Materials and methods
The prepared compounds' melting points are uncorrected and were determined with MEL TEMP II equipment. A Perkin-Elmer FTIR spectrophotometer was used to record the IR spectra (KBr). The NMR spectrum, including 1H NMR and 13C NMR, was registered on a Bruker spectrometer (400 MHz for 1H NMR and 100 MHz for 13C NMR) in DMSO-d6 as solvent using tetramethyl-silane (TMS) as internal reference standard. Chemical shift values are expressed in parts per million (ppm) and are abbreviated as follows: (s) for singlet signals, (d) for doublet signals, (t) for triplet signals and (m) for multiplet signals. The NMR spectra were obtained at Kafr Elsheikh University's Faculty of Science. Elements microanalyses were carried out at El-azhr University's Micro Analytical Center. At Cairo University's Micro Analytical Unit, mass spectra were collected using a DI analysis Shimadzu QP-2010 plus mass spectrometer.TLC analytical silica gel plate 60 F254 was used to track the success of the chemical reaction and the purity of the compounds.
Chemistry
General method for synthesis of chalcone 3a-c
3-acetyl-1-methylpyrrole 1 (10 mmol, 1.23 g) was added dropwise to 100 mL of 60% aqueous ethanol solution of sodium hydroxide (30 mmol, 1.20 g) in an ice bath with stirring for 30 min. The 5-substituted thiophene-2-carbaldehyde 2a-c (10 mmol) was added dropwise over 15 min followed by stirring for 3 h in the ice bath. The reaction mixture was left overnight in a refrigerator, the separated solid was filtered, washed with water, dried and recrystallized from ethanol to give the corresponding 1-(1-Methyl-1H-pyrrol-2-yl)-3-(5-substituted-thiophen-2-yl)-propen- one 3a-c. Melting points, yield % and IR spectral data of compounds 3a-c were collected in Table1.
General method for synthesis of 6-(1-Methyl-1H-pyrrol-2-yl)-4-(5-substituted-thiophen-2-yl)-3,4-dihydro-1H-pyrimidine-2-thione 4a-c
A mixture of chalcone 3a-c (10 mmol), thiourea (0.76 g, 10 mmol) and potassium hydroxide (0.85 g, 15 mmol) was heated in 50 mL of absolute ethanol under reflux for 7 h. The reaction mixture was allowed to cool, neutralized with diluted hydrochloric acid, filtrated and washed with water and then the product recrystallized from ethanol to give the corresponding 4a-c compounds.
6-(1-Methyl-1H-pyrrol-2-yl)-4-thiophen-2-yl-3,4-dihydro-1H-pyrimidine-2-thione 4a
According to the previous general method yellow crystals were obtained. Yield (2.23 g, 81%); mp (149–151) °C; IR (KBr) νmax: 3377, 32,215 (2 NH), (1612–1589) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.42 (S, 3H, NCH3), 4.76 (d, 1H, H-4 of pyrimidine, J = 7.7 Hz), 6.33- 7.31 (m, 7H, Ar–H protons), 8.89 (s, br, H, 1NH, D2O exchangeable), 9.78 ppm (br, 1H, NH, D2O exchangeable). 13C NMR (100 MHz, DMSO-d6) δ 39.57 (NCH3), 65.37 (C-4 of pyrimidine), 108.30 (C-5 of pyrimidine), 119.86, 12.05, 124.58, 127.12,128.66, 130.18 (8 C of aryl carbons), 141.18 (C-6 of pyrimidine), 176.13 ppm (C=S). Anal. Calcd for C13H13N3S2 (275.39): C, 56.65; H, 4.72; N, 15.25. Found: C, 56.52; H, 4.65; N, 15.27.
6-(1-Methyl-1H-pyrrol-2-yl)-4-(5-methyl-thiophen-2-yl)-3,4-dihydro-1H-pyrimidine-2-thione 4b
Yellow crystals were obtained according to the previous general method. Yield (2.46 g, 85%); mp (155–157) °C; IR (KBr) νmax: 3387, 3263 (2 NH), (1618–1601) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3H, CH3), 3.56 (S, 3H, NCH3), 4.94 (d, 1H, H-4 of pyrimidine, J = 8.0 Hz), 6.08 (d, 1H, H-5 of pyrimidine, J = 6.1 Hz), 7.06 (d, 1H, H-3 of pyrrole, J = 6.09 Hz), 7.27 (dd, 1H, H-4 of pyrrole), 7.43 (d, 1H, H-5 of pyrrole, J = 6.5 Hz), 7.75 (d, 1H, H-3 of thiophene, J = 5.0 Hz), 7.92 (d, 1H, H-4 of thiophene, J = 5.9 Hz), 9.41 (s, br, H, 1NH, D2O exchangeable), 9.96 ppm (br, 1H, NH, D2O exchangeable). Anal. Calcd for C14H15N3S2 (289.42): C, 58.05; H, 5.18; N, 14.51. Found: C, 58.11; H, 5.14; N, 14.43.
[6-(5-Chloro-thiophen-2-yl)-4-(1-methyl-1H-pyrrol-2-yl)-3,4-dihydro-1H-pyrimidine-2-thione 4c
Dark yellow crystals were obtained according to the previous general method. Yield (2.70 g, 87%); mp (160–162) °C; IR (KBr) νmax: 3394, 3275 (2 NH), (1611–1597) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.36 (S, 3H, NCH3), 4.83 (d, 1H, H-4 of pyrimidine, J = 7.3 Hz), 6.13 (d, 1H, H-5 of pyrimidine, J = 6.5 Hz), 6.87 (d, 1H, H-3 of pyrrole, J = 5.9 Hz), 7.34 (dd, 1H, H-4 of pyrrole), 7.56 (d, 1H, H-5 of pyrrole, J = 6.0 Hz), 7.63 (d, 1H, H-3 of thiophene, J = 4.76 Hz), 8.19 (d, 1H, H-4 of thiophene, J = 5.6 Hz), 9.65 (s, br, H, 1NH, D2O exchangeable), 10.08 ppm (br, 1H, NH, D2O exchangeable). Anal. Calcd for C13H12N3S2Cl (309.84): C, 50.35; H, 3.87; N, 13.56. Found: C, 50.21; H, 3.90; N, 13.48.
General method for synthesis of Ethyl [4-(1-methyl-1H-pyrrol-2-yl)-6-(5-substituted-thiophen-2-yl)-1,6-dihydro-pyrimidin-2-ylsulfanyl]-acetate 6a-c
A solution of 3,4-dihydro-1H-pyrimidine-2-thione 4a-c (5 mmol) and 8 mL of ethyl chloroacetate was heated in 50 mL of absolute ethanol on a water bath for 6 h. The reaction mixture was cooled, neutralized, filtrated and washed with ethyl acetate and then the product was recrystallized from ethanol to give the corresponding ethyl ester 6a-c.
Ethyl[4-(1-Methyl-1H-pyrrol-2-yl)-6-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanyl]acetate 6a
Applying the previous general preparation method pale yellow powder was obtained. Yield (1.34 g, 74%); mp (138–140) °C; IR (KBr) νmax: 3222 (NH), 1722 (C=O), 1631(C=N), (1571) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, 3H, CH3 of ethyl group, J = 6.9 Hz), 3.48 (S, 3H, NCH3), 3.91 (q, 2H,OCH2 J = 7.1 Hz), 4.15 (s, 2H, SCH2), 4.93 (d, 1H, H-4 of pyrimidine), 6.27 (d, 1H, H-5 of pyrimidine, J = 6.0 Hz), 6.84 (d, 1H, H-3 of pyrrole, J = 5.6 Hz), 7.18 (dd, 1H, H-4 of pyrrole), 7.28 (d, 1H, H-5 of pyrrole, J = 6.9 Hz), 7.47 (d, 1H, H-3 of thiophene, J = 5.18 Hz), 7.73 (dd, 1H, H-4 of thiophene), 8.04 (d, 1H, H-5 of thiophene, J = 6.1 Hz), 8.58 ppm (br, 1H, NH, D2O exchangeable). 13C NMR (100 MHz, DMSO-d6) δ 41.42 (NCH3), 46.52 (SCH2), 65.17 (C-4 of pyrimidine), 120.09, 123.51, 126.11, 128.69 (4 C of pyrrole) 136.13, 138.21, 139.79, 142.32 (4 C of thiophene), 163.74 (C=N), 169.87 (C=O). Anal. Calcd for C17H19N3O2S2 (361.48): C, 56.43; H, 5.26; N, 11.62. Found: C, 56.45; H, 5.28; N, 11.57.
Ethyl [4-(1-Methyl-1H-pyrrol-2-yl)-6-(5-methyl-thiophen-2-yl)-1,6-dihydro-pyrimidin-2-ylsulfanyl] acetate 6b
Yellow powder was obtained according to the previous general procedure. Yield (1.46 g, 78%); mp (147–149) °C; IR (KBr) νmax: 3262 (NH), 1739 (C=O), 1629(C=N), (16,015–1602) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t, 3H, CH3 of ethyl group, J = 6.5 Hz), 2.46 (s, 3H, CH3 of thiophene), 3.58 (S, 3H, NCH3), 4.04 (q, 2H,OCH2 J = 7.1 Hz), 4.23 (s, 2H, SCH2), 4.99 (d, 1H, H-4 of pyrimidine), 6.61 (s, 1H, H-5 of pyrimidine, J = 6.1 Hz), 6.93 (d, 1H, H-3 of pyrrole, J = 5.3 Hz), 7.1 (dd, 1H, H-4 of pyrrole), 7.23 (d, 1H, H-5 of pyrrole, J = 7.0 Hz), 7.38 (d, 1H, H-3 of thiophene, J = 5.3 Hz), 7.89 (d, 1H, H-4 of thiophene, J = 6.3 Hz), 8.48 ppm (br, 1H, NH, D2O exchangeable). Anal. Calcd for C18H21N3O2S2 (375.51): C, 57.52; H, 5.60; N, 11.18. Found: C, 57.43; H, 5.55; N, 11.13.
Ethyl [6-(5-Chloro-thiophen-2-yl)-4-(1-methyl-1H-pyrrol-2-yl)-1,6-dihydro-pyrimidin-2-ylsulfanyl] acetate 6c
After recrystallization according to the previous general procedure, pale orange powder was obtained. Yield (1.62 g, 82%); mp (157–157) °C; IR (KBr) νmax: 3271 (NH), 1732 (C=O), 1624(C=N), (16,011–1603) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 1.23 (t, 3H, CH3 of ethyl group, J = 6.8 Hz), 3.34 (S, 3H, NCH3), 3.89 (q, 2H,OCH2 J = 7.4 Hz), 4.11 (s, 2H, SCH2), 4.88 (d, 1H, H-4 of pyrimidine), 6.43 (d, 1H, H-5 of pyrimidine, J = 5.78 Hz), 6.81 (d, 1H, H-3 of pyrrole, J = 5.3 Hz), 7.2 (dd, 1H, H-4 of pyrrole), 7.11 (d, 1H, H-5 of pyrrole, J = 7.5 Hz), 7.23 (d, 1H, H-3 of thiophene, J = 5.6 Hz), 7.74 (d, 1H, H-4 of thiophene, J = 6.6 Hz), 8.71 ppm (br, 1H, NH, D2O exchangeable). Anal. Calcd for C17H18N3O2S2Cl (395.93): C, 51.52; H, 4.54; N, 10.61. Found: C, 51.47; H, 4.49; N, 10.57.
General method for synthesis of 7-(1-Methyl-1H-pyrrol-2-yl)-5-(5-substitued-thiophen-2-yl)-5H-thiazolo[3,2-a]pyrimidin-3-one 7a-c
A solution of ethyl dihydro-pyrimidin-2-yl sulfan- yl]-acetate 6a-c (5 mmol) in 20 mL of absolute ethanol was treated with ammonia until alkaline (pH > 7) with stirring for 30 min at room temperature. The reaction mixture was allowed to evaporate, the residue was washed with water, dried and recrystallized from n-hexane/ethanol to give thiazolo[3,2-a]pyrimidin-3-one 7a-c at good yields.
7-(1-Methyl-1H-pyrrol-2-yl)-5-thiophen-2-yl-5H-thiazolo[3,2-a]pyrimidin-3-one 7a
According to the previous general method, pale yellow crystals were obtained. Yield (1.32 g, 84%); mp (123–125) °C; IR (KBr) νmax: 1701 (C=O), 1632(C=N), 1597 cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.37 (S, 3H, NCH3), 4.15 (s, 2H, SCH2), 5.65 (d, 1H, H-4 of pyrimidine), 6.38 (d, 1H, H-5 of pyrimidine, J = 6.8 Hz), 6.67 (d, 1H, H-3 of pyrrole, J = 6.7 Hz), 7.02 (dd, 1H, H-4 of pyrrole), 7.32 (d, 1H, H-5 of pyrrole, J = 6.6 Hz), 7.23 (d, 1H, H-3 of thiophene, J = 5.6 Hz), 7.56 (dd, 1H, H-4 of thiophene), 7.89 ppm (d, 1H, H-5 of thiophene, J = 6.8 Hz. 13C NMR (100 MHz, DMSO-d6) δ 46.11 (NCH3), 49.34 (SCH2), 67.34 (C-4 of pyrimidine), 121.18, 125.72, 127.32, 129.66 (4 C of pyrrole) 133.45, 135.18, 136.75, 139.12 (4 C of thiophene), 161.15 (C=N), 172.12 ppm (C=O). Anal. Calcd for C15H13N3OS2 (315.42): C, 57.07; H, 4.12; N, 13.32. Found: C, 56.98; H, 4.08; N, 13.17.
7-(1-Methyl-1H-pyrrol-2-yl)-5-(5-methyl-thiophen-2-yl)-5H-thiazolo[3,2-a]pyrimidin-3-one 7b
According to the previous general method, yellow crystals were obtained. Yield (1.38 g, 88%); mp (128–130) °C; IR (KBr) νmax: 1711 (C=O), 1622(C=N), (1616–1600) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 2.63 (s, 3H, CH3 of thiophene), 3.41 (S, 3H, NCH3), 4.23 (s, 2H, SCH2), 5.63 (d, 1H, H-4 of pyrimidine), 6.45 (d, 1H, H-5 of pyrimidine, J = 5.8 Hz), 6.91 (d, 1H, H-3 of pyrrole, J = 6.3 Hz), 7.22 (dd, 1H, H-4 of pyrrole), 7.47 (d, 1H, H-5 of pyrrole, J = 7.3 Hz), 7.65 (d, 1H, H-3 of thiophene, J = 6.9 Hz), 7.97 ppm (d, 1H, H-4 of thiophene, J = 7.1 Hz). Anal. Calcd for C16H15N3OS2 (329.44): C, 58.28; H, 4.55; N, 12.75. Found: C, 58.17; H, 4.49; N, 12.67.
5-(5-Chloro-thiophen-2-yl)-7-(1-methyl-1H-pyrrol-2-yl)-5H-thiazolo[3,2-a]pyrimidin-3-one 7c
Yellow crystals were obtained According to the previous general method,. Yield (1.49 g, 85%); mp (136–138) °C; IR (KBr) νmax: 1702 (C=O), 1627(C=N), (1622–1607) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.69 (S, 3H, NCH3), 4.47 (s, 2H, SCH2), 5.82 (d, 1H, H-4 of pyrimidine), 6.67 (d, 1H, H-5 of pyrimidine, J = 6.3 Hz), 6.87 (d, 1H, H-3 of pyrrole, J = 6.9 Hz), 7.31 (dd, 1H, H-4 of pyrrole), 7.39 (d, 1H, H-5 of pyrrole, J = 6.9 Hz), 7.73 (d, 1H, H-3 of thiophene, J = 7.3 Hz), 8.09 ppm (d, 1H, H-4 of thiophene, J = 7.6 Hz). (m/z): 349 (M+, 349, M + 2+, 351) (3:1) ratio. Anal. Calcd for C15H12N3OS2Cl (349.86): C, 51.45; H, 3.43; N, 12.00. Found: C, 51.39; H, 3.40; N, 11.89.
General method for synthesis of 2-Benzylidene-7-(1-methyl-1H-pyrrol-2-yl)-5-(5-substituted-thiophen-2-yl)-5H-thiazolo[3,2-a]pyrimidin-3-one 8a-c
A solution of 5H-thiazolo[3,2-a]pyrimidin-3-one 7a-c (5 mmol), benzaldehyde (0.53 g, 5 mmol), and freshly prepared sodium acetate (0.41 g, 5 mmol) in 20 mL of glacial acetic acid-acetic anhydride mixture (1:1) was heated under reflux for 5 h. The reaction mixture was left to cool down and poured into ice water, filtered and recrystallized from n-hexane/ethanol to give the corresponding compounds 7a-c at good yields.
2-Benzylidene-7-(1-methyl-1H-pyrrol-2-yl)-5-thiophen-2-yl-5H-thiazolo[3,2-a] pyrimidin-3-one 8a
After recrystallization a yellow powder was obtained. Yield (1.51 g, 75%); mp (147–149) °C; IR (KBr) νmax: 1694 (C=O), 1628 (C=N), (1622–1607) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.49 (S, 3H, NCH3), 5.76 (s, 1H, H-4 of pyrimidine, J = 8.1 Hz), 6.45 (d, 1H, H-5 of pyrimidine, J = 6.2 Hz), (6.42–7.19) (m, 3H of pyrrole), 7.35 (s, 1H, = CH), (7.61–8.23) ppm (m, 8H, of thiophene and phenyl). 13C NMR (100 MHz, DMSO-d6) δ 42.65 (NCH3), 64.22 (C-4 of pyrimidine), 122.23, 126.15, 128.49, 130.23, 134.47, 136.45, 138.23, 140.55,144.76, 147.88, 149. (18C, C-aryl), (163.10 (C=N), 167.34 ppm (C=O). Anal. Calcd for C22H17N3OS2 (403.52): C, 65.42; H, 4.21; N, 10.41. Found: C, 65.33; H, 4.18; N, 10.39.
2-Benzylidene-7-(1-methyl-1H-pyrrol-2-yl)-5-(5-methyl-thiophen-2-yl)-5H-thiazolo[3,2 -a]pyrimidin-3-one 8b
According to the previous general method, dark yellow powder was obtained. Yield (1.52 g, 73%); mp (153–145) °C; IR (KBr) νmax: 1700 (C=O), 1623 (C=N), (1615–1601) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H, CH3 of thiophene), 3.36 (S, 3H, NCH3), 5.44 (d, 1H, H-4 of pyrimidine, J = 7.8 Hz), 6.31 (s, 1H, H-5 of pyrimidine, J = 5.9 Hz), (6.56–7.21) (m, 3H of pyrrole), 7.43 (s, 1H, = CH), (7.57–8.17) ppm (m, 7H, of thiophene and phenyl). Anal. Calcd for C23H19N3OS2 (417.55): C, 66.10; H, 4.55; N, 10.06. Found: C, 66.02; H, 4.52; N, 10.05.
2-Benzylidene-5-(5-chloro-thiophen-2-yl)-7-(1-methyl-1H-pyrrol-2-yl)-5H-thiazolo[3,2-a]pyrimidin-3-one 8c
According to the previous general method, orange powder was obtained. Yield (1.52 g, 78%); mp (159–161) °C; IR (KBr) νmax: 1698 (C=O), 1629 (C=N), (1620–1607) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.56 (S, 3H, NCH3), 5.79 (d, 1H, H-4 of pyrimidine, J = 7.5 Hz), 6.53(s, 1H, H-5 of pyrimidine, J = 6.0 Hz), (6.81–7.28) (m, 3H of pyrrole), 7.49 (s, 1H, =CH), (7.65–8.31) ppm (m, 7H, of thiophene and phenyl). (m/z): 437 (M+, 437, M + 2+, 439) (3:1) ratio. Anal. Calcd for C22H16N3OS2 Cl (437.97): C, 60.28; H, 3.65; N, 9.59. Found: C, 60.19; H, 3.58; N, 9.53.
General method for synthesis of 6-(1-methyl-1H-pyrrol-2-yl)-8-(5-substituted-thiophen-2-yl)-3-phenyl-2,3-dihydro-8H-isoxazolo[5′,4′:4,5]thiazolo[3,2-a]pyrimidine 9a-c
A solution of compound 7a-c (5 mmol), hydroxylamine hydrochloride (0.35 g, 5 mmol), and freshly prepared sodium acetate (0.41 g, 5 mmol) in 20 mL of glacial acetic acid was heated under reflux for 8 h. The reaction mixture was left to cool down and poured into ice water, filtered and recrystallized from ethyl acetate to give the corresponding compounds 9a-c at good yields.
6-(1-methyl-1H-pyrrol-2-yl)-3-phenyl-8-(thiophen-2-yl-2,3-dihydro-8H-isoxazolo[5′,4′:4,5]thiazolo[3,2-a]pyrimidine 9a
After applied the previous procedure a pale yellow powder was obtained. Yield (1.46 g, 70%); mp (172–174) °C; IR (KBr) νmax: 3225 (NH), 1617 (C=N), 1595 cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.38 (S, 3H, NCH3), 5.56 (d, 1H, H-4 of pyrimidine), 5.83 (s, 1H, H-3 of isoxazole), 6.68 (d, 1H, H-5 of pyrimidine), (6.63–7.23) (m, 3H of pyrrole), (7.43–8.11) (m, 8H, of thiophene and phenyl), 9.98 ppm (br, 1H, NH, D2O exchangeable). 13C NMR (100 MHz, DMSO-d6) δ 45.44 (NCH3), 64.22 (C-4 of pyrimidine), 74.93 (C-3 of isoxazole), 123.55, 127.67, 128.83, 130.78, 135.40, 137.33, 139.22, 141.43,144.38, 148.49, 149.32 (18C, C-aryl), 161.10 ppm (C=N). Anal. Calcd for C22H18N4OS2 (418.54): C, 63.08; H, 4.30; N, 13.38. Found: C, 62.97; H, 4.28; N, 13.34.
6-(1-methyl-1H-pyrrol-2-yl)-8-(5-methyl-thiophen-2-yl)-3-phenyl-2,3-dihydro-8H-isoxazolo[5′,4′:4,5]- thiazolo[3,2-a]pyrimidine 9b
After applied the previous procedure a yellow powder was obtained. Yield (1.58 g, 73%); mp (177–179) °C; IR (KBr) νmax: 3207 (NH), 1627 (C=N), (1621–1596) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H, CH3 of thiophene), 3.46 (S, 3H, NCH3), 5.41 (d, 1H, H-4 of pyrimidine), 5.65 (s, 1H, H-3 of isoxazole), 6.68 (d, 1H, H-5 of pyrimidine), (6.56–7.29) (m, 3H of pyrrole), (7.28–8.19) (m, 7H, of thiophene and phenyl), 10.54 ppm (br, 1H, NH, D2O exchangeable). Anal. Calcd for C23H20N4OS2 (432.56): C, 63.81; H, 4.62; N, 12.95. Found: C, 63.85; H, 4.57; N, 12.86.
8-(5-Chloro-thiophen-2-yl)-6-(1-methyl-1H-pyrrol-2-yl)-3-phenyl-2,3-dihydro-8H-isoxazolo[5′,4′:4,5-] thiazolo[3,2-a]pyrimidine 9c
According to the previous general procedure a yellow powder was obtained. Yield (1.72 g, 76%); mp (186–188) °C; IR (KBr) νmax: 3233 (NH), 1625 (C=N), (1618–1595) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.61 (S, 3H, NCH3), 5.69 (d, 1H, H-4 of pyrimidine), 5.91 (s, 1H, H-3 of isoxazole), 6.57 (d, 1H, H-5 of pyrimidine), (6.81–7.33) (m, 3H of pyrrole), (7.42–8.28) (m, 7H, of thiophene and phenyl), 10.73 ppm (br, 1H, NH, D2O exchangeable). (m/z): 452 (M+, 452, M + 2+, 454) (3:1) ratio. Anal. Calcd for C22H17N4OS2Cl (452.598): C, 58.28; H, 3.75; N, 12.36. Found: C, 58.19; H, 3.72; N, 12.29.
General method for synthesis of [4-(1-Methyl-1H-pyrrol-2-yl)-6-(5-substituted-thiophen-2-yl)-2-thioxo-3,6-dihydro-2H-pyrimidin-1-yl]-phenyl-methanone 10a-c
A solution of 3,4-dihydro-1H-pyrimidine-2-thione 4a-c (5 mmol), benzoyl chloride (1.40 g, 10 mmol), and few drops of triethylamine in 25 mL of ethanol was heated under reflux for 4 h. The reaction mixture was left to cool down and poured into ice water, filtered and recrystallized from ethanol to afford compounds 10a-c.
[4-(1-Methyl-1H-pyrrol-2-yl)-6-thiophen-2-yl-2-thioxo-3,6-dihydro-2H-pyrimidin-1-yl]-phenylmethan- one 10a
Applying the previous general preparation method yellow powder was obtained. Yield (1.54 g, 81%); mp (161–163) °C; IR (KBr) νmax: 3224 (NH), 1682 (C=O), (1605–1547) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.38 (S, 3H, NCH3), 5.51 (d, 1H, H-4 of pyrimidine, J = 6.7 Hz), 6.19 (d, 1H, H-5 of pyrimidine, J = 7.6 Hz), 6.65 (d, 1H, H-3 of pyrrole, J = 6.8 Hz), 7.07 (dd, 1H, H-4 of pyrrole), 7.22 (d, 1H, H-5 of pyrrole, J = 6.4 Hz), (7.47–8.35) (m, 8H, of thiophene and phenyl), 10.98 ppm (br, 1H, NH, D2O exchangeable). 13C NMR (100 MHz, DMSO-d6) δ 49.23 (NCH3), 61.96 (C-4 of pyrimidine), 121.78, 125.63, 128.01, 130.12, 136.63, 138.45, 140.33 145.08, 147.24 (16C, C-aryl), 169.55 (C=O), 181.16 ppm (C = S). Anal. Calcd for C20H17N3OS2 (379.50): C, 63.24; H, 4.48; N, 11.07. Found: C, 63.18; H, 4.42; N, 10.97.
[4-(1-Methyl-1H-pyrrol-2-yl)-6-(5-methyl-thiophen-2-yl)-2-thioxo-3,6-dihydro-2H-pyrimidin-1-yl]-phenyl-methanone 10b
Yellow solid was obtained according to the previous general preparation. Yield (1.63 g, 83%); mp (173–175) °C; IR (KBr) νmax: 3249 (NH), 1685 (C=O), (1613–1600) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 2.17 (s, 3H, CH3 of thiophene), 3.49 (S, 3H, NCH3), 5.32 (d, 1H, H-4 of pyrimidine, J = 5.7 Hz), 6.07 (d, 1H, H-5 of pyrimidine, J = 7.4 Hz), 6.71 (d, 1H, H-3 of pyrrole, J = 6.6 Hz), 7.01 (dd, 1H, H-4 of pyrrole), 7.19 (d, 1H, H-5 of pyrrole, J = 6.8 Hz), (7.34–8.18) (m, 7H, of thiophene and phenyl), 11.34 ppm (br, 1H, NH, D2O exchangeable). Anal. Calcd for C21H19N3OS2 (393.53): C, 64.04; H, 4.83; N, 11.67. Found: C, 63.95; H, 4.78; N, 11.68.
[6-(5-Chloro-thiophen-2-yl)-4-(1-methyl-1H-pyrrol-2-yl)-2-thioxo-3,6-dihydro-2H-pyrimidin-1-yl]-phenyl-methanone 10c
According to the previous general procedure a yellow powder was obtained. Yield (1.82 g, 88%); mp (178–180) °C; IR (KBr) νmax: 3263 (NH), 1697 (C=O), (1615–1602) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.61 (S, 3H, NCH3), 5.73 (d, 1H, H-4 of pyrimidine, J = 7.9 Hz), 6.23 (d, 1H, H-5 of pyrimidine, J = 6.1 Hz), (7.34–8.18) (m, 10H, of aryl protons), 11.42 ppm (br, 1H, NH, D2O exchangeable). (m/z): 413 (M+, 413, M + 2+, 415) (3:1) ratio. Anal. Calcd for C20H16N3OS2Cl (413.95): C, 57.97; H, 3.86; N, 10.15. Found: C, 57.89; H, 3.79; N, 10.12.
General method for synthesis of 7-(1-Methyl-1H-pyrrol-2-yl)-5-(5-substituted-thiophen-2-yl)-3-phenyl-5H-[1,2,4]thiadiazolo[4,5-a]pyrimidine 11a-c
A solution of compounds 10a-c (3 mmol), 10% sodium hypochlorite (10 mL), 10 mL NH4OH and 10% of NaOH (10 mL) was heated under reflux for 3 h. The reaction mixture was left to cool down and poured into ice water, filtered and recrystallized from ethanol to obtain colored compounds 11a-c.
7-(1-Methyl-1H-pyrrol-2-yl)-3-phenyl-5-thiophen-2-yl-5H-[1,2,4]thiadiazolo[4,5-a]pyrimidine 11a
Accordi ng to the previous general preparation method yellow powder was obtained. Yield (0.73 g, 64%); mp (124–126) °C; IR (KBr) νmax: 1624, 1631 (2C=N), (1608–1599) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.58 (S, 3H, NCH3), 5.64 (d, 1H, H-4 of pyrimidine, J = 5.9 Hz), 6.28 (d, 1H, H-5 of pyrimidine, J = 7.4 Hz), (6.57–8.26) ppm (m, 12H, of pyrrole thiophene and phenyl). 13C NMR (100 MHz, DMSO-d6) δ 53.76 (NCH3), 65.13 (C-4 of pyrimidine), 118.34, 120.15, 124.66, 127.13, 130.87, 133.23, 137.22 139.88, 141.22 (17C, C-aryl), 150.11, 153.34 ppm (2C=N). Anal. Calcd for C20H16N4S2 (376.50): C, 63.75; H, 4.25; N, 14.87. Found: C, 63.69; H, 4.19; N, 14.82.
7-(1-Methyl-1H-pyrrol-2-yl)-5-(5-methyl-thiophen-2-yl)-3-phenyl-5H-[1,2,4]thiadiazolo[4,5-a]pyramid- ine 11b
A yellow powder of 10b was obtained according to the aforementioned preparation method.Yield (0.70 g, 60%); mp (129–131) °C; IR (KBr) νmax: 1619, 1627 (2C=N), (1610–1602) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 2.31 (s, 3H, CH3 of thiophene), 3.41 (S, 3H, NCH3), 5.42 (d, 1H, H-4 of pyrimidine, J = 8.1 Hz), 6.19 (d, 1H, H-5 of pyrimidine, J = 6.2 Hz), 6.43 (d, 1H, H-3 of pyrrole, J = 6.8 Hz), 7.06 (dd, 1H, H-4 of pyrrole), 7.17 (d, 1H, H-5 of pyrrole, J = 6.8 Hz), (7.31–8.17) ppm (m, 7H, of thiophene and phenyl). Anal. Calcd for C21H18N4S2 (390.53): C, 64.53; H, 4.61; N, 14.34. Found: C, 64.46; H, 4.53; N, 14.54.
5-(5-Chloro-thiophen-2-yl)-7-(1-methyl-1H-pyrrol-2-yl)-3-phenyl-5H-[1,2,4]thiadi- azolo[4,5-a]pyrimidine 11c
According to the previous general procedure a yellow powder was obtained.Yield (0.84 g, 68%); mp (137–139) °C; IR (KBr) νmax: 1615, 1623 (2C=N), (1612–1593) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.53 (S, 3H, NCH3), 5.64 (d, 1H, H-4 of pyrimidine, J = 5.9 Hz), 6.31 (d, 1H, H-5 of pyrimidine), 6.52 (d, 1H, H-3 of pyrrole, J = 6.4 Hz), 7.11 (dd, 1H, H-4 of pyrrole), 7.25 (d, 1H, H-5 of pyrrole, J = 6.3 Hz), (7.45–8.28) ppm (m, 7H, of thiophene and phenyl). (m/z): 410 (M+, 410, M + 2+, 412) (3:1) ratio. Anal. Calcd for C20H15N4S2Cl (410.94): C, 58.39; H, 3.65; N, 13.63. Found: C, 58.25; H, 3.59; N, 13.57.
General method for synthesis of [4-(1-Methyl-1H-pyrrol-2-yl)-6-(5-substituted-thiophen-2-yl)-1,6-dihydro-pyrimidin-2-yl]-hydrazine 12a-c
A mixture of pyrimidine-2-thione 4a-c (5 mmol) and 10 mL hydrazine hydrate in 30 mL ethanol was refluxed for 6 h. The reaction mixture was allowed to cool and poured onto ice water. After filtration the crystallization took place from ethanol to obtain the corresponding hydrazine derivatives 12a-c.
[4-(1-Methyl-1H-pyrrol-2-yl)-6-thiophen-2-yl-1,6-dihydro-pyrimidin-2-yl]-hydrazine 12a
After recrystallization of the product from ethanol according to the previous general preparation method, pale yellow powder was obtained. Yield (1.08 g, 79%); mp (167–169) °C; IR (KBr) νmax: (33,025–3177) (2NH, NH2), 1617 (C=N); 1H NMR (400 MHz, DMSO-d6) δ 3.32 (S, 3H, NCH3), 4.62 ppm (s, br, 2H, NH2, D2O exchangeable), 4.83 (d, 1H, H-4 of pyrimidine, J = 6.3 Hz), 6.21 (d, 1H, H-5 of pyrimidine, J = 7.8 Hz), 6.67 (d, 1H, H-3 of pyrrole, J = 6.3 Hz), 7.17 (dd, 1H, H-4 of pyrrole), 7.27 (d, 1H, H-5 of pyrrole, J = 6.9 Hz), 7.37 (d, 1H, H-3 of thiophene, J = 5.2 Hz), 7.73 (dd, 1H, H-4 of thiophene), 8.06 (d, 1H, H-5 of thiophene, J = 6.5 Hz), 9.11 (s, br, H, 1NH of pyrimidine, D2O exchangeable), 10.39 ppm (br, 1H, NH of hydrazine, D2O exchangeable). Anal. Calcd for C13H15N5S (273.36): C, 57.07; H, 5.48; N, 25.61. Found: C, 56.98; H, 5.43; N, 25.57.
[4-(1-Methyl-1H-pyrrol-2-yl)-6-(5-methyl-thiophen-2-yl)-1,6-dihydro-pyrimidin-2-yl]-hydrazine 12b
According to the previous general preparation method, yellow powder was obtained.. Yield (1.07 g, 75%); mp (174–176) °C; IR (KBr) νmax: (3367–3181) (2NH, NH2), 1632 (C=N), (1619–1604) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 2.09 (s, 3H, CH3 of thiophene), 3.49 (S, 3H, NCH3), 4.46 ppm (s, br, 2H, NH2, D2O exchangeable), 4.90 (d, 1H, H-4 of pyrimidine, J = 5.8 Hz), 6.35 (d, 1H, H-5 of pyrimidine, J = 7.4 Hz), 6.73 (d, 1H, H-3 of pyrrole, J = 6.5 Hz), 7.23 (dd, 1H, H-4 of pyrrole), 7.43 (d, 1H, H-5 of pyrrole, J = 6.7 Hz), 7.56 (d, 1H, H-3 of thiophene, J = 5.8 Hz), 7.90 (d, 1H, H-4 of thiophene, J = 6.7 Hz), 8.79 (s, br, H, 1NH of pyrimidine, D2O exchangeable), 9.85 ppm (br, 1H, NH of hydrazine, D2O exchangeable). Anal. Calcd for C14H17N5S (287.39): C, 58.46; H, 5.92; N, 24.36. Found: C, 58.42; H, 5.86; N, 24.29.
[6-(5-Chloro-thiophen-2-yl)-4-(1-methyl-1H-pyrrol-2-yl)-1,6-dihydro-pyrimidin-2-yl]-hydrazine 12c
According to the previous general preparation method, yellow powder was obtained.. Yield (1.23 g, 80%); mp (182–184) °C; IR (KBr) νmax: (3376–3173) (2NH, NH2), 1635 (C=N), (1623–1608) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.64 (S, 3H, NCH3), 4.65 ppm (s, br, 2H, NH2, D2O exchangeable), 5.08 (d, 1H, H-4 of pyrimidine, J = 6.1 Hz), 6.57 (d, 1H, H-5 of pyrimidine), 6.61 (d, 1H, H-3 of pyrrole, J = 6.3 Hz), 7.28 (dd, 1H, H-4 of pyrrole), 7.38 (d, 1H, H-5 of pyrrole, J = 7.0 Hz), 7.82 (d, 1H, H-3 of thiophene, J = 6.6 Hz), 8.18 (d, 1H, H-4 of thiophene, J = 7.2 Hz), 9.32 (s, br, H, 1NH of pyrimidine, D2O exchangeable), 10.49 ppm (br, 1H, NH of hydrazine, D2O exchangeable). Anal. Calcd for C13H14N5SCl (307.80): C, 50.68; H, 4.55; N, 22.74. Found: C, 50.63; H, 4.49; N, 22.68.
General method for synthesis of 5-Methyl-2-[4-(1-methyl-1H-pyrrol-2-yl)-6-(5-methyl-thiophen-2-yl)-1,6-dihydro-pyrimidin-2-yl]-2,4-dihydro-pyrazol-3-one. 13a-c
A solution of compound 12a-c (4 mmol) and 10 mL ethyl acetoacetate in 20 mL acetic acid was heated under reflux for 5 h. The reaction mixture was allowed to cool and poured onto ice water. After filtration, the obtained product was dried and recrystallized from ethanol to obtain the corresponding pyrazol-3-one derivatives 13a-c.
5-Methyl-2-[4-(1-methyl-1H-pyrrol-2-yl)-6-thiophen-2-yl-1,6-dihydro-pyrimidin-2-yl]-2,4-dihydro-pyrazol-3-one 13a
According to the previous general preparation method, dark yellow crystals were obtained. Yield (0.99 g, 73%); mp (196–198) °C; IR (KBr) νmax: (3176) (NH), 1692 (C=O), 1637, 1625 (2 C=N); 1H NMR (400 MHz, DMSO-d6) δ 1.89 (s, 3H, CH3 of pyrazol), 2.89 (s, 2H, CH2 of pyrazol), 3.63 (S, 3H, NCH3), 5.94 (d, 1H, H-4 of pyrimidine, J = 5.4 Hz), 6.44 (d, 1H, H-5 of pyrimidine, J = 7.9 Hz), 6.73 (d, 1H, H-3 of pyrrole, J = 6.5 Hz), 7.31 (dd, 1H, H-4 of pyrrole), 7.51 (d, 1H, H-5 of pyrrole, J = 6.4 Hz), 7.48 (d, 1H, H-3 of thiophene, J = 5.3 Hz), 7.82 (dd, 1H, H-4 of thiophene), 8.17 (d, 1H, H-5 of thiophene, J = 6.8 Hz), 9.38 ppm (s, br, H, 1NH of pyrimidine, D2O exchangeable). 13C NMR (100 MHz, DMSO-d6) δ 25.54 (CH3), 49.34 (NCH3), 69.75 (C-4 of pyrimidine), 119.19, 121.33, 125.55, 127.32, 130.78, 135.59, 138.84, 145.77 (11 C of aryl C), 158.73, 160.22 (2C=N), 177.04 ppm (C=O). Anal. Calcd for C17H17N5OS (339.42): C, 60.10; H, 5.01; N, 20.62. Found: C, 59.97; H, 4.97; N, 20.60.
5-Methyl-2-[4-(1-methyl-1H-pyrrol-2-yl)-6-(5-methyl-thiophen-2-yl)-1,6-dihydro-pyrimidin-2-yl]-2,4-dihydro-pyrazol-3-one 13b
Dark yellow crystals were obtained according to the previous general preparation method. Yield (0.97 g, 69%); mp (189–191) °C; IR (KBr) νmax: (3178) (NH), 1683 (C=O), 1642, 1629 (2 C=N), (1615–1603) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 1.75 (s, 3H, CH3 of pyrazol), 2.13 (s, 3H, CH3 of thiophene), 2.73 (s, 2H, CH2 of pyrazol), 3.43 (S, 3H, NCH3), 5.46 (d, 1H, H-4 of pyrimidine, J = 6.7 Hz), 6.24 (d, 1H, H-5 of pyrimidine, J = 7.3 Hz), 6.81 (d, 1H, H-3 of pyrrole, J = 7.0 Hz), 7.29 (dd, 1H, H-4 of pyrrole), 7.42 (d, 1H, H-5 of pyrrole, J = 6.8 Hz), 7.57 (d, 1H, H-3 of thiophene, J = 6.8 Hz), 7.98 (d, 1H, H-4 of thiophene), 10.51 ppm (s, br, H, 1NH of pyrimidine, D2O exchangeable). Anal. Calcd for C18H19N5OS (353.44): C, 61.11; H, 5.38; N, 19.81. Found: C, 61.04; H, 5.35; N, 19.74.
2-[6-(5-Chloro-thiophen-2-yl)-4-(1-methyl-1H-pyrrol-2-yl)-1,6-dihydro-pyrimidin-2-yl]-5-methyl-2,4-dihydro-pyrazol-3-one 13c
Brown crystals were obtained according to the previous general preparation method. Yield (1.12 g, 75%); mp (205–207) °C; IR (KBr) νmax: (3208) (NH), 1688 (C=O), 1637, 1625 (2 C=N), (1617–1601) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 1.82 (s, 3H, CH3 of pyrazol), 3.09 (s, 2H, CH2 of pyrazol), 3.51 (S, 3H, NCH3), 5.29 (d, 1H, H-4 of pyrimidine, J = 6.1 Hz), 6.11 (d, 1H, H-5 of pyrimidine, J = 6.9 Hz), 6.88 (d, 1H, H-3 of pyrrole, J = 7.5 Hz), 7.24 (dd, 1H, H-4 of pyrrole), 7.52 (d, 1H, H-5 of pyrrole, J = 6.1 Hz), 7.71 (d, 1H, H-3 of thiophene, J = 6.3 Hz), 8.23 (d, 1H, H-4 of thiophene, J = 7.2 Hz), 10.32 ppm (s, br, H, 1NH of pyrimidine, D2O exchangeable). (m/z): 373 (M+, 373, M + 2+, 375) (3:1) ratio. Anal. Calcd for C17H16N5OSCl (373.86): C, 54.57; H, 4.28; N, 18.72. Found: C, 54.48; H, 4.22; N, 18.66.
General method for synthesis of 7-(1-Methyl-1H-pyrrol-2-yl)-5-(5-substitured-thiophen-2-yl)-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine 14a-c
A mixture of compound 13a-c (4 mmol) and 20 mL formic acid was heated under reflux for 7 h. The reaction mixture was allowed to cool and poured onto ice water. After filtration, the obtained product was dried and recrystallized from ethanol to afford the corresponding [1, 2, 4]triazolo[4,3-a]pyrimidine 14a-c.
7-(1-Methyl-1H-pyrrol-2-yl)-5-thiophen-2-yl-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine 14a
According to the previous general preparation method, brown crystals were obtained. Yield (0.74 g, 65%); mp (178–180) °C; IR (KBr) νmax: (3275) (NH), 1643, 1632 (2 C=N), (1611–1594) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.37 (S, 3H, NCH3), 5.38 (d, 1H, H-4 of pyrimidine, J = 6.0 Hz), 6.23 (d, 1H, H-5 of pyrimidine, J = 7.3 Hz), (6.81–7.53) (m, 3H, of pyrrole), (7.89–8.11) (m, 3H, of thiophene), 8.42 ppm (s, H-3 of triazole), 12.83 ppm (s, br, H, 1NH of trizole, D2O exchangeable). Anal. Calcd for C14H13N5S (283.35): C, 59.29; H, 4.59; N, 24.70. Found: C, 59.16; H, 4.54; N, 24.62.
7-(1-Methyl-1H-pyrrol-2-yl)-5-(5-methyl-thiophen-2-yl)-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine. 14b
Brown crystals were obtained according to the previous general preparation method. Yield (0.81 g, 68%); mp (174–176) °C; IR (KBr) νmax: (3251) (NH), 1637, 1626 (2 C=N), (1613–1598) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 1.99 (s, 3H, CH3 of thiophene), 3.42 (S, 3H, NCH3), 5.19 (d, 1H, H-4 of pyrimidine, J = 6.7 Hz), 6.09 (d, 1H, H-5 of pyrimidine, J = 7.7 Hz), 6.57 (d, 1H, H-3 of pyrrole, J = 6.3 Hz), 7.08 (dd, 1H, H-4 of pyrrole), 7.34 (d, 1H, H-5 of pyrrole, J = 5.7 Hz), 7.72 (d, 1H, H-3 of thiophene, J = 6.1 Hz), 7.99 (d, 1H, H-4 of thiophene,, J = 6.3 Hz), 8.25 ppm (s, H-3 of triazole), 12.09 ppm (s, br, H, 1NH of trizole, D2O exchangeable). Anal. Calcd for C15H15N5S (297.38): C, 60.53; H, 5.04; N, 23.54. Found: C, 60.51; H, 5.04; N, 23.57.
5-(5-Chloro-thiophen-2-yl)-7-(1-methyl-1H-pyrrol-2-yl)-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine. 14c
Dark brown crystals were obtained according to the previous general preparation method. Yield (0.92 g, 72%); mp (182–184) °C; IR (KBr) νmax: (3272) (NH), 1635, 1621 (2 C=N), (1608–1591) cm−1 (C=C); 1H NMR (400 MHz, DMSO-d6) δ 3.27 (S, 3H, NCH3), 5.08 (d, 1H, H-4 of pyrimidine, J = 7.8 Hz), 6.11 (d, 1H, H-5 of pyrimidine, J = 7.9 Hz), 6.61 (d, 1H, H-3 of pyrrole, J = 6.8 Hz), 7.01 (dd, 1H, H-4 of pyrrole), 7.27 (d, 1H, H-5 of pyrrole, J = 6.5 Hz), 7.61 (d, 1H, H-3 of thiophene, J = 7.3 Hz), 7.74 (d, 1H, H-4 of thiophene,, J = 6.8 Hz), 8.36 ppm (s, H-3 of triazole), 12.56 ppm (s, br, H, 1NH of trizole, D2O exchangeable). Anal. Calcd for C14H12N5SCl (317.80): C, 52.86; H, 3.78; N, 22.03. Found: C, 52.72; H, 3.73; N, 21.96.