3.2.2. Synthesis of Ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-3(5)-carboxylates (2a–h and 3a,f–h)
Appropriate pyrazole 1a–h (1 eq) was dissolved in dry dimethyl formamide (0.4 M) and NaH (1.5 eq; 60% dispersion in mineral oil) was added followed by 2-(chloromethyl)oxirane (1.5 eq). The reaction mixture was stirred at 40 °C for 1–5 h. Upon completion, the reaction mixture was concentrated to approximately 1/3 volume, diluted with ethyl acetate, and washed with brine. Organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.
Ethyl 1-(oxiran-2-ylmethyl)-3-phenyl-1H-pyrazole-5-carboxylate 2a
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 10/1 to 8/1, v/v). White solid, mp 53–54 °C, 60% (3.13 g). Rf = 0.72 (n-hexane/ethyl acetate 7/3, v/v). IR (KBr) νmax, cm−1: 2981, 1721 (C=O), 1261, 1086, 1073, 764, 758, 693, 436. 1H NMR (400 MHz, CDCl3) δH ppm: 1.41 (t, J = 7.1 Hz, 3H, CH3), 2.58–2.63 (m, 1H, Ox CHaHb), 2.81 (t, J = 4.4 Hz, 1H, CHaHb), 3.40–3.47 (m, Ox 1H, CH), 4.38 (q, J = 7.1 Hz, 2H, CH2CH3), 4.83 (qd, J = 14.2, 4.6 Hz, 2H, NCH2), 7.15 (s, 1H, 4-H), 7.29–7.37 (m, 1H, Ph 4-H), 7.38–7.44 (m, 2H, Ph 3,5-H), 7.78–7.84 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, CDCl3) δC ppm: 14.4 (CH3), 45.8 (Ox CH2), 50.7 (Ox CH), 53.0 (NCH2), 61.4 (CH2CH3), 108.4 (C-4), 125.8 (Ph C-2,6), 128.3 (Ph C-4), 128.8 (Ph C-3,5), 132.5 (Ph C-1), 134.3 (C-5), 150.7 (C-3), 159.9 (C=O). 15N NMR (40 MHz, CDCl3) δN ppm: −175.6 (N-1), −66.2 (N-2). HRMS (ESI) for C15H16N2NaO3 ([M+Na]+): calcd m/z 295.1053, found m/z 295.1053.
Ethyl 3-(4-fluorophenyl)-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2b
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 98–99 °C, 59% (2.04 g). Rf = 0.56 (n-hexane/ethyl acetate 7/3, v/v). IR (KBr) νmax, cm−1: 3140, 3061, 2979, 1730 (C=O), 1445, 1263, 1214, 1086, 849, 761. 1H NMR (400 MHz, DMSO-d6) δH ppm: 1.33 (t, J = 7.1 Hz, 3H, CH3), 2.48–2.51 (m, 1H, Ox CHaHb), 2.72 (t, J = 4.5 Hz, 1H, Ox CHaHb), 3.36–3.42 (m, 1H, Ox CH), 4.33 (q, J = 7.1 Hz, 2H, CH2CH3), 4.60 (dd, J = 14.5, 5.5 Hz, 1H, NCHa), 4.85 (dd, J = 14.5, 3.6 Hz, 1H, NCHb), 7.21–7.29 (m, 2H, Ph 3,5-H), 7.38 (s, 1H, 4-H), 7.86–7.95 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 14.0 (CH3), 44.8 (Ox CH2), 50.2 (Ox CH), 52.8 (NCH2), 61.1 (CH2CH3), 108.0 (C-4), 115.65 (d, 2JCF = 21.6 Hz, Ph C-3,5), 127.35 (d, 3JCF = 8.3 Hz, Ph C-2,6), 128.54 (d, 4JCF = 3.0 Hz, Ph C-1), 134.1 (C-5), 148.6 (C-3), 159.0 (C=O), 162.07 (d, JCF = 244.8 Hz, Ph C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −173.3 (N-1), −65.1 (N-2). 19F NMR (376 MHz, DMSO-d6) δF ppm: −113.8 (Ph 6-F). HRMS (ESI) for C15H15FN2NaO3 ([M+Na]+): calcd m/z 313.0959, found m/z 313.0959.
Ethyl 3-(4-chlorophenyl)-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2c
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 8/1 to 7/1, v/v). Pale yellow solid, mp 110–111 °C, 53% (551 mg). Rf = 0.57 (n-hexane/ethyl acetate 7/3, v/v). IR (KBr) νmax, cm−1: 3127, 2982, 2960, 1715 (C=O), 1460, 1266, 1123, 1088, 835, 766. 1H NMR (400 MHz, DMSO-d6) δH ppm: 1.34 (t, J = 7.1 Hz, 3H, CH3), 2.51–2.53 (m, 1H, Ox CHaCHb), 2.79 (t, J = 4.5 Hz, 1H, Ox CHaHb), 3.37–3.43 (m, 1H, Ox CH), 4.34 (q, J = 7.1 Hz, 2H, CH2CH3), 4.61 (dd, J = 14.5, 5.6 Hz, 1H, NCHa), 4.86 (dd, J = 14.4, 3.6 Hz, 1H, NCHb), 7.42 (s, 1H, 4-H), 7.45–7.51 (m, 2H, Ph 3,5-H), 7.86–7.93 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 14.0 (CH3), 44.8 (Ox CH2), 50.1 (Ox CH), 52.9 (NCH2), 61.1 (CH2CH3), 108.3 (C-4), 127.0 (Ph C-2,6), 128.8 (Ph C-3,5), 130.8 (Ph C-1), 132.7 (Ph C-4), 134.2 (C-5), 148.3 (C-3), 159.0 (C=O). 15N NMR (40 MHz, DMSO-d6) δN ppm: −172.3 (N-1), −65.2 (N-2). HRMS (ESI) for C15H15ClN2NaO3 ([M+Na]+): calcd m/z 329.0663, found m/z 329.0663.
Ethyl 3-(4-bromophenyl)-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2d
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 10/1 to 8/1, v/v). White solid, mp 120–121 °C, 58% (1.88 g). Rf = 0.60 (n-hexane/ethyl acetate 7/3, v/v). IR (KBr) νmax, cm−1: 3127, 2979, 1716 (C=O), 1459, 1436, 1267, 1123, 1092, 832, 766. 1H NMR (400 MHz, DMSO-d6) δH ppm: 1.33 (t, J = 7.1 Hz, 3H, CH3), 2.48–2.52 (m, 1H, Ox CHaHb), 2.78 (t, J = 4.5 Hz, 1H, Ox CHaHb), 3.37–3.42 (m, 1H, Ox CH), 4.33 (q, J = 7.1 Hz, 2H, CH2CH3), 4.60 (dd, J = 14.5, 5.6 Hz, 1H, NCHa), 4.86 (dd, J = 14.5, 3.6 Hz, 1H, NCHb), 7.43 (s, 1H, 4-H), 7.58–7.64 (m, 2H, Ph 3,5-H), 7.79–7.86 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 14.0 (CH3), 44.8 (Ox CH2), 50.1 (Ox CH), 52.9 (NCH2), 61.1 (CH2CH3), 108.3 (C-4), 121.3 (Ph C-4), 127.3 (Ph C-2,6), 131.2 (Ph C-3,5), 131.7 (Ph C-1), 134.2 (C-5), 148.4 (C-3), 159.0 (C=O). 15N NMR (40 MHz, DMSO-d6) δN ppm: −172.3 (N-1), −64.8 (N-2). HRMS (ESI) for C15H15BrN2NaO3 ([M+Na]+): calcd m/z 373.0158, found m/z 373.0158 and 375.0136.
Ethyl 3-(4-methoxyphenyl)-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2e
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 75–76 °C, 61% (1.9 g). Rf = 0.49 (n-hexane/ethyl acetate 7/2 v/v). IR (KBr) νmax, cm−1: 3139, 2975, 2938, 2836, 1726 (C=O), 1447, 1086, 1029, 846, 758. 1H NMR (400 MHz, DMSO-d6) δH ppm: 1.33 (t, J = 7.1 Hz, 3H, CH3), 2.47–2.50 (m, 1H, Ox CHaCHb), 2.78 (t, J = 4.5 Hz, 1H, Ox CHaHb), 3.35–3.42 (m, 1H, Ox CH), 3.79 (s, 3H, OCH3), 4.33 (q, J = 7.1 Hz, 2H, CH2CH3), 4.59 (dd, J = 14.5, 5.5 Hz, 1H, NCHa), 4.84 (dd, J = 14.4, 3.5 Hz, 1H, NCHb), 6.93–7.02 (m, 2H, Ph 3,5-H), 7.30 (s, 1H, 4-H), 7.75–7.83 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 14.1 (CH3), 44.8 (Ox CH2), 50.2 (Ox CH), 52.7 (NCH2), 55.2 (OCH3), 61.0 (CH2CH3), 107.5 (C-4), 114.2 (Ph C-3,5), 124.6 (Ph C-1), 126.6 (Ph C-2,6), 133.9 (C-5), 149.4 (C-3), 159.1 (C=O), 159.3 (Ph C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −174.5 (N-1) −67.0 (N-2). HRMS (ESI) for C16H18N2NaO4 ([M+Na]+): calcd m/z 325.1159, found m/z 325.1159.
Ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2f
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 4/1, v/v). Colorless liquid, 21% (30 mg). Rf = 0.57 (n-hexane/ethyl acetate 2/1, v/v). IR (KBr) νmax, cm−1: 2985, 1722 (C=O), 1518, 1312, 1254, 1121, 1105, 1039, 765. 1H NMR (400 MHz, CDCl3) δH ppm: 1.39 (t, J = 7.1 Hz, 3H, CH3), 2.54–2.56 (m, 1H, Ox CHaHb), 2.80 (t, J = 4.4 Hz, 1H, Ox CHaHb), 3.37–3.40 (m, 1H, Ox CH), 4.36 (q, J = 7.1 Hz, 2H, CH2CH3), 4,73 (dd, J = 14.2, 5.2 Hz, 1H, NCHaHb), 4.86 (dd, J = 14.2, 4.2 Hz, 1H, NCHaHb), 6.86 (d, J = 1.5 Hz, 1H, 4-H), 7.53 (d, J = 1.4 Hz, 1H, 3-H). 13C NMR (101 MHz, CDCl3) δC ppm: 14.3 (CH3), 45.8 (Ox CH2), 50.7 (Ox CH), 53.0 (NCH2), 61.3 (CH2CH3), 111.6 (C-4), 133.0 (C-5), 138.8 (C-3), 159.9 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –173.5 (N-1), –60.2 (N-2). HRMS (ESI) for C9H13N2O3 ([M+H]+): calcd m/z 197.0921, found m/z 197.0916.
Ethyl 4-methyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2g
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 4/1, v/v). Colorless liquid, 26% (36 mg). Rf = 0.47 (n-hexane/ethyl acetate 2/1, v/v). IR (KBr) νmax, cm−1: 2983, 1716 (C=O), 1449, 1277, 1113, 1042. 1H NMR (400 MHz, CDCl3) δH ppm: 1.40 (t, J = 7.1 Hz, 3H, CH2CH3), 2.26 (s, 3H, 4-CH3), 2.52–2.54 (m, 1H, Ox CHaHb), 2.78 (t, J = 4.4 Hz, 1H, Ox CHaHb), 3.34–3.37 (m, 1H, Ox CH), 4.38 (q, J = 7.1 Hz, 2H, CH2CH3), 4.68 (dd, J = 14.3, 5.1 Hz, 1H, NCHaHb), 4.80 (dd, J = 14.3, 4.1 Hz, 1H, NCHaHb), 7.36 (s, 1H, 3-H). 13C NMR (101 MHz, CDCl3) δC ppm: 10.9 (4-CH3), 14.3 (CH2CH3), 45.7 (Ox CH2), 50.8 (Ox CH), 53.5 (NCH2), 61.0 (CH2CH3), 123.1 (C-4), 130.1 (C-5), 140.2 (C-3), 160.7 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –174.6 (N-1), –63.9 (N-2). HRMS (ESI) for C10H15N2O3 ([M+H]+): calcd m/z 211.1077, found m/z 211.1067.
Ethyl 3-methyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2h
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 4/1, v/v). Colorless liquid, 24% (32 mg). Rf = 0.42 (n-hexane/ethyl acetate 2/1, v/v). IR (KBr) νmax, cm−1: 2962, 2909, 1722 (C=O), 1461, 1262, 1085, 767. 1H NMR (400 MHz, CDCl3) δH ppm: 1.37 (t, J = 7.1 Hz, 3H, CH2CH3), 2.28 (s, 3H, 3-CH3), 2.55–2.57 (m, 1H, Ox CHaHb), 2.79 (t, J = 4.4 Hz, 1H, Ox CHaHb), 3.34–3.38 (m, 1H, Ox CH), 4.33 (q, J = 7.1 Hz, 2H, CH2CH3), 4.63 (dd, J = 14.3, 5.2 Hz, 1H, NCHaHb), 4.78 (dd, J = 14.3, 4.1 Hz, 1H, NCHaHb), 6.64 (s, 1H, 4-H). 13C NMR (101 MHz, CDCl3) δC ppm: 13.5 (3-CH3), 14.4 (CH2CH3), 45.8 (Ox CH2), 50.8 (Ox CH), 52.7 (NCH2), 61.2 (CH2CH3), 111.0 (C-4), 133.4 (C-5), 148.0 (C-3), 160.0 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –178.6 (N-1), –64.1 (N-2). HRMS (ESI) for C10H15N2O3 ([M+H]+): calcd m/z 211.1077, found m/z 211.1075.
Ethyl 1-(oxiran-2-ylmethyl)-5-phenyl-1H-pyrazole-3-carboxylate 3a
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 8/1 to 1/1, v/v). Colorless resin, 56% (20 mg). Rf = 0.37 (n-hexane/ethyl acetate 1/1, v/v). IR (KBr) νmax, cm−1: 2986, 1729 (C=O), 1214, 765, 701. 1H NMR (400 MHz, CDCl3) δH ppm: 1.41 (t, J = 7.1 Hz, 3H, CH3), 2.49–2.53 (m, 1H, Ox CHaHb), 2.81 (t, J = 4.3 Hz, 1H, Ox CHaHb), 3.40–3.45 (m, 1H, Ox CH), 4.26–4.47 (m, 4H, CH2CH3, NCH2), 6.84 (s, 1H, 4-H), 7.42–7.51 (m, 5H, Ph 2,3,4,5,6-H). 13C NMR (101 MHz, CDCl3) δC ppm: 14.6 (CH3), 46.0 (Ox CH2), 50.7 (Ox CH), 51.6 (NCH2), 61.2 (CH2CH3), 109.2 (C-4), 129.0 (Ph C-1,2,6), 129.4 (Ph C-4), 129.5 (Ph C-3,5), 143.7 (C-3), 146.2 (C-5), 162.5 (C=O). 15N NMR (40 MHz, CDCl3) δN ppm: −174.4 (N-1), −70.0 (N-2). HRMS (ESI) for C15H16N2NaO3 ([M+Na]+): calcd m/z 295.1053, found m/z 295.1051.
Ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-3-carboxylate 3f
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 2/1, v/v). Colorless liquid, 28% (39 mg). Rf = 0.49 (n-hexane/ethyl acetate 1/2, v/v). IR (KBr) νmax, cm−1: 2986, 1721 (C=O), 1375, 1237, 1173, 1154, 1027, 765. 1H NMR (400 MHz, CDCl3) δH ppm: 1.40 (t, J = 7.1, 3H, CH3), 2.49–2.51 (m, 1H, Ox CHaHb), 2.87 (t, J = 4.2 Hz, 1H, Ox CHaHb), 3.36–3.38 (m, 1H, Ox CH), 4.21 (dd, J = 14.7, 6.0 Hz, 1H, NCHaHb), 4.41 (q, J = 7.1 Hz, 2H, CH2CH3), 4.62 (dd, J = 14.7, 2.6 Hz, 1H, NCHaHb), 6.84 (d, J = 2.1 Hz, 1H, 4-H), 7.53 (d, J = 2.1 Hz, 1H, 5-H). 13C NMR (101 MHz, CDCl3) δC ppm: 14.5 (CH3), 45.5 (Ox CH2), 50.4 (Ox CH), 54.6 (NCH2), 61.2 (CH2CH3), 109.5 (C-4), 131.7 (C-5), 144.2 (C-3), 162.4 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –171.8 (N-1), –68.9 (N-2). HRMS (ESI) for C9H13N2O3 ([M+H]+): calcd m/z 197.0921, found m/z 197.0915.
Ethyl 4-methyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-3-carboxylate 3g
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 2/1, v/v). Colorless liquid, 35% (48 mg). Rf = 0.47 (n-hexane/ethyl acetate 1/2, v/v). IR (KBr) νmax, cm−1: 2983, 2932, 1716 (C=O), 1448, 1367, 1254, 1108. 1H NMR (400 MHz, CDCl3) δH ppm: 1.41 (t, J = 7.1 Hz, 3H, CH2CH3), 2.29 (s, 3H, 4-CH3), 2.49–2.51 (m, 1H, Ox CHaHb), 2.86 (t, J = 4.2 Hz, 1H, Ox CHaHb), 3.33–3.35 (m, 1H, Ox CH), 4.13 (dd, J = 14.7, 6.0 Hz, 1H, NCHaHb), 4.41 (q, J = 7.1 Hz, 2H, CH2CH3), 4.55 (dd, J = 14.7, 2.5 Hz, 1H, NCHaHb), 7.33 (s, 1H, 5-H). 13C NMR (101 MHz, CDCl3) δC ppm: 9.9 (4-CH3), 14.5 (CH2CH3), 45.4 (Ox CH2), 50.5 (Ox CH), 54.5 (NCH2), 60.8 (CH2CH3), 121.5 (C-4), 131.0 (C-5), 141.4 (C-3), 163.0 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –175.7 (N-1), –69.2 (N-2). HRMS (ESI) for C10H15N2O3 ([M+H]+): calcd m/z 211.1077, found m/z 211.1072.
Ethyl 5-methyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-3-carboxylate 3h
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 2/1, v/v). White solid, mp 31–33 °C, 29% (40 mg). Rf = 0.47 (n-hexane/ethyl acetate 1/2, v/v). IR (KBr) νmax, cm−1: 2985, 1721 (C=O), 1446, 1386, 1228, 1032, 780. 1H NMR (400 MHz, CDCl3) δH ppm: 1.39 (t, J = 7.1 Hz, 3H, CH2CH3), 2.34 (s, 3H, 5-CH3), 2.47–2.49 (m, 1H, Ox CHaHb), 2.82 (t, J = 4.3 Hz, 1H, Ox CHaHb), 3.33–3.37 (m, 1H, Ox CH), 4.21 (dd, J = 15.0, 5.2 Hz, 1H, NCHaHb), 4.39 (q, J = 7.1 Hz, 2H, CH2CH3) 4.53 (dd, J = 15.0, 2.4 Hz, 1H, NCHaHb), 6.57 (s, 1H, 4-H). 13C NMR (101 MHz, CDCl3) δC ppm: 11.4 (5-CH3), 14.5 (CH2CH3), 45.3 (Ox CH2), 50.9 (Ox CH), 51.4 (NCH2), 61.0 (CH2CH3), 108.6 (C-4), 141.3 (C-5), 143.1 (C-3), 162.6 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –173.3 (N-1), –70.8 (N-2). HRMS (ESI) for C10H15N2O3 ([M+H]+): calcd m/z 211.1077, found m/z 211.1070.
3.2.3. Synthesis of 7-Hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones (4a–x)
Procedure a. Carboxylate 2a–h (1 eq) was dissolved in 2M ammonia (30 eq) solution in methanol, sealed in a pressure tube and stirred at 70 °C for 5–18 h. After completion, excess of ammonia in methanol was evaporated under reduced pressure. The residue was purified by column chromatography.
Procedure b. To a solution of carboxylate 2a–e (1 eq) in methanol (5 M), appropriate primary amine (3 eq) was added, the reaction mixture was sealed in a pressure tube and was stirred at 70 °C for 7 h. After completion, the reaction mixture was poured into water and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.
7-Hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4a
Purified by column chromatography on silica gel (gradient from n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/15/0.5, v/v). White solid, decomp. 246 °C, procedure a −34% (27 mg). Rf = 0.40 (dichloromethane/methanol 100/5, v/v). IR (KBr) νmax, cm−1: 3270, 3196, 3074, 2925, 1681 (C=O), 1460, 1440, 771, 752, 685. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.85–2.96 (m, 1H, 6-Ha), 3.21–3.30 (m, 1H, 6-Hb), 4.20–4.33 (m, 2H, 7-H, 8-Ha), 4.54 (dd, J = 13.8, 4.8 Hz, 1H, 8-Hb), 5.49 (d, J = 3.8 Hz, 1H, OH), 7.16 (s, 1H, 3-H), 7.28–7.35 (m, 1H, Ph 4-H), 7.36–7.45 (m, 2H, Ph 3,5-H), 7.80–7.88 (m, 2H, Ph 2,6-H), 8.24–8.31 (m, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.5 (C-6), 56.2 (C-8), 69.4 (C-7), 105.8 (C-3), 125.1 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.5 (Ph C-1), 139.4 (C-3a), 149.0 (C-2), 163.2 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −270.4 (N-5), −175.4 (N-9), −73.6 (N-1). HRMS (ESI) for C13H13N3NaO2 ([M+Na]+): calcd m/z 266.0900, found m/z 266.0900.
2-(4-Fluorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4b
Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/15/0.5, v/v). Pale yellow solid, decomp. 216 °C, procedure a −56% (86 mg). Rf = 0.38 (dichloromethane/methanol 100/5, v/v). IR (KBr) νmax, cm−1: 3305, 3206, 3071, 2947, 2923, 1681, 1457, 1442, 841, 809. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.74 (dt, J = 12.2, 5.8 Hz, 1H, 6-Ha), 4.09 (dt, J = 14.5, 5.4 Hz, 1H, 6-Hb), 5.02–5.15 (m, 2H, 7-H, 8-Ha), 5.36 (dd, J = 13.9, 5.0 Hz, 1H, 8-Hb), 8.00 (s, 1H, 3-H), 8.04–8.11 (m, 2H, Ph 3,5-H), 8.67–8.75 (m, 2H, Ph 2,6-H), 9.12–9.18 (m, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.5 (C-6), 56.2 (C-8), 69.3 (C-7), 105.8 (C-3), 115.59 (d, 2JCF = 21.5 Hz, Ph C-3,5), 127.12 (d, 3JCF = 8.2 Hz, Ph C-2,6), 129.10 (d, 4JCF = 3.0 Hz, Ph C-1), 139.6 (C-3a), 148.2 (C-2), 161.83 (d, JCF = 244.3 Hz, Ph C-4), 163.1 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −270.5 (N-5), −175.3 (N-9), −73.8 (N-1). 19F NMR (376 MHz, DMSO-d6) δF ppm: −114.4 (Ph 6-F). HRMS (ESI) for C13H12FN3NaO2 ([M+Na]+): calcd m/z 284.0806, found m/z 284.0806.
2-(4-Chlorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4c
Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/20/0.5, v/v). White solid, decomp. 249 °C, procedure a −48% (59 mg). Rf = 0.38 (dichloromethane/methanol 100/5, v/v). IR (KBr) νmax, cm−1: 3297, 3210, 3080, 2917, 1683 (C=O), 1451, 1435, 1089, 834, 809. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.86–2.95 (m, 1H, 6-Ha), 3.21–3.30 (m, 1H, 6-Hb), 4.19–4.31 (m, 2H, 7-H, 8-Ha), 4.54 (dd, J = 13.9, 4.9 Hz, 1H, 8-Hb), 5.53 (br s, 1H, OH), 7.20 (s, 1H, 3-H), 7.43–7.50 (m, 2H, Ph 3,5-H), 7.82–7.91 (m, 2H, Ph 2,6-H), 8.28–8.33 (m, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.5 (C-6), 56.3 (C-8), 69.3 (C-7), 106.0 (C-3), 126.8 (Ph C-2,6), 128.8 (Ph C-3,5), 131.4 (Ph C-1), 132.3 (Ph C-4), 139.6 (C-3a), 147.9 (C-2), 163.0 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −270.4 (N-5), −174.0 (N-9), −69.7 (N-1). HRMS (ESI) for C13H12ClN3NaO2 ([M+Na]+): calcd m/z 300.0510, found m/z 300.0510.
2-(4-Bromophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4d
Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/12/0.5, v/v). White solid, decomp. 230 °C, procedure a −51% (50 mg). Rf = 0.40 (dichloromethane/methanol 100/5, v/v). IR (KBr) νmax, cm−1: 3292, 3214, 3079, 1680 (C=O), 1455 and 1434 (doublet), 1071, 991, 922, 816 and 807 (doublet). 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.90 (dt, J = 12.2, 5.8 Hz, 1H, 6-Ha), 3.26 (dt, J = 14.4, 5.3 Hz, 1H, 6-Hb), 4.19–4.33 (m, 2H, 7-H, 8-Ha), 4.54 (dd, J = 13.9, 4.9 Hz, 1H, 8-Hb), 5.49 (d, J = 41 Hz, 1H, OH), 7.20 (s, 1H, 3-H), 7.57–7.64 (m, 2H, Ph 3,5-H), 7.76–7.84 (m, 2H, Ph 2,6-H), 8.29 (t, J = 5.1 Hz, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.5 (C-6), 56.3 (C-8), 69.3 (C-7), 106.0 (C-3), 120.8 (Ph C-4), 127.1 (Ph C-2,6), 131.7 (Ph C-3,5), 131.8 (Ph C-1), 139.6 (C-3a), 148.0 (C-2), 163.0 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −173.4 (N-9), −72.7 (N-1). HRMS (ESI) for C13H12BrN3NaO2 ([M+Na]+): calcd m/z 344.0005, found m/z 344.0005 and 345.9983.
7-Hydroxy-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4e
Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/10/0.5, v/v). White solid, decomp. 239 °C, procedure a −40% (38 mg). Rf = 0.41 (dichloromethane/methanol 100/5, v/v). IR (KBr) νmax, cm−1: 3200, 3078, 2928, 1681 (C=O), 1463, 1447, 1251, 1176, 1027, 821. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.91 (dt, J = 11.9, 5.7 Hz, 1H, 6-Ha), 3.25 (dt, J = 14.6, 5.4 Hz, 1H, 6-Hb), 3.78 (s, 3H, OCH3), 4.18–4.32 (m, 2H, 7-H, 8-Ha), 4.51 (dd, J = 14.1, 5.1 Hz, 1H, 8-Hb), 5.48 (d, J = 4.2 Hz, 1H, OH), 6.94–7.00 (m, 2H, Ph 3,5-H), 7.07 (s, 1H, 3-H), 7.73–7.79 (m, 2H, Ph 2,6-H), 8.22–8.27 (m, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.6 (C-6), 55.1 (CH3), 56.1 (C-8), 69.4 (C-7), 105.2 (C-3), 114.1 (Ph C-3,5), 125.2 (Ph C-1), 126.4 (Ph C-2,6), 139.3 (C-3a), 149.0 (C-3), 156.0 (Ph C-4), 163.2 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −270.1 (N-5), −176.5 (N-9), −74.9 (N-1). HRMS (ESI) for C14H15N3NaO3 ([M+Na]+): calcd m/z 296.1006, found m/z 296.1006.
7-Hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4f
Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 195 °C, procedure a −89% (76 mg). Rf = 0.41 (dichloromethane/methanol 9/1, v/v). IR (KBr) νmax, cm−1: 3210, 3127, 3081, 2933, 1685 (C=O), 1387, 1351, 1182, 825. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.81–2.87 (m, 1H, 6-Ha), 3.16–3.22 (m, 1H, 6-Hb), 4.18 (dd, J = 14.0, 4.3 Hz, 1H, 8-Ha), 4.21–4.27 (m, 1H, 7-H), 4.48 (dd, J = 14.0, 5.1 Hz, 1H, 8-Hb), 5.44 (d, J = 4.0 Hz, 1H, OH), 6.66 (d, J = 0.7 Hz, 1H, 3-H), 7.47 (d, J = 0.6 Hz, 1H, 2-H), 8.22 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.6 (C-6), 55.9 (C-8), 69.4 (C-7), 108.8 (C-3), 137.79 (C-3a), 137.83 (C-2), 163.4 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: –271.1 (N-5), –173.3 (N-9), –66.0 (N-1). HRMS (ESI) for C7H10N3O2 ([M+H]+): calcd m/z 168.0768, found m/z 168.0763.
7-Hydroxy-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4g
Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 213 °C, procedure a −77% (67 mg). Rf = 0.45 (dichloromethane/methanol 9/1, v/v). IR (KBr) νmax, cm−1: 3301, 3203, 3078, 2932, 1678 (C=O), 1382, 1320, 1247, 1099, 922. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.10 (s, 3H, CH3), 2.77–2.84 (m, 1H, 6-Ha), 3.12–3.19 (m, 1H, 6-Hb), 4.09 (dd, J = 14.2, 4.2 Hz, 1H, 8-Ha), 4.17–4.23 (m, 1H, 7-H), 4.40 (dd, J = 14.1, 5.4 Hz, 1H, 8-Hb), 5.39 (d, J = 4.1 Hz, 1H, OH), 7.29 (s, 1H, 2-H), 8.14 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 8.7 (CH3), 45.5 (C-6), 55.7 (C-8), 69.7 (C-7), 119.4 (C-3), 133.8 (C-3a), 138.4 (C-2), 164.0 (COO). 15N NMR (40 MHz, DMSO-d6) δN ppm: –270.3 (N-5), –176.2 (N-9), –69.1 (N-1). HRMS (ESI) for C8H12N3O2 ([M+H]+): calcd m/z 182.0924, found m/z 182.0923.
7-Hydroxy-2-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4h
Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 232 °C, procedure a −90% (78 mg). Rf = 0.44 (dichloromethane/methanol 9/1, v/v). IR (KBr) νmax, cm−1: 3254, 3144, 2936, 1689 (C=O), 1635, 1464, 1453, 1135, 1054, 758. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.16 (s, 1H, CH3), 2.82–2.89 (m, 1H, 6-Ha), 3.15–3.21 (m, 1H, 6-Hb), 4.08 (dd, J = 14.2, 4.4 Hz, 1H, 8-Ha), 4.17–4.24 (m, 1H, 7-H), 4.38 (dd, J = 14.2, 5.4 Hz, 1H, 8-Hb), 5.40 (d, J = 4.1 Hz, 1H, OH), 6.43 (s, 1H, 3-H), 8.15 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 13.0 (CH3), 45.6 (C-6), 55.5 (C-8), 69.5 (C-7), 108.1 (C-3), 138.4 (C-3a), 146.1 (C-2), 163.4 (COO). 15N NMR (40 MHz, DMSO-d6) δN ppm: –271.6 (N-5), –178.8 (N-9), –68.9 (N-1). HRMS (ESI) for C8H12N3O2 ([M+H]+): calcd m/z 182.0924, found m/z 182.0923.
7-Hydroxy-5-(2-methoxyethyl)-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4i
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/9, v/v). White solid, mp 134–135 °C, procedure b −81% (99 mg). Rf = 0.40 (ethyl acetate). IR (KBr) νmax, cm−1: 3274, 3135, 2932, 1651 (C=O), 1435, 1296, 1177, 1113, 764, 691. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.15 (dd, J = 15.0, 7.5 Hz, 1H, 5-CHa), 3.29 (s, 3H, CH3), 3.41–3.56 (m, 4H, 5-CHb, CH2O, 6-Ha), 3.89 (dt, J = 13.5, 5.2 Hz, 1H, 6-Hb), 4.24 (dd, J = 14.1, 3.2 Hz, 1H, 8-Ha), 4.35–4.42 (m, 1H, 7-H), 4.47 (dd, J = 14.1, 5.1 Hz, 1H, 8-Hb), 5.52 (d, J = 4.3 Hz, 1H, OH), 7.17 (s, 1H, 3-H), 7.28–7.34 (m, 1H, Ph 4-H), 7.37–7.45 (m, 2H, Ph 3,5-H), 7.81–7.86 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 46.8 (C-6), 52.8 (5-CH2), 55.9 (C-8), 58.0 (CH3), 69.5 (C-7), 69.9 (CH2O), 105.4 (C-3), 125.1 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.5 (Ph C-1), 139.3 (C-3a), 149.0 (C-2), 161.6 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −264.8 (N-5), −175.6 (N-9), −73.7 (N-1). HRMS (ESI) for C16H19N3NaO3 ([M+Na]+): calcd m/z 324.1319, found m/z 324.1319.
2-(4-Fluorophenyl)-7-hydroxy-5-(2-methoxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4j
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 1/5, v/v). White solid, mp 133–134 °C, procedure b −84% (285 mg). Rf = 0.46 (ethyl acetate). IR (KBr) νmax, cm−1: 3299, 2941, 2903, 2819, 1620, 1471, 1215, 1113, 827, 806. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.14 (dd, J = 15.0, 7.5 Hz, 1H, 6-Ha), 3.28 (s, 3H, CH3), 3.39–3.57 (m, 4H, 5-CHa, 6-Hb, CH2O), 3.89 (dt, J = 10.6, 5.0 Hz, 1H, 5-CHb), 4.23 (dd, J = 14.1, 2.6 Hz, 1H, 8-Ha), 4.34–4.50 (m, 2H, 7-H, 8-Hb), 5.52 (d, J = 3.9 Hz, 1H, OH), 7.17 (s, 1H, 3-H), 7.20–7.28 (m, 2H, Ph 3,5-H), 7.84–7.92 (m, 5.9 Hz, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 46.8 (5-CH2), 52.8 (C-6), 55.9 (C-8), 58.0 (CH3), 69.5 (C-7), 69.9 (CH2O), 105.4 (C-3), 115.59 (d, 2JCF = 21.5 Hz, Ph C-3,5), 127.09 (d, 3JCF = 8.2 Hz, Ph C-2,6), 129.1 (d, 4JCF = 3.0 Hz, Ph C-1), 139.4 (C-3a), 148.1 (C-2), 161.5 (C-4), 161.82 (d, JCF = 244.3 Hz, Ph C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −264.6 (N-5), −175.6 (N-9), −75.2 (N-1). 19F NMR (376 MHz, DMSO-d6) δF ppm: −114.4 (1F, m, Ph 6-F). HRMS (ESI) for C16H18FN3NaO3 ([M+Na]+): calcd m/z 342.1224, found m/z 342.1224.
2-(4-Chlorophenyl)-7-hydroxy-5-(2-methoxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4k
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 1/9, v/v). Pale pink solid, mp 148–149 °C, procedure b −98% (221 mg). Rf = 0.41 (ethyl acetate). IR (KBr) νmax, cm−1: 3300, 2941, 2877, 1623 (C=O), 1469, 1400, 1111, 1068, 826, 756. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.14 (dd, J = 14.9, 7.4 Hz, 1H, 6-Ha), 3.29 (s, 3H, CH3), 3.40–3.58 (m, 4H, 5-CHa, 6-Hb, CH2O), 3.84–3.94 (m, 1H, 5-CHb), 4.24 (dd, J = 14.1, 2.5 Hz, 1H, 8-Ha), 4.35–4.51 (m, 2H, 7-H, 8-Hb), 5.53 (d, J = 3.8 Hz, 1H, OH), 7.21 (s, 1H, 3-H), 7.37–7.54 (m, 2H, Ph 3,5-H), 7.77–7.95 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 46.8 (5-CH2), 52.8 (C-6), 56.0 (C-8), 58.0 (CH3), 69.5 (C-7), 69.9 (CH2O), 105.7 (C-3), 126.8 (Ph C-2,6), 128.8 (Ph C-3,5), 131.4 (Ph C-1), 132.3 (Ph C-4), 139.5 (C-3a), 147.9 (C-2), 161.4 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −264.3 (N-5), −174.7 (N-9), −74.3 (N-1). HRMS (ESI) for C16H18ClN3NaO3 ([M+Na]+): calcd m/z 358.0929, found m/z 358.0929.
2-(4-Bromophenyl)-7-hydroxy-5-(2-methoxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4l
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 3/1 to 1/9, v/v). White solid, mp 143–144 °C, procedure b −84% (339 mg). Rf = 0.43 (ethyl acetate). IR (KBr) νmax, cm−1: 3292, 2943, 2876, 1621 (C=O), 1545, 1467, 1107, 1070, 1007, 812. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.14 (dd, J = 15.0, 7.6 Hz, 1H, 6-Ha), 3.28 (s, 3H, CH3), 3.40–3.57 (m, 4H, 6-Hb, NCHa, CH2O), 3.89 (dt, J = 10.6, 5.1 Hz, 1H, NCHb), 4.23 (dd, J = 14.1, 2.9 Hz, 1H, 8-Ha), 4.35–4.42 (m, 1H, 7-H), 4.47 (dd, J = 14.1, 5.0 Hz, 1H, 8-Hb), 5.53 (d, J = 3.2 Hz, 1H, OH), 7.21 (s, 1H, 3-H), 7.56–7.63 (m, 2H, Ph 3,5-H), 7.76–7.83 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 46.8 (NCH2), 52.8 (C-6), 56.0 (C-8), 58.0 (CH3), 69.5 (7-H), 69.9 (CH2O), 105.6 (C-3), 120.8 (Ph C-4), 127.1 (Ph C-2,6), 131.7 (Ph C-3,5), 131.8 (Ph C-1), 139.5 (C-3a), 147.9 (C-2), 161.4 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −264.5 (N-5), –174.5 (N-9), −73.9 (N-1). HRMS (ESI) for C16H18BrN3NaO3 ([M+Na]+): calcd m/z 402.0424, found m/z 402.0424 and 404.0409.
7-Hydroxy-5-(2-methoxyethyl)-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4m
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 3.5/1 to 1/9, v/v). White solid, mp 147–148 °C, procedure b −80% (274 mg). Rf = 0.38 (ethyl acetate). IR (KBr) νmax, cm−1: 3212, 2982, 2943, 2882, 2838, 1651 (C=O), 1448, 1249, 1020, 834. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.15 (dd, J = 15.0, 7.4 Hz, 1H, 6-Ha), 3.28 (s, 3H, OCH3), 3.39–3.57 (m, 4H, 5-CHa, CH2O, 6-Hb), 3.78 (s, 3H, Ph 4-OCH3), 3.89 (dt, J = 13.6, 5.2 Hz, 1H, 5-CHb), 4.21 (dd, J = 14.0, 3.1 Hz, 1H, 8-Ha), 4.34–4.47 (m, 2H, 7-H, 8-Hb), 5.52 (d, J = 4.2 Hz, 1H, OH), 6.93–6.99 (m, 2H, Ph 3,5-H), 7.07 (s, 1H, 3-H), 7.73–7.80 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 46.8 (5-CH2), 52.9 (C-6), 55.1 (CH3), 55.8 (C-8), 58.1 (OCH3), 69.6 (C-7), 70.0 (CH2O), 104.9 (C-3), 114.1 (Ph C-3,5), 125.2 (Ph C-1), 126.4 (Ph C-2,6), 139.2 (C-3a), 148.9 (C-2), 159.0 (Ph C-4), 161.7 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −264.5 (N-5), −176.2 (N-9), −77.0 (N-1). HRMS (ESI) for C17H21N3NaO4 ([M+Na]+): calcd m/z 354.1424, found m/z 354.1424.
5-Allyl-7-hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4n
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/9, v/v). White solid, mp 126–127 °C, procedure b −71% (231 mg). Rf = 0.42 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) νmax, cm−1: 3346, 2939, 1619 (C=O), 1470, 1431, 1286, 1055, 942, 749, 690. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.09 (dd, J = 15.0, 7.3 Hz, 1H, 6-Ha), 3.38 (dd, J = 15.0, 5.1 Hz, 1H, 6-Hb), 3.94 (dd, J = 15.1, 6.4 Hz, 1H, 5-CHa), 4.20–4.31 (m, 2H, 5-CHb, 8-Ha), 4.34–4.42 (m, 1H, 7-H), 4.55 (dd, J = 14.4, 5.4 Hz, 1H, 8-Hb), 5.18–5.29 (m, 2H, CH2-CH=CH2), 5.55 (d, J = 4.2 Hz, 1H, OH), 5.87 (ddd, J = 22.5, 10.8, 5.9 Hz, 1H, CH2-CH=CH2), 7.19 (s, 1H, 3-H), 7.29–7.35 (m, 1H, Ph 4-H), 7.37–7.44 (m, 2H, Ph 3,5-H), 7.81–7.88 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 49.6 (5-CH2), 51.3 (C-6), 55.9 (C-8), 69.3 (C-7), 105.8 (C-3), 117.8 (CH2-CH=CH2), 125.1 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.5 (Ph C-1), 133.5 (CH2-CH=CH2), 139.2 (C-3a), 149.0 (C-2), 161.3 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −263.8 (N-5), −175.4 (N-9), −73.8 (N-1). HRMS (ESI) for C16H17N3NaO2 ([M+Na]+): calcd m/z 306.1213, found m/z 306.1213.
5-Allyl-2-(4-fluorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4o
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 7/2 to 1/9, v/v). White solid, mp 143–144 °C, procedure b −89% (175 mg). Rf = 0.39 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) νmax, cm−1: 3230, 2951, 2892, 1651, 1461, 1440, 933, 837, 816, 756. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.08 (dd, J = 15.0, 7.3 Hz, 1H, 6-Ha), 3.38 (dd, J = 15.0, 5.1 Hz, 1H, 6-Hb), 3.94 (dd, J = 15.2, 6.3 Hz, 1H, 5-CHa), 4.19–4.32 (m, 2H, 5-CHb, 8-Ha), 4.34–4.42 (m, 1H, 7-H), 4.54 (dd, J = 14.3, 5.3 Hz, 1H, 8-Hb), 5.18–5.28 (m, J = 14.0 Hz, 2H, CH2-CH=CH2), 5.55 (d, J = 4.1 Hz, 1H, OH), 5.87 (dq, J = 10.9, 5.8 Hz, 1H, CH2-CH=CH2), 7.20 (s, 1H, 3-H), 7.21–7.29 (m, 2H, Ph 3,5-H), 7.84–7.92 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 49.6 (5-CH2), 51.3 (C-6), 55.9 (C-8), 69.3 (C-7), 105.7 (C-3), 115.59 (d, 2JCF = 21.5 Hz, Ph C-3,5), 117.8 (CH2-CH=CH2), 127.10 (d, 3JCF = 8.2 Hz, Ph C-2,6), 129.07 (d, 4JCF = 3.0 Hz, Ph C-1), 133.5 (CH2-CH=CH2), 139.2 (C-3a), 148.1 (C-2), 161.3 (C-4), 161.83 (d, JCF = 244.3 Hz, Ph C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −264.0 (N-5), −175.1 (N-9), −74.3 (N-1). 19F NMR (376 MHz, DMSO-d6) δF ppm: −114.4 (Ph 6-F). HRMS (ESI) for C16H16FN3NaO2 ([M+Na]+): calcd m/z 324.1119, found m/z 324.1119.
5-Allyl-2-(4-chlorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4p
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 7/2 to 1/9, v/v). White solid, mp 179–180 °C, procedure b −92% (188 mg). Rf = 0.42 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) νmax, cm−1: 3363, 2939, 2891, 1620, 1470, 1091, 1053, 939, 812, 753. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.08 (dd, J = 15.0, 7.3 Hz, 1H, 6-Ha), 3.38 (dd, J = 15.0, 5.1 Hz, 1H, 6-Hb), 3.94 (dd, J = 15.1, 6.3 Hz, 1H, 5-Ha), 4.19–4.42 (m, 3H, 5-CHb, 7-H, 8-Ha), 4.55 (dd, J = 14.4, 5.4 Hz, 1H, 8-Hb), 5.19–5.29 (m, 2H, CH2-CH=CH2), 5.55 (d, J = 4.2 Hz, 1H, OH), 5.86 (ddd, J = 22.5, 10.8, 5.9 Hz, 1H, CH2-CH=CH2), 7.23 (s, 1H, 3-H), 7.43–7.51 (m, 2H, Ph 3,5-H), 7.83–7.91 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 49.6 (5-CH2), 51.2 (C-6), 56.0 (C-8), 69.3 (C-7), 106.0 (C-3), 117.8 (CH2-CH=CH2), 126.8 (Ph C-2,6), 128.8 (Ph C-3,5), 131.4 (Ph C-1), 132.3 (Ph C-4), 133.4 (CH2-CH=CH2), 139.3 (C-3a), 147.9 (C-2), 161.2 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −264.1 (N-5), −174.4 (N-9), −73.7 (N-1). HRMS (ESI) for C16H16ClN3NaO2 ([M+Na]+): calcd m/z 340.0823, found m/z 340.0823.
5-Allyl-2-(4-bromophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4r
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient 1/9, v/v). White solid, mp 186–187 °C, procedure b −76% (277 mg). Rf = 0.43 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) νmax, cm−1: 3366, 2938, 1621 (C=O), 1469, 1434, 1052, 1006, 933, 811, 752. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.08 (dd, J = 14.9, 7.3 Hz, 1H, 6-Ha), 3.35–3.42 (m, 1H, 6-Hb), 3.94 (dd, J = 15.1, 6.2 Hz, 1H, 5-CHa), 4.19–4.32 (m, 2H, 5-CHb, 8-Ha), 4.34–4.41 (m, 1H, 7-H), 4.55 (dd, J = 14.3, 5.3 Hz, 1H, 8-Hb), 5.18–5.28 (m, 2H, CH2-CH=CH2), 5.56 (d, J = 4.0 Hz, 1H, OH), 5.81–5.92 (m, 1H, CH2-CH=CH2), 7.23 (s, 1H, 3-H), 7.57–7.63 (m, 2H, Ph 3,5-H), 7.78–7.84 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 49.6 (5-CH2), 51.2 (C-6), 56.0 (C-8), 69.3 (C-7), 106.0 (C-3), 117.8 (CH2-CH=CH2), 120.9 (Ph C-4), 127.1 (Ph C-2,6), 131.67 (Ph C-3,5), 131.73 (Ph C-1), 133.4 (CH2-CH=CH2), 139.3 (C-3a), 147.9 (C-2), 161.2 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −263.2 (N-5), −173.1 (N-9), −74.0 (N-1). HRMS (ESI) for C16H16BrN3NaO2 ([M+Na]+): calcd m/z 384.0318, found m/z 384.0318 and 386.0303.
5-Allyl-7-hydroxy-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4s
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 1/9, v/v). White solid, mp 134–135 °C, procedure b −85% (301 mg). Rf = 0.35 (n-hexane/ethyl acetate 1.5/3.5, v/v). IR (KBr) νmax, cm−1: 3284, 2932, 2835, 1624 (C=O), 1467, 1285, 1061, 1026, 935, 828. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.08 (dd, J = 15.0, 7.2 Hz, 1H, 6-Ha), 3.37 (dd, J = 14.8, 4.9 Hz, 1H, 6-Hb), 3.78 (s, 3H, Ph 4-OCH3), 3.94 (dd, J = 15.1, 6.4 Hz, 1H, 5-CHa), 4.20 (dd, J = 14.3, 3.8 Hz, 1H, 8-Ha), 4.28 (dd, J = 15.1, 5.3 Hz, 1H, 5-CHb), 4.33–4.40 (m, 1H, 7-H), 4.51 (dd, J = 14.3, 5.4 Hz, 1H, 8-Hb), 5.17–5.28 (m, 2H, CH2-CH=CH2), 5.54 (d, J = 4.2 Hz, 1H, OH), 5.86 (ddd, J = 22.5, 10.3, 5.9 Hz, 1H, CH2-CH=CH2), 6.93–7.00 (m, 2H, Ph 3,5-H), 7.10 (s, 1H, 3-H), 7.72–7.80 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 49.6 (5-CH2), 51.3 (C-6), 55.1 (Ph 4-OCH3), 55.8 (C-8), 69.4 (C-7), 105.2 (C-3), 114.1 (Ph C-3,5), 117.8 (CH2-CH=CH2), 125.2 (Ph C-1), 126.4 (Ph C-2,6), 133.5 (CH2-CH=CH2), 139.0 (C-3a), 148.9 (C-2), 159.0 (Ph C-4), 161.4 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −176.8 (N-9), −75.9 (N-1). HRMS (ESI) for C17H19N3NaO3 ([M+Na]+): calcd m/z 336.1319, found m/z 336.1319.
5-Benzyl-7-hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4t
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/9, v/v). Pale yellow solid, mp 167–168 °C, procedure b −87% (138 mg). Rf = 0.55 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) νmax, cm−1: 3257, 3143, 2892, 1649 (C=O), 1451, 1235, 765 and 754 (doublet), 705 and 692 (doublet). 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.08 (dd, J = 14.9, 7.5 Hz, 1H, 6-Ha), 3.37 (dd, J = 15.0, 5.2 Hz, 1H, 6-Hb), 4.12–4.19 (m, 1H, 7-H), 4.24 (dd, J = 14.4, 3.5 Hz, 1H, 8-Ha), 4.43–4.56 (m, 2H, 5-CHa, 8-Hb), 4.96 (d, J = 14.7 Hz, 1H, 5-CHb), 5.51 (d, J = 4.1 Hz, 1H, OH), 7.25 (s, 1H, 3-H), 7.29–7.35 (m, 2H, CPh 4-H, CH2Ph 4-H), 7.36–7.44 (m, 6H, CPh 3,5-H, CH2Ph 2,3,5,6-H), 7.82–7.88 (m, 2H, CPh 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 50.3 (5-CH2), 51.3 (C-6), 55.9 (C-8), 69.3 (C-7), 105.9 (C-3), 125.1 (CPh C-2,6), 127.5 (CH2Ph C-4), 127.8 (CPh C-4), 128.1 (CH2Ph C-2,6), 128.6 (CH2Ph C-3,5), 128.7 (CPh C-3,5), 132.5 (CPh C-1), 137.5 (CH2Ph C-1), 139.0 (C-3a), 149.0 (C-2), 161.7 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −259.1 (N-5), −176.3 (N-9), −73.3 (N-1). HRMS (ESI) for C20H19N3NaO2 ([M+Na]+): calcd m/z 356.1369, found m/z 356.1370.
5-Benzyl-2-(4-fluorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4u
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 1/9, v/v). Pale yellow solid, mp 192–193 °C, procedure b −70% (301 mg). Rf = 0.52 (n-hexane/ethyl acetate 1.5/3.5, v/v). IR (KBr) νmax, cm−1: 3291, 3144, 2945, 1617 (C=O), 1470, 1442, 1230, 839, 701, 639. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.07 (dd, J = 14.9, 7.5 Hz, 1H, 6-Ha), 3.34–3.40 (m, 1H, 6-Hb), 4.11–4.26 (m, 2H, 7-H, 8-Ha), 4.43–4.55 (m, 2H, 5-CHa, 8-Hb), 4.96 (d, J = 14.7 Hz, 1H, 5-CHb), 5.50 (d, J = 4.0 Hz, 1H, OH), 7.20–7.41 (m, 8H, 3-H, CPh 3,5-H, CH2Ph 2,3,4,5,6-H), 7.85–7.93 (m, 2H, CPh 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 50.3 (5-CH2), 51.3 (C-6), 55.9 (C-8), 69.2 (C-7), 105.9 (C-3), 115.61 (d, 2JCF = 21.5 Hz, CPh C-3,5), 127.10 (d, 3JCF = 8.2 Hz, CPh C-2,6), 127.5 (CH2Ph C-4), 128.1 (CH2Ph C-2,6), 128.6 (CH2Ph C-3,5), 129.06 (d, 4JCF = 2.8 Hz, CPh C-1), 137.5 (CH2Ph C-1), 139.1 (C-3a), 148.2 (C-2), 161.6 (C-4), 161.84 (d, JCF = 244.3 Hz, CPh C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −259.9 (N-5), −175.3 (N-9), −74.4 (N-1). 19F NMR (376 MHz, DMSO-d6) δF ppm: −114.3 (CPh 6-F). HRMS (ESI) for C20H18FN3NaO2 ([M+Na]+): calcd m/z 374.1275, found m/z 374.1275.
5-Benzyl-2-(4-chlorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4v
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 7/2 to 1/9, v/v). White solid, mp 181–182 °C, procedure b −96% (419 mg). Rf = 0.57 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) νmax, cm−1: 3246, 2939, 1619 (C=O), 1455, 1434, 1091, 830 and 819 (doublet), 757, 699. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.08 (dd, J = 14.9, 7.5 Hz, 1H, 6-Ha), 3.37 (dd, J = 15.0, 5.0 Hz, 1H, 6-Hb), 4.11–4.27 (m, 2H, 7-H, 8-Ha), 4.43–4.57 (m, 2H, 5-CHa, 8-Hb), 4.96 (d, J = 14.7 Hz, 1H, 5-CHb), 5.51 (d, J = 3.6 Hz, 1H, OH), 7.28–7.41 (m, 6H, 3-H, CH2Ph 2,3,4,5,6-H), 7.44–7.50 (m, 2H, CPh 3,5-H), 7.84–7.91 (m, 2H, CPh 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 50.3 (5-CH2), 51.3 (C-6), 56.0 (C-8), 69.2 (C-7), 106.1 (C-3), 126.8 (CPh C-2,6), 127.5 (CH2Ph C-4), 128.1 (CH2Ph C-2,6), 128.6 (CH2Ph C-3,5), 128.8 (CPh C-3,5), 131.4 (CPh C-1), 132.3 (CPh C-4), 137.5 (CH2Ph C-1), 139.2 (C-3a), 147.9 (C-2), 161.6 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −259.6 (N-5), −174.8 (N-9), −73.4 (N-1). HRMS (ESI) for C20H18ClN3NaO2 ([M+Na]+): calcd m/z 390.0980, found m/z 390.0980.
5-Benzyl-2-(4-bromophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4w
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/9, v/v). Pale yellow solid, mp 157–158 °C, procedure b −72% (287 mg). Rf = 0.57 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) νmax, cm−1: 3270, 1619 (C=O), 1460, 1429, 1247, 1068, 1009, 816, 756, 701. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.08 (dd, J = 14.9, 7.6 Hz, 1H, 6-Ha), 3.34–3.41 (m, 1H, 6-Hb), 4.12–4.18 (m, 1H, 7-H), 4.20–4.27 (m, 1H, 8-Ha), 4.46 (d, J = 14.7 Hz, 1H, 5-CHa), 4.52 (dd, J = 14.4, 5.3 Hz, 1H, 8-Hb), 4.96 (d, J = 14.7 Hz, 1H, 5-CHb), 5.51 (d, J = 4.1 Hz, 1H, OH), 7.28–7.34 (m, 2H, 3-H, CH2Ph 4-H), 7.35–7.39 (m, 4H, CH2Ph 2,3,5,6-H), 7.56–7.64 (m, 2H, CPh 3,5-H), 7.78–7.85 (m, 2H, CPh 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 50.4 (5-CH2), 51.3 (C-6), 56.0 (C-8), 69.2 (C-7), 106.1 (C-3), 120.9 (CPh C-4), 127.1 (CPh C-2,6), 127.5 (CH2Ph C-4), 128.2 (CH2Ph C-3,5), 128.6 (CH2Ph C-2,6), 131.68 (CPh C-3,5), 131.72 (CPh C-1), 137.5 (CH2Ph C-1), 139.2 (C-3a), 148.0 (C-2), 161.6 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −259.5 (N-5), −174.5 (N-9), −73.7 (N-1). HRMS (ESI) for C20H18BrN3NaO2 ([M+Na]+): calcd m/z 434.0475, found m/z 434.0475 and 436.0445.
5-Benzyl-7-hydroxy-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4x
Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 3.5/1 to 1/9, v/v). White solid, mp 179–180 °C, procedure b −72% (313 mg). Rf = 0.46 (n-hexane/ethyl acetate 1.5/3.5, v/v). IR (KBr) νmax, cm−1: 3204, 1651 (C=O), 1462, 1436, 1250, 1180, 1029, 833, 753, 705. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.07 (dd, J = 14.9, 7.5 Hz, 1H, 6-Ha), 3.36–3.40 (m, 1H, 6-Hb), 3.78 (s, 3H, -OCH3), 4.11–4.24 (m, 2H, 7-H, 8-Ha), 4.42–4.53 (m, 2H, 5-CHa, 8-Hb), 4.96 (d, J = 14.7 Hz, 1H, 5-CHb), 5.50 (s, 1H, OH), 6.94–7.00 (m, 2H, CPh 3,5-H), 7.15 (s, 1H, 3-H), 7.28–7.34 (m, 1H, CH2Ph 4-H), 7.35–7.41 (m, 4H, CH2Ph 2,3,5,6-H), 7.74–7.81 (m, 2H, CPh 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 50.4 (5-CH2), 51.4 (C-6), 55.1 (OCH3), 55.8 (C-8), 69.3 (C-7), 105.3 (C-3), 114.1 (CPh C-3,5), 125.1 (CPh C-1), 126.4 (CPh C-2,6), 127.5 (CH2Ph C-4), 128.1 (CH2Ph C-2,6), 128.6 (CH2Ph C-3,5), 137.6 (CH2Ph C-1), 138.9 (C-3a), 149.0 (C-2), 159.0 (CPh C-4), 161.8 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −258.9 (N-5), −176.9 (N-9), −75.4 (N-1). HRMS (ESI) for C21H21N3NaO3 ([M+Na]+): calcd m/z 386.1475, found m/z 386.1475.
3.2.4. Synthesis of Ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylates (6a–e) and Ethyl 1-(oxiran-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylate (6f)
Procedure a. Indole-2-carboxylate 5a–e (1 eq) was dissolved in dry dimethyl formamide (0.2 M) and KOH (3 eq; flakes) was added followed by 2-(chloromethyl)oxirane (1.5 eq). The reaction mixture was stirred at 40 °C for 1 h under argon atmosphere. Upon completion, the mixture was concentrated to approximately 1/3 volume, diluted with ethyl acetate, and washed with brine. Organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.
Procedure b. Benzimidazole-2-carboxylate 5f (1 eq) was dissolved in dry dimethyl formamide (0.3 M) and NaH (1.5 eq; 60% dispersion in mineral oil) was added followed by 2-(chloromethyl)oxirane (1.5 eq). The reaction mixture was stirred at 60 °C for 4 h. Upon completion, the reaction mixture was cooled to 0 °C, quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.
Ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6a
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 47–49 °C, procedure a −73% (94 mg). Rf = 0.29 (n-hexane/ethyl acetate 6/1, v/v). IR (KBr) νmax, cm−1: 3064, 2974, 2928, 1713 (C=O), 1408, 1265, 1205, 1140, 1096, 744. 1H NMR (400 MHz, CDCl3) δH ppm: 1.41 (t, J = 7.1 Hz, 3H, CH3), 2.49–2.53 (m, 1H, Ox CHaHb), 2.77 (t, J = 4.2 Hz, 1H, Ox CHaHb), 3.33–3.39 (m, 1H, Ox CH), 4.38 (q, J = 7.1 Hz, 2H, CH2CH3), 4.56 (dd, J = 15.1, 5.0 Hz, 1H, NCHaHb), 5.03 (dd, J = 15.1, 2.4 Hz, 1H, NCHaHb), 7.14–7.18 (m, 1H, 5-H), 7.34–7.37 (m, 2H, 3-H, 6-H), 7.45–7.47 (m, 1H, 7-H), 7.66–7.68 (m, 1H, 4-H). 13C NMR (101 MHz, CDCl3) δC ppm: 14.5 (CH3), 45.5 (Ox CHaHb), 46.2 (NCHaHb), 51.6 (Ox CH), 60.8 (CH2CH3), 110.9 (C-7), 111.1 (C-3), 121.1 (C-5), 122.7 (C-4), 125.5 (C-6), 126.1 (C-3a), 127.7 (C-2), 140.0 (C-7a), 162.3 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –250.9 (N). HRMS (ESI) for C14H16NO3 ([M+H]+): calcd m/z 246.1125, found m/z 246.1119.
Ethyl 5-fluoro-1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6b
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 65–66 °C, procedure a −39% (50 mg). Rf = 0.19 (n-hexane/ethyl acetate 6/1, v/v). IR (KBr) νmax, cm−1: 2974, 2930, 1713 (C=O), 1527, 1266, 1246, 1177, 1091, 756. 1H NMR (400 MHz, CDCl3) δH ppm: 1.41 (t, J = 7.1 Hz, 3H, CH3), 2.45–2.53 (m, 1H, Ox CHaHb), 2.79 (t, J = 4.2 Hz, 1H, Ox CHaHb), 3.32–3.40 (m, 1H, Ox CH), 4.38 (q, J = 7.1 Hz, 2H, CH2CH3), 4.47 (dd, J = 15.2, 5.3 Hz, 1H, NCHaHb), 5.08 (dd, J = 15.2, 2.4 Hz, 1H, NCHaHb), 7.07–7.15 (m, 1H, 6-H), 7.24–7.33 (m, 2H, 3-H, 7-H), 7.38–7.45 (m, 1H, 4-H). 13C NMR (101 MHz, CDCl3) δH ppm: 14.5 (CH3), 45.3 (Ox CHaHb), 46.6 (NCHaHb), 51.7 (Ox CH), 61.0 (CH2CH3), 106.7 (d, J = 23.2 Hz, C-7), 110.7 (d, J = 5.1 Hz, C-3), 112.1 (d, J = 10.1 Hz, C-4), 114.6 (d, J = 27.3 Hz, C-6), 126.1 (d, J = 11.1 Hz, C-3a), 129.0 (C-2), 136.7 (C-7a), 158.4 (d, J = 238.4 Hz, C-5), 162.0 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –250.9 (N). 19F NMR (376 MHz, DMSO-d6) δF ppm: –127.7 (F). HRMS (ESI) for C14H15FNO3 ([M+H]+): calcd m/z 264.1030, found m/z 264.1031.
Ethyl 5-chloro-1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6c
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 79–80 °C, procedure a −69% (72 mg). Rf = 0.23 (n-hexane/ethyl acetate 6/1, v/v). IR (KBr) νmax, cm−1: 2984, 2928, 1703 (C=O), 1517, 1457, 1252, 1199, 763. 1H NMR (400 MHz, CDCl3) δH ppm: 1.42 (t, J = 7.1 Hz, 3H, CH3), 2.48 (dd, J = 4.4, 2.6 Hz, 1H, Ox CHaHb), 2.78 (t, J = 4.3 Hz, 1H, Ox CHaHb), 3.32–3.38 (m, 1H, Ox CH), 4.38 (q, J = 7.1 Hz, 2H, CH2CH3), 4.47 (dd, J = 15.2, 5.4 Hz, 1H, NCHaHb), 5.07 (dd, J = 15.2, 2.6 Hz, 1H, NCHaHb), 7.25–7.26 (m, 1H, 3-H), 7.28–7.30 (m, 1H, 6-H), 7.39–7.41 (m, 1H, 7-H), 7.62–7.63 (m, 1H, 4-H). 13C NMR (101 MHz, CDCl3) δC ppm: 14.5 (CH3), 45.3 (Ox CHaHb), 46.5 (NCHaHb), 51.6 (Ox CH), 61.1 (CH2CH3), 110.3 (C-3), 112.3 (C-7), 121.7 (C-4), 125.9 (C-6), 126.8 (C-5), 126.9 (C-3a), 128.8 (C-2), 138.3 (C-7a), 162.0 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –250.0 (N). HRMS (ESI) for C14H15ClNO3 ([M+H]+): calcd m/z 280.0735, found m/z 280.0733.
Ethyl 5-methyl-1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6d
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 72–74 °C, procedure a −75% (96 mg). Rf = 0.27 (n-hexane/ethyl acetate 6/1, v/v). IR (KBr) νmax, cm−1: 2976, 1706 (C=O), 1408, 1263, 1211, 1128, 1096, 763. 1H NMR (400 MHz, CDCl3) δH ppm: 1.41 (t, J = 7.1 Hz, 3H, CH2CH3), 2.44 (s, 3H, 5-CH3), 2.49 (dd, J = 4.4, 2.6 Hz, 1H, Ox CHaHb), 2.76 (t, J = 4.4 Hz, 1H, Ox CHaHb), 3.32–3.37 (m, 1H, Ox CH), 4.37 (q, J = 7.1 Hz, 2H, CH2CH3), 4.55 (dd, J = 15.1, 5.0 Hz, 1H, NCHaHb), 4.99 (dd, J = 15.1, 3.2 Hz, 1H, NCHaHb), 7.16–7.20 (m, 1H, 6-H), 7.22–7.27 (m, 1H, 3-H), 7.33–7.37 (m, 1H, 7-H), 7.42–7.48 (m, 1H, 4-H). 13C NMR (101 MHz, CDCl3) δH ppm: 14.5 (CH2CH3), 21.5 (5-CH3), 45.5 (Ox CHaHb), 46.2 (NCHaHb), 51.7 (Ox CH), 60.7 (CH2CH3), 110.59 (C-7), 110.62 (C-3), 121.9 (C-4), 126.3 (C-3a), 127.5 (C-6), 127.6 (C-2), 130.4 (C-5), 138.5 (C-7a), 162.3 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: –251.8 (N). HRMS (ESI) for C15H18NO3 ([M+H]+): calcd m/z 260.1281, found m/z 260.1277.
Ethyl 3-methyl-1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6e
Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 9/1 to 8/1, v/v). Colorless liquid, procedure a −47% (60 mg). Rf = 0.14 (petroleum ether/ethyl acetate 10/1, v/v). IR (KBr) νmax, cm−1: 1698 (C=O), 1273, 1250, 1208, 1129, 1111, 741. 1H NMR (500 MHz, CDCl3) δH ppm: 1.44 (t, J = 7.2 Hz, 3H, CH2CH3), 2.49 (dd, J = 4.9, 2.8 Hz, 1H, Ox CHaHb), 2.59 (s, 3H, 5-CH3), 2.74–2.77 (m, 1H, OxCHaHb), 3.33–3.37 (m, 1H, Ox CH), 4.42 (q, J = 7.1 Hz, 2H, CH2CH3), 4.50 (dd, J = 15.3, 5.2 Hz, 1H, NCHaHb), 4.94 (dd, J = 15.3, 3.4 Hz, NCHaHb), 7.13–7.17 (m, 1H, 5-H), 7.33–7.37 (m, 1H, 6-H), 7.39–7.43 (m, 1H, 7-H), 7.64–7.69 (m, 1H, 4-H). 13C NMR (125 MHz, CDCl3) δC ppm: 11.0 (3-CH3), 14.5 (CH2CH3),45.4 (Ox CHaHb), 46.4 (NCHaHb), 51.8 (Ox CH), 60.6 (CH2CH3), 110.6 (C-7), 120.2 (C-5), 120.8 (C-4), 121.5 (Cq), 124.6 (Cq), 125.7 (C-6), 127.4 (Cq), 139.1 (Cq), 163.2 (COO). 15N NMR (40 MHz, CDCl3) δN ppm: −254.7 (N). HRMS (ESI) for C15H18NO3 ([M+H]+): calcd m/z 260.1281, found m/z 260.1276.
Ethyl 1-(oxiran-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylate 6f
Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 1/1 to 2/3, v/v). White solid, mp 49–52 °C, procedure b −33% (86 mg). Rf = 0.37 (petroleum ether/ethyl acetate 1/1, v/v). IR (KBr) νmax, cm−1: 2360, 2341, 1709 (C=O), 1494, 1457, 1410, 1338, 1283, 1202, 1138, 743. 1H NMR (500 MHz, DMSO-d6) δH ppm: 1.34 (t, J = 7.2 Hz, 3H, CH3), 2.42–2.45 (m, 1H, Ox CHaHb), 2.72 (t, J = 4.4 Hz, OxCHaHb), 3.33–3.38 m, 1H, Ox CH), 4.37 (q, J = 7.1 Hz, 2H, CH2CH3), 4.58 (dd, J = 15.1, 8.7 Hz, 1H, NCHaHb), 5.03 (dd, J = 15.3, 3.1 Hz, NCHaHb), 7.29–7.34 (m, 1H, 5-H), 7.37–7.42 (m, 1H, 6-H), 7.69–7.72 (m, 1H, 7-H), 7.74–7.78 (m, 1H, 4-H). 13C NMR (125 MHz, DMSO-d6) δC ppm: 14.5 (CH3), 45.2 (Ox CHaHb), 46.8 (NCHaHb), 50.9 (Ox CH), 62.2 (CH2CH3), 112.5 (C-7), 121.4 (C-4), 124.0 (C-5), 125.7 (C-6), 136.8 (Cq), 141.5 (Cq), 141.6 (Cq), 160.1 (COO). 15N NMR (40 MHz, DMSO-d6) δN ppm: −229.8 (N). HRMS (ESI) for C13H14N2O3 ([M+H]+): calcd m/z 247.1077, found m/z 247.1071.
3.2.5. Synthesis of 4-Hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-ones (7a–f) and 4-Hydroxy-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one (7g)
Procedure a. Ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6a–e or ethyl 1-(oxiran-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylate 6f (1 eq) was dissolved in 7M ammonia (100 eq) solution in methanol, sealed in a pressure tube and stirred at 70 °C for 18 h. After completion, the reaction mixture was cooled to 0 °C, quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.
Procedure b. To a solution of ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 7a (1eq) in methanol (5 M) benzylamine (3 eq) was added, the reaction mixture was sealed in a pressure tube and stirred at 70 °C for 18 h. After completion, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.
4-Hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7a
Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 216 °C, procedure a −93% (82 mg). Rf = 0.45 (dichloromethane/methanol 9/1, v/v). IR (KBr) νmax, cm−1: 3318, 3194, 3049, 2895, 1660 (C=O), 1643 (C=O), 1549, 1461, 1407, 740. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.83 (dt, J = 12.0, 5.6 Hz, 1H, 3-Ha), 3.21 (dt, J = 11.3, 5.4 Hz, 1H, 3-Hb), 4.18–4.28 (m, 2H, 5-Ha, 4-H), 4.42 (dd, J = 13.9, 4.1 Hz, 1H, 5-Hb), 5.37 (d, J = 3.8 Hz, 1H, OH), 6.93 (s, 1H, 11-H), 7.06–7.10 (m, 1H, 9-H), 7.25–7.29 (m, 1H, 8-H), 7.55–7.57 (m, 1H, 7-H), 7.62–7.64 (m, 1H, 10-H), 8.08–8.10 (m, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.6 (C-3), 48.2 (C-5), 69.5 (C-4), 105.3 (C-11), 110.5 (C-7), 119.9 (C-9), 121.6 (C-10), 123.5 (C-8), 126.0 (C-10a), 134.7 (C-11a), 137.5 (C-6a), 165.5 (C-1). 15N NMR (40 MHz, DMSO-d6) δN ppm: –272.6 (N-2), –249.8 (N-6). HRMS (ESI) for C12H13N2O2 ([M+H]+): calcd m/z 217.0972, found m/z 217.0969.
9-Fluoro-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7b
Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 220 °C, procedure a −63% (56 mg). Rf = 0.55 (dichloromethane/methanol 9/1, v/v). IR (KBr) νmax, cm−1: 3335, 3283, 3200, 3047, 1647 (C=O), 1548, 1408, 1203, 796. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.78–2.87 (m, 1H, 3-Ha), 3.16–3.26 (m, 1H, 3-Hb), 4.16–4.30 (m, 2H, 5-Ha, 4-H), 4.43 (dd, J = 14.0, 4.2 Hz, 1H, 5-Hb), 5.38 (d, J = 4.0 Hz, 1H, OH), 6.91 (s, 1H, 11-H), 7.08–7.19 (m, 1H, 8-H), 7.36–7.43 (m, 1H, 10-H), 7.56–7.63 (m, 1H, 7-H), 8.12–8.20 (m, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.6 (C-3), 48.5 (C-5), 69.5 (C-4), 105.0 (d, 4JCF = 5.1 Hz, C-11), 105.8 (d, 2JCF = 23.3 Hz, C-10), 111.9 (d, 3JCF = 9.8 Hz, C-7), 112.1 (d, 2JCF = 26.6 Hz, C-8), 126.1 (d, 3JCF = 10.6 Hz, C-10a), 134.2 (C-6a), 136.3 (C-11a), 157.2 (d, JCF = 233.1 Hz, C-9), 165.2 (C-1). 15N NMR (40 MHz, DMSO-d6) δN ppm: –271.8 (N-2), –250.1 (N-6). HRMS (ESI) for C12H12FN2O2 ([M+H]+): calcd m/z 235.0877, found m/z 235.0876.
9-Chloro-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7c
Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 210 °C, procedure a −84% (75 mg). Rf = 0.52 (dichloromethane/methanol 9/1, v/v). IR (KBr) νmax, cm−1: 3325, 3275, 3191, 3046, 1660 (C=O), 1643 (C=O), 1545, 1408, 797. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.86–2.75 (m, 1H, 3-Ha), 3.27–3.14 (m, 1H, 3-Hb), 4.29–4.16 (m, 2H, 4-H, 5-Ha), 4.43 (dd, J = 13.8, 3.9 Hz, 1H, 5-Hb), 5.39 (d, J = 3.8 Hz, 1H, OH), 6.91 (s, 1H, 11-H), 7.24–7.31 (m, 1H, 8-H), 7.57–7.65 (m, 1H, 7-H), 7.68–7.73 (m, 1H, 10-H), 8.14–8.22 (m, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 45.5 (C-3), 48.5 (C-5), 69.4 (C-4), 104.7 (C-11), 112.3 (7-C), 120.6 (C-10), 123.5 (C-8), 124.4 (C-9), 127.0 (C-10a), 135.9 (C-6a), 136.1 (C-11a), 165.1 (C-1). 15N NMR (40 MHz, DMSO-d6) δN ppm: –271.5 (N-2), –248.7 (N-6). HRMS (ESI) for C12H12ClN2O2 ([M+H]+): calcd m/z 251.0582, found m/z 251.0580.
4-Hydroxy-9-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7d
Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 225 °C, procedure a −86% (76 mg). Rf = 0.66 (dichloromethane/methanol 9/1, v/v). IR (KBr) νmax, cm−1: 3319, 3194, 3046, 1659 (C=O), 1640 (C=O), 1552, 1463, 1407, 790. 1H NMR (400 MHz, DMSO-d6) δH ppm: 2.38 (s, 3H, CH3), 2.78–2.87 (m, 1H, 3-Ha), 3.15–3.24 (m, 1H, 3-Hb), 4.16 (dd, J = 14.3, 4.3 Hz, 1H, 5-Ha), 4.20–4.27 (m, 1H, 4-H), 4.38 (dd, J = 14.2, 4.7 Hz, 1H, 5-Hb), 5.35 (d, J = 4.1 Hz, 1H, OH), 6.83 (s, 1H, 11-H), 7.06–7.14 (m, 1H, 8-H), 7.37–7.42 (m, 1H, 10-H), 7.41–7.47 (m, 1H, 7-H), 8.02–8.09 (m, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δC ppm: 21.0 (CH3), 45.7 (C-3), 48.3 (C-5), 69.6 (C-4), 104.8 (C-11), 110.2 (C-7), 120.9 (C-10), 125.3 (C-8), 126.2 (C-9), 128.5 (C-10a), 134.6 (C-11a), 136.0 (C-6a), 165.6 (C-1). 15N NMR (40 MHz, DMSO-d6) δN ppm: –273.1 (N-2), –250.9 (N-6). 19F NMR (376 MHz, DMSO-d6) δF ppm: –123.9 (F). HRMS (ESI) for C13H15N2O2 ([M+H]+): calcd m/z 231.1128, found m/z 231.1124.
4-Hydroxy-11-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7e
Purified by column chromatography on silica gel (petroleum ether/ethyl acetate/methanol gradient from 1/3/0 to 5/20/1, v/v/v). White solid, decomp. 218 °C, procedure a −66% (66 mg). Rf = 0.42 (ethyl acetate/methanol 10/1, v/v). IR (KBr) νmax, cm−1: 3308, 1631 (C=O), 1556, 1461, 1418, 1383, 1362, 1341, 1329, 1259, 1066, 733. 1H NMR (500 MHz, DMSO-d6) δH ppm: 2.36 (s, 3H, CH3), 2.76 (dt, J = 14.4, 6.0 Hz, 1H, 3-Ha), 3.13 (dt, J = 14.4, 5.8 Hz, 1H, 3-Hb), 4.10 (dd, J = 14.2, 4.4 Hz, 1H, 5-Ha), 4.12–4.19 (m, 1H, 4-H), 4.32 (dd, J = 14.4, 4.9 Hz, 1H, 5-Hb), 5.30 (d, J = 4.0 Hz, 1H, OH), 7.02–7.10 (m, 1H, 9-H), 7.22–7.29 (m, 1H, 8-H), 7.47–7.52 (m, 1H, 7-H), 7.57–7.62 (m, 1H, 10-H), 7.97–8.02 (m, 1H, NH). 13C NMR (125 MHz, DMSO-d6) δC ppm: 9.6 (CH3), 46.1 (C-3), 48.6 (C-5), 69.4 (C-4), 110.6 (C-7), 115.5 (Cq), 119.6 (C-9), 120.3 (C-10), 124.3 (C-8), 127.4 (Cq), 130.3 (Cq), 137.0 (Cq), 166.3 (C-1). 15N NMR (40 MHz, DMSO-d6) δN ppm: −271.4 (N-2), −254.4 (N-6). HRMS (ESI) for C13H15N2O2 ([M+H]+): calcd m/z 231.1128, found m/z 231.1126.
2-Benzyl-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7f
Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 7/1 to 1/6, v/v). White solid, mp 183–184 °C, procedure b −87% (142.1 mg). Rf = 0.53 (petroleum ether/ethyl acetate 3/1, v/v). IR (KBr) νmax, cm−1: 3313 (OH), 2360, 2341, 1610 (C=O), 1541, 1421, 1079, 740. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.01 (dd, J = 14.8, 7.4 Hz, 1H, 3-Ha), 3.31 (dd, J = 14.8, 5.2 Hz, 1H, 3-Hb), 4.06–4.14 (m, 1H, 4-H), 4.23 (dd, J = 14.6, 3.8 Hz, 1H, 5-Ha), 4.38 (dd, J = 14.6, 4.9 Hz, 1H, 5-Hb), 4.46 (d, J = 14.6 Hz, 1H, 2-CHa), 5.00 (d, J = 14.6 Hz, 1H, 2-CHb), 5.40 (d, J = 4.0 Hz, 1H, OH), 6.99–7.01 (m, 1H, 11-H), 7.05–7.11 (m, 1H, 9-H), 7.23–7.35 (m, 2H, 8-H, CH2Ph 4-H), 7.36–7.41 (m, 4H, CH2Ph 2,3,5,6-H), 7.50–7.57 (m, 1H, 7-H), 7.61–7.67 (m, 1H, 10-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 48.1 (C-5), 50.4 (CH2Ph), 51.4 (C-3), 69.1 (C-4), 105.5 (C-11), 110.4 (C-7), 120.0 (C-9), 121.6 (C-10), 123.6 (C-8), 126.0 (C-10a), 127.4 (CH2Ph C-4), 128.2 (CH2Ph C-3,5), 128.7 (CH2Ph C-2,6), 134.3 (C-11a), 137.3 (C-6a), 137.9 (CH2Ph C-1), 163.9 (C-1). 15N NMR (40 MHz, DMSO-d6) δN ppm: –255.0 (N-6), -265.7 (N-2). HRMS (ESI) for C19H19N2O2 ([M+H]+): calcd m/z 307.1441, found m/z 307.1388.
4-Hydroxy-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one 7g
Purified by column chromatography on silica gel (petroleum ether/ethyl acetate/methanol gradient from 1/5/0 to 1/12/1, v/v/v). White solid, decomp. 190 °C, procedure a −19% (18 mg). Rf = 0.21 (ethyl acetate/methanol 9/1, v/v). IR (KBr) νmax, cm−1: 3379, 3220, 1676 (C=O), 1522, 1466, 1458, 1418, 1336, 1079, 741. 1H NMR (500 MHz, DMSO-d6) δH ppm: 2.75 (dt, J = 15.0 Hz, 6.1 Hz, 1H, 3-Ha), 3.21 (dt, J = 14.7 Hz, 5.8 Hz, 1H, 3-Hb), 4.22–4.31 (m, 2H, 5-Ha, 4-H), 4.49 (dd, J = 14.1 Hz, 4.3 Hz, 1H, 5-Hb), 5.35–5.55 (br s, 1H, OH), 7.23–7.28 (m, 1H, 9-H), 7.31–7.37 (m, 1H, 8-H), 7.63–7.73 (m, 2H, 7-H, 10-H), 8.56–8.63 (m, 1H, NH). 13C NMR (125 MHz, DMSO-d6) δC ppm: 45.4 (C-3), 48.2 (C-5), 69.9 (C-4), 111.5 (C-7), 120.7 (C-10), 123.1 (C-9), 124.6 (C-8), 135.2 (Cq), 142.0 (Cq), 147.4 (Cq), 163.2 (C-1). HRMS (ESI) for C11H12N3O2 ([M+H]+): calcd m/z 218.0924, found m/z 218.0918.
3.2.6. Synthesis of O-Alkylated 5-Substituted 7-Hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones (8a–f) and 2-Benzyl-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (9a,b)
Pyrazolo-diazepinone 4i,n,t or indole-diazepinone 7f (1 eq) was dissolved in dimethyl formamide (0.1 M) and NaH (1.5 eq; 60% dispersion in mineral oil) was added followed by appropriate alkylating agent (1.5 eq). The reaction mixture was stirred at 25–50 °C for 5–8 h. Upon completion, the mixture was concentrated to approximately 1/3 volume, diluted with ethyl acetate, and washed with brine. Organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.
7-Methoxy-5-(2-methoxyethyl)-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8a
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/1, v/v). White solid, mp 88–89 °C, 77% (104 mg). Rf = 0.41 (n-hexane/ethyl acetate 1/4, v/v). IR (KBr) νmax, cm−1: 3120, 2933, 2890, 2828, 1638 (C=O), 1470, 1354, 1016, 771, 700. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.23 (dd, J = 15.2, 7.6 Hz, 1H, 5-CHa), 3.29 (s, 3H, CH2OCH3), 3.37 (s, 3H, 7-OCH3), 3.39–3.47 (m, 1H, 6-Ha), 3.51–3.62 (m, 3H, 5-CHb, CH2O), 3.90 (dt, J = 13.6, 5.2 Hz, 1H, 6-Hb), 4.05–4.12 (m, 1H, 7-H), 4.46 (qd, J = 14.7, 4.3 Hz, 2H, 8-HaHb), 7.18 (s, 1H, 3-H), 7.29–7.35 (m, 1H, Ph 4-H), 7.38–7.45 (m, 2H, Ph 3,5-H), 7.8 –7.87 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 46.6 (C-6), 50.0 (5-CH2), 52.1 (C-8), 56.3 (7-OCH3), 58.0 (CH2OCH3), 69.8 (CH2O), 79.2 (C-7), 105.5 (C-3), 125.2 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.4 (Ph C-1), 139.3 (C-3a), 149.1 (C-2), 161.6 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −266.0 (N-5), −176.2 (N-9), −74.1 (N-1). HRMS (ESI) for C17H21N3NaO3 ([M+Na]+): calcd m/z 338.1475, found m/z 338.1475.
5-Allyl-7-methoxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8b
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 3.5/1, v/v). White solid, mp 89–90 °C, 84% (78 mg). Rf = 0.47 (n-hexane/ethyl acetate 1/1, v/v). IR (KBr) νmax, cm−1: 2984, 2929, 2826, 1657 (C=O), 1461, 1243, 1206, 1089, 770, 697. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.19 (dd, J = 15.2, 6.9 Hz, 1H, 6-Ha), 3.36 (s, 3H, CH3), 3.46 (dd, J = 15.2, 5.0 Hz, 1H, 6-Hb), 3.97 (dd, J = 15.1, 6.2 Hz, 1H, 5-CHa), 4.09 (dt, J = 10.4, 5.1 Hz, 1H, 7-H), 4.23 (dd, J = 15.1, 5.5 Hz, 1H, 5-CHb), 4.40 (dd, J = 14.7, 4.0 Hz, 1H, 8-Ha), 4.58 (dd, J = 14.7, 5.4 Hz, 1H, 8-Hb), 5.18–5.31 (m, 2H, CH2-CH=CH2), 5.81–5.92 (m, 1H, CH2-CH=CH2), 7.20 (s, 1H, 3-H), 7.29–7.36 (m, 1H, Ph 4-H), 7.37–7.45 (m, 2H, Ph 3,5-H), 7.81–7.88 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 48.4 (C-6), 49.6 (5-CH2), 52.3 (C-8), 56.3 (CH3), 78.9 (C-7), 105.8 (C-3), 117.9 (CH2-CH=CH2), 125.1 (Ph C-2,6), 127.9 (Ph C-4), 128.7 (Ph C-3,5), 132.4 (Ph C-1), 133.4 (CH2-CH=CH2), 139.1 (C-3a), 149.1 (C-2), 161.3 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −176.0 (N-9), −73.9 (N-1). HRMS (ESI) for C17H19N3NaO2 ([M+Na]+): calcd m/z 320.1369, found m/z 320.1370.
5-Benzyl-7-methoxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8c
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 7/2, v/v). Pale yellow solid, mp 176–177 °C, 70% (57 mg). Rf = 0.41 (n-hexane/ethyl acetate 3/2, v/v). IR (KBr) νmax, cm−1: 3146, 2988, 2928, 2871, 1651 (C=O), 1449, 1241, 1101, 764, 695. 1H NMR (400 MHz, DMSO-d6) δH ppm: 3.19 (dd, J = 15.2, 7.1 Hz, 1H, 6-Ha), 3.28 (s, 3H, CH3), 3.48 (dd, J = 15.2, 5.0 Hz, 1H, 6-Hb), 3.86–3.93 (m, 1H, 7-H), 4.42 (dd, J = 14.8, 3.8 Hz, 1H, 8-Ha), 4.48–4.59 (m, 2H, 8-Hb, 5-CHa), 4.88 (d, J = 14.7 Hz, 1H, 5-CHb), 7.26 (s, 1H, 3-H), 7.30–7.35 (m, 2H, CPh 4-H, CH2Ph 4-H), 7.36–7.44 (m, 6H, CPh 3,5-H, CH2Ph 2,3,5,6-H), 7.82–7.87 (m, 2H, CPh 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 48.6 (C-6), 50.4 (5-CH2), 52.3 (C-8), 56.3 (CH3), 78.8 (C-7), 106.0 (C-3), 125.1 (CPh C-2,6), 127.5 (CH2Ph C-4), 127.9 (CPh C-4), 128.1 (CH2Ph C-2,6), 128.6 (CH2Ph C-3,5), 128.7 (CPh C-3,5), 132.4 (CPh C-1), 137.4 (CH2Ph C-1), 139.0 (C-3a), 149.2 (C-2), 161.7 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −261.2 (N-5), −176.7 (N-9), −74.1 (N-1). HRMS (ESI) for C21H21N3NaO2 ([M+Na]+): calcd m/z 370.1526, found m/z 370.1526.
7-Ethoxy-5-(2-methoxyethyl)-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8d
Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol 1/1/0.05, v/v). Yellowish resin, 75% (118 mg). Rf = 0.54 (n-hexane/ethyl acetate 1/4, v/v). IR (KBr) νmax, cm−1: 2977, 2931, 2893, 1647 (C=O), 1461, 1440, 1104, 1077, 769, 695. 1H NMR (400 MHz, DMSO-d6) δH ppm: 1.14 (t, J = 7.0 Hz, 3H, 7-OCH2CH3), 3.24 (dd, J = 15.3, 7.4 Hz, 1H, 5-CHa), 3.29 (s, 3H, CH2OCH3), 3.41–3.49 (m, 1H, 6-Ha), 3.51–3.68 (m, 5H, 5-CHb, CH2OCH3, 7-OCH2), 3.88 (dt, J = 13.5, 5.0 Hz, 1H, 6-Hb), 4.15–4.22 (m, 1H, 7-H), 4.44 (ddd, J = 18.2, 14.6, 4.4 Hz, 2H, 8-HaHb), 7.18 (s, 1H, 3-H), 7.29–7.36 (m, 1H, Ph 4-H), 7.38–7.45 (m, 2H, Ph 3,5-H), 7.81–7.87 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 15.3 (7-OCH2CH3), 46.6 (C-6), 50.4 (5-CH2), 52.7 (C-8), 58.0 (CH2OCH3), 63.9 (7-OCH2), 69.8 (CH2OCH3), 77.4 (C-7), 105.5 (C-3), 125.1 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.4 (Ph C-1), 139.3 (C-3a), 149.1 (C-2), 161.5 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −265.2 (N-5), −175.8 (N-9), −74.2 (N-1). HRMS (ESI) for C18H23N3NaO3 ([M+Na]+): calcd m/z 352.1632, found m/z 352.1632.
5-Allyl-7-ethoxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8e
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 7/2, v/v). Pale yellow solid, mp 113–144 °C, 77% (116 mg). Rf = 0.59 (n-hexane/ethyl acetate 1/1, v/v). IR (KBr) νmax, cm−1: 3118, 2980, 1645 (C=O), 1460, 1438, 1396, 1248, 1101, 770, 696. 1H NMR (400 MHz, DMSO-d6) δH ppm: 1.13 (t, J = 6.9 Hz, 3H, CH3), 3.20 (dd, J = 15.1, 6.8 Hz, 1H, 6-Ha), 3.44 (dd, J = 15.1, 4.7 Hz, 1H, 6-Hb), 3.50–3.65 (m, 2H, OCH2), 3.98 (dd, J = 15.1, 6.0 Hz, 1H, 5-CHa), 4.15–4.27 (m, 2H, 5-CHb, 7-H), 4.37 (dd, J = 14.6, 3.8 Hz, 1H, 8-Ha), 4.58 (dd, J = 14.6, 5.4 Hz, 1H, 8-Hb), 5.18–5.31 (m, 2H, CH2-CH=CH2), 5.81–5.93 (m, 1H, CH2-CH=CH2), 7.20 (s, 1H, 3-H), 7.29–7.36 (m, 1H, Ph 4-H), 7.38–7.45 (m, 2H, Ph 3,5-H), 7.81–7.87 (m, 2H, Ph 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 15.3 (CH3), 48.8 (C-6), 49.6 (5-CH2), 52.9 (C-8), 63.9 (OCH2), 77.1 (C-7), 105.8 (C-3), 117.8 (CH2-CH=CH2), 125.1 (Ph C-2,6), 127.9 (Ph C-4), 128.7 (Ph C-3,5), 132.4 (Ph C-1), 133.4 (CH2-CH=CH2), 139.1 (C-3a), 149.1 (C-2), 161.3 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −265.6 (N-5), −176.4 (N-9), −73.9 (N-1). HRMS (ESI) for C18H21N3NaO2 ([M+Na]+): calcd m/z 334.1526, found m/z 334.1526.
5-Benzyl-7-ethoxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8f
Purified by column chromatography on silica gel (n-hexane/ethyl acetate 3.5/1, v/v). Pale yellow solid, mp 115–116 °C, 72% (92 mg). Rf = 0.55 (n-hexane/ethyl acetate 3/2, v/v). IR (KBr) νmax, cm−1: 3121, 2982, 2871, 1658 (C=O), 1460 and 1440 (doublet), 1239, 1105, 771, 693. 1H NMR (400 MHz, DMSO-d6) δH ppm: 1.06 (t, J = 7.0 Hz, 3H, CH3), 3.20 (dd, J = 15.2, 7.1 Hz, 1H, 6-Ha), 3.39–3.58 (m, 3H, 6-Hb, OCH2), 3.95–4.02 (m, 1H, 7-H), 4.38 (dd, J = 14.7, 3.8 Hz, 1H, 8-Ha), 4.48–4.59 (m, 2H, 8-Hb, 5-CHa), 4.88 (d, J = 14.7 Hz, 1H, 5-CHb), 7.26 (s, 1H, 3-H), 7.29–7.35 (m, 2H, CPh 4-H, CH2Ph 4-H), 7.36–7.44 (m, 6H, CPh 3,5-H, CH2Ph 2,3,5,6-H), 7.81–7.88 (m, 2H, CPh 2,6-H). 13C NMR (101 MHz, DMSO-d6) δC ppm: 15.2 (CH3), 49.0 (C-6), 50.4 (5-CH2), 52.9 (C-8), 63.8 (OCH2), 77.0 (C-7), 106.0 (C-3), 125.1 (CPh C-2,6), 127.4 (CH2Ph C-4), 127.9 (CPh C-4), 128.1 (CH2Ph C-2,6), 128.6 (CH2Ph C-3,5), 128.7 (CPh C-3,5), 132.4 (CPh C-1), 137.4 (CH2Ph C-1), 149.2 (C-2), 161.7 (C-4). 15N NMR (40 MHz, DMSO-d6) δN ppm: −261.6 (N-5), −176.1 (N-9), −73.5 (N-1). HRMS (ESI) for C22H23N3NaO2 ([M+Na]+): calcd m/z 384.1682, found m/z 384.1682.
2-Benzyl-4-methoxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 9a
Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 5/1 to 2/1, v/v). White solid, mp 97–98 °C, 92% (50 mg). Rf = 0.63 (petroleum ether/ethyl acetate 2/1, v/v). IR (KBr) νmax, cm−1: 1642 (C=O), 1541, 1457, 1421, 1099, 741. 1H NMR (400 MHz, CDCl3) δH ppm: 3.31–3.37 (m, 5H, CH3, 3-HaHb), 3.68 (p, J = 5.2 Hz, 1H, 4-H), 4.27 (dd, J = 14.7, 5.2 Hz, 1H, 5-Ha), 4.33–4.41 (m, 2H, 2-CHa, 5-Hb), 5.26 (d, J = 14.6 Hz, 1H, 2-CHb), 7.11–7.16 (m, 1H, 9-H), 7.19 (s, 1H, 11-H), 7.28–7.41 (m, 7H, 7-H, 8-H, CH2Ph 2,3,4,5,6-H), 7.66–7.71 (m, 1H, 10-H). 13C NMR (101 MHz, CDCl3) δC ppm: 45.1 (C-5), 48.5 (C-3), 51.5 (2-CH2), 57.0 (CH3), 79.7 (C-4), 107.5 (C-11), 109.4 (C-7), 120.5 (C-9), 122.5 (C-10), 124.4 (C-8), 126.9 (C-10a), 127.9 (CH2Ph C-4), 128.7 (CH2Ph C-3,5), 128.9 (CH2Ph C-2,6), 134.0 (C-11a), 137.4 (C-6a), 137.6 (CH2Ph C-1), 165.0 (C=O). 15N NMR (40 MHz, CDCl3): δN ppm: −259.5 (N-6), −267.8 (N-2). HRMS (ESI) for C20H21N2O2 ([M+H]+): calcd m/z 321.1598, found m/z 321.1596.
2-Benzyl-4-ethoxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 9b
Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 5/1 to 4/1, v/v). Colorless resin, 73% (45 mg). Rf = 0.57 (petroleum ether/ethyl acetate 2/1, v/v). IR (KBr) νmax, cm−1: 2360, 2341, 1641 (C=O), 1540, 1417, 1100, 741. 1H NMR (400 MHz, CDCl3) δH ppm: 1.14–1.20 (m, 3H, CH3), 3.29–3.35 (m, 2H, 3-HaHb), 3.43–3.59 (m, 2H, OCH2), 3.73– 3.81 (m, 1H, 4-H), 4.23–4.31 (m, 1H, 5-Ha), 4.33–4.42 (m, 2H, 2-CHa, 5-Hb), 5.22–5.30 (m, 1H, 2-CHb), 7.10–7.21 (m, 2H, 9-H, 11-H), 7.27–7.41 (m, 7H, 7-H, 8-H, CH2Ph 2,3,4,5,6-H), 7.66–7.72 (m, 1H, 10-H). 13C NMR (101 MHz, CDCl3) δC ppm: 15.5 (CH3). 45.5 (C-5), 49.0 (C-3), 51.5 (2-CH2), 64.8 (OCH2), 77.9 (C-4), 107.4 (C-11), 109.4 (C-7), 120.4 (C-9), 122.5 (C-10), 124.3 (C-8), 126.9 (C-10a), 127.90 (CH2Ph C-4), 128.7 (CH2Ph C-3,5), 128.9 (CH2Ph C-2,6), 134.1 (C-11a), 137.5 (C-6a), 137.6 (CH2Ph C-1), 165.1 (C-1). 15N NMR (40 MHz, CDCl3): δN ppm: −259.8 (N-6), −268.6 (N-2). HRMS (ESI) for C21H23N2O2 ([M+H]+): calcd m/z 335,1781, found m/z 335.1798.