Experimental Section
General
Melting points were determined on an Electrothermal apparatus in an open capillary tube and are uncorrected. The IR spectra were recorded in cm-1 for KBr pellets on a Buck Scientific spectrophotometer. 1H-NMR spectra were recorded on a Varian 300MHz spectrometer using DMSO-d6 or CDCl3 as the solvent and TMS as the internal reference standard. Chemical shifts are expressed in δ ppm. Mass spectra were taken on a LKB 9000 mass spectrometer. The purity of the compounds was routinely checked by TLC using Silica G and the spots were exposed in iodine vapour for visualization.
Synthesis of 7,9-disubstituted 7H-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 3a-l: General Procedure.
Method A: A mixture of sodium azide (0.011 mole, 0.072 g) and ammonium chloride (0.011 mole, 0.059 g) in DMSO (20 mL) was stirred for five min. at 90°C and the 5,7-disubstituted 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.01 mole) was added in portions with stirring. After the addition the reaction mixture was further stirred for 2.0-2.5 hr at the same temperature and for 1 hr at room temperature. Then it was decomposed on ice. The solid obtained was filtered, washed with water, dried and crystallized from toluene or a mixture of ethanol-chloroform (8:2) to give the title compounds 3.
Method B: An aqueous solution of sodium nitrite (20% w/v, 4.2 mL) was slowly added in portions to a stirred mixture of 5,7-disubstituted 4-hydrazino-7H-pyrrolo[2,3-d]pyrimidine (2, 0.01 mole) in acetic acid (40 mL) at 0-5°C. The reaction mixture was then further stirred for 2 hr at the same temperature, then it was diluted with cold water and the solid obtained was filtered, washed with water, sodium bicarbonate (20 % w/v), followed by water, dried and crystallized to furnish compounds 3.
7,9-Diphenyltetrazolo[1,5-c]pyrrolo-7H-[3,2-e]pyrimidine (3a): Yield: 61 % (Method A), 60 % (Method B); mp: 215-17°C; IR: 1608, 1504 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.0-7.1 (m, 12H, ArH); MS: 312 m/z (M+); Anal. Calcd. for C19H12N6: C 73.06, H 3.87, N 26.11 %, found: C 73.26, H 3.71, N 26.60 %.
7-(4-Fluorophenyl)-9-phenyltetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3b): Yield: 70 % (Method A), 56 % (Method B); mp: 217-19°C; IR: 1604, 1516 (C=C, C=N ring); 1H NMR (DMSO-d6): 8.0-7.2 (m, 11H, ArH); MS: 330 m/z (M+); Anal. Calcd. for C18H11FN6: C 65.45, H 3.36, N 25.45 %, found: C 65.66, H 3.27, N 25.09 %.
7-(4-Chlorophenyl)-9-phenyl-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3c): Yield: 70 % (Method A), 64 % (Method B); mp: 218-20°C; IR: 1612, 1492 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.0-7.3 (m, 11H, ArH); MS: 347 m/z (M+); Anal. Calcd. for C18H11ClN6: C 62.34, H 3.20, N 24.24 %, found: C 62.46, H 3.27, N 24.56 %.
7-(3-Chloro-4-fluorophenyl)-9-phenyl-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3d): Yield: 64 % (Method A), 63 % (Method B); mp: 212-14°C; IR: 1604, 1492 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.1-7.2 (m, 10H, ArH); MS: 365 m/z (M+); Anal. Calcd. for C18H10ClFN6: C 59.27, H 2.76, N 23.04 %, found: C 59.54, H 2.50, N 22.86 %.
7-Phenyl-9-(4-methoxyphenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3e): Yield: 70 % (Method A), 56 % (Method B); mp: 216-18°C; IR: 1604, 1516 (C=C, C=N ring); 1H-NMR (DMSO-d6): 3.9 (s, 3H, OCH3), 8.0-7.2 (m, 11H, ArH); MS: 342 m/z (M+); Anal. Calcd. for C19H14N6O: C 66.65, H 4.12, N 24.55 %, found: C 66.46, H 4.27, N 24.78 %.
7,9-Di(4-methoxyphenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3f): Yield: 77 % (Method A), 75 % (Method B); mp: 237-39°C; IR: 1596, 1500 (C=C, C=N ring); 1H-NMR (DMSO-d6): 3.95 (s, 6H, OCH3), 8.1-7.3 (m, 10H, ArH); MS: 372 m/z (M+); Anal. Calcd. for C20H16FN6O2: C 64.50, H 4.33, N 22.57 %, found: C 64.39, H 4.28, N 22.33 %.
7-(4-Fluoropheny)l-9-(4-methoxyphenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3g): Yield: 63 % (Method A), 61 % (Method B); mp: 245-47°C; IR: 1600, 1504 (C=C, C=N ring); 1H-NMR (DMSO-d6): 4.0 (s, 3H, OCH3), 8.1-7.3 (m, 10H, ArH); MS: 360 m/z (M+); Anal. Calcd. for C19H13FN6O: C 63.33, H 3.64, N 23.33 %, found: C 63.09, H 3.45, N 23.44 %.
7-(3-Chloro-4-fluorophenyl)-9-(4-methoxyphenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3h): Yield: 56 % (Method A), 58 % (Method B); mp: 219-21°C; IR: 1608, 1504 (C=C, C=N ring); 1H-NMR (DMSO-d6): 3.95 (s, 3H, OCH3), 8.3-7.3 (m, 9H, ArH); MS: 395 m/z (M+); Anal. Calcd. for C19H12ClFN6O: C 57.80, H 3.07, N 21.29 %, found: C 57.45, H 3.25, N 21.60 %.
7-(4-Phenyl)-9-(4-chlorophenyl)-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3i): Yield: 80 % (Method A), 71 % (Method B); mp: 233-35°C; IR: 1608, 1508 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.0-7.2 (m, 11H, ArH); MS: 347 m/z (M+); Anal. Calcd. for C18H10ClN6: C 62.45, H 3.36, N 24.24 %, found: C 62.46, H 3.27, N 24.56 %.
7-(4-Fluorophenyl)-9-(4-chlorophenyl)-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3j): Yield: 67 % (Method A), 66 % (Method B); mp: 226-28°C; IR: 1612, 1496 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.2-7.1 (m, 10H, ArH); MS: 365 m/z (M+); Anal. Calcd. for C18H12ClFN6: C 59.27, H 2.76, N 23.04 %, found: C 59.06, H 2.49, N 23.46 %.
7,9-Di(4-chlorophenyl)-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3k): Yield: 77 % (Method A), 70 % (Method B); mp: 224-25°C; IR: 1608, 1500 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.2-7.1 (m, 11H, ArH); MS: 381 m/z (M+); Anal. Calcd. for C18H10Cl2N6: C 56.70, 2.64, N 22.05 %, found: C 56.49, H 2.39, N 21.88 %.
7-(3-Chloro-4-fluoropheny)l-9-(4-chlorophenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3l): Yield: 65 % (Method A), 63 % (Method B); mp: 220-22°C; IR: 1604, 1508 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.3-7.2 (m, 9H, ArH); MS: m/z 399 (M+); Anal. Calcd. for C18H9Cl2FN6: C 54.15, H 2.27, N 21.05 %, found: C 54.01, H 2.11, N 20.88 %.
Synthesis of 1,4-disubstituted N-ethoxymethylene-2-amino-3-cyanopyrroles 6a-e: General Procedure.
A mixture of 1,4-disubstituted 2-amino-3-cyanopyrrole (5, 0.01 mole) in triethylorthoformate (10 mL) was refluxed for 3-4 hr, then the excess reagent was distilled in vacuo. The solid thus obtained was treated with ice water, filtered, washed with water, dried and crystallized from ethanol.
1-(4-Chlorophenyl)-N-ethoxymethylene-2-amino-3-cyano-4-phenylpyrrole (6a): Yield: 70 %; mp: 130-31°C; IR: 2210 (CN), 1720 (C=O), 1616, 1504 (C=C, C=N ring); 1H-NMR (CDCl3): 1.4-1.2 (J = 6Hz, t, 3H, OCH2CH3), 4.3-4.2 (J = 6Hz, q, 2H, OCH2CH3), 7.8-7.2 (m, 10H, ArH), 8.5 (s, 1H, N=CHOEt); Anal. Calcd. for C20H16ClN3O: C 68.67, H 4.61, N 12.01 %, found: C 68.77, H 4.62, N 12.23 %.
1-Phenyl-N-ethoxymethylene-2-amino-3-cyano-4-(4-methoxyphenyl)pyrrole (6b): Yield: 72 %; mp: 159-60°C; IR: 2220 (CN), 1716 (C=O), 1632, 1520 (C=C, C=N ring); 1H-NMR (CDCl3): 1.4-1.25 (J = 5.9Hz, t, 3H, OCH2CH3), 3.9 (s, 3H, OCH3), 4.3-4.2 (J = 5.9Hz, q, 2H, OCH2CH3), 7.8-7.1 (m, 10H, ArH), 8.45 (s, 1H, N=CHOEt); Anal. Calcd. for C21H19N3O2: C 72.88, H 5.55, N 12.17 %, found: C 73.02, H 5.32, N 12.02 %.
1,4-Di(4-methoxyphenyl)-N-ethoxymethylene-2-amino-3-cyanopyrrole (6c): Yield: 73 %; mp: 117-18°C; IR: 2210 (CN), 1712 (C=O), 1616, 1504 (C=C, C=N ring); 1H-NMR (CDCl3): 1.41-1.2 (J = 6Hz, t, 3H, OCH2CH3), 3.95 (s, 6H, OCH3), 4.32-4.2 (J = 6Hz, q, 2H, OCH2CH3), 7.9-7.2 (m, 9H, ArH), 8.5 (s, 1H, N=CHOEt); Anal. Calcd. for C22H21N3O3: C 70.38, H 5.64, N 11.19 %, found: C 70.28, H 5.44, N 11.01 %.
1-Phenyl-N-ethoxymethylene-2-amino-3-cyano-4-(4-chlorophenyl)pyrrole (6d): Yield: 70 %; mp: 167- 68°C; IR: 2210 (CN), 1710 (C=O), 1616, 1504 (C=C, C=N ring); 1H-NMR (CDCl3): 1.42-1.2 (J = 6.5Hz, t, 3H, OCH2CH3), 4.32-4.2 (J = 6.5Hz, q, 2H, OCH2CH3), 7.9-7.2 (m, 10H, ArH), 8.5 (s, 1H, N=CHOEt); Anal. Calcd. for C20H16ClN3O: C 68.67, H 4.61, N 12.01 %, found: C 68.77, H 4.62, N 12.23 %.
1,4-Di(4-chlorophenyl)-N-ethoxymethylene-2-amino-3-cyanopyrrole (6e): Yield: 81 %; mp: 200-01°C; IR: 2200 (CN), 1720 (C=O), 1600, 1508 (C=C, C=N ring); 1H-NMR (CDCl3): 1.41-1.22 (J = 6Hz, t, 3H, OCH2CH3), 4.3-4.21 (J = 6Hz, q, 2H, OCH2CH3), 7.9-7.1 (m, 9H, ArH), 8.45 (s, 1H, N=CHOEt); Anal. Calcd. for C20H15Cl2N3O: C 62.50, H 3.93, N 10.93 %, found: C 62.81, H 3.81, N 11.09 %.
Synthesis of 5,7-Disubstituted 3-amino-4-imino-7H-pyrrolo[2,3-d]pyrimidines 7a-e: General Procedure.
1,4-Disubstituted N-ethoxymethylene-2-amino-3-cyanopyrroles (6, 0.01 mole) were treated with refluxing hydrazine hydrate (99 %, 10 mL) for 3-4 hr. The reaction mixture was allowed to cool, poured onto crushed ice and neutralized with 50 % acetic acid. The solid obtained was filtered, washed with water, dried and recrystallized from benzene or dioxane.
3-Amino-4-imino-5-phenyl-7-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (7a): Yield: 89 %; mp: 201-02°C; IR: 3380, 3270, 3170, 1640 (NH), 1600, 1504 (C=C, C=N ring); 1H-NMR (DMSO-d6): 5.45 (s, 2H, NH2), 7.9-7.2 (m, 11H, ArH), 8.0 (s, 1H, NH); Anal. Calcd. for C18H14ClN5: C 64.38, H 4.20, N 20.86 %, found: C 64.49, H 4.33, N 20.99 %.
3-Amino-4-imino-5-(4-methoxyphenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (7b): Yield: 88 %; mp: 193-95°C; IR: 3400, 3320, 3280, 1648 (NH), 1624, 1508 (C=C, C=N ring); 1H-NMR (CDCl3): 3.9 (s, 3H, OCH3), 5.43 (s, 2H, NH2), 7.85-7.2 (m, 11H, ArH), 8.05 (s, 1H, NH); Anal. Calcd. for C19H17N5O: C 68.886, H 5.17, N 21.123 %, found: C 68.53, H 5.27, N 21.01 %.
3-Amino-4-imino-5,7-di(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (7c): Yield: 84 %: mp: 154- 55°C; IR: 3330, 3380, 3150, 1644 (NH), 1620, 1488 (C=C, C=N ring); 1H-NMR (CDCl3): 3.95 (s, 6H, OCH3), 5.44 (s, 2H, NH2), 7.8-7.1 (m, 10H, ArH), 8.1 (s, 1H, NH); Anal. Calcd. for C20H19N5O2: C 66.47, H 5.29, N 19.39 %, found: C 66.27, H 5.14, N 19.11 %.
3-Amino-4-imino-5-(4-chlorophenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (7d): Yield: 86 %; mp: 204-06°C; IR: 3380, 3270, 3170, 1644 (NH), 1620, 1504 (C=C, C=N ring); 1H-NMR (DMSO-d6): 5.44 (s, 2H, NH2), 7.9-7.1 (m, 11H, ArH), 8.05 (s, 1H, NH); Anal. Calcd. for C18H14ClN5: C 64.38, H 4.20, N 20.86 %, found: C 64.21, H 4.01, N 20.49 %.
3-Amino-4-imino-5,7-di(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (7e): Yield: 70 %; mp: 224- 25°C; IR: 3340, 3280, 3190, 1648 (NH), 1620, 1516 (C=C, C=N ring); 1H-NMR (DMSO-d6): 5.46 (s, 2H, NH2), 7.95-7.2 (m, 10H, ArH), 8.0 (s, 1H, NH); Anal. Calcd. for C18H13ClN5: C 58.39, H 3.54, N 18.92 %, found: C 58.09, H 3.44, N 18.62 %.
Synthesis of 7,9-disubstituted 7H-triazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 4a-e: General Procedure.
Method A. A mixture of 5,7-disubstituted 4-hydrazino-7H-pyrrolo[2,3-d]pyrimidine (2, 0.01 mole) in formic acid (20 mL) was heated under reflux for 7-8 hr. The reaction mixture was poured onto crushed ice, neutralized with 1N sodium hydroxide solution and the solid obtained was filtered off, washed with water, dried and recrystallized from toluene or a mixture of DMF-EtOH (6:4) to give the title compounds.
Method B: A mixture of 5,7-disubstituted 3-amino-4-imino-7H-pyrrolo[2,3-d]pyrimidine (7, 0.01 mole) in formic acid (15 mL) was heated under reflux for 3-4 hr. The cold reaction mixture was poured onto crushed ice, treated with 1N sodium hydroxide solution and the solid obtained was filtered, washed with water, dried and recrystallized to give the identical compounds 4.
7-(4-Chorophenyl)-9-phenyl-7H-triazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4a): Yield: 69 % (Method A), 57 % (Method B); mp: 256-58°C, IR: 1616, 1504 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.4-7.3 (m, 11H, ArH), 9.12 (s, 1H, H at C2); MS: 346 (M+); Anal. Calcd. for C19H12ClN5: C 65.99, H 3.50, N 20.26 %, found: C 66.17, H 3.30, N 20.01 %.
7-Phenyl-9-(4-methoxyphenyl)triazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4b): Yield: 55 % (Method A), 62 % (Method B); mp: 225-26°C; IR: 1616, 1498 (C=C, C=N ring); 1H-NMR (DMSO-d6): 3.82 (s, 3H, OCH3), 8.3-6.95 (m, 11H, ArH), 9.1 (s, 1H, H at C2); MS: 341 m/z (M+); Anal. Calcd. for C20H15N5O: C 72.42, H 4.56, N 20.51 %, found: C 72.09, H 4.36, N 20.31 %.
7,9-Di(4-methoxyphenyltriazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4c): Yield: 85 % (Method A), 75 % (Method B); mp: 204-05°C; IR: 1608, 1496 (C=C, C=N ring); 1H-NMR (DMSO-d6): 3.8 (s, 6H, OCH3), 8.2-7.0 (m, 10H, ArH), 9.1 (s, 1H, H at C2); MS: 371 m/z (M+); Anal. Calcd. for C21H17N5O2: C 67.91, H 4.62, N 18.86 %, found: C 67.71, H 4.50, N 18.66 %.
7-(4-Phenyl)-9-(4-chlorophenyl)-7H-triazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4d): Yield: 70 % (Method A), 72 % (Method B); mp: 240-42°C; IR: 1616, 1500 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.3-7.3 (m, 11H, ArH), 9.12 (s, 1H, H at C2); MS: 346 m/z (M+); Anal. Calcd. for C19H12ClN5: C 65.99, H 3.50, N 20.26 %, found: C 66.17, H 3.66, N 20.06 %.
7,9-Di(4-chlorophenyl)-7H-triazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4e): Yield: 85 % (Method A), 82 % (Method B); mp: 237-39°C; IR: 1616, 1500 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.3-7.2 (m, 10H, ArH), 9.15 (s, 1H, H at C2); MS: 380 m/z (M+); Anal. Calcd. for C19H11Cl2N5: C 60.01, H 2.92, N 18.42 %, found: C 60.11, H 3.08, N 18.31 %.