HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 1, 2014, pp. 113-125
Received, 28th October, 2013, Accepted, 25th November, 2013, Published online, 10th December, 2013.
DOI: 10.3987/COM-13-12873

■ Synthesis of Novel Benzimidazole and Benzothiazole Derivatives

Ahmed F. Darweesh, Ahmed E. M. Mekky, Amani A. Salman, and Ahmad M. Farag*

Department of Chemistry, Faculty of Science, Cairo University, Giza 12013, Egypt

Abstract

1-(Benzothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1) and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2) were used as potential scaffolds for biologically interesting azoloazine derivatives via their reaction with the diazonium salts of 5-aminopyrazole, 5-amino[1,2,4]triazole and 2-aminobenzimidazole. Coupling of the β-ketosulfones 1 or 2 with diazotized aromatic amines afforded the corresponding arylhydrazone derivatives which have been utilized as versatile building blocks for the synthesis of biologically interesting pyridazine ring systems.

INTRODUCTION
Benzothiazole and benzimidazole ring systems are very important classes of compounds due to their wide spectrum of biological activities. Many of their derivatives are used as antiviral,1-4 antifungal,5-8 antitumor9-12 and antihelminthic agents in veterinary medicinel.13-15 Some of benzimidazole derivatives are now included in many of commercialized drugs.16-18 On the other hand, β-ketosulfone moiety is readily available from a variety of precursor functionalities and displays a broad range of synthetic versatility.19,20 These are also important group of intermediates in Michael and Knoevengel reactions.21
Compounds containing β-ketosulfones moiety have attracted considerable attention of synthetic chemists in the past decade.22 As part of our ongoing research program directed towards the synthesis of a variety of heterocycles for biological evaluation,23,34 we report here on the synthesis of several heterocyclic ring systems incorporation benzothiazole and benzimidazole moieties starting from the versatile hitherto unreported 1-(benzothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1) and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2).

RESULTS AND DISCUSSION
Treatment of each of the 1-(benzothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1) and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2) with the diazonium salts of 3-(4-chlorophenyl)-5-amino-1H-pyrazole (3) and 4-cyano-5-amino-1H-pyrazole (4) afforded the corresponding non-isolable azo intermediates 5 and 6, respectively. The latter intermediates underwent in situ intramolecular cyclization, yielding the corresponding pyrazolo[5,1-c][l,2,4]triazine derivatives 7a,b and 8a,b, respectively (Scheme 1). The structures of the isolated products 7a,b and 8a,b were established on the basis of their elemental analyses and spectral data. For example, the IR spectrum of the compounds 7b and 8b revealed, in each case, no bands corresponding to the endocyclic NH group and showed absorption band due to nitrile group near 2233 cm-1. Their mass spectra showed, in each case, a peak corresponding to the molecular ion. Their 1H NMR spectra revealed, in each case, a singlet signal near 8.64 ppm due pyrazole CH proton and a multiplet signal corresponding to aromatic protons in the range 7.20-8.14 ppm.

In a similar manner, the β-ketosulfones 1 and 2 reacted with the diazonium salts of 5-amino-l,2,4-triazole (9) and afforded products identified as 4-(benzothiazol-2-yl)-3-(phenylsulfonyl)-[1,2,4]triazolo[5,1-c][1,2,4]triazine (12) and 4-(1-methylbenzimidazol-2-yl)-3-(phenysulfonyl)-[1,2,4]triazolo[5,1-c][1,2,4]triazine (13), respectively (Scheme 2).
The structures of the reaction products 12 and 13 were established on the basis of their elemental analyses and spectral data (see Experimental part).

Also, the β-ketosulfones 1 and 2 reacted with the diazonium salt of 2-amino-1H-benzimidazole (14) to afford the corresponding 4-(benzothiazol-2-yl)-3-(phenylsulfonyl)-1,2,4-triazino[4,3-a]benzimidazole (17) and 4-(1-methylbenzimidazol-2-yl)-3-(phenylsulfonyl)-1,2,4-triazino[4,3-a]benzimidazole (18), respectively (Scheme 3). The mass spectra of the reaction products showed, in each case, a peak corresponding to the molecular ion. The 1H NMR spectrum of compound 18, taken as an example of the prepared compounds revealed a singlet signal at δ 4.02 due to N-CH3 protons and a multiplet signals at δ 7.38-8.16 due to aromatic protons.

Similar to their behavior towards diazotized heterocyclic amines 3, 9, 14, the β-ketosulfones 1 and 2 coupled with diazotized aromatic amines derivatives 19a-c, to give the corresponding arylhydrazone derivatives 22a-c and 23a-c, respectively (Scheme 4). The structures of the compounds 22a-c and 23a-c were established on the basis of their elemental analyses and spectral data (see Experimental part).

The obtained arylhydrazones 22a-c and 23a-c have been utilized as building blocks for the synthesis of biologically interesting pyridazine ring system. Thus, the arylhydrazones 22a-c and 23a-c undergo cyclocondensation with 2-cynomethylbenzothiazole (24) under both heating in ethanol and under microwave irradiation conditions, to afford the corresponding pyridazine derivatives 27a-c and 28a-c, respectively in almost quantitative yield (Scheme 5). The IR spectra of the obtained compounds revealed, in each case, absorption band near 3332 cm-1 due to NH function whereas their 1H NMR spectra revealed, in each case, a singlet signal near 11.88 ppm due NH protons. Other signals appeared at their respective chemical shifts.

Similarly, condensation of the arylhydrazones 22a-c and 23a-c with malononitril afforded the corresponding 1-aryl-4-(benzothiazol-2-yl)-5-(cyano)-1,6-dihydro-6-imino-3-(phenylsulfonyl)pyridazine (31a-c) and 1-aryl-4-(1-methylbenzimidazol-2-yl)-5-(cyano)-1,6-dihydro-6-imino-3-(phenylsulfonyl)pyridazine (32a-c), respectively (Scheme 6). The structures of the products 31a-c and 32a-c were established on the basis of their elementals analysis and spectral data (see Experimental part).

EXPERIMENTAL
Melting points were determined in open glass capillaries with a Gallenkamp apparatus. The IR spectra were recorded using KBr disks on a Pye Unicam SP 3-300 or a Shimadzu FTIR 8101 PC IR spectrophotometer. The NMR spectra were recorded with a Varian Mercury VXR-300 NMR spectrometer at 300 and 75 MHz (1H and 13C NMR spectra, respectively) using CDCl3 and DMSO-d6 as solvents. Chemical shifts were related to that of the solvent. Mass spectra (EI) were obtained at 70 eV with a Shimadzu GCMQP 1000 EX spectrometer. TLC analyses were performed using precoated silica gel 60778 plates (Fluka), and the spots were visualized with UV light at 254 nm. Fluka silica gel 60741 (70–230 mesh) was used for flash column chromatography. Microwave experiments were carried out using a CEM Discover LabMate microwave apparatus (300 W with ChemDriver Software). 2-Bromo-1-(1-methyl-1H-benzimidazol-2-yl)ethanone35 3-(4-chlorophenyl)-(1H)-pyrazole-5-diazonium chloride (3),36 4-cyano-1H-pyrazole-3-diazonium chloride (4),37 1H-1,2,4-triazole-5-diazonium salt (9),37 1H-benzimidazol-2-diazonium salt (14),37 benzothiazole-2-acetonitrile (24),38 2-bromo-1-benzothiazol-2-yl-ethanone,39 were prepared following literature procedures.
1-(Benzothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1). A mixture of 2-bromo-1-benzothiazol-2-yl-ethanone (2.56 g, 10 mmol) and sodium benzenesulfinate (1.64 g 10 mmol), in absolute EtOH (20 mL) was refluxed for 3 h, and then left to cool to rt. The precipitated solid was filtrated off, washed with water and dried. Recrystallization from EtOH afforded the title compound. Yield (79%); mp 142 °C; IR (KBr) vmax/cm-1: 1690 (C=O), 1325, 1160 (SO2); 1H NMR (DMSO-d6) δ 5.41 (s, 2H, CH2), 7.35−8.03 (m, 9H, ArH); 13C NMR (DMSO-d6) δ 60.45, 121.66, 123.43, 124.60, 128.34, 129.34, 133.56, 136.01, 138.69, 145.47, 155.12, 182.34; MS (m/z, %): 317 (M+, 23.7). Anal. Calcd for C15H11NO3S2 (317.38): C, 56.76; H, 3,49; N, 4.41; S, 20.21%. Found: C, 56.55; H, 3.44; N, 4.49; S, 20.23%.
1-(1-Methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2). To a solution of triethylbenzylammonium chloride (TEBAC) (0.2 g) in MeCN (25 mL) was added sodium benzenesulfinate (1.80 g, 12 mmol) and the suspension was stirred at rt for 15 min. To this mixture was added a solution of 2-bromo-1-(1-methyl-1H-benzimidazol-2yl)ethanone (2.58 g 10 mmol) in MeCN (20 mL). The progress of the reaction was monitored by TLC till the disappearance of the reactants. After the reaction was complete (about 1h), the mixture was filtered off, and the solid material (NaBr) was washed with MeCN. The washings along with mother liquor were mixed and evaporated under reduced pressure. The residue was taken up in CH2Cl2 (50 mL) and washed with water (2 × 10 mL). The organic layer was separated and dried over anhydrous MgSO4 then evaporated under reduced pressure. The residue was crystallized from hexane-benzene (9:1) to afford 2. Yield (90%), mp 159−161 °C; IR (KBr) νmax/cm-1: 1690 (C=O), 1325 and 1160 (SO2); 1H NMR (DMSO-d6) δ 4.03 (s, 3H, NCH3), 5.41 (s, 2H, CH2), 7.38−7.95 (m, 9H, ArH); 13C NMR (DMSO-d6) δ 31.97, 60.45, 111.01, 120.43, 123.31, 128.32, 129.34, 133.56, 134.01, 138.29, 138.41, 140.12, 179.34; MS (m/z, %): 314 (M+, 29.2). Anal. Calcd for C16H14N2O3S (314.36): C, 61.13; H, 4.49; N, 8.91; S, 10.20%. Found: C, 61.16; H, 4.46; N, 8.93; S, 10.18%.

Reaction of the β-ketosulfones 1 and 2 with diazotized heterocyclic amines.
General procedure:
To a stirred cold solution (ice bath at 0−5 °C) of the appropriate β-ketosulphone 1 or 2 (2 mmol), in pyridine (30 mL) was added the appropriate heterocyclic diazonium salt of the heterocyclic amines 3, 4, 9 and 14 (2 mmol) portionwise over a period of 30 min. The reaction mixture was stirred for further 3 h at 0−5 °C. The precipitate solid was collected by filtration, washed with water and dried. Recrystallization from DMF/H2O afforded the corresponding fused ring systems 7a,b, 8a,b, 12, 13, 17 and 18, respectively.
4-(Benzothiazol-2-yl)-7-(4-chlorophenyl)-3-(phenylsulfonyl)pyrazolo[5,1-c][1,2,4]triazine (7a): Yield (78%), mp 170−172 °C; IR (KBr) νmax/cm-1: 1597 (C=N); 1H NMR (DMSO-d6) δ 6.99 (s, 1H, pyrazole-8-CH), 7.42-8.13 (m, 13H, ArH’s); MS (m/z, %): 503 (M+, 100%). Anal. Calcd for C24H14N5ClO2S2 (503.98): C, 57.20; H, 2.80; N, 13.90; S, 12.72%. Found: C, 57.24; H, 2.83; N, 13.94; S, 12.68%.
4-(Benzothiazol-2-yl)-3-(phenylsulfonyl)pyrazolo[5,1-c][1,2,4]triazine-8-carbonitrile (7b): Yield (79%), mp 152−154 °C; IR (KBr) νmax/cm-1: 2233 (C≡N); 1H NMR (DMSO- d6) δ 7.42−8.14 (m, 9H, ArH’s), 8.64 (s, 1H, pyrazole-7-CH); MS (m/z, %): 418 (M+, 100%); Anal. Calcd for C19H10N6O2S2 (418.45): C, 54.54; H, 2.41; N, 20.08; S, 15.33%. Found: C, 54.49; H, 2.40; N, 20.05; S, 15.35 %.
7-(4-Chlorophenyl)-4-(1-methyl-1H-benzimidazol-2-yl)-3-(phenylsulfonyl)pyrazolo[5,1-c][1,2,4]triazine (8a): Yield (72%), mp 188−189 °C. IR (KBr) νmax/cm-1: 1597 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.89 (s, 1H, pyrazole-8-CH), 7.20−7.89 (m, 13H, ArH’s); MS (m/z, %): 500 (M+, 100%); Anal. Calcd for C25H17N6ClO2S (500.96): C, 59.94; H, 3.42; N, 16.78; S, 6.40%. Found: C, 59.96; H, 3.39; N, 16.80; S, 6.41%.
4-(1-Methyl-1H-benzimidazol-2-yl)-3-(phenylsulfonyl)pyrazolo[5,1-c][1,2,4]triazine-8-carbonitrile (8b): Yield (77%), mp 168−170 °C; IR (KBr) νmax/cm-1: 2233 (C≡N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 7.20−8.04 (m, 9H, ArH’s), 8.64 (s, 1H, pyrazole-7-CH). MS (m/z, %): 415 (M+, 100%); Anal. Calcd for C20H13N7O2S (415.43): C, 57.82; H, 3.15; N, 23.60; S, 7.72%. Found: C, 57.85; H, 3.18; N, 23.62; S, 7.75%.
4-(Benzothiazol-2-yl)-3-(phenylsulfonyl)-[1,2,4]triazolo[5,1-c][1,2,4]triazine (12): Yield (72%), mp 205−206 °C; IR (KBr) νmax /cm–1: 1607 (C=N); 1H NMR (DMSO-d6) δ 7.43−8.14 (m, 9H, ArH’s), 8.57 (s, 1H, triazole-7-CH). 13C NMR (DMSO-d6) δ 120.23, 121.53, 124.30, 125.32, 128.10, 129.57, 133.43, 133.02, 136.22, 152.54, 156.04, 156.05,156.63; MS (m/z, %): 394 (M+, 100%); Anal. Calcd for C17H10N6O2S2 (394.43): C, 51.77; H, 2.56; N, 21.31; S, 16.26%. Found: C, 51.73; H, 2.59; N, 21.34; S, 16.23%.
4-(1-Methylbenzimidazol-2-yl)-3-(phenysulfonyl)-[1,2,4]triazolo[5,1-c][1,2,4]triazine (13): Yield (72%), mp 160−162 °C; IR (KBr) νmax/cm-1: 1607 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 7.20−8.04 (m, 9H, ArH’s), 8.47 (s, 1H, triazole-7-CH); 13C NMR (DMSO-d6) δ 31.97 (NCH3), 111.67, 121.43, 123.60, 128.10, 129.22, 133.36, 134.01, 136.02, 140.54 (aromatic carbons), 141.11 (C-2 benzimidazole ring), 148.45, 148.57 (-N-CH, triazole ring); MS (m/z, %): 391 (M+, 100%); Anal. Calcd for C18H13N7O2S (391.41): C, 55.23; H, 3.35; N, 25.05; S, 8.19%. Found: C, 55.19; H, 3.29; N, 25.09; S, 8.21%.
4-(Benzothiazol-2-yl)-3-(phenylsulfonyl)-[1,2,4]triazino[4,3-a]benzimidazole (17): Yield (70%), mp 166−167 °C; IR (KBr) νmax/cm-1: 1607 (C=N). 1H NMR (DMSO-d6) δ 7.41−8.16 (m, 13H, ArH’s); MS (m/z, %): 443(M+, 100%); Anal. Calcd for C22H13N5O2S2 (443.50); C, 59.58; H, 2.95; N, 15.79; S, 14.46%. Found: C, 59.53; H, 2.98; N, 15.76; S, 14.42%.
4-(1-Methylbenzimidazol-2-yl)-3(phenylsulfonyl)-1,2,4-triazino[4,3-a]benzimidazole (18): Yield (70%), mp 175−176 °C; IR (KBr) νmax/cm-1: 1607 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 7.38−7.94 (m, 13H, ArH’s); MS (m/z, %): 440 (M+, 100%); Anal. Calcd for C23H16N6O2S (440.48): C, 62.72; H, 3.66; N, 19.08; S, 7.28%. Found: C, 62.68; H, 3.64; N, 19.12; S, 7.33%.

Reaction of the β-ketosulfones 1 and 2 with arene diazonium chlorides (19a-c). To a stirred solution of the appropriate ketosulfone 1 or 2 (20 mmol), in EtOH (50 mL) was added sodium acetate trihydrate (8 g). After stirring for 10 min, the mixture was cooled to 0 °C then treated with the appropriate arene diazonium salt 19 [prepared by diazotizing the corresponding aromatic amine (20 mmol) in hydrochloric acid (6M, 6 mL) with sodium nitrite solution [(1.4 g, 20 mmol), in H2O (15 mL)]. The addition of the diazonium salt was carried out with rapid stirring over a period of 30 min. The reaction mixture was stirred for further 2 h at 0 °C, and then left for 6 h at 4 °C in a refrigerator. The resulting solid was collected by filtration, washed thoroughly with water then dried. The crude product was recrystallized from EtOH to afford the corresponding hydrazone derivatives 22a-c and 23a-c, respectively.
1-(Benzothiazol-2-yl)-2-(2-phenylhydrazono)-2-(phenylsulfonyl)ethanone (22a): Yield (80%), mp 180−182 °C; IR (KBr) νmax/cm-1: 3215 (NH), 1630 (CO), 1597 (C=N); 1H NMR (DMSO-d6) δ 7.07−8.33 (m, 14H, ArH’s), 11.11 (s, 1H, D2O-exchangable, NH); 13C NMR (DMSO-d6) δ 113.05, 120.94, 122.74, 124.35, 125.29, 128.40, 129.20, 129.28, 133.52, 138.27, 139.40, 142.16, 160.25, 162.67, 182.35, 154.21; MS (m/z, %): 421 (M+, 100%); Anal. Calcd for C21H15N3O3S2 (421.49): C, 59.84; H, 3.59; N, 9.97; S, 15.21%. Found: C, 59.79; H, 3.62; N, 10.00; S, 15.23%.
1-(Benzothiazol-2-yl)-2-(2-(4-chlorophenyl)hydrazono)-2-(phenylsulfonyl)ethanone (22b): Yield (68%), mp 210−212 °C; IR (KBr) νmax/cm-1: 3243 (NH), 1634 (CO), 1611 (C=N); 1H NMR (DMSO-d6) δ 7.09−8.14 (m, 13H, ArH’s), 11.08 (s, 1H, D2O-exchangable, NH); 13C NMR (DMSO-d6) δ 116.39, 119.31, 122.82, 123.41, 125.13, 125.44, 127.93, 128.1, 128.87, 129.36, 133.79, 136.59, 139.74, 140.67, 141.24, 152.46, 181.8; MS (m/z, %): 455 (M+, 100%); Anal. Calcd for C21H14ClN3O3S2 (455.94): C, 55.32; H, 3.09; N, 9.22; S, 14.07%. Found: C, 55.30; H, 3.11; N, 9.26; S, 14.05 %.
1-(Benzothiazol-2-yl)-2-(phenylsulfonyl)-2-(2-p-tolylhydrazono)ethanone (22c): Yield (74%), mp 188−190 °C; IR (KBr) νmax/cm-1: 3227 (NH), 1637 (CO), 1601 (C=N); 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 6.48−8.14 (m, 13H, ArH’s), 11.10 (s, 1H, D2O-exchangable, NH); 13C NMR (DMSO-d6) δ 20.52, 117.58, 123.34, 125.26, 127.41, 127.84, 128.22 128.66, 129.39, 129.96, 133.62, 134.61, 135.9, 136.45, 139.91, 141.15, 152.85, 182.43; MS (m/z, %): 435 (M+, 100%); Anal. Calcd for C22H17N3O3S2 (435.52): C, 60.67; H, 3.93; N, 9.65; S, 14.72%. Found: C, 60.71; H, 3.91; N, 9.68; S, 14.74%.
1-(1-Methyl-1H-benzimidazol-2-yl)-2-(2-phenylhydrazono)-2-(phenylsulfonyl)ethanone (23a): Yield (74%), mp 204−206 °C; IR (KBr) νmax/cm-1: 3240 (NH), 1648 (CO), 1611 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.79−7.86 (m, 14H, ArH’s), 11.02 (s, 1H, D2O-exchangable, NH). 13C NMR (DMSO-d6) δ 31.95, 111.67, 114.62, 121.40, 121.43, 123.60, 128.10, 129.11, 129.22, 133.36, 134.01, 137.05, 139.45, 141.11, 142.36, 145.21, 182.34; MS (m/z, %): 418 (M+, 100%); Anal. Calcd for C22H18N4O3S (418.47): C, 63.14; H, 4.34; N, 13.39; S, 7.66%. Found: C, 63.12; H, 4.31; N, 13.36; S, 7.70%.
2-(2-(4-Chlorophenyl)hydrazono)-1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (23b): Yield (75%), mp 210−212 °C; IR (KBr) νmax/cm-1: 3251 (NH), 1648 (CO), 1612 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 7.08−7.83 (m, 13H, ArH’s), 11.10 (s, 1H, D2O-exchangable, NH); 13C NMR (DMSO-d6) δ 32.13, 111.88, 116.02, 121.61, 124.25, 126.92, 127.05, 128.01, 128.12, 129.25, 129.4, 133.65, 136.97, 137.67, 140.92, 141.46, 145.18, 180.44; MS (m/z, %): 452 (M+, 100%); Anal. Calcd for C22H17ClN4O3S (452.91): C, 58.34; H, 3.78; N, 12.37; S, 7.08%. Found: C, 58.32; H, 3.81; N, 12.39; S, 7.05%.
1-(1-Methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-2-(2-p-tolylhydrazono)ethanone (23c): Yield (76%), mp 180−182 °C; IR (KBr) νmax/cm-1: 3247 (NH), 1638 (CO), 1611 (C=N); 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 4.02 (s, 3H, NCH3), 6.49−7.83 (m, 13H, ArH’s), 11.12 (s, 1H, D2O-exchangable, NH); MS (m/z, %): 432 (M+, 100%); Anal. Calcd for C23H20N4O3S (432.49): C, 63.87; H, 4.66; N, 12.95; S, 7.41%. Found: C, 63.83; H, 4.69; N, 12.97; S, 7.45%.

Reactions of the hydrazones 22a-c and 23a-c with (benzothiazol-2-yl)acetonitrile (24) and malononitrile.
(A)-Thermal method
General procedure:
To a solution of the appropriate hydrazone 22 or 23 (10 mmol) and (benzothiazol-2-yl)acetonitrile (24) or malononitrile (10 mmol), in EtOH (50 mL), was added few drops of piperdine. The reaction mixture was refluxed for 3-4 h, then poured into ice cold water, and neutralized with dil. HCl. The resulting solid product was collected by filtration washed with EtOH, dried and finally recrystalized from DMF, to afford the corresponding pyridazine derivatives 27a-c, 28a-c, 31a-c, and 32a-c, respectively.
(B)-Microwave method (MW)
General procedure:
A mixture of the appropriate hydrazone 22a or 23a (1mmol) and (benzothiazol-2-yl)acetonitrile (24) or malononitrile (1 mmol) and a catalytic amount of triethylamine was added in a process vial. The vial was capped properly and irradiated under the appropriate condition (17.2 bars, 150 °C) for 15 min. The reaction mixture was left to cool then poured into ice cold water, and neutralized with dil. HCl. The resulting solid product was collected by filtration washed with ethanol, dried and recrystallized from DMF, to afford the pyridazine derivative 27a, 28a, 31a and 32a, respectively. The isolated products were found to be identical in all respects [mp, mixture mp and spectra] with those obtained by method (A) above.
4,5-(Bisbenzothiazol-2-yl)-1,6-dihydro-6-imino-3-(phenylsulfonyl)-1-(phenyl)pyridazine (27a): Yield (MW) 79%; yield (thermally) 70%, mp 258−260 °C; IR (KBr) νmax/cm-1: 3332 (NH), 1620 (C=N); 1H NMR (DMSO-d6) δ 6.74−8.14 (m, 18H, ArH’s), 11.88 (s, 1H, D2O-exchangable, NH); MS (m/z, %): 577 (M+, 100%); Anal. Calcd for C30H19N5O2S3 (577.70): C, 62.37; H, 3.32; N, 12.12; S, 16.65%. Found: C, 62.35; H, 3.34; N, 12.08; S, 16.68%.
4,5-(Bisbenzothiazol-2-yl)-1,6-dihydro-6-imino-3-(phenylsulfonyl)-1-(4-chlorophenyl)pyridazine (27b): Yield (65%), mp > 300 °C; IR (KBr) νmax/cm-1: 3339 (NH), 1610 (C=N); 1H NMR (DMSO-d6) δ 6.60−8.14 (m, 17H, ArH’s), 11.82 (br. s, 1H, D2O-exchangable, NH); MS (m/z, %): 611 (M+, 100%); Anal. Calcd for C30H18ClN5O2S3 (612.14): C, 58.86; H, 2.96; N, 11.44; S, 15.71%. Found: C, 58.83; H, 2.97; N, 11.41; S, 15.75%.
4,5-(Bisbenozthiazol-2-yl)-1,6-dihydro-6-imino-3-(phenylsulfonyl)-1-(4-methylphenyl)pyridazine (27c): Yield (72%), mp > 300 °C; IR (KBr) νmax /cm-1: 3328 (NH), 1598 (C=N); 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 6.42−8.14 (m, 17H, ArH’s), 11.80 (s, br, 1H, D2O-exchangable, NH); MS (m/z, %): 591 (M+, 100%); Anal. Calcd for C31H21N5O2S3 (591.73): C, 62.92; H, 3.58; N, 11.84; S, 16.26%. Found: C, 62.89; H, 3.61; N, 11.85; S, 16.24%.
5-(Benzothiazol-2-yl)-1,6-dihydro-6-imino-3-(1-methylbenzimidazol-2-yl)-3-(phenylsulphonyl)-1-(phenyl)pyridazine (28a): Yield (MW) 82%; yield (thermally) 75%, mp 258−260 °C; IR (KBr) νmax/cm-1: 3330 (NH), 1645 (CO); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.67- 8.14 (m, 18H, ArH’s), 11.85 (br. s, 1H, D2O-exchangable, NH); 13C NMR (DMSO-d6) δ 32.03, 111.43, 113.32, 120.23, 123.25, 123.48, 124.66, 124.9, 125.51, 126.16, 126.4, 127.5, 127.64, 128.48, 128.6, 129.1, 129.32, 129.56, 131.62, 133.83, 134.19, 135.72, 137.88, 140.45, 142.77, 151.46, 157.42; MS (m/z, %): 574 (M+, 100%); Anal. Calcd for C31H22N6O2S2 (574.68): C, 64.79; H, 3.86; N, 14.62; S, 11.16%. Found: C, 64.75; H, 3.89; N, 14.65; S, 11.14%.
5-(Benzothiazol-2-yl)-1,6-dihydro-6-imino-3-(1-methylbenzimidazol-2-yl)-3-(phenylsulphonyl)-1-(4-chlorophenyl)pyridazine (28b): Yield (68%), mp > 300 °C; IR (KBr) νmax/cm-1: 3325 (NH), 1651 (CO); 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 4.02 (s, 3H, NCH3), 6.43−8.14 (m, 17H, ArH’s), 11.75 (s, br, 1H, D2O-exchangable, NH); MS (m/z, %): 588 (M+, 100%); Anal. Calcd for C32H24N6O2S2 (588.70); C, 65.29; H, 4.11; N, 14.28; S, 10.89%. Found: C, 65.25; H, 4.09; N, 14.30; S, 10.85%.
4-(Benzohiazol-2-yl)-5-cyano-1,6-dihydro-6-imino-3-(phenylsulfonyl)-1-(phenyl)pyridazine (31a): Yield (thermally) 75%; yield (MW) 88%, mp 240−242 °C; IR (KBr) νmax/cm-1: 3332 (NH), 2233 (C≡N), 1597 (C=N); 1H NMR (DMSO-d6) δ 6.94−8.14 (m, 14H, ArH’s), 11.78 (br. s, 1H, D2O-exchangable, NH). MS (m/z, %): 469 (M+, 100%); Anal. Calcd for C24H15N5O2S2 (469.54): C, 61.39; H, 3.22; N, 14.92; S, 13.66%. Found: C, 61.42; H, 3.24; N, 14.88; S, 13.62%.
4-(Benzothiazol-2-yl)-5-cyano-1,6-dihydro-6-imino-3-(phenylsulfonyl)-1-(4-chlorophenyl)pyridazine (31b): Yield (69%), mp > 300 °C; IR (KBr) νmax/cm-1: 3332 (NH), 2233 (C≡N), 1597 (C=N); 1H NMR (DMSO-d6) δ 6.64−8.14 (m, 13H, ArH’s), 11.88 (s, br, 1H, D2O-exchangable, NH); 13C NMR (DMSO-d6) δ 114.88, 123.01, 124.86, 125.41, 126.16, 126.75, 127.54, 128.03, 129.07, 129.46, 129.69, 130.51, 133.33, 133.69, 135.2, 138.48, 140.05, 141.79, 151.06, 156.04; MS (m/z, %): 503 (M+, 100%); Anal. Calcd for C24H14ClN5O2S2 (503.98): C, 57.20; H, 2.80; N, 13.90; S, 12.72%. Found: C, 57.23; H, 2.82; N, 13.87; S, 12.74%.
4-(Benzothiazol-2-yl)-5-cyano-1,6-dihydro-6-imino-3-(phenylsulfonyl)-1-(4-methylphenyl)pyridazine (31c): Yield (71%), mp 290−292 °C; IR (KBr) νmax/cm-1: 3352 (NH), 2267 (C≡N), 1593 (C=N); 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 6.44−8.14 (m, 13H, ArH’s), 11.88 (s, br, 1H, D2O-exchangable, NH); 13C NMR (DMSO-d6) δ 20.88, 113.37, 123.01, 124.86, 125.45, 126.16, 126.66, 127.41, 127.58, 127.99, 129.53, 129.76, 130.87, 131.51, 133.48, 135.11, 136.07, 137.15, 140.22, 150.9, 156.04; MS (m/z, %): 483 (M+, 100%); Anal. Calcd for C25H17N5O2S2 (483.56): C, 62.09; H, 3.54; N, 14.48; S, 13.26%. Found: C, 62.11; H, 3.51; N, 14.52; S, 13.23%.
4-(1-Methylbenzimidazol-2-yl)-5-cyano-1,6-dihydro-6-imino-3-(phenylsulfonyl)-1-(phenyl)pyridazine (32a: Yield (thermally) 77%; yield (MW) 89%, mp 220−222 °C; IR (KBr) νmax/cm-1: 3332 (NH), 2233 (C≡N), 1597 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.54−7.92 (m, 14H, ArH’s), 11.79 (br. s, 1H, D2O-exchangable, NH); MS (m/z, %): 466 (M+, 100%); Anal. Calcd for C25H18N6O2S (466.51): C, 64.36; H, 3.89; N, 18.01; S, 6.87%. Found: C, 64.41; H, 3.86; N, 18.04; S, 6.89%.
4-(1-Methylbenzimidazol-2-yl)-5-cyano-1,6-dihydro-6-imin-3-(phenylsulfonyl)-1-(4-chlorophenyl)pyridazine (32b): Yield (74%), mp >300 °C; IR (KBr) νmax/cm-1: 3352 (NH), 2267 (C≡N), 1593 (C=N); 1H NMR (DMSO-d6) δ 4.05 (s, 3H, CH3), 6.59−7.92 (m, 13H, ArH’s), 11.82 (br. s, 1H, D2O-exchangable, NH); MS (m/z, %): 500 (M+, 100%); Anal. Calcd for C25H17ClN6O2S (500.96): C, 59.94; H, 3.42; N, 16.78; S, 6.40%. Found: C, 59.90; H, 3.46; N, 16.80; S, 6.36%.
4-(1-Methylbenzimidazol-2-yl)-5-cyano-1,6-dihydro-6-imin-3-(phenylsulfonyl)-1-(4-methylphenyl)pyridazine (32c): Yield (78%), mp 242−244 °C; IR (KBr) νmax/cm-1: 3352 (NH), 2267 (C≡N), 1593 (C=N); 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 4.12 (s, 3H, CH3), 6.40−7.92 (m, 13H, ArH’s), 11.81 (br. s, 1H, D2O-exchangable, NH); MS (m/z, %): 480 (M+, 100%); Anal. Calcd for C26H20N6O2S (480.54): C, 64.98; H, 4.20; N, 17.49; S, 6.67%. Found: C, 64.95; H, 4.18; N, 17.51; S, 6.70%.

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