, 12.53%. 3. Results and Discussion 2-Oxo-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3-carbonitrile (2) was obtained by heating of 2-(benzo[d]thiazol-2-yl)-4-chloro-3-oxobutanenitrile (1) in boiling alcoholic potassium hydroxide. Compound 2 act as a precursor for the synthesis of fused pyrrazolo, pyrimido, pyrano and pyrido heterocyclic compounds. Thus, treatment of 2 with hydrazine hydrate in refluxing dimethylformamide afforded only one product in good yield that was established as 1Hbenzo[d]pyrazolo[4',3':3,4]pyrrolo[2,1-b]thiazol-3-amine (3) (Scheme 1), on the basis of its elemental analyses and spectroscopic data. The mass spectrum of compound 3 showed, among other fragments, a peak at m/z 228 due to its molecular ion. The IR spectrum of compound 3 showed the absence of any absorption bands at cm -1 and cm -1 due to carbonyl and nitrile groups respectively, which confirm that both carbonyl and cyano groups were involved in the cyclization reaction, also the IR spectrum showed absorption bands at 3401 and 3388 cm -1 due to NH 2 group and at 3211 cm -1 due to NH. It s 1 H NMR spectrum showed two singlet signals at δ 6.44 due to CH proton and at δ due to NH group, in addition to multiplets at δ ppm due to aromatic protons and amino group. Heating of 2 with benzaldehyde in refluxing dimethylformamide containing a catalytic amount of triethylamine, afforded 1-benzylidene-2-oxo-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3- carbonitrile (4). 3-Phenyl-3,3a-dihydro-2H-benzo[d]pyrazolo[3',4':4,5]pyrrolo[2,1-b]thiazole-10- carbonitrile (5) obtained by reaction of 4 with hydrazine hydrate in refluxing dimethylformamide

6 198 (Scheme 1). The products 4 and 5 gave satisfactory analytical and spectral data in full accord with their assigned structures. The assignment of 1 H chemical shifts is described in the Experimental part. Scheme 1. Synthesis of 3-phenyl-3,3a-dihydro-2H-benzo[d]pyrazolo[3',4':4,5]pyrrolo[2,1-b]thiazole- 10-carbonitrile (5) Coupling reaction of 2 with p-nitropheyl diazonium chloride afforded 6 in good yield. The structure of the latter product established on the basis of its spectral data and molecular analysis. Thus, the IR spectrum of the reaction product showed an absorption band at 3289 cm -1 due to NH group in addition to a strong absorption band at 2178 cm -1 and 1644 cm -1 for the cyano and carbonyl groups. 1 H-NMR spectrum of the reaction product 6 revealed, besides the aromatic multiplet, a singlet signal of D 2 O exchangeable proton at δ 9.10 due to NH group. In addition, all attempts to synthesize pyrazolo[4',3':4,5]pyrrolo[2,1-b]benzothiazolethiazole derivatives 8a and 8b by reaction of 6 with chloroacetonitrile 7a and/or chloroacetone 7b, respectively in refluxing dimethylformamide containing a catalytic amount of triethylamine were failed. Scheme 2. Coupling reaction of compound 5 with diazonium salt of p-nitroaniline

7 199 The key compound 4 was used for the synthesis of fused heterocyclic containing pyrano and pyridine ring by refluxing 4 with malononitrile as shown in Scheme 3. Compounds 9 and 10 are assumed to be formed via initial Michael addition of the methylene group in malononitrile to an activated double bond in 4 followed by cyclization to afford 9 or 10, depending on reactions conditions. The structures of 9 and 10 were established via their analytical and spectroscopic data. The mass spectrum of 9 revealed a molecular ion peak m/z at 368 (M + ). The 1 H-NMR spectrum of the reaction product 9 showed in addition to the aromatic signals, two singlet signals at δ 4.89 and 9.20 ppm assigned to the pyran CH and NH 2 groups. The latter signal underwent a facile hydrogen deuterium exchange upon addition of deuterium oxide. The mass spectrum of 10 revealed a molecular ion peak with m/z 365 (M + ). Moreover, the structures of 9 and 10 were established via their alternative synthesis by reaction of 2 with benzylidenemalononitrile (11) which gave compounds similar in all respects (m.p., IR, 1 H-NMR and mass spectroscopy) to 9 and 10. Scheme 3. Synthesis of benzo[d]pyrano[2',3':4,5]pyrrolo[2,1-b]thiazole (9) and benzo[4',5']thiazolo [3',2':1,5]pyrrolo[3,2-b]pyridine (10) Treatment of 2 with guanidine hydrochloride and thiourea in refluxing dimethylformamide gave fused pyrimidine derivatives 12a and 12b, respectively. The structure of the reaction product was ascertained on the basis of its elemental analysis and spectral (IR, MS, and 1 H NMR) data as benzo[4',5']thiazolo[3',2':1,5]pyrrolo[3,4-d]pyrimidine-2,4-diamine (12a) and 4-aminobenzo[4',5'] thiazolo[3',2':1,5]pyrrolo[3,4-d]pyrimidine-2-thiol (12b) quantitatively as shown in Scheme 4. The 1 H NMR spectrum of 12a displayed two singlets at δ 6.49 ppm due to pyrrole H, broad signal at 6.96 ppm (NH 2 ) in addition to the multiplet in the aromatic region. The mass spectrum of 12a showed an intense peak at m/z 255 corresponding to its molecular ion peak.

8 200 Fused diazepine heterocyclic ring was synthesized by refluxing of 2 with ethylenediamine in the presence of dimethylformamide containing catalytic amount of triethylamine to afford 2,3-dihydro- 1H-benzo[4',5']thiazolo[3',2':1,5]pyrrolo[3,4-e][1,4]diazepin-5-amine (13) (Scheme 4). The structure of the reaction product 13 was ascertained on the basis of its elemental analysis and spectral (IR, MS, and 1 H NMR) data. The mass spectrum of 13 revealed a molecular ion peak m/z at 256. The 1 H NMR spectrum of the reaction product showed in addition to the aromatic signals, two triplet signals at δ 1.8 and 3.2 ppm due to CH 2 CH 2, singlet signal at δ 6.44 ppm due to pyrrole CH proton and two D 2 O exchangeable singlet signals at δ 7.84 and 8.20 ppm due to NH 2 and NH, respectively. Scheme 4. Reactions of 2-oxo-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3-carbonitrile (2) with binucleophiles 4. Conclusion This work reported the synthesis of pyrrolo[2,1-b]thiazole derivative 2 and its reactions with different reagents in order to obtain novel heterocycles incorporated benzothiazole moiety. The reaction of compound 2 with hydrazine hydrate afforded aminopyrazole 3. Moreover, the reaction of 2 with benzaldehyde afforded pyrrolo[2,1-b]thiazole derivative 4 which was then followed reaction with hydrazine hydrate to give pyrazolo[3',4':4,5]pyrrolo[2,1-b]thiazole 5. Coupling reaction of 5 with diazonium chloride afforded monoaryl azo derivative 6. On the other hand, compound 4 reacted with malononitrile in DMF catalyzed by triethylamine or ammonium acetate to give pyrano[2',3':4,5] pyrrolo[2,1-b]thiazole 9 and thiazolo[3',2':1,5]pyrrolo[3,2-b]pyridine 10, respectively. In another route, compounds 9 and 10 were obtained via the reaction of 2 with benzylidene malononitrile using the same previous reaction conditions. Finally, the reaction of compound 2 with guanidine, thiourea and ethylene diamine afforded thiazolo[3',2':1,5]pyrrolo[3,4-d]pyrimidine 12a,b and thiazolo[3',2':1,5]

9 201 pyrrolo[3,4-e][1,4]diazepine 13, respectively. The newly synthesized compounds were characterized by elemental analysis and spectral data. Potential Conflicts of Interest The authors declare no conflict of interest. References [1] Fadda, AA; Amer, FA; Zaki, MEA; Samir, K., Revised synthesis of some new derivatives of biological interest 2-heterocyclic benzothiazolyl derivatives of biological interest. Phosphorus, Sulfur, and Silicon and Rel. Elem. 1999, 155: [2] Zaki, MEA; Fadda, AA; Samir, K; Amer, FA., Nitriles in organic synthesis: synthesis of pyrido[2,1-b]benzothiazole derivatives and polyfunctionally-substituted pyridines. Chem. Heterocycl. Comp. 2003, 39: [3] Zaki, MEA; Fadda, AA; Samir, K;Amer, FA., Nitriles in organic synthesis: a convenient route to some heterocycles incorporating a benzothiazole moiety. Phosphorus, Sulfur, and Silicon and Rel. Elem. 2006, 181: [4] Fadda, AA; Zaki, MEA; Samir, K; Amer, FA., Nitriles in organic synthesis: synthesis of some new 2-heterocyclic benzothiazole derivatives. Phosphorus, Sulfur, and Silicon and Rel. Elem. 2007, 182: [5] Vicini, P; Zani, F; Cozzini, P; Doytchinova, I., Hydrazones of 1,2-benzisothiazole hydrazides: synthesis, antimicrobial activity and QSAR investigations. Eur. J. Med. Chem. 2002, 37: [6] Geronikaki, A; Lagunin, A; Poroikov, V; Filimonov, D; Hadjipavlou-Litina, D; Vicini, P., Computer aided prediction of biological activity spectra: Evaluating versus known and predicting of new activities for thiazole derivatives. SAR QSAR Environ Res. 2002, 13: [7] Vicini, P; Amoretti, L; Ballabeni, V; Tognolini, M; Barocelli, E., 2-Amino-Benzo[d]isothiazol-3- one derivatives: synthesis and assessment of their antiplatelet/spasmolytic effects. Bioorg. Med. Chem. 2000, 8: [8] Vicini, P; Manotti, C; Caretta, A; Amoretti, L., Comparison of in vitro and ex vivo antiplatelet effects of 1,2-benzisothiazolin-3-one and its 2-amino derivative. Arzneimittelforschung. 1999, 49: [9] Hadjipavlou-Litina, DJ; Geronikaki, A., Thiazolyl and benzothiazolyl Schiff bases as novel possible lipoxygenase inhibitors and anti-inflammatory agents. Drug Des. Discov. 1998, 15:

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