HETEROCYCLES

Note | Regular issue | Vol. 81, No. 2, 2010, pp. 395-406
Received, 27th September, 2009, Accepted, 22nd December, 2009, Published online, 25th December, 2009.
DOI: 10.3987/COM-09-11845

■ Synthesis of Some New Pyridazinylspirohetarylindoles and Hetarylpyridazine Derivatives

Yassin Gabr,* Mohamed Abdel-Megid, Mohamed Abdel-Hamid Awas, and Naser Mohamed Abdel-Fatah

Department of Chemistry, Faculty of Education, Ain Shams University, El-Maqreezy St, Roxy, Heliopolis, Cairo 11757, Egypt

Abstract

Condensation of 4-acetyl-5,6-diphenylpyridazine-3(2H)-one (1) with 1H-indol-2,3-dione afforded the biheterocyclic enone 2. Interaction of 2 with some bifunctional nitrogen nucleophiles and dimedone yielded some novel pyridazinyl spirohetarylindoles 3-6. The reaction of 3-chloropyridazine derivative 7 with some heterocyclic compounds having vicinal amino and cyano groups gave hetarylaminopyridazines 9 and 13. Treatment of acetylpyridazinone 1 with arylidenecyanoacetate and arylidenemalononitrile afforded pyridylpyridazines 16 and 19, respectively. The effect of some active methylene compounds and thioacetamide on biheterocyclic enone 22 was also studied.

Pyridazines and indoles occupy a conspicuous place in domain of heterocyclic chemistry in view of their biological activities and medicinal importance. The pyridazine structure is found within a number of herbicides such as credazine, pyridafol and pyridate. It is also found within the structure of several pharmaceutical drugs such as cefozopran, cadralazine, minaprine, hydralazine, and cilazapril. There is also a recent article summarizing syntheses directed mainly to selected herbicidal, insecticidal and fungicidal pyridazines.1 Moreover, pyridazines used as chemotherapeutics, antithrombotic, antisecretory and anti-ulcer agents, analgesic and anti-inflammatory agents as well as with various central nervous system stimulants and depressants.2 On the other hand, Indole derivatives, formed during digestion of cruciferous vegetables, have been shown to have chemopreventative properties inhibiting human papilloma virus (HPV) transcription and influencing oestrogen metabolism.3 Furthermore, indole derivatives used as a chemoprotective agent in breast and prostate cancer,4,5 In continuation of our studies on the synthesis of new substituted pyridazines6,8 and indole9 derivatives, the present investigation aimed to incorporate both pyridazine and indole in a molecular frame-work starting from 4-acetyl-5,6-diphenylpyridazine-3(2H)-one (1).10

One of our targets is the synthesis of some new spiro heterocyclic compounds having pyridazinone and indole moieties in their structures. For this purpose, 3-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yloxoethylidene)-1,3-dihydro-2H-indol-2-one (2) was synthesized from compound 1 with 1H-indole-2,3-dione in boiling ethanol containing catalytic amount of piperidine. The structure of compound 2 was confirmed by its correct elemental analysis and spectroscopic data. IR spectrum showed three absorption vibration bands at 1717, 1680 and 1650 cm–1 due to carbonyl groups of enone, indole and pyridazinone respectively. Furthermore, its 1H NMR spectrum (DMSO-d6) exhibited signals at δ 2.31 attributed to ethylidene protons. Compound 2 is used as a suitable precursor for the synthesis of some novel spiro heterocyclic compounds having indolone moiety in their structures. Thus, 3’-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-1’,4’-dihydrospiro[2-oxo-2,3-dihydroindole-3,5’-pyrazole] (3) was obtained from the reaction of compound 2 with hydrazine hydrate in boiling ethanol.11 The mass spectrum of compound 3 showed a molecular ion peak at m/z 433. When compound 2 was allowed to react with aminoguanidine bicarbonate or thiosemicarbazide in boiling ethanol 3’-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-1’-(1-iminocarboxamido)-4’H-spiro[2-oxo-1H-indol-3,5’-pyrazole] (4) and 3’-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-1’-(1-thiocarboxamido-4’H-spiro[2-oxo-1H-indol-3,5’-pyrazole] (5) were obtained, respectively. The structure of compound 4 was established on the basis of its correct elemental analysis and spectroscopic data. The mass spectrum of compound 5 showed peak at m/z 476 for (M–16) indicating the loss of amino radical from the molecular ion peak.
On the other hand, treatment of compound 2 with dimedone12 in boiling ethanol containing catalytic amount of triethylamine, cyclocondensation took place giving 2’-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-5’-oxo-7’,7’-dimethyl-6’,8’-dihydrospiro[2-oxo-1H-indol-3,4’-chromen] (6). The structure of compound 6 was confirmed by mass spectrum which revealed the presence of molecular ion peak at m/z 541 (Scheme 1).

Recently, it has been reported that, compound 1 was reacted with phosphorous oxychloride to give 4-acetyl-3-chloro-5,6-diphenylpyridazine (7).13 The reaction of 3-chloropyridazine derivative 7 with some heterocyclic compounds having vicinal amino and cyano groups in their structures was studied. Thus, when compound 7 was subjected to react with 5-amino-1-phenylpyrazolo-4-carbonitrile (8) in boiling dimethylformamide two possible compounds 9 and 10 may be produced. Compound 9 is formed via direct nucleophilic displacement of chlorine atom yielding 4-acetyl-3-[(4-cyano-1-phenylpyrazol-5-yl)amino]-5,6-diphenylpyridazine (9), while compound 10 is formed via condensation of amino group with the carbonyl one. Compound 10 was ruled out based on the IR spectrum of the product which exhibited absorption band attributed to the carbonyl stretching frequency at 1708 cm–1 and element test showed the absence of chlorine atom. A trial was done to obtain a ring-chain tautomer of compound 9 was failed and the triheterocyclic compound 11 did not formed as IR spectrum of the product displayed absorption band at 2219 cm–1 which could be attributed to C≡N function. The structure of compound 9 was further supported by its mass spectrum which exhibited signals at 456 attributed to the molecular ion. Similarly, the interaction of chloropyridazine derivative 7 with 2-amino-4-(4-chlorophenyl)-3-cyanopyridine (12) yielded 4-acetyl-3-{[4-(4-chlorophenyl)-3-cyano-6-(4-hydroxyphenyl)pyridin-2-yl]amino}-5,6-diphenylpyridazine (13). The structure of compound 13 was confirmed via its mass spectrum which showed a peak at m/z 593 corresponding to the molecular ion.

Furthermore, treatment of chloropyridazine derivative 7 with 4-methylbenzenediazonium chloride afforded 3-chloro-4-[(4-methylphenyl)diazenylmethylcarbonyl]-5,6-diphenylpyridazine (14). The IR spectrum of compound 14 showed absorption bands at 1708 cm–1 which strongly support presence of conjugated carbonyl group. A trial to cyclized 14 to give pyridazinopyridazine 15 via removal of HCl was failed.

Because of biological importance of pyridines,14,15 it was of interest to use acetylpyridazine derivative 1 to synthesize some new pyridazines bearing pyridine moiety via interaction of acetylpyridazinone 1 with arylidenemalononitrile and arylidenecyanoacetate. Thus, when the acetylpyridazinone 1 was allowed to react with 4-chlorobenzylidene cayanoacetate in boiling ethanol containing ammonium acetate, 4-[4-(4-chlorophenyl)-3-cyano-2-oxo-1H-pyridin-6-yl]-5,6-diphenylpyridazin-3(2H)-one (16) was obtained, while 4-[2-amino-4-(4-chlorophenyl)-3-ethoxycarbonylpyridine-6-yl]-5,6-diphenylpyridazin-3(2H)-one (17) did not obtained based on the IR spectrum of the product which showed the presence of C≡N function at 2218. Also, the structure of compound 16 was supported by its mass spectrum which exhibited a molecular ion peak at m/z 476. Treatment of compound 16 with phosphorous oxychloride yielded 3-chloro-4-[2-chloro-4-(4-chlorophenyl)-3-cyanopyridin-6-yl]-5,6-diphenylpyridazine (18).
On the other hand, the interaction of compound 1 with 4-chlorobenzylidene malononitrile in boiling ethanol afforded 4-[2-amino-4-(4-chlorophenyl)-3-cyanopyridin-6-yl]-5,6-diphenylpyridazin-3(2H)-one (19) which condensed with formamide to give 4-[4-(4-chlorophenyl)-3-cyano-2-(aminomethylideneimino)pyridin-6-yl]-5,6-diphenylpyridazin-3(2H)-one (20) not 8-amino-5-[3-oxo-5,6-diphenyl-2H-pyridazin-4-yl]-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine (21) (Scheme 3).

Other goal of our interest is the use of acetylpyridazinone derivative 1 to synthesize some new pyridazines having thiazine and chromen moieties. For this purpose we previously synthesized the biheterocyclic enone 22 from interaction of equimolar amount of compound 1 with 3-formyl-6-chlorochromenone.8 2-Methyl-4-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-6-(6-chloro-4-oxochromen-3-yl)-6H-1,3-thiazine (23) was obtained on treatment the enone 22 with thioacetamide in boiling ethanol containing catalytic amount of piperidine. Formation of compound 23 involves nucleophilic attack of sulphur in thioacetamide to the β-position of the enone. The mass spectrum of 23 exhibited peaks at m/z 522 due to loss of methyl radical from the parent ion peak.
The effect of active methylene compounds, namely acetylacetone and dimedone on the biheterocyclic enone 22 was also studied. Thus, treatment of compound 22 with acetylacetone in boiling ethanol containing catalytic amount of piperidine afforded 3-acetyl-2-methyl-6-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-4-(6-chloro-4-oxochromen-3-yl)-4H-pyran (24). While the reaction of compound 22 with dimedone in boiling ethanol containing catalytic amount of triethylamine as a base, afforded 7,7-dimethyl-2-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-4-(6-chloro-4-oxochromen-3-yl)-4,6,8-tetrahydrochromen (25). Formation of compound 24 and 25 involves nucleophilic attack of methylidene anion, formed from action of base on active methylene compounds, to the β-position of the α,β unsaturated bond. The structure of compound 24 and 25 was established on the basis of elemental analysis and spectral data (Scheme 4).

EXPERIMENTAL
Melting points were determined on a Stuart SMP10 apparatus. The IR spectra were recorded on FTIR Brücher Vector 22 spectrophotometer using KBr wafer technique. 1H NMR spectra were measured on Varian Gemini spectrophotometer 200 MHz using TMS as internal standard. Mass spectra were obtained using Gas Chromatography Mass Spectrometry (GCMS) Hewlet packed 5988 Scheimadzu instrument at 70 eV. Elemental Analyses were done at microanalytical center, Cairo University.

4-Acetyl-5,6-diphenylpyridazin-3(2H)-one (1). This compound was prepared according to the reported method.10
3-(3-Oxo-5,6-diphenyl-2H-pyridazin-4-yloxoethylidene)-1,3-dihydro-2H-indol-2-one (2). A mixture of compound 1 (2.9 g, 10 mmol) and 1H-indol-2,3-dione (1.47 g, 10 mmol) in EtOH (50 mL) containing few drops of piperidine was heated under reflux for 8 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid so obtained was neutralized with very dilute hydrochloric acid to separate fine material, and was filtered off and recrystallized from EtOH-water to give compound 2 as red crystals (2.5 g, 58.5%): mp 94 °C; IR (ν cm–1): 3189 (NH), 3058 (aromatic CH), 1717 (CO of enone), 1680 (CO of indole); 1652 (CO of pyridazinone), 1615 (C=N); 1H NMR (DMSO-d6) δ 2.31 (s, 1H, ethylidene H), 6.91–7.89 (m, 14H, aromatic H), 10.89 (s, 1H, NH indole), 13.70 (s, 1H, enolic OH pyridazinone); MS m/z (%): 418 [M–1] (0.1), 105 (100), 383 (1.9), 353 (2.0), 289 (30.0), 191 (16.6), 165 (20.8), 77 (76.93), 56 (5.62); Anal. Calcd for C26H17N3O3 (%): C, 74.46; H, 4.06; N, 10.02. Found: C, 74.23; H, 4.27; N, 10.41.
3’-(3-Oxo-5,6-diphenyl-2H-pyridazin-4-yl)-1’,4’-dihydrospiro[2-oxo-1H-indol-3,5’-pyrazole] (3). To a solution of compound 2 (4.195 g, 10 mmol) in EtOH (10 mL) was added dropwise over 5 min, a solution of hydrazine hydrate (0.5 g, 10 mmol) in EtOH (10 mL) and the reaction mixture was refluxed for 8 h. After cooling, the reaction mixture was poured onto crushed ice. The solid so obtained was filtered off and recrystallized from EtOH-water to give compound 3 as yellow crystals (4.0 g, 93%): mp 143 °C; IR (ν cm–1): 3260-3150 (br NH), 3059 (aromatic CH), 1680 (CO of indole), 1651 (CO of pyridazinone); 1H NMR (DMSO-d6) δ 3.08 (s, 2H, CH2), 6.87–7.86 (m, 14H, aromatic H), 9.95 (s, 1H, NH pyrazole), 10.61 (s, 1H, NH indole), 13.64 (s, 1H, enolic OH pyridazinone); MS m/z (%): 432 [M–1] (0.1), 383 (4.1), 298 (32.9), 248 (9.4), 149 (8.27), 105 (88.0), 77 (100), 56 (7.1); Anal. Calcd for C26H19N5O2 (%): C, 72.05; H, 4.39; N, 16.17. Found: C, 71.91; H, 4.13; N, 15.91.
3’-(3-Oxo-5,6-diphenyl-2H-pyridazin-4-yl)-1’-(1-iminocarboxamido)-4’H-spiro[2-oxo-1H-indol-3,5’-pyrazole] (4). A mixture of compound 2 (4.195 g, 10 mmol) and aminoguanidine carbonate (0.74 g, 10 mmol) in EtOH (20 mL) was refluxed for 4 h. The reaction mixture was cooled and poured onto crushed ice. The solid obtained was filtered off and then dried and recrystallized from EtOH-water to give compound 4 as reddish crystals (3.5 g, 73.5%): mp 108–111 °C; IR (ν cm–1): 3566–3195 (NH2 and 3NH), 3059 (aromatic CH), 1685 and 1654 (2CO), 1599 (C=N and C=C); 1H NMR (DMSO-d6) δ 3.77 (s, 2H, CH2), 5.2–6.1 (s, br, 3H, NH and NH2), 6.85–7.81 (m, 14H, aromatic H), 10.71 (s, 1H, NH indole), 13.54 (s, 1H, enolic OH pyridazinone); MS m/z (%): 477 [M+2] (9.04); 476 [M+1] (16.5), 419 (11.2), 370 (7.5), 189 (24.5), 105 (88.3), 77 (100); Anal. Calcd for C27H21N7O2 (%): C, 68.21; H, 4.42; N, 20.63; Found, %: C, 68.50; H, 4.72; N, 20.99.
3’-(3-Oxo-5,6-diphenyl-2H-pyridazin-4-yl)-1’-(1-thiocarboxamido)-4’H-spiro[2-oxo-1H-in-dol-5,5’-pyrazole] (5). To compound 2 (4.195 g, 10 mmol) in EtOH (10 mL) was added a solution of thiosemicarbazide (0.911 g, 10 mmol) in EtOH (10 mL) and the reaction mixture was refluxed for 4 h. Afterward, the reaction mixture was cooled and poured onto crushed ice. The solid given was collected by filtration, then dried and recrystallized from DMF–water to give compound 5 as brown crystals (3.90 g, 79%): mp 118–121 °C; IR (ν cm–1): 3560–3184 (NH2 and 2NH), 3058 (aromatic CH), 1683 and 1651 (2CO), 1599 (C=N), 1221 (C=S); 1H NMR (DMSO-d6) δ 3.85 (s, 2H, CH2), 5.8–6.3 (s, br, 2H, NH2), 6.80–7.87 (m, 14H, aromatic H), 10.61 (s, 1H, NH indole), 13.58 (s, 1H, enolic OH pyridazinone); MS m/z (%): 476 [M–16] (0.73), 383 (14.5), 178 (18.1), 105 (96.3), 77 (100), 55 (53.4); Anal. Calcd for C27H20N6O2S (%): C, 65.85; H, 4.07; N, 17.07; S, 6.50. Found: C, 65.45; H, 4.21; N, 16.93; S, 6.99.
2’-(3-Oxo-5,6-diphenyl-2H-pyridazin-4-yl)-5’-oxo-7’,7’-dimethyl-6’,8’-dihydrospiro-[2-oxo-1H-indol-3,4’-chromen] (6). To a mixture of compound 2 (4.195 g, 10 mmol) and dimedone (1.40g, 10 mmol) in EtOH (20 mL) was added few drops of triethylamine. The reaction mixture was heated under reflux for 4 h. After cooling, the solid product so formed was collected and recrystallized from DMF-water to give compound 6 as dark brown crystals (3.83 g, 71%): mp 163 °C; IR (ν cm–1): 3215 and 3150 (2NH), 3058 (aromatic CH), 2994 (aliphatic CH), 1682-1653 (3CO), 1583 (C=N), 1106 (C–O); 1H NMR (DMSO-d6) δ 1.59 (s, 3H, CH3), 2.19 (s, 3H, CH3), 3.03 (s, 2H, C8–H), 3.36 (s, 2H, C6–H), 4.26 (s, 1H, C3–H), 6.94–8.05 (m, 14H, aromatic H), 10.06 (s, 1H, NH) and 13.67 (s, 1H, enolic OH pyridazinone); MS m/z (%): 539 [M–2] (1.12%), 491 (11.1), 476 (100), 419 (24.3), 208 (27.5), 126 (18.4), 77 (1.3), 60 (33.9), 55 (25.1); Anal. Calcd for C34H27N3O4 (%): C, 75.41; H, 4.99; N, 7.76. Found: C, 75.94; H, 4.61; N, 7.71.
4-Acetyl-3-chloro-5,6-diphenylpyridazine (7). This compound was prepared according to the reported method.6
4-Acetyl-3-[(4-cyano-1-phenylpyrazol-5-yl)amino]-5,6-diphenylpyridazine (9). A solution of 5-amino-1-phenylpyrazolo-4-carbonitrile (8) (1.86 g, 10 mmol) in DMF (10 mL) was added to a solution of compound 7 (3.09 g, 10 mmol) in DMF (10 mL) and the reaction mixture was heated under reflux for 6 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was collected by filtration, washed then dried and recrystallized from EtOH to give compound 9 as colorless crystals (3.90 g, 86%): mp 198–200 °C; IR (ν cm–1): 3222 (NH), 3056 (aromatic CH), 2953 (aliphatic CH), 2219 (C≡N), 1708 (CO); 1H NMR (DMSO-d6) δ 2.19 (s, 3H, CH3), 6.70 (s, 1H, C3–H pyrazole), 7.22–7.52 (m, 15H, aromatic H) and 7.80 (s, 1H, NH); MS m/z (%): 456 [M+] (1.36), 359 (1.8), 313 (8.1), 239 (7.8), 185 (5.3), 129 (18.2), 77 (7.83), 55 (100); Anal. Calcd for C28H20N6O (%): C, 73.68; H, 4.39; N, 18.42. Found: C, 73.91; H, 4.38; N, 18.00.
4-Acetyl-3-{[4-(4-chlorophenyl)-3-cyano-6-(4-hydroxyphenyl)pyridin-2-yl]amino}-5,6-diphenylpyridazine (13). To a solution of compound 7 (3.09 g, 10 mmol) in DMF (10 mL) was added dropwise a solution of 2-amino-3-cyanopyridine derivative 12 (3.24 g, 10 mmol) in DMF (10 mL) and the reaction mixture was refluxed for 6 h. Afterwards, the reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off and recrystallized from EtOH-water to give 13 as pale yellow crystals (4.0 g, 68%): mp 228 °C; IR (ν cm–1): 3469 (OH), 3362 (NH), 3064 (aromatic CH), 2959 (aliphatic CH), 2205 (CN), 1709 (CO); 1H NMR (DMSO-d6) δ 2.19 (s, 3H, CH3), 6.84–8.04 (m, 20H, NH, aromatic H), 5.61 (s, 1H, C5–H pyridine) and 9.95 (s, 1H, OH); MS m/z (%): 593 [M+] (26.3), 595 [M+2] (8.8), 550 (10.4), 522 (53.0), 535 (10.2), 282 (8.90), 250 (17.4), 128 (42.8), 79 (7.2), 57 (100); Anal. Calcd for C36H24N5O2Cl (%): C, 72.78; H, 4.04; N, 11.79; Cl, 5.98. Found: C, 73.00; H, 4.19; N, 11.31; Cl, 5.91.
3-Chloro-4-[(4-methylphenyl)diazenylmethylcarbonyl]-5,6-diphenylpyridazine (14). Sodium nitrite (0.69 g, 10 mmol) was dissolved in concentrated hydrochloric acid at room temperature, followed by the addition of 4-methylaniline (1.07 g, 10 mmol). The mixture was stirred at room temperature for 2 h then added to a cooled solution (0–5 °C) of compound 7 (3.09 g, 10 mmol) in alcoholic solution of sodium acetate and dropwise addition of concentrated hydrochloric acid. The mixture was stirred for 30 min; the precipitate product was collected and purified by column chromatography to give compound 14 as orange crystals (1.54 g, 36%): mp 223 °C. IR (ν cm–1): 3058 (aromatic CH), 2954 (aliphatic CH), 1708 (CO); 1H NMR (DMSO-d6) δ 2.19 (s, 3H, CH3), 3.35 (s, 2H, CH2), 7.18–7.39 (m, 14H, aromatic H); MS m/z (%): 425 [M+] (24.5), 427 [M+2] (8.0), 424 [M–1] (8.0), 339 (43.9), 313 (87.1), 262 (71.5), 207 (49.4), 144 (100), 98 (77.9), 84 (92.3), 77 (4.91); Anal. Calcd for C25H19N4OCl (%): C, 70.34; H, 4.46; N, 13.13; Cl, 8.32. Found: C, 70.33; H, 4.45; N, 13.10; Cl, 8.25.
4-[4-(4-Chlorophenyl)-3-cyano-2-oxo-1H-pyridin-6-yl]-5,6-diphenylpyridazin-3(2H)-one (16). In absolute EtOH containing ammonium acetate (4.7 g, 80 mmol), a mixture of compound 1 (2.9 g, 10 mmol) and arylidene cyanoacetate (2.36 g, 10 mmol) was heated under reflux for 6 h. The reaction mixture was cooled and the solid produced was filtered off and recrystallized to from petroleum ether 60–80 °C give compound 16 as yellowish crystals (3.30 g, 69.5%): mp 293 °C; IR (ν cm–1): 3177 (NH), 3019 (aromatic CH), 2218 (CN), 1740 (CO pyridine), 1638 (CO pyridazinone); 1H NMR (DMSO-d6) δ 5.70 (s, 1H, C5-H pyridine), 6.78–7.91 (m, 15H, aromatic H and NH pyridine), 13.78 (s, 1H, enolic OH pyridazinone); MS m/z (%): 476 [M+] (16.5), 478 [M+2] (5.5), 288 (62.0), 215 (15.6), 189 (27.2), 105 (33.3), 77 (100); Anal. Calcd for C28H17N4O2Cl (%): C, 70.51; H, 3.57; N, 11.75; 7.45; Cl, 7.45. Found: C, 70.47; H, 3.48; N, 11.43; Cl, 7.71.
3-Chloro-4-[2-chloro-4-(4-chlorophenyl)-3-cyanopyridin-6-yl]-5,6-diphenylpyridazine (18). A mixture of compound 16 (4.77g, 10 mmol) in phosphoryl chloride (30 mL) was warmed to 60 °C for 2 h. After cooling to room temperature, excess of phosphoryl chloride was removed under vacuum and then brought to pH 6 with sodium carbonate; the resulting oily product was solidified by stirring with water and collected by fraction and recrystallized from water to give compound 18 as brown crystals (4.83 g, 94%): mp 289 °C; IR (ν cm–1): 3058 (aromatic CH), 2222 (CN), 1654 (C=N); 1H NMR (DMSO-d6) δ 5.76 (s, 1H, C5-H pyridine), 6.74–7.87 (m, 14H, aromatic H); MS m/z (%): 512 [M+] (23.85), 514 [M+2] (12.8), 476 (22.7), 364 (26.9), 306 (51.9), 284 (98.5), 264 (100), 201 (57.9), 177 (45.9), 148 (30.0), 77 (28.2); Anal. Calcd for C28H15N4Cl3 (%): C, 65.43; H, 2.92; N, 10.91; Cl, 20.74. Found: C, 65.23; H, 3.10; N, 10.81; Cl, 20.93.
4-[2-Amino-4-(4-chlorophenyl)-3-cyanopyridin-6-yl]-5,6-diphenylpyridazin-3(2H)-one (19). In absolute ethanol (20 mL) containing ammonium acetate (4.7 g, 80 mmol), a mixture of compound 1 (2.9 g, 10 mmol) and arylidene malononitrile (1.89 g, 10 mmol) was heated under reflux for 6 h. The reaction mixture was cooled and the solid produced was filtered off and dried then recrystallized from EtOH to give compound 19 as brownish red crystals (3.43 g, 72%): mp 180 °C; IR (ν cm–1): 3250 and 3190 (NH2), 3118 (NH), 2208 (CN), 1656 (CO); 1H NMR (DMSO-d6) δ 5.21–5.61 (s, br, 2H, NH2), 5.71 (s, 1H, C5-H pyridine), 6.82–7.91 (m, 14H, aromatic H), 13.63 (s, 1H, enolic OH pyridazinone); MS m/z (%): 448 [M–HCN] (1.1), 414 (25.3), 344 (8.8), 330 (6.6), 311 (11.9), 269 (2.9), 178 (15.7), 105 (100), 104 (14.42), 77 (34.05); Anal. Calcd for C28H18N5OCl (%): C, 70.66; H, 3.79; N, 14.72; Cl, 7.47. Found: C, 70.99; H, 3.52; N, 14.50; Cl, 7.74.
4-[4-(4-Chlorophenyl)-3-cyano-2-(aminomethylideneimino)pyridin-6-yl]-5,6-diphenylpyridazin-3(2H)-one (20) A mixture of compound 19 (4.76 g, 10 mmol) and formamide (0.45 g, 10 mmol) was refluxed for 6 h at 100 °C and cooled. The solid obtained was filtered off and recrystallized from EtOH to give compound 20 as colorless crystals (3.27 g, 65%): mp 300 °C; IR (ν cm–1): 3320 and 3250 (NH2), 3196 (NH), 2208 (CN), 1686 (CO), 1648 (C=N); 1H NMR (DMSO-d6) δ 2.55 (s, 1H, N=CH), 4.61 (s, 2H, NH2), 5.47 (s, 1H, H-5 pyridine), 6.93–7.97 (m, 14H, aromatic H), 13.55 (s, 1H, enolic OH pyridazinone); MS m/z (%): 502 [M+] (12.0), 504 [M+2] (4.0), 409 (3.2), 383 (27.8), 289 (19.7), 236 (6.2), 178 (100), 151 (12.3), 105 (24.2); Anal. Calcd for C29H19N6OCl (%): C, 69.25; H, 3.78; N, 16.72; Cl, 7.06. Found: C, 69.22; H, 3.76; N, 16.21; Cl, 6.90.
2-Methyl-4-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-6-(6-chloro-4-oxochromen-3-yl)-6H-1,3-thiazine (23) A mixture of compound 22 (4.8 g, 10 mmol) and thioacetamide (0.75 g, 10 mmol) in DMF (30 mL) containing few drops of piperidine was heated under reflux for 4 h. The reaction mixture was cooled and poured onto crushed ice. The solid obtained was filtered off and recrystallized from EtOH to give compound 23 as deep yellow crystals (3.10 g, 57%): mp 192 °C; IR (ν cm–1): 3337 (NH), 3067 (aromatic CH), 2924 (aliphatic CH), 1794 (CO pyrone), 1648 (CO pyridazinone), 1595 (C=N), 1150 (C–S); 1H NMR (DMSO-d6) δ 2.1 (s, 3H, CH3), 6.55 (d, 1H, H-6 thiazine), 6.81 (d, 1H, H-5 thiazine), 7.08–7.89 (m, 13H, aromatic H), 8.02 (s, 1H, H-2 pyrone), 13.51 (s, 1H, enolic OH pyridazinone); MS m/z (%): 522 [M–CH3] (8.1), 396 (8.4), 299 (10.6), 239 (23.8), 185 (27.4), 79 (20.2), 56 (31.6), 55 (100); Anal. Calcd
for C30H20N3O3SCl (%): C, 66.98; H, 3.72; N, 7.81; Cl, 6.60. Found: C, 66.55; H, 3.52; N, 8.21; Cl, 7.13.
3-Acetyl-2-methyl-6-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-4-(6-chloro-4-oxochromen-3-yl)-4H-pyran (24). In dioxane (20 mL) containing few drops of piperidine, a mixture of compound 22 (4.8 g, 10 mmol) and acetylacetone (1 mL) was heated under reflux for 4 h and cooled. The solid obtained was filtered off, then dried and recrystallized from EtOH to give compound 24 as brownish red crystals (3.30 g, 59%): mp 220 °C; IR (ν cm–1): 3185 (NH), 3055 (aromatic CH), 2931 (aliphatic CH), 1731 (CO pyrone), 1685 (CO acetyl), 1640 (CO pyridazinone), 1178 (C–O–C); 1H NMR (DMSO-d6) δ 1.95 (s, 3H, CH3), 2.65 (s, 3H, COCH3), 6.44 (d, 1H, H-4 pyran), 6.73 (d, 1H, H-5 pyran), 7.11–7.91 (m, 13H, aromatic H), 8.05 (s, 1H, H-2 pyrone), 13.58 (s, 1H, enolic OH pyridazinone); MS m/z (%): 562 [M+] (0.4), 564 [M+2] (0.1), 290 (19.9), 289 (100), 275 (34.8), 264 (15.8), 190 (49.9), 164 (17.1), 129 (12.5), 77 (13.2), 55 (5.0); Anal. Calcd for C33H23N2O5Cl (%): C, 70.40; H, 4.09; N, 4.98; Cl, 6.31. Found: C, 70.64; H, 4.59; N, 4.45; Cl, 6.11.
7,7-Dimethyl-2-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)-4-(6-chloro-4-oxochromen-3-yl)-4,8-dihydrochrom-5(6H)-one (25) To a mixture of compound 22 (4.8 g, 10 mmol) and dimedone (1.4 g, 10 mmol) in EtOH (20 mL) was added few drops of piperidine and the reaction mixture was heated under reflux for 4 h. After cooling, the solid so formed, was collected and recrystallized from to give compound 25 as yellowish crystals (3.80 g 63%): mp 297 °C; IR (ν cm–1): 3239 (NH), 3068 (aromatic CH), 2930 (aliphatic CH), 1775 (CO chromen), 1710 (CO benzopyran), 1632 (CO pyridazinone), 1155 (C–O–C); 1H NMR (DMSO-d6) δ 1.19 (s, 6H, 2CH3), 2.03 (s, 2H, C8–H), 2.61 (s, 2H, C6–H), 4.64 (d, 1H, C3–H), 6.50 (d, 1H, H-4 pyran), 6.94–8.05 (m, 14H, aromatic H and C2–H pyrone), 13.61 (s, 1H, enolic OH pyridazinone); MS m/z (%): 602 [M+] (13.5), 604 [M+2] (4.5), 567 (6.1), 503 (6.3), 409 (7.8), 371 (16.2), 191 (12.6), 189 (49.0), 129 (22.9), 77 (47.0), 65 (16.0), 63 (100); Anal. Calcd for C36H27N2O5Cl (%): C, 71.70; H, 4.48; N, 4.65; Cl, 5.89. Found: C, 71.68; H, 4.54; N, 4.25; Cl, 5.91.

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