HETEROCYCLES

Paper | Regular issue | Vol. 92, No. 8, 2016, pp. 1397-1414
Received, 14th March, 2016, Accepted, 31st May, 2016, Published online, 9th June, 2016.
DOI: 10.3987/COM-16-13467

■ A Simple and Convenient Synthesis of Isolated Fused Heterocycles Based on: 6-Phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one and 5-Acetyl-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one

Mohamed Ahmed Mahmoud Abdel Reheim,* Ibrahim Saad Abdel Hafiz, and Mohamed Ahmed Elian

Department of Chemistry, Faculty of Science, Suez Canal Univeristy, Arish 45511, Egypt

Abstract

The reaction of 6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one 1 with acetylchloride in acetic anhydride in the presence of sodium acetate afforded 5-acetyl-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one 2 which reacted with bromine, hydrazine hydrate, phenylhydrazine, cyanothioacetamide, aldehydes and (malononitrile/sulfur) to give 2-thioxo-2,3-dihydropyrimidine derivatives 4, 7a,b, 8, 10 and 11 respectively. In the present investigation 6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one 1 was reacted with chloroacetylchloride yielded the corresponding compound 13. Compound 1 was reacted with some electrophilic reagents such as (benzylidene cyanothioacetamide derivatives, 2-cyano-2-cyclopentylethanethioamide, 2-cyano-2-cyclohexylethanethioamide and aromatic diazonium salts) to give compounds 23, 27a,b and 35 respectively. The newly synthesized heterocycles were characterized on the basis of their chemical properties and spectral data.

introduction
Heterocyclic compounds have drawn special attention in organic chemistry because of their abundance in natural products and their diverse biological properties.1 Pyrimidine and its derivatives have been recognized as important heterocyclic compounds due to their variety of chemical and biological significance to medicinal chemistry.2-4 As antiviral,5 antibacterial,6 antimalarial,7 antihypertensive8 and anti-inflammatory9 agents. In addition, pyrimidine derivatives form the basis of a large number of pharmacological products with anticancer and tein kinase inhibitory activity.10 Many substituted pyrimidine rings play an important role as analgesic, antipyretic also as pesticides, herbicides, plant growth regulators and organic calcium channel modulators.11-17 In continuation of our search of new compounds with anticipated biological activity, we aimed to obtain new compounds of the fused thiophene system, with similar therapeutic properties and other noteworthy chemical and biological activities.

RESULTS AND DISCUSSION
The key intermediate 5-acetyl-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one 2 was prepared in good yield from the reaction of 6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-(5H)-one 1 with acetyl chloride in acetic anhydride and sodium acetate at reflux temperature. The infrared spectrum of compound 2 revealed absorption bands at 3318, 3046, 1698 and 1374 cm-1 for amino, aromatic, carbonyl and thiocarbonyl function groups, respectively. 1H-NMR spectrum of compound 2 showed the following signals at 3.36 (s, 3H, CH3), 3.84 (s, 1H, CH), 7.31-7.72 (m, 5H, aromatic H), 10.62 (s, 1H, NH); 13C-NMR spectrum of compound 2 showed the following signals at 27.0, 56.3, 127.1, 127.1, 127.1, 127.1, 130.1, 133.1, 160, 170.1, 179.1, 200. Also, its mass spectrum showed a molecular ion peak at m/z 246 (M+).18

Bromination of 5-acetyl-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one 2 with bromine in acetic acid gave 5-(2-bromoacetyl)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one 4. The structure of compound 4 was established through microanalysis, IR, 1H-NMR, mass spectral data and chemical reactivity. So, acetonitrile derivative 5 was prepared in excellent yield by reaction of compound 4 with potassium cyanide in aqueous ethanol. The structure of compound 5 was characterized by analytical and spectral data. The IR spectrum of compound 5 showed bands 3388 (NH), 2225 (CN), 1694, 1637 (2CO) cm-1, 1H-NMR spectrum of compound 5 in DMSO-d6 revealed signals at 3.84 (s, 1H, CH), 4.10 (s, 2H, CH2), 7.23-7.75 (m, 5H, aromatic H), 10.62 (s ,1H, NH). Its mass spectrum showed a molecular ion peak m/z at 271 (M+) with a base peak at 116 and other significant peaks appeared at 197 (86%), 218 (79%) and 262 (89%).19,20 Treatment of compound 2 with hydrazine hydrate afforded 3-methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-(7H)-thione 7a which was established by the disappearance of two carbonyl group in the infrared spectrum. Its 1H-NMR spectrum showed a singlet signal at 2.27 ppm assigned for the methyl group and at 10.65, 10.80 ppm assigned for 2NH groups. The mass spectrum revealed a molecular ion peak at m/z 244 (M++2) corresponding to the molecular formula C12H10N4S. Similarly, when compound 2 was treated with phenylhydrazine in ethanolic solution afforded compounds 7b. The structure of compound 7b was proved by analytical and spectral data. Cyclocondensation of compound 2 with cyanothioacetamide in pyridine solution yielded the 5-methyl-4-phenyl-2,7-dithioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile 8 in good yield. The structure of compound 8 was confirmed on the basis of its analytical and spectral data. So, the IR spectrum showed the disappearance of carbonyl group and showed absorption bands at 3327, 3177 cm-1 due to 2NH groups in addition to the absorption band at 2206 cm-1 which can be assigned to CN group. Its 1H-NMR spectrum in DMSO-d6 displayed signals characteristic for amino, methyl and aromatic protons, the mass spectrum of compound 8 is in agreement with the proposed structure. An equimolar quantity of aromatic aldehydes 9a-c and methyl ketone 2 react in the presence of sodium hydroxide to give chalcones derivatives by cross aldol condensation reaction. The structures of the synthesized compounds were confirmed by IR, 1H-NMR and mass spectra. The IR spectrum of compound 10a as example was characterized by disappearance of methyl group and showed an absorption bands at 1629 cm-1 due to the carbonyl group. Its 1H-NMR spectrum in DMSO-d6 revealed signals at 3.43 (s, 1H, CH), 5.44 (br s, 1H, CH-olefinic), 6.86 (br s, 1H, CH-olefinic),7.19-7.87 (m, 11H, aromatic H and NH). The mass spectrums of compound 10a-c are in agreement with the proposed structure.21-23 In addition to this the behaviour of thioxo-2,3-dihydropyrimidin-4(5H)-one derivative 2 toward active methylene reagent and elemental sulfur was also investigated. Thus, compound 2 reacted with a mixture of malononitrile and elemental sulfur to afford the thiophene derivative 11 (Scheme 2). Assignment of structure 11 for the reaction product was based on its compatible spectroscopic data. Thus, its IR spectrum showed absorption band at 3428, 3320 cm-1 for NH2, 3212 cm-1 for NH and 2204 cm-1 for CN group.24 5-(2-Chloroacetyl)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one 13 was obtained by treatment of compound 1 with chloroacetyl chloride in dry toluene. The structure of the newly synthesized compound was confirmed by IR, 1H-NMR, 13C-NMR and mass spectra. Compound 13 underwent an intramolecular heterocyclization, upon boiling in toluene to afford 4-phenyl-2-thioxo-1,2-dihydrofuro[2,3-d]pyrimidin-5(6H)-one 14. The mass spectrum of compound 14 is in agreement with the proposed structure. On the other hand, when respective aryl amines were treated with ammonium thiocyanate under acidic conditions. It led to the formation of substitution arylthioureas 15a-c.25

Compound 13 and 15a-c were refluxed in dry acetone for 12 h to afford 2-thioxo-2,3-dihydropyrimidin-4(5H)-one derivatives 16a-c. All the synthesized compounds were characterized by IR, 1H-NMR and mass spectra. The IR spectrum of compound 16a as example showed bands at 3417, 3343 cm-1 for 2NH and band at 1675 cm-1 for carbonyl group. 1H-NMR spectra showed the following signals at 3.98 (s, 1H, CH), 5.44 (s, 1H, CH-thiazole), 7.17-7.60 (m, 10H, aromatic H), 9.00-9.80 (hump, 2H, 2NH) (Scheme 3).

The active methylene group in pyrimidinethione derivative 1 was exploited to synthesize novel tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile 23a-d and pyrido[2,3-d]pyrimidine-6'-carbonitrile 27a,b derivatives through its reaction with some electrophiles. Thus, the tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile 23a-d derivatives were obtained in quantitative yield from the reaction of 1 with arylidene-cyanothioacetamide 18a-d in ethanolic piperidine. Compounds 23a-d were confirmed on the basis of the spectroscopic analysis. Thus, IR spectrum of compound 23a as example revealed the presence of characteristic bands for amino and cyano functional groups. In addition, the 1H-NMR spectrum of compound 23a in DMSO-d6 revealed the absence of methylene moiety. The structure of compound 23a was supported by its mass spectrum which revealed molecular ion peak at m/z 374 (M+). The expected pyrimidine 22 formations was ruled out on the basis of analytical and spectral data.26 Similarly, cyclocondensation of 6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-(5H)-one 1 with cyclopentanone or cyclohexanone and cyanothioacetamide (1:1:1 molar ratio) afforded pyrido[2,3-d]pyrimidine-6'-carbonitrile of type 27a,b. Compounds 27a,b were confirmed based on the spectroscopic data. Thus, the infrared spectrum of 27a showed 2NH at 3354, 3215 cm-1 and CN at 2198 cm-1. Mass spectrum of 27a showed amolecular ion peak at m/z 354 (M++2) with a base peak at m/z 84.27 Condensation of compound 1 with aromatic aldehydes 9a-d in ethanol at reflux temperature in the presence of potassium hydroxide produced the 2-thioxo-2,3-dihydropyrimidin-4-(5H)-one derivatives 28a-d. The structure of the isolated product 28a-d was verified by elemental analysis and spectroscopic methods IR, 1H-NMR and mass spectra.28

Compounds 28b,d were reacted with thiourea in ethanol in the presence of potassium hydroxide to yield dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione derivatives 30b,d. The structures of all products 30b,d were established on the basis of IR, 1H-NMR, mass and elemental analysis.29,30 Our intention was extended to prepare pyrimidine derivatives with incorporating an active amino heterocyclic moiety. Thus, 6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one 1 reacted with equimolar amounts of malononitrile and elemental sulfur in dioxane/TEA solution to afford in 69% yield the corresponding 6-amino-4-phenyl-2-thioxo-1,2-dihydrthieno[3,2-d]pyrimidine-7-carbonitrile 31. The structure of 31 was established through microanalysis, IR, 1H-NMR and mass spectral data. The IR spectrum of compound 31 revealed the existence of absorption band at 2211 cm-1 corresponding to the CN group. The 1H-NMR spectrum of compound 31 revealed the presence of singlet signals for the NH2 group at 12.10 ppm. The mass spectra showed molecular ion peak at m/z 284 (M+) besides a base peak at m/z 128. Refluxing of compound 31 with triethyl orthoformate in the presence of acetic anhydride yielded the ethoxymethylene amino derivatives 32. The IR spectrum of 32 showed bands at 3316 (NH), 2930 (CH-aliph), 2218 (CN) and 1620 cm-1 (C=N), the 1H-NMR spectrum of 32 in CDCl3 revealed signals at 1.36 (t, 3H, CH3), 4.39 (q, 2H, CH2), 6.98-8.02 (m, 6H, aromatic H and CH-olefinic), 12.75 (s, 1H, NH). Attempts cyclization of 32 using hydrazine aiming at preparation of a series of fused pyrimidines failed and afforded the thienopyrimidine 31 in a quantitive yield.27, 31, 32

Compound 1 could be readily coupled with aryldiazonium salts to yield the corresponding arylazo derivatives 34a-c or isomeric structure 35. The structure of 35a-c were established through microanalysis, IR, 1H-NMR, mass spectra and its chemical reactivity of this molecule to active methylene reagent. So, treatment of compounds 35a-c with malononitrile without solvent in the presence of ammonium acetate afforded pyrimido[5,4-c]pyridazine-4-carbonitrile derivatives 38a-c in quantitative yield. The structures of 38a-c were established through elemental analysis and spectral data. The IR spectrum of 38a as example showed bands at 3328, 3181 (2NH), 2195 cm-1 (CN). Its 1H-NMR spectrum in CDCl3 exhibited signals at 6.95-7.93 (m, 12H, aromatic H and 2NH), mass spectrum of 38a showed a molecular ion peak m/z at 358 (M++2) corresponding to the molecular formula C19H12N6S.33, 34

EXPERIMENTAL
All melting points were measured using Akofler Block instrument and are uncorrected. IR spectra (KBr) were recorded on a FTIR 5300 spectrometer (υ, cm-1). The 1H-NMR spectra were recorded in DMSO-d6, CDCl3 at 300 MHz on a Varian Gemini NMR. 1000 EX mass spectrometer at 70 eV. The purity of synthesized compounds was checked by Thin layer chromatography TLC (aluminum sheets) using n-hexane, EtOAc (9:1, V/V, 7:3 V/V) eluent. Elemental analyses were carried out by the Microanalytical Research Center, Faculty of Science, Cairo University.
Preparation of compound (2). A mixture of pyrimidinethione derivatives 1 (0.01 mol) and acetyl chloride (0.01 mol) in acetic anhydride and sodium acetate was heated under reflux for 9 h. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from the proper solvent to give 2.
5-Acetyl-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (2). It was obtained as yellow crystals from EtOH; yield (85%); Mp 140-142 oC; IR (KBr) cm-1 3318 (NH), 3046 (CH-arom), 1698 (CO), 1374 (C=S); 1H-NMR (DMSO-d6) 3.36 (s, 3H, CH3), 3.84 (s, 1H, CH), 7.31-7.72 (m, 5H, aromatic H), 10.62 (s, 1H, NH); 13C NMR 27.0, 56.3, 127.1, 127.1, 127.1, 127.1, 130.1, 133.1, 160, 170.1, 179.1, 200; MS: m/z (%) 246 (M+). Anal. Calcd for C12H10N2O2S (246): C, 58.52; H, 4.09; N, 11.37. Found: C, 58.53; H, 4.10; N, 11.38%.
Preparation of compound (4). To a hot solution (60 oC) of 2 (0.01 mol) in acetic acid (40 mL), bromine (0.01 mol) in acetic acid (10 mL) was added dropwise with stirring for 10 min. The reaction mixture was allowed to attain room temperature and was poured into ice/water, the formed solid product was collected by filtration and crystallized from the proper solvent to give 4.
5-(2-Bromoacetyl)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (4). It was obtained as yellow crystals from EtOH; yield (59%); Mp 200-202 oC; IR (KBr) cm-1 3259 (NH), 3077 (CH-arom), 2985 (CH-aliph), 1658, 1641 (2CO); 1H-NMR (DMSO-d6) 3.60 (s, 1H, CH), 4.18 (s, 2H, CH2), 6.12-7.00 (m, 5H, aromatic H), 8.97 (s, 1H, NH); MS: m/z (%) 325 (M++1). Anal. Calcd for C12H9BrN2O2S (324): C, 44.32; H, 2.79; N, 8.61. Found: C, 44.33; H, 2.81; N, 8.62%.
Preparation of compound (5). To a hot solution (50 oC) of 4 (0.01 mol) in EtOH (40 mL), a solution (in 5 mL water) of potassium cyanide (0.01 mol) was added dropwise. The reaction mixture was left at room temperature for 4 h with stirring. The solid product, formed upon pouring into ice/water containing HCl (to pH 6) was collected by filtration and crystallized from the proper solvent to give 5.
3-Oxo-3-(6-oxo-4-phenyl-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)propanenitrile (5). It was obtained as white crystals from EtOH; yield (80%); Mp 150-152 oC; IR (KBr) cm-1 3388 (NH), 2225 (CN), 1694, 1637(2CO); 1H-NMR (DMSO-d6) 3.84 (s, 1H, CH), 4.10 (s, 2H, CH2), 7.23-7.75 (m, 5H, aromatic-H), 10.62 (s, 1H, NH); MS: m/z (%) 271 (M+). Anal. Calcd for C13H9N3O2S (271): C, 57.55; H, 3.34; N, 15.49. Found: C, 57.56; H, 3.35; N, 15.51%.
Preparation of compound (7a). A mixture of dihydropyrimidinone derivative 2 (0.01 mol) and hydrazine hydrate (3 mL) in EtOH was heated under reflux for 12 h. The reaction mixture was allowed to cool. The separated solid was filtered, washed with EtOH and crystallized from the proper solvent to give 7a.
3-Methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6(7H)-thione (7a). It was obtained as white crystals from EtOH; yield (72%); Mp 225-227 oC; IR (KBr) cm-1 3430, 3264 (2NH); 1H-NMR (DMSO-d6) 2.27 (s, 3H, CH3), 7.01-8.49 (m, 5H, aromatic H), 10.65 (s, 1H, NH), 10.80(s, 1H, NH); MS: m/z (%) 244 (M++2). Anal. Calcd for C12H10N4S (242): C, 59.48; H, 4.16; N, 23.12. Found: C, 59.49; H, 4.18; N, 23.13%.
Preparation of compound (7b). A mixture of dihydropyrimidinone derivative 2 (0.01 mol) and phenyl- hydrazine (0.01 mol) in EtOH containing catalytic amount of piperidine was heated under reflux for 12 h. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered off, washed with water and crystallized from the proper solvent to give 7b.
3,4-Diphenyl-1H-pyrazolo[3,4-d]pyrimidine-6(7H)-thione (7b). It was obtained as brown crystals from EtOH; yield (84%); Mp 100-102 oC; IR (KBr) cm-1 3454 (NH), 3055 (CH-arom), 2923 (CH-aliph); 1H-NMR (CDCl3) 2.46 (s, 3H, CH3), 7.21-7.50 (m, 10H, aromatic H), 8.10 (s, 1H, NH); MS: m/z (%) 320 (M++2). Anal. Calcd for C18H14N4S (318): C, 67.08; H, 3.97; N, 18.41. Found: C, 67.09; H, 3.99; N, 18.42%.
Preparation of compound (8). A mixture of dihydropyrimidinone derivative 2 (0.01 mol) and cyanothioacetamide (0.01 mol) in pyridine (30 mL) was heated under reflux for 12 h. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from the proper solvent to give 8.
5-Methyl-4-phenyl-2,7-dithioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (8). It was obtained as brown crystals from EtOH; yield (81%); Mp 180-182 oC; IR (KBr) cm-1 3327, 3177 (2NH), 2925 (CH-aliph), 2206 (CN); 1H-NMR (DMSO-d6) 1.91 (s, 3H, CH3); 7.41-7.97 (m, 7H, aromatic H and 2NH); 13C NMR 12.5, 79.4, 103.2, 120.6, 126.9, 126.9, 128.1, 128.1, 129, 134.1, 151.9, 160, 163, 163.8, 179; MS: m/z (%) 311 (M++1). Anal. Calcd for C15H10N4S2 (310): C, 58.04; H, 3.25; N, 18.05. Found: C, 58.05; H, 3.27; N, 18.06%.
General procedure for the preparation of compound (10a-c). A mixture of dihydropyrimidinone derivative 2 (0.01 mol), appropriate aromatic aldehydes 9a-c (0.01 mol) and 10% aqueous sodium hydroxide (10 mL) in EtOH (50 mL) was stirred at room temperature for about 3 h. The resulting solid was filtered off, washed with water, dried and crystallized from the proper solvent to give 10a-c.
6-Phenyl-5-(3-phenylacryloyl)-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (10a). It was obtained as white crystals from EtOH; yield (79%); Mp 300-302 oC; IR (KBr) cm-1 3455 (NH), 1629 (CO); 1H-NMR (DMSO-d6) 3.43 (s, 1H, CH), 5.44 (br s, 1H, CH-olefinic), 6.86 (br s, 1H, CH-olefinic); 7.19-7.87 (m, 11H, aromatic H and NH); MS: m/z (%) 335 (M++1). Anal. Calcd for C19H14N2O2S (334): C, 68.24; H, 4.22; N, 8.38. Found: C, 68.25; H, 4.24; N, 8.39%.
5-(3-(4-Chlorophenyl)acryloyl)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (10b). It was obtained as yellow crystals from EtOH; yield (68%); Mp 210-212 oC; IR (KBr) cm-1 3468 (NH), 1659, 1630 (2CO); 1H-NMR (CDCl3) 3.38 (s, 1H, CH); 5.90 (br s, 1H, CH-olefinic), 6.85 (br s, 1H, CH-olefinic), 6.87-7.55 (m, 10H, aromatic H and NH); MS: m/z (%) 369 (M++1). Anal. Calcd for C19H13ClN2O2S (368): C, 61.87; H, 3.55; N, 7.60. Found: C, 61.88; H, 3.57; N, 7.61%.
5-(3-(4-Methoxyphenyl)acryloyl)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (10c). It was obtained as yellow crystals from EtOH; yield (64%); Mp 190-192 oC; IR (KBr) cm-1 3438 (NH), 2922 (CH-aliph), 1797, 1627 (2CO); MS: m/z (%) 364 (M+). Anal. Calcd for C20H16N2O3S (364): C, 65.92; H, 4.43; N, 7.69. Found: C, 65.93; H, 4.45; N, 7.70%.
Preparation of compound (11). A mixture of dihydropyrimidinone derivative 2 (0.01 mol), malononitrile and sulfur (0.01 mol) in DMF (50 mL) containing catalytic amount of piperidine was heated under reflux for 12 h. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from the proper solvent to give 11.
2-Amino-4-(6-oxo-4-phenyl-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)thiophene-3-carbonitrile (11). It was obtained as brown crystals from EtOH; yield (81%); Mp 182-184 oC; IR (KBr) cm-1 3428, 3320 (NH2), 3212 (NH), 2923 (CH-aliph), 2204 (CN), 1629 (CO); 1H-NMR (DMSO-d6) 3.03 (s, 1H, CH), 6.40 (s, 2H, NH2), 7.49-7.84 (m, 6H, aromatic H and CH-thiophene), 11.76 (s, 1H, NH); MS: m/z (%) 327 (M++1). Anal. Calcd for C15H10N4OS2 (326): C, 55.20; H, 3.09; N, 17.17. Found: C, 55.21; H, 3.11; N, 17.18%.
Preparation of compound (13). A mixture of pyrimidinethione derivative 1 (0.01 mol) and chloroacetyl chloride 12 (0.01 mol) in dry toluene (30 mL) at 0-5 oC. The reaction mixture was stirred for 4 h at room temperature and reflux for 6 h. The solid obtained was washed with petroleum ether (40-60 oC) and kept in refrigerator. The solid obtained was recrystallized from the proper solvent to give 13.
5-(2-Chloroacetyl)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (13). It was obtained as white crystals from EtOH; yield (77%); Mp 140-142 oC; IR (KBr) cm-1 3476 (NH), 2980 (CH-aliph), 1776, 1711 (2CO) cm-1; 1H-NMR (DMSO-d6) 2.40 (s, 1H, CH), 4.07 (s, 2H, CH2), 5.25-7.12 (m, 5H, aromatic H), 8.39 (s, 1H, NH); 13C NMR 46.0, 53.1, 127.1, 127.1 128.1, 128.1, 129.0, 130.7, 160.9, 170.2, 179.1, 200; MS: m/z (%) 282 (M++2). Anal. Calcd for C12H9ClN2O2S (280): C, 51.34; H, 3.23; N, 9.98. Found: C, 51.35; H, 3.25; N, 9.99%.
Preparation of compound (14). Compound 13 (2.80 g) in toluene (30 mL) was fused for 8 h at 170 oC. The reaction mixture was left to stand; the solid product so formed was collected by filtration and recrystallized from the proper solvent to give 14.
4-Phenyl-2-thioxo-1,2-dihydrofuro[2,3-d]pyrimidin-5(6H)-one (14). It was obtained as pale brown crystals from EtOH; yield (81%); Mp 160-162 oC; IR (KBr) cm-1 3224 (NH), 2954 (CH-aliph), 1655 (CO); 1H-NMR (DMSO-d6) 4.33 (s, 2H, CH2), 6.94-7.28 (m, 6H, aromatic H and NH); MS: m/z (%) 244 (M+). Anal. Calcd for C12H8N2O2S (244): C, 59.00; H, 3.30; N, 11.47. Found: C, 59.01; H, 3.31; N, 11.49%.
General procedure for the preparation of compound (16a-c). A mixture of compound 13 (0.01 mol) and thiourea derivatives 15a-c (0.01 mol) in dry acetone (30 mL) was heated under reflux for 12 h. The reaction mixture was evaporated in vacuo. The separated solid was filtered, washed with ether and crystallized from the proper solvent to give 16a-c.
6-Phenyl-5-(2-(phenylamino)thiazol-4-yl)-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (16a). It was obtained as pale yellow crystals from Et2O; yield (79%); Mp 174-176 oC; IR (KBr) cm-1 3417, 3343 (2NH), 2977 (CH-aliph), 1675 (CO); 1H-NMR (DMSO-d6) 3.98 (s, 1H, CH), 5.44 (s, 1H, CH-thiazole), 7.17-7.60 (m, 10H, aromatic H), 9.00-9.80 (hump, 2H, 2NH); MS: m/z (%) 378 (M+). Anal. Calcd for C19H14N4OS2 (378): C, 60.30; H, 3.73; N, 14.80. Found: C, 60.31; H, 3.75; N, 14.81%.
5-(2-(4-Chlorophenylamino)thiazol-4-yl)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (16b). It was obtained as pale yellow crystals from EtOH; yield (74%); Mp 182-184 oC; IR (KBr) cm-1 3473, 3415 (2NH), 2977 (CH-aliph), 1675 (CO); 1H-NMR (DMSO-d6) 4.29 (s, 1H, CH), 5.44 (s, 1H, CH- thiazole), 7.16-7.50 (m, 9 H, aromatic H), 8.60-10.40 (hump, 2H, 2NH); MS: m/z (%) 415 (M++3). Anal. Calcd for C19H13ClN4OS2 (412): C, 55.27; H, 3.17; N, 13.57. Found: C, 55.28; H, 3.18; N, 13.59%.
Methyl-4-(4-(6-oxo-4-phenyl-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)thiazol-2-ylamino)benzoate (16c). It was obtained as pale yellow crystals from EtOH; yield (76%); Mp 198-200 oC; IR (KBr) cm-1 3419, 3343 (2NH), 2976 (CH-aliph), 1745, 1676 (2CO); 1H-NMR (DMSO-d6) 2.51 (s, 3H, OCH3), 4.14 (s, 1H, CH), 5.46 (s, 1H, CH- thiazole), 7.19-7.53 (m, 9H, aromatic H), 10.00-10.80 (s, 2H, 2NH); MS: m/z (%) 435 (M+-1). Anal. Calcd for C21H16N4O3S2 (436): C, 57.78; H, 3.69; N, 12.84. Found: C, 57.79; H, 3.71; N, 12.85%.
General procedure for the preparation of compound (23a-d). A mixture of compound 1 (0.01 mol) and benzylidene-cyanothioacetamide derivatives 18a-d (0.01 mol) in EtOH with catalytic amount of piperidine was heated under reflux for 10 h. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from the proper solvent to give 23a-d.
7-Mercapto-4,5-diphenyl-2-thioxo-1,2,5,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (23a). It was obtained as pale yellow crystals from EtOH; yield (73%); Mp 118-120 oC; IR (KBr) cm-1 3339, 3208 (2NH), 2931 (CH-aliph), 2198 (CN); 1H-NMR (DMSO-d6) 1.65 (hump, 1H, SH), 4.18 (s, 1H, 4H-pyridine), 6.94-7.93 (m, 10H, aromatic H), 8.40 (hump, 1H, NH), 10.00 (s, 1H, NH); MS: m/z (%) 374 (M+). Anal. Calcd for C20H14N4S2 (374): C, 64.15; H, 3.77; N, 14.96. Found: C, 64.12; H, 3.73; N, 14.92%.
5-(4-Chlorophenyl)-7-mercapto-4-phenyl-2-thioxo-1,2,5,8-tetrahydropyrido[2,3-d]pyrimidine-6- carbonitrile (23b). It was obtained as pale yellow crystals from EtOH; yield (76%); Mp 110-112 oC; IR (KBr) cm-1 3325, 3189 (2NH), 2940 (CH-aliph), 2214 (CN); 1H-NMR (CDCl3) 1.65 (hump, 1H, SH), 4.34 (s, 1H, 4H-pyridine), 6.73-8.01 (m, 11H, aromatic H and 2NH); MS: m/z (%) 409 (M++1). Anal. Calcd for C20H13ClN4S2 (408): C, 58.74; H, 3.20; N, 13.70. Found: C, 58.75; H, 3.22; N, 13.71%.
7-Mercapto-5-(4-methoxyphenyl)-4-phenyl-2-thioxo-1,2,5,8-tetrahydropyrido[2,3-d]pyrimidine-6- carbonitrile (23c). It was obtained as pale yellow crystals from EtOH; yield (69%); Mp 98-100 oC; IR (KBr) cm-1 3331, 3179 (2NH), 2935 (CH-aliph), 2213 (CN); 1H-NMR (CDCl3) 1.62 (hump, 1H, SH), 3.82 (s, 3H, OCH3), 5.91 (s, 1H, 4H-pyridine), 6.82-7.54 (m, 11H, aromatic H + 2NH); 13C NMR 37.2, 54.2, 76.8, 80.0, 117.1, 117.1, 120.0, 127.1, 127.1, 128.1, 128.1, 129.0, 130.0, 130.3, 130.6, 136, 138.6, 154.3, 155.3, 160.2, 179.0; MS: m/z (%) 404 (M+). Anal. Calcd for C21H16N4OS2 (404): C, 62.35; H, 3.99; N, 13.85. Found: C, 62.36; H, 4.01; N, 13.86%.
5-(2,4-Dichlorophenyl)-7-mercapto-4-phenyl-2-thioxo-1,2,5,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (23d). It was obtained as pale yellow crystals from EtOH; yield (80%); Mp 116-118 oC; IR (KBr) cm-1 3346, 3207 (2NH), 3086 (CH-arom), 2938 (CH-aliph), 2192 (CN); 1H-NMR (CDCl3) 1.68 (hump, 1H, SH), 5.61 (s, 1H, 4H-pyridine), 7.27-8.22 (m, 8H, aromatic H ), 10.18 (s,1H, NH), 10.42 (s,1H, NH); MS: m/z (%) 445 (M++3). Anal. Calcd for C20H12Cl2N4S2 (442): C, 54.18; H, 2.73; N, 12.64. Found: C, 54.15; H, 2.70; N, 12.62%.
General procedure for the preparation of compound (27a,b). A mixture of compound 1 (0.01 mol), cyclohexanone (or cyclopentanone) (0.0l mol) and cyanothioacetamide (0.01 mol) in EtOH containing catalytic amount of piperidine was heated under reflux for 10 h. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from the proper solvent to give 27a,b.
7'-Mercapto-4'-phenyl-2'-thioxo-2',8'-dihydro-1'H-spiro[cyclopentane-1,5'-pyrido[2,3-d]pyrimidine-6'-carbonitrile (27a). It was obtained as pale brown crystals from EtOH; yield (82%); Mp 270-272 oC; IR (KBr) cm-1 3354, 3215 (2NH), 2930 (CH-aliph), 2198 (CN); 1H-NMR (DMSO-d6) 0.85 (br, 1H, SH), 1.17-1.23 (m, 4H, 2CH2), 1.51-1.98 (m, 4H, 2CH2), 6.73-8.11 (m, 5H, aromatic H), 8.54 (hump, 2H, 2NH); 13C NMR 25.6, 27.0, 27.0, 38.1, 38.1, 79.0, 100.1, 120.2, 126.9, 126.9, 128.1, 128.1, 129.1, 130.1, 137.1, 147.9, 160.1, 179.1; MS: m/z (%) 354 (M++2). Anal. Calcd for C18H16N4S2 (352): C, 61.34; H, 4.58; N, 15.90. Found: C, 61.35; H, 4.60; N, 15.91%.
7'-Mercapto-4'-phenyl-2'-thioxo-2',8'-dihydro-1'H-spiro[cyclohexane-1,5'-pyrido[2,3-d]pyrimidine-6'-carbonitrile (27b). It was obtained as brown crystals from EtOH; yield (75%); Mp 140-142 oC; IR (KBr) cm-1 3336, 3185 (2NH), 2935 (CH-aliph), 2194 (CN); 1H-NMR (DMSO-d6) 1.32 (hump, 1H, SH), 1.34-1.38 (m, 2H, CH2), 1.51-1.79 (m, 4H, 2CH2), 2.56-2.89 (m, 4H, 2CH2), 6.94-7.28 (m, 5H, aromatic H), 7.95 (s, 2H, 2NH); MS: m/z (%) 367 (M++1). Anal. Calcd for C19H18N4S2 (366): C, 62.27; H, 4.95; N, 15.29. Found: C, 62.28; H, 4.97; N, 15.30%.
General procedure for the preparation of compound (28a-d). A mixture of compound 1 (0.01 mol) and appropriate aromatic aldehydes 9a-d (0.01 mol) in ethanolic potassium hydroxide (50 mL, 10%) was heated under reflux for 8 h. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The resulting solid was filtered off, washed with water, dried and crystallized from the proper solvent to give 28a-d.
5-Benzylidene-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-(5H)-one (28a). It was obtained as white crystals from EtOH; yield (70%); Mp 180-182 oC; IR (KBr) cm-1 3178 (NH), 2924 (CH-aliph), 1653 (CO); 1H-NMR (DMSO-d6) 5.15 (s, 1H, CH-oliffinic), 7.13-8.01 (m, 11H, aromatic H + NH); MS: m/z (%) 294 (M++2). Anal. Calcd for C17H12N2OS (292): C, 69.84; H, 4.14; N, 9.58. Found: C, 69.85; H, 4.16; N, 9.59%.
5-(4-Chlorobenzylidene)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-(5H)-one (28b). It was obtained as yellow crystals from EtOH; yield (81%); Mp 218-220 oC; IR (KBr) cm-1 3404 (NH), 2925 (CH-aliph), 1684 (CO); 1H-NMR (CDCl3) 7.27-8.05 (m, 10H, aromatic H and CH-oliffinic), 10.00 (s, 1H, NH); MS: m/z (%) 328 (M++2). Anal. Calcd for C17H11ClN2OS (326): C, 62.48; H, 3.39; N, 8.57. Found: C, 62.45; H, 3.37; N, 8.54%.
5-(4-Methoxybenzylidene)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-(5H)-one (28c). It was obtained as yellow crystals from EtOH; yield (68%); Mp 100-102 oC; IR (KBr) cm-1 3197 (NH), 2926 (CH-aliph), 1671 (CO); 1H-NMR (DMSO-d6) 3.90 (s, 3H, OMe), 8.73-8.95 (m, 9H, aromatic H, CH-oliffinic and NH); MS: m/z (%) 322 (M+). Anal. Calcd for C17H12N2OS (322): C, 67.06; H, 4.38; N, 8.69. Found: C, 67.07; H, 4.39; N, 8.71%.
5-(4-Hydroxybenzylidene)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-(5H)-one (28d). It was obtained as pale yellow crystals from EtOH; yield (68%); Mp 200-202 oC; IR (KBr) cm-1 3420 (NH), 2924 (CH-aliph), 1665 (CO); 1H-NMR (DMSO-d6) 7.03-8.88 (m, 12H, aromatic H, CH-oliffinic, NH and OH); MS: m/z (%) 308 (M+). Anal. Calcd for C17H12N2O2S (308): C, 66.22; H, 3.92; N, 9.08. Found: C, 66.23; H, 3.94; N, 9.10%.
General procedure for the preparation of compound (30b,d). To boiling solution of compound 28b,d (0.01 mol) in ethanolic potassium hydroxide (30 mL, 10%), thiourea (0.01 mol) was added. The reaction mixture was refluxed for 20 h, then allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from the proper solvent to give 30b,d.
5-(4-Chlorophenyl)-7-mercapto-4-phenyl-5,8-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione (30b). It was obtained as pale yellow crystals from EtOH; yield (64%); Mp 205-207 oC; IR (KBr) cm-1 3369, 3175 (2NH), 3064 (CH-arom), 2966 (CH-aliph); 1H-NMR (DMSO-d6) 1.17 (s, 1H, SH), 5.43 (s, 1H, 4H-pyrimidine), 6.67-7.73 (m, 10H, aromatic H and NH), 9.78 (hump, 1H, NH); 13C NMR 49.6, 79.0, 126.9, 126.9, 127.1, 127.1, 128.1, 128.1, 129.1, 130.0, 130.0, 130.1, 133.0, 138.9, 155.0, 160.0, 160.9, 179.2; MS: m/z (%) 386 (M++2). Anal. Calcd for C18H13ClN4S2 (384): C, 56.17; H, 3.40; N, 14.56. Found: C, 56.18; H, 3.42; N, 14.58%.
5-(4-Hydroxyphenyl)-7-mercapto-4-phenyl-5,8-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione (30d). It was obtained as white crystals from EtOH; yield (61%); Mp 310-312 oC; IR (KBr) cm-1 3425, 3212 (2NH), 2927 (CH-aliph); 1H-NMR (DMSO-d6) 1.67 (hump, 1H, SH), 6.24 (s, 1H, 4H-pyrimidine), 6.85-8.12 (m, 10H, aromatic H and NH), 9.78 (s, 1H, OH), 10.80 (s, 1H, NH); MS: m/z (%) 366 (M+). Anal. Calcd for C18H14N4OS2 (366): C, 58.99; H, 3.85; N, 15.29. Found: C, 59.00; H, 3.87; N, 15.30%.
Preparation of compound (31). Method (A): A solution of compound 1 (0.01 mol), malononitrile and sulfur (0.01 mol) in dioxane (30 mL) containing catalytic amount of TEA was heated under reflux for 12 h. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from the proper solvent to give 31. Method (B): to a solution of compound 32 (0.01 mol) in dry benzene (30 mL), hydrazine hydrate (10 mL) was added with stirring at room temperature for 1 h, the obtained product was filtered off, dried and recrystallized from dioxane to give compound 31.
6-Amino-4-phenyl-2-thioxo-1,2-dihydrthieno[3,2-d]pyrimidine-7-carbonitrile (31). It was obtained as brown crystals from EtOH; yield (69%); Mp 114-116 oC; IR (KBr) cm-1 3336, 3200 (NH2), 2939 (CH-aliph), 2211 (CN); 1H-NMR (DMSO-d6) 7.36-8.90 (m, 5H, aromatic H), 10.63 (hump, 1H, NH), 12.10 (hump, 2H, NH2) ; MS: m/z (%) 284 (M+). Anal. Calcd for C13H8N4S2 (284): C, 54.91; H, 2.84; N, 19.70. Found: C, 54.92; H, 2.85; N, 19.71%.
Preparation of compound (32). A mixture of compound 31 (2.82 g) and triethylorthoformate (3 mL) in acetic anhydride (10 mL) was heated under reflux for 6 h. The reaction mixture was evaporated in vacuo. The separated solid was filtered, washed with ether and crystallized from the proper solvent to give 32.
Ethyl-N-[7-cyano-4-phenyl-2-thioxo-1,2-dihydrthieno[3,2-d]pyrimidin-6-yl]formimidate (32). It was obtained as brown crystals from EtOH; yield (65%); Mp 100-102 oC; IR (KBr) cm-1 3316 (NH), 2930 (CH-aliph), 2218 (CN), 1620 (C=N); 1H-NMR (CDCl3) 1.36 (t, 3H, CH3), 4.39 (q, 2H, CH2), 6.98-8.02 (m, 6H, aromatic H and CH-oleffinic), 12.75 (s, 1H, NH); 13C NMR 15.2, 19.2, 60.8, 119.5, 121.1, 127.1, 127.1, 129, 129.2, 130.1, 132.3, 133, 158.9, 159.0, 160.0, 179.1; MS: m/z (%) 340 (M+). Anal. Calcd for C16H12N4S2 (340): C, 56.45; H, 3.55; N, 16.46. Found: C, 56.46; H, 3.57; N, 16.47%.
General procedure for the preparation of compound (35a-c). A cold suspension of aryldiazonium salts 33a-c (0.002 mol) (prepared from 0.002 mol of aromatic amine with the appropriate quantities of sodium nitrite and hydrochloric acid) was gradually added to a cold solution (0-5 oC) of compound 1 (0.002 mol) in EtOH (50 mL) containing anhydrous sodium acetate (5 g) with continuous stirring for 1 h. The resulting reaction product was filtered off, washed with water and crystallized from the proper solvent to give compounds 35a-c.
6-Phenyl-5-(phenylhydrazono)-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (35a). Formed as brown crystals from EtOH; yield (86%); Mp 100-102 oC; IR (KBr) cm-1 3218, 3184 (2NH), 3053 (CH-arom), 1676 (CO); 1H-NMR (CDCl3) 6.92-7.79 (m, 11H, aromatic H and NH), 12.71 (s, 1H, NH); MS: m/z (%) 308 (M+). Anal. Calcd for C16H12N4OS (308): C, 62.32; H, 3.92; N, 18.17. Found: C, 62.33; H, 3.94; N, 18.18%.
5-(2-(4-Chlorophenyl)hydrazono)-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4(5H)-one (35b). Formed as yellow crystals from EtOH; yield (89%); Mp 110-112 oC; IR (KBr) cm-1 3429, 3186 (2NH), 3082 (CH-arom), 1652 (CO); 1H-NMR (CDCl3) 6.91-7.78 (m, 10H, aromatic H and NH), 12.72 (s, 1H, NH); MS: m/z (%) 342 (M+). Anal. Calcd for C16H11ClN4OS (342): C, 56.06; H, 3.23; N, 16.34. Found: C, 56.07; H, 3.25; N, 16.35%.
6-Phenyl-2-thioxo-5-(p-tolyldiazenyl)-2,3-dihydropyrimidin-4(5H)-one (35c). Formed as brown crystals from EtOH; yield (82%); Mp 98-100 oC; IR (KBr) cm-1 3181 (NH), 3059 (CH-arom), 2962 (CH-aliph), 1678 (CO); 1H-NMR (DMSO-d6) 3.34 (s, 3H, CH3),7.00-7.80 (m, 10H, aromatic H and NH), 10.61 (s, 1H, NH); MS: m/z (%) 322 (M+). Anal. Calcd for C17H14N4OS (322): C, 63.33; H, 4.38; N, 17.38. Found: C, 63.34; H, 4.40; N, 17.39%.
General procedure for the preparation of compound (38a-c). A mixture of compounds 35a-c (0.01 mol), malononitrile (0.01 mol) and ammonium acetate (2 g) was exposed to microwave irradiation (power input 20%) for 3 min, the reaction mixture was allowed to reach room temperature, then diluted with EtOH with stirring and solid product that formed, was filtrated and crystallized from the proper solvent to give 38a-c.
3-Imino-2,8-diphenyl-6-thioxo-2,3,5,6-tetrahydropyrimido[5,4-c]pyridazine-4-carbonitrile (38a). Formed as red crystals from EtOH; yield (79%); Mp 122-124 oC; IR (KBr) cm-1 3328, 3181 (2NH), 2195 (CN); 1H-NMR (CDCl3) 6.95-7.93 (m, 12H, aromatic H and 2NH); MS: m/z (%) 358 (M++2). Anal. Calcd for C19H12N6S (356): C, 64.03; H, 3.39; N, 23.58. Found: C, 64.04; H, 3.40; N, 23.60%.
2-(4-Chlorophenyl)-3-imino-8-phenyl-6-thioxo-2,3,5,6-tetrahydropyrimido[5,4-c]pyridazine-4- carbonitrile (38b). Formed as brown crystals from EtOH; yield (74%); Mp 134-136 oC; IR (KBr) cm-1 3335, 3209 (2NH), 2195 (CN); 1H-NMR (CDCl3) 6.95-8.47 (m, 11H, aromatic H and 2NH); MS: m/z (%) 392 (M++2). Anal. Calcd for C19H11ClN6S (390): C, 58.39; H, 2.84; N, 21.50. Found: C, 58.40; H, 2.85; N, 21.52%.
3-Imino-8-phenyl-6-thioxo-2-p-tolyl-2,3,5,6-tetrahydropyrimido[5,4-c]pyridazine-4-carbonitrile (38c). Formed as brown crystals from EtOH; yield (76%); Mp 116-118 oC; IR (KBr) cm-1 3340, 3212 (2NH), 3030 (CH-arom), 2916 (CH-aliph), 2193 (CN); 1H-NMR (CDCl3) 1.23 (s, 3H, CH3), 7.23-7.52 (m, 11H, aromatic H and 2NH); 13C NMR 18.9, 80.1, 113.1, 119.2, 120.3, 127.1, 127.1, 128.6, 129.2, 129.2, 129.8, 130.1, 130.8, 133.1, 133.3, 151.2, 153.4, 160.0, 162.1, 179.1; MS: m/z (%) 370 (M+). Anal. Calcd for C20H14N6S (370): C, 64.85; H, 3.81; N, 22.69. Found: C, 64.86; H, 3.82; N, 22.71%.

ACKNOWLEDGEMENTS
The authors are very grateful to Prof. Dr. A. E. Khodair, Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt, for valuable support and reviewing this manuscript.

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