3.2. General Procedure for the Preparation of Dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3′′-indole] 3a–e and 4a–e
Dipolarophile 1a–d (0.5 mmol), paraformaldehyde (0.060 g, 2.0 mmol) and N-alkylglycine 1a,b (2.0 mmol) were charged in a flask and acetonitrile (40 mL) was added. The resulting suspension was refluxed with stirring for 10–14 h until the red color disappeared. The solvent was then removed under reduced pressure to afford a solid product. This solid was dissolved in isopropyl alcohol (10 mL) and separated via column chromatography using isopropyl alcohol as eluent. Anti-diastereomers 3a–e have a retention factor Rf = 0.20–0.39, syn-diastereomers 4a–e have a retention factor Rf = 0.43–0.60.
(3aR*,4′R*,6S*,9aS*)-1,1′,1″,3-Tetramethyl-3,3a,9,9a-tetrahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2,2″,7(1H)-trione (3a). Yield 95 mg (43%); Rf = 0.21; white solid; mp: 280–282 °C. IR (KBr): ν 3414 (NH), 3065, 3055 (ArH), 2936, 2861 (Alk), 1700, 1653, 1644, 1611 (C=O, C=N) cm−1. 1H NMR (500 MHz, DMSO-d6): δ 2.45 (s, 3H, NCH3), 2.49 (s, 3H, 1′-NCH3), 2.59 (s, 3H, NCH3), 3.11 (d, J = 10.2 Hz, 1H, CH2), 3.14 (s, 3H, 1′′-NCH3), 3.40 (d, J = 10.2 Hz, 1H, CH2), 3.48 (d, J = 9.9 Hz, 1H, CH2), 3.74 (d, J = 10.5 Hz, 1H, CH2), 4.56–4.60 (m, 2H, 3a-H, 9a-H), 6.75 (d, J = 1.8 Hz, 1H, 9-NH), 6.98–7.03 (m, 2H, 5′′-H, 7′′-H), 7.09 (d, J = 7.2 Hz, 1H, 4′′-H), 7.34 (t, J = 6.9 Hz, 1H, 6′′-H). 13C NMR (75 MHz, DMSO-d6): δ 26.07, 26.64, 27.54 (1,1′′,3-NCH3), 42.03 (1′-NCH3), 60.04, 60.20 (C-3′, C-3′′), 61.89, 63.96 (C-2′, C-5′), 64.73, 65.54 (C-3a, C-9a), 109.12 (C-7′′), 122.54, 123.14, 123.88, 129.54 (C-3a′′, C-4′′, C-5′′, C-6′′), 144.41 (C-7a′′), 148.60 (4a-C=N), 158.26 (2-C=O), 168.50 (7-C=O), 176.12 (2′′-C=O). HRMS (ESI): Calculated for C20H23N7O3S [M + H]+: 442.1647, Found: 442.1656.
(3aR*,4′R*,6S*,9aS*)-1,3-Diethyl-1′,1″-dimethyl-3,3a,9,9a-tetrahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2,2″,7(1H)-trione (3b). Yield 73 mg (31%); Rf = 0.24; white solid; mp: 252–254 °C. IR (KBr): ν 3245, 3163 (NH), 3063, 3015 (ArH), 2967, 2873, 2876 (Alk), 1756, 1676, 1682, 1635 (C=O, C=N) cm−1. 1H NMR (500 MHz, DMSO-d6): δ 0.88 (t, J = 6.9 Hz, 3H, CH3), 1.01 (t, J = 7.2 Hz, 3H, CH3), 2.48 (s, 3H, 1′-NCH3), 2.85–2.99 (m, 3H, NCH2), 3.10 (d, J = 10.2 Hz, CH2), 3.13 (s, 3H, 1′′-NCH3), 3.16–3.23 (m, 1H, NCH2), 3.41 (d, J = 10.5 Hz, 1H, CH2), 3.50 (d, J = 10.1 Hz, 1H, CH2), 3.73 (d, J = 10.4 Hz, 1H, CH2), 4.68 (d, J = 5.8 Hz, 1H, 3a-H), 4.72 (d, J = 5.6 Hz, 1H, 9a-H), 6.73 (s, 1H, 9-NH), 6.96–7.02 (m, 2H, 5′′-H, 7′′-H), 7.13 (d, J = 7.4 Hz, 1H, 4′′-H), 7.33 (t, J = 7.7 Hz, 1H, 6′′-H). 13C NMR (150 MHz, DMSO-d6): δ 13.43, 14.45 (2CH3), 27.28 (1′′-NCH3), 35.00, 35.85 (1,3-NCH2), 43.24 (1′-NCH3), 60.98, 61.56 (C-3′, C-3′′), 63.37 (C-2′, C-5′), 64.39, 65.88 (C-3a, C-9a), 110.28 (C-7′′), 123.89, 124.58, 125.58, 130.69 (C-3a′′, C-4′′, C-5′′, C-6′′), 145.62 (4a-C=N), 149.93 (C-7a′′), 158.58 (2-C=O), 169.61 (7-C=O), 177.43 (2′′-C=O). HRMS (ESI): Calculated for C22H27N7O3S [M + H]+: 470.1974, Found: 470.1969.
(3aR*,4′S*,6R*,9aR*)-1,1′,1″,3-Tetramethyl-2-thioxo-1,2,3,3a,9,9a-hexahydro-7H-dispro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2″,7-dione (3c). Yield 80 mg (35%); Rf = 0.20; white solid; mp: 228–230 °C. IR (KBr): ν 3513 (NH), 3024 (ArH), 2966, 2927, 2849 (Alk), 1733, 1708, 1633, 1615 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 2.47 (s, 3H, 1′-NCH3), 2.89 (s, 3H, NCH3), 2.99 (s, 3H, NCH3), 3.10–3.14 (m, 4H, 1′′-NCH3, CH2), 3.37 (d, J = 10.8 Hz, 1H, CH2), 3.46 (d, J = 9.9 Hz, 1H, CH2), 3.70 (d, J = 10.5 Hz, 1H, CH2), 4.82–4.89 (m, 2H, 3a-H, 9a-H), 7.03–7.07 (m, 3H, 5′′-H, 7′′-H, 9-NH), 7.17 (d, J = 7.5 Hz, 1H, 4′′-H), 7.37 (t, J = 7.5 Hz, 1H, 6′′-H). 13C NMR (75 MHz, DMSO-d6): δ 26.07 (1′′-NCH3), 30.80, 31.05 (1,3-NCH3), 41.92 (1′-NCH3), 60.23, 60.43 (C-3′, C-3′′), 61.60, 63.02 (C-2′, C-5′), 66.79, 67.84 (C-3a, C-9a), 108.96 (C-7′′), 122.98, 123.11, 124.27, 129.65 (C-3a′′, C-4′′, C-5′′, C-6′′), 144.53 (C-7a′′), 149.30 (4a-C=N), 167.82 (7-C=O), 175.96 (2′′-C=O), 182.69 (2-C=S). HRMS (ESI): Calculated for C20H23N7O2S2 [M + H]+: 458.1427, Found: 458.1427.
(3aR*,4′S*,6R*,9aR*)-1,3-Diethyl-1′,1″-dimethyl-2-thioxo-1,2,3,3a,9,9a-hexahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2″,7-dione (3d). Yield 80 mg (33%); Rf = 0.25; white solid; mp: 155–157 °C. IR (KBr): ν 3433 (NH), 3233 (ArH), 2973, 2939, 2876 (Alk), 1707, 1641, 1613 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J = 7.0 Hz, 3H, CH3), 1.07 (t, J = 7.0 Hz, 3H, CH3), 2.49 (s, 3H, 1′-NCH3), 3.10–3.32 (m, 6H, 1′′-NCH3, CH2), 3.41–3.51 (m, 3H, CH2), 3.71–3.81 (m, 2H, CH2), 4.88 (d, J = 6.7 Hz, 1H, 3a-H), 5.03 (dd, J = 6.7, 2.4 Hz, 1H, 9a-H), 6.85 (d, J = 2.3 Hz, 1H, 9-NH), 6.95–7.02 (m, 2H, 5′′-H, 7′′-H), 7.12 (d, J = 7.5 Hz, 1H, 4′′-H), 7.33 (t, J = 7.6 Hz, 1H, 6′′-H). 13C NMR (75 MHz, DMSO-d6): δ 11.63, 12.84 (2CH3), 26.07 (1′′-NCH3), 37.63, 37.88 (1,3-NCH2), 42.02 (1′-NCH3), 59.70, 60.33 (C-3′, C-3′′), 62.06, 63.82, 64.56, 65.84 (2CH2, C-3a, C-9a), 109.09 (C-7′′), 122.74, 123.20, 124.28, 129.51 (C-3a′′, C-4′′, C-5′′, C-6′′), 144.34 (4a-C=N), 149.99 (C-7a′′), 168.24 (7-C=O), 176.16 (2′′-C=O), 180.72 (2-C=S). HRMS (ESI): Calculated for C22H27N7O2S2 [M + H]+: 486.1729, Found: 486.1740.
(3aR*,4′R*,6S*,9aS*)-1′-Cyclohexyl-9-((cyclohexyl(methyl)amino)methyl)-1,1″,3-trimethyl-3,3a,9,9a-tetrahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2,2″,7(1H)-trione (3e). Yield 110 mg (35%); Rf = 0.39; white solid; mp: 179–181 °C. IR (KBr): ν 2930, 2854 (Alk), 1709, 1641, 1610 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 1.14–1.28 (m, 10H, Cy), 1.52–1.83 (m, 10H, Cy), 2.36–2.41 (m, 4H, NCH3, Cy), 2.47 (s, 3H, NCH3), 2.60–2.63 (m, 4H, NCH3, Cy), 3.15 (s, 3H, 1′′-NCH3), 3.20 (d, J = 9.9 Hz, 1H, CH2), 3.47–3.57 (m, 2H, CH2), 3.72 (d, J = 12.7 Hz, 1H, 9-NCH2), 3.79 (d, J = 10.0 Hz, 1H, CH2), 4.05 (d, J = 12.7 Hz, 1H, 9-NCH2), 4.70 (d, J = 5.8 Hz, 1H, 9a-H), 4.76 (d, J = 5.7 Hz, 1H, 3a-H), 6.99–7.05 (m, 2H, 5′′-H, 7′′-H), 7.11 (d, J = 7.4 Hz, 1H, 4′′-H), 7.35 (t, J = 7.6 Hz, 1H, 6′′-H). 13C NMR (75 MHz, DMSO-d6): δ 23.78, 23.93, 25.49, 25.59, 26.01, 26.61, 27.41, 28.26, 28.92, 30.88, 31.31, 36.23 (4NCH3, Cy), 57.40, 58.80, 59.29, 59.74, 60.17, 62.06, 63.46, 68.70, 72.42 (C-2′, C-3′, C-3′′, C-5′, C-3a, C-9a, 9-NCH2, 2Cy), 109.00 (C-7′′), 122.43, 123.33, 124.09, 129.47 (C-3a′′, C-4′′, C-5′′, C-6′′), 144.41 (C-7a′′), 147.85 (4a-C=N), 157.80 (2-C=O), 167.59 (7-C=O), 175.97 (2′′-C=O). HRMS (ESI): Exact mass calcd for C33H46N8O3S [M + H]+: 635.3486, Found: 635.3497.
(3aR*,4′S*,6R*,9aS*)-1,1′,1″,3-Tetramethyl-3,3a,9,9a-tetrahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2,2″,7(1H)-trione (4a). Yield 92 mg (42%); Rf = 0.53; white solid; mp: 164–166 °C. IR (KBr): ν 3468, 3188 (NH), 3053, 3026 (ArH), 2934, 2854 (Alk), 1716, 1700, 1644 (C=O, C=N) cm−1. 1H NMR (500 MHz, DMSO-d6): δ 2.47 (s, 3H, 1′-NCH3), 2.57 (s, 3H, NCH3), 2.64 (s, 3H, NCH3), 3.11 (d, J = 10.2 Hz, 1H, CH2), 3.14 (s, 3H, 1′′-NCH3), 3.40 (d, J = 10.7 Hz, 1H, CH2), 3.47 (d, J = 10.2 Hz, 1H, CH2), 3.71 (d, J = 10.7 Hz, 1H, CH2), 4.52 (dd, J = 5.7, 2.5 Hz, 1H, 9a-H), 4.60 (d, J = 5.8 Hz, 1H, 3a-H), 6.83 (d, J = 2.1 Hz, 1H, 9-NH), 7.05–7.06 (m, 2H, 5′′-H, 7′′-H), 7.17 (d, J = 7.4 Hz, 1H, 4′′-H), 7.37 (t, J = 7.6 Hz, 1H, 6′′-H). 13C NMR (75 MHz, DMSO-d6): δ 26.07, 26.71, 27.69 (1,1′′,3-NCH3), 41.96 (1′-NCH3), 60.42, 61.67, 63.20 (C-2′, C-3′, C-3′′, C-5′), 65.03, 65.64 (C-3a, C-9a), 108.96 (C-7′′), 123.06, 123.10, 124.29, 129.66 (C-3a′′, C-4′′, C-5′′, C-6′′), 144.58 (C-7a′′), 148.24 (4a-C=N), 158.62 (2-C=O), 167.97 (7-C=O), 176.05 (2′′-C=O). HRMS (ESI): Calculated for C20H23N7O3S [M + H]+: 442.1665, Found: 442.1656.
(3aR*,4′S*,6R*,9aS*)-1,3-Diethyl-1′,1″-dimethyl-3,3a,9,9a-tetrahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2,2″,7(1H)-trione (4b). Yield 70 mg (30%); Rf = 0.60; white solid; mp: 217–219 °C. IR (KBr): ν 3495, 3175 (NH), 3057 (ArH), 2980, 2959, 2935, 2898, 2874 (Alk), 1738, 1709, 1693, 1634, 161 (C=O, C=N) cm−1. 1H NMR (500 MHz, DMSO-d6): δ 0.95 (t, J = 7.1 Hz, 3H, CH3), 1.04 (t, J = 7.2 Hz, 3H, CH3), 2.47 (s, 3H, 1′-NCH3), 2.93–3.07 (m, 2H, NCH2), 3.10–3.17 (m, 5H, 1′′-NCH3, CH2, NCH2), 3.21–3.30 (m, 2H, CH2, NCH2), 3.49 (d, J = 10.2 Hz, 1H, CH2), 3.73 (d, J = 10.6 Hz, 1H, CH2), 4.63–4.68 (m, 2H, 3a-H, 9a-H), 6.85 (d, J = 2.2 Hz, 1H, 9-NH), 7.04–7.07 (m, 2H, 5′′-H, 7′′-H), 7.18 (d, J = 7.3 Hz, 1H, 4′′-H), 7.37 (t, J = 7.7 Hz, 1H, 6′′-H). 13C NMR (125 MHz, DMSO-d6): δ 13.22, 13.28 (2CH3), 26.15 (1′′-NCH3), 34.25, 35.29 (1,3-NCH2), 42.07 (1′-NCH3), 60.36, 60.57 (C-3′, C-3′′), 61.76, 63.00, 63.53, 64.35 (C-2′, C-3a, C-5′, C-9a), 109.05 (C-7′′), 123.11, 123.20, 124.45, 129.75 (C-3a′′, C-4′′, C-5′′, C-6′′), 144.69 (4a-C=N), 148.17 (C-7a′′), 157.84 (2-C=O), 168.00 (7-C=O), 176.14 (2′′-C=O). HRMS (ESI): Calculated for C22H27N7O3S [M + H]+: 470.1965, Found: 470.1969.
(3aR*,4′R*,6S*,9aR*)-1,1′,1″,3-Tetramethyl-2-thioxo-1,2,3,3a,9,9a-hexahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2″,7-dione (4c). Yield 87 m (38%); Rf = 0.43; white solid; mp: 273–275 °C. IR (KBr): ν 3399 (NH), 3125 (ArH), 2936, 2921, 2855 (Alk), 1726, 1707, 1603, 1609 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 2.51 (s, 3H, 1′-NCH3), 2.79 (s, 3H, NCH3), 2.94 (s, 3H, NCH3), 3.12–3.16 (m, 4H, CH2, 1′′-NCH3), 3.42 (d, J = 10.5 Hz, 1H, CH2), 3.49 (d, J = 10.2 Hz, 1H, CH2), 3.75 (d, J = 10.5 Hz, 1H, CH2), 4.85 (d, J = 6.3 Hz, 1H, 3a-H), 4.92 (d, J = 6.3 Hz, 1H, 9a-H), 6.95 (s, 1H, 9-NH), 7.02–7.11 (m, 3H, 4′′-H, 5′′-H, 7′′-H), 7.35 (t, J = 7.5 Hz, 1H, 6′′-H). 13C NMR (75 MHz, DMSO-d6): δ 26.06 (1′′-NCH3), 30.62, 30.95 (1,3-NCH3), 41.98 (1′-NCH3), 59.98, 60.15 (C-3′, C-3′′), 61.80, 63.88 (C-2′, C-5′), 66.41, 67.88 (C-3a, C-9a), 109.11 (C-7′′), 122.62, 123.01, 123.72, 129.54 (C-3a′′, C-4′′, C-5′′, C-6′′), 144.34 (C-7a′′), 149.80 (4a-C=N), 168.35 (7-C=O), 176.05 (2′′-C=O), 182.36 (2-C=S). HRMS (ESI): Calculated for C20H23N7O2S2 [M + H]+: 458.1426, Found: 458.1427.
(3aR*,4′R*,6S*,9aR*)-1,3-Diethyl-1′,1″-dimethyl-2-thioxo-1,2,3,3a,9,9a-hexahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2″,7-dione (4d). Yield 73 mg (30%); Rf = 0.54; white solid; mp: 224–226 °C. IR (KBr): ν 3433 (NH), 3261, 3210 (ArH), 2969, 2932, 2858 (Alk), 1728, 1701, 1641, 1612 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 0.99 (t, J = 6.9 Hz, 3H, CH3), 1.11 (t, J = 7.1 Hz, 3H, CH3), 2.46 (s, 3H, 1′-NCH3), 3.10–3.14 (m, 4H, 1′′-NCH3, CH2), 3.19–3.34 (m, 2H, NCH2, CH2), 3.41–3.56 (m, 3H, NCH2, CH2), 3.71–3.83 (m, 2H, NCH2, CH2), 4.88 (d, J = 6.6 Hz, 1H, 3a-H), 4.96 (dd, J = 6.7, 2.7 Hz, 1H, 9a-H), 7.03–7.07 (m, 3H, 5′′-H, 7′′-H, 9-NH), 7.18 (d, J = 7.6 Hz, 1H, 4′′-H), 7.37 (t, J = 7.7 Hz, 1H, 6′′-H). 13C NMR (75 MHz, DMSO-d6): δ 12.30, 12.92 (2CH3), 26.14 (1′′-NCH3), 38.24, 38.34 (1,3-NCH2), 42.04 (1′-NCH3), 60.36 (C-3′, C-3′′), 61.67, 63.30 (C-2′, C-5′), 64.73, 66.71 (C-3a, C-9a), 109.06 (C-7′′), 123.00, 123.19, 124.43, 129.79 (C-3a′′, C-4′′, C-5′′, C-6′′), 144.62 (4a-C=N), 149.24 (C-7a′′), 167.87 (7-C=O), 176.06 (2′′-C=O), 181.23 (2-C=S). HRMS (ESI): Calculated for C22H27N7O2S2 [M + H]+: 486.1749, Found: 486.1740.
(3aR*,4′S*,6R*,9aS*)-1′-Cyclohexyl-1,1″,3-trimethyl-3,3a,9,9a-tetrahydro-7H-dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indoline]-2,2″,7(1H)-trione (4e). Yield 49 mg (24%); Rf = 0.56; white solid; mp: 217–219 °C. IR (KBr): ν 3434, 3175 (NH), 2931, 2854 (Alk), 1706, 1638, 1612 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 1.12–1.24 (m, 5H, Cy), 1.48–1.52 (m, 1H, Cy), 1.61–1.70 (m, 2H, Cy), 1.76–1.81 (m, 2H, Cy), 2.56–2.59 (m, 4H, NCH3, Cy), 2.65 (s, 3H, NCH3), 3.14 (s, 3H, 1′′-NCH3), 3.19 (d, J = 10.0 Hz, 1H, CH2), 3.42–3.50 (m, 2H, CH2), 3.72 (d, J = 10.3 Hz, 1H, CH2), 4.52 (dd, J = 5.9, 2.5 Hz, 1H, 9a-H), 4.60 (d, J = 5.8 Hz, 1H, 3a-H), 6.80 (d, J = 2.5 Hz, 1H, 9-NH), 7.02–7.06 (m, 2H, 5′′-H, 7′′-H), 7.17 (d, J = 7.2 Hz, 1H, 4′′-H), 7.36 (t, J = 7.4 Hz, 1H, 6′′-H). 13C NMR (75 MHz, DMSO-d6): δ 24.45, 24.59, 26.15, 26.57, 27.21, 28.26, 31.45, 31.89 (3NCH3, Cy), 57.77, 59.70, 59.88, 60.10, 61.09, 65.46, 66.14 (C-2′, C-3′, C-3′′, C-5′, C-3a, C-9a, Cy), 109.41 (C-7′′), 123.50, 123.86, 124.84, 130.11 (C-3a′′, C-4′′, C-5′′, C-6′′), 145.11 (C-7a′′), 148.85 (4a-C=N), 159.13 (2-C=O), 168.39 (7-C=O), 176.38 (2′′-C=O). HRMS (ESI): Calculated for C25H31N7O3S [M + H]+: 510.2282, Found: 510.2274.
3.3. General Procedure for the Preparation of Dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indole] 6a–e and 7a–e
Method A. Dipolarophile 5a–d (0.5 mmol), paraformaldehyde (0.060 g, 2.0 mmol) and N-alkylglycine 1a,b (2.0 mmol) were charged in a flask and acetonitrile (40 mL) was added. The resulting suspension was refluxed with stirring for 10–16 h until the red color disappeared. The solvent was then removed under reduced pressure to afford a solid product. This solid was dissolved in isopropyl alcohol (10 mL) and separated via column chromatography using isopropyl alcohol as eluent. Anti-diastereomers 6a–e have a retention factor Rf = 0.35–0.54, syn-diastereomers 7a–e have a retention factor Rf = 0.58–0.73.
Method B. To a stirred suspension of compound 3a (0.442 g, 0.1 mmol) or 4a (0.442 g, 0.1 mmol) in refluxing methanol (2 mL), 0.010 mL of 40% aqueous KOH (0.1 mmol) was added. The resulting mixture was refluxed with stirring for 1 h. After cooling, the precipitate of compounds 7a or 6a was filtered off, washed with methanol and dried.
(3aR*,4′R*,7S*,9aS*)-1,1′,1″,3-Tetramethyl-1,3a,4,9a-tetrahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2,2″,8(3H)-trione (6a). Method A: yield 97 mg (44%); method B: yield 41 mg (92%); Rf = 0.35; white solid; mp: 218–220 °C. IR (KBr): ν 3414 (NH), 3429, 3310 (ArH), 2967, 2941, 2853 (Alk), 1727, 1684, 1651 (C=O, C=N) cm−1. 1H NMR (500 MHz, DMSO-d6): δ 2.46 (s, 3H, NCH3), 2.47 (s, 3H, 1′-NCH3), 2.90 (s, 3H, NCH3), 3.10 (d, J = 10.2 Hz, 1H, CH2), 3.13 (s, 3H, 1′′-NCH3), 3.44–3.47 (m, 2H, CH2), 3.65 (d, J = 10.6 Hz, 1H, CH2), 4.54 (dd, J = 5.6, 2.0 Hz, 1H, 3a-H), 5.36 (d, J = 5.7 Hz, 1H, 9a-H), 6.98 (t, J = 7.5 Hz, 1H, 5′′-H), 7.03 (d, J = 7.8 Hz, 1H, 7′′-H), 7.19 (d, J = 7.5 Hz, 1H, 4′′-H), 7.33 (t, J = 7.7 Hz, 1H, 6′′-H), 7.47 (d, J = 1.9 Hz, 1H, 4-NH). 13C NMR (75 MHz, DMSO-d6): δ 26.02, 27.87, 31.62 (1,1′′,3-NCH3), 41.88 (1′-NCH3), 60.29, 61.67, 62.54, 63.77, 64.77, 66.24 (C-2′, C-3a, C-3′, C-3′′, C-5′, C-9a), 108.88 (C-7′′), 122.43, 123.52, 124.66, 129.50 (C-3a′′, C-4′′, C-5′′, C-6′′), 134.15 (5a-C=N), 144.42 (C-7a′′), 159.25 (2-C=O), 171.97 (8-C=O), 176.25 (2′′-C=O). HRMS (ESI): Calculated for C20H23N7O3S [M + H]+: 442.1655, Found: 442.1656.
(3aR*,4′R*,7S*,9aS*)-1,3-Diethyl-1′,1″-dimethyl-1,3a,4,9a-tetrahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2,2″,8(3H)-trione (6b). Yield 101 mg (43%); Rf = 0.38; white solid; mp: 205–207 °C. IR (KBr): ν 3287 (NH), 3070 (ArH), 2972, 2939, 2876 (Alk), 1717, 1655, 1613 (C=O, C=N) cm−1. 1H NMR (500 MHz, DMSO-d6): δ 0.89 (t, J = 7.1 Hz, 3H, CH3), 1.09 (t, J = 7.0 Hz, 3H, CH3), 2.46 (s, 3H, 1′-NCH3), 2.85–2.90 (m, 1H, NCH2), 3.07–3.14 (m, 6H, 1′′-NCH3, CH2, NCH2), 3.43–3.50 (m, 3H, CH2, NCH2), 3.63 (d, J = 10.5 Hz, 1H, CH2), 4.60 (dd, J = 5.5, 1.9 Hz, 1H, 3a-H), 5.44 (d, J = 5.5 Hz, 1H, 9a-H), 6.98–7.04 (m, 2H, 5′′-H, 7′′-H), 7.18 (d, J = 7.5 Hz, 1H, 4′′-H), 7.33 (t, J = 7.7 Hz, 1H, 6′′-H), 7.43 (d, J = 1.9 Hz, 1H, 4-NH). 13C NMR (150 MHz, DMSO-d6): δ 13.69, 13.87 (2CH3), 27.27 (1′′-NCH3), 35.83, 38.61 (1,3-NCH2), 43.07 (1′-NCH3), 61.56, 62.41, 63.01, 63.88, 64.67, 66.15 (C-2′, C-3a, C-3′, C-3′′, C-5′, C-9a), 110.05 (C-7′′), 123.80, 124.91, 125.92, 130.68 (C-3a′′, C-4′′, C-5′′, C-6′′), 135.19 (5a-C=N), 145.64 (C-7a′′), 159.11 (2-C=O), 173.22 (8-C=O), 177.52 (2′′-C=O). HRMS (ESI): Calculated for C22H27N7O3S [M + H]+: 470.1967, Found: 470.1969.
(3aR*,4′R*,7S*,9aR*)-1,1′,1″,3-Tetramethyl-2-thioxo-1,2,3,3a,4,9a-hexahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2″,8-dione (6c). Yield 84 mg (37%); Rf = 0.41; white solid; mp: 228–231 °C. IR (KBr): ν 3436 (NH), 3027 (ArH), 2969, 2945, 2916, 2798 (Alk), 1727, 1703, 1653, 1612 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 2.47 (s, 3H, CH3), 2.78 (s, 3H, CH3), 3.10–3.17 (m, 7H, 2CH3, CH2), 3.45–3.52 (m, 2H, CH2), 3.66 (d, J = 10.4 Hz, 1H, CH2), 4.85 (d, J = 5.9 Hz, 1H, 3a-H), 5.57 (d, J = 5.6 Hz, 1H, 9a-H), 7.02–7.08 (m, 2H, 5′′-H, 7′′-H), 7.19 (d, J = 7.2 Hz, 1H, 4′′-H), 7.33 (t, J = 7.5 Hz, 1H, 6′′-H), 7.66 (s, 1H, 4-NH). 13C NMR (75 MHz, DMSO-d6): δ 26.07 (1′′-NCH3), 31.46, 35.53 (1,3-NCH3), 41.90 (1′-NCH3), 60.19, 61.76, 62.57, 65.01 (C-2′, C-3′,C-3′′, C-5′), 66.71, 67.53 (C-3a), C-9a), 108.95 (C-7′′), 122.93, 123.55, 124.69, 129.47 (C-3a′′, C-4′′, C-5′′, C-6′′), 134.68 (5a-C=N), 144.34 (C-7a′′), 171.65 (8-C=O), 176.20 (2′′-C=O), 184.33 (2-C=S). HRMS (ESI): Calculated for C20H23N7O2S2 [M + H]+: 458.1427, Found: 458.1427.
(3aS*,3′R*,3′′S*,9aS*)-1,3-Diethyl-1′,1′′-dimethyl-2-thioxo-1,3,3a,4,9,9a-hexahydrodispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3′′-indole]-2′′,8(1′′H)-dione (6d). Yield 102 mg (42%); Rf = 0.44; white solid; mp: 225–227 °C. IR (KBr): ν 3327 (NH), 3069, 3055 (ArH), 2967, 2936, 2884, 2829, 2795 (Alk), 1707, 1640, 1612 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 0.96 (t, J = 7.0 Hz, 3H, CH3), 1.13 (t, J = 7.0 Hz, 3H, CH3), 2.46 (s, 3H, 1′-NCH3), 3.08–3.26 (m, 6H, 1′′-NCH3, NCH2, CH2), 3.42–3.51 (m, 2H, CH2), 3.61–3.66 (m, 2H, CH2, NCH2), 3.93–3.99 (m, 1H, NCH2), 4.85 (d, J = 5.6 Hz, 1H, 3a-H), 5.61 (d, J = 5.4 Hz, 1H, 9a-H), 7.02–7.10 (m, 2H, 5′′-H, 7′′-H), 7.19 (d, J = 6.9 Hz, 1H, 4′′-H), 7.33 (t, J = 6.3 Hz, 1H, 6′′-H), 7.60 (d, J = 1.9 Hz, 1H, 4-NH). 13C NMR (75 MHz, DMSO-d6): δ 11.84, 11.91 (2CH3), 26.07 (1′′-NCH3), 38.13, 40.13 (1,3-NCH2), 41.77 (1′-NCH3), 60.26, 61.99, 62.75, 63.76, 64.97, 65.33 (C-2′, C-3′, C-3′′, C-3a, C-5′, C-9a), 108.88 (C-7′′), 122.95, 123.85, 124.74, 129.41 (C-3a′′, C-4′′, C-5′′, C-6′′), 134.28 (5a-C=N), 144.32 (C-7a′′), 171.68 (8-C=O), 176.24 (2′′-C=O), 182.04 (2-C=S). HRMS (ESI): Calculated for C22H27N7O2S2 [M + H]+: 486.1733, Found: 486.1740.
(3aR*,4′R*,7S*,9aS*)-1′-Cyclohexyl-1,1″,3-trimethyl-1,3a,4,9a-tetrahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2,2″,8(3H)-trione (6e). Yield 117 mg (46%); Rf = 0.54; white solid; mp: 244–245 °C. IR (KBr): ν 3435, 3306 (NH), 2931, 2854 (Alk), 1711, 1651, 1611, 1577 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 1.18–1.27 (m, 5H, Cy), 1.49–1.53 (m, 1H, Cy), 1.67–1.71 (m, 2H, Cy), 1.80–1.84 (m, 2H, Cy), 2.49 (s, 3H, NCH3), 2.57–2.60 (m, 1H, Cy), 2.92 (s, 3H, NCH3), 3.15 (s, 3H, 1′′-NCH3), 3.19 (d, J = 9.9 Hz, 1H, CH2), 3.50 (d, J = 10.0 Hz, 1H, CH2), 3.59 (d, J = 10.4 Hz, 1H, CH2), 3.68 (d, J = 10.3 Hz, 1H, CH2), 4.55 (d, J = 4.4 Hz, 1H, 3a-H), 5.38 (d, J = 5.7 Hz, 1H, 9a-H), 6.97–7.05 (m, 2H, 5′′-H, 7′′-H), 7.23 (d, J = 7.5 Hz, 1H, 4′′-H), 7.34 (t, J = 7.8 Hz, 1H, 6′′-H). 7.47 (s, 1H, 4-NH). 13C NMR (125 MHz, DMSO-d6): δ 23.99, 24.11, 25.74, 26.12, 27.96, 31.05, 31.52, 31.74 (3NCH3, Cy), 57.46, 59.21, 60.60, 60.65, 61.93, 63.88, 66.38 (C-2′, C-3′, C-3′′, C-5′, C-3a, C-9a, Cy), 108.95 (C-7′′), 122.52, 123.97, 124.84, 129.58 (C-3a′′, C-4′′, C-5′′, C-6′′), 134.42 (5a-C=N), 144.56 (C-7a′′), 159.38 (2-C=O), 171.88 (8-C=O), 176.29 (2′′-C=O). HRMS (ESI): Calculated for C25H31N7O3S [M + H]+: 510.2282, Found: 510.2277.
(3aR*,4′S*,7R*,9aS*)-1,1′,1″,3-Tetramethyl-1,3a,4,9a-tetrahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2,2″,8(3H)-trione (7a). Method A: yield 79 mg (36%); method B: yield 35 mg (80%); Rf = 0.58; white solid; mp: 264–266 °C. IR (KBr): ν 3357 (NH), 3065, 3025 (ArH), 2966, 2934, 2894, 2851 (Alk), 1736, 1717, 1704, 1646 (C=O, C=N) cm−1. 1H NMR (500 MHz, DMSO-d6): δ 2.49 (s, 3H, NCH3), 2.50 (s, 3H, NCH3), 2.91 (s, 3H, NCH3), 3.10 (d, J = 10.2 Hz, 1H, CH2), 3.14 (s, 3H, 1′′-NCH3), 3.41 (d, J = 10.7 Hz, 1H, CH2), 3.45 (d, J = 10.3 Hz, 1H, CH2), 3.66 (d, J = 10.7 Hz, 1H, CH2), 4.59 (d, J = 5.6 Hz, 1H, 3a-H), 5.34 (d, J = 5.6 Hz, 1H, 9a-H), 7.03–7.06 (m, 2H, 5′′-H, 7′′-H), 7.16 (d, J = 7.4 Hz, 1H, 4′′-H), 7.36 (t, J = 7.7 Hz, 1H, 6′′-H), 7.45 (s, 1H, 4-NH). 13C NMR (125 MHz, DMSO-d6): δ 26.16, 27.68, 31.35 (1,1′′,3-NCH3), 42.13 (1′-NCH3), 60.44, 61.48, 63.19, 63.67, 65.24, 66.39 (C-2′, C-3a, C-3′, C-3′′, C-5′, C-9a), 109.09 (C-7′′), 122.85, 123.32, 123.93, 129.76 (C-3a′′, C-4′′, C-5′′, C-6′′), 135.13 (5a-C=N), 144.74 (C-7a′′), 158.86 (2-C=O), 172.09 (8-C=O), 176.36 (2′′-C=O). HRMS (ESI): Calculated for C20H23N7O3S [M + H]+: 442.1643, Found: 442.1656.
(3aR*,4′S*,7R*,9aS*)-1,3-Diethyl-1′,1″-dimethyl-1,3a,4,9a-tetrahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2,2″,8(3H)-trione (7b). Yield 96 mg (41%); Rf = 0.60; white solid; mp: 252–254 °C. IR (KBr): ν 3325 (NH), 3093, 3053 (ArH), 2988, 2974, 2966, 2936, 2899, 2865, 2837 (Alk), 1707, 1641, 1611 (C=O, C=N) cm−1. 1H NMR (500 MHz, DMSO-d6): δ 0.91 (t, J = 7.1 Hz, 3H, CH3), 1.13 (t, J = 7.1 Hz, 3H, CH3), 2.49 (s, 3H, 1′-NCH3), 2.91–2.95 (m, 1H, NCH2), 3.09–3.15 (m, 5H, 1′′-NCH3, CH2, NCH2), 3.21–3.27 (m, 1H, NCH2), 3.38 (d, J = 10.6 Hz, 1H, CH2), 3.45–3.51 (m, 2H, CH2, NCH2), 3.67 (d, J = 10.6 Hz, 1H, CH2), 4.68 (d, J = 6.6 Hz, 1H, 3a-H), 5.60 (d, J = 6.6 Hz, 1H, 9a-H), 7.04–7.07 (m, 2H, 5′′-H, 7′′-H), 7.17 (d, J = 7.5 Hz, 1H, 4′′-H), 7.35 (t, J = 7.5 Hz, 1H, 6′′-H), 7.43 (s, 1H, 4-NH). 13C NMR (75 MHz, DMSO-d6): δ 12.26, 13.61 (2CH3), 26.02 (1′′-NCH3), 34.46, 37.97 (1,3-NCH2), 41.96 (1′-NCH3), 60.30. 61.33, 62.80, 63.13, 63.33, 64.27 (C-2′, C-3a, C-3′, C-3′′, C-5′, C-9a), 108.91 (C-7′′), 122.72, 123.20, 123.85, 129.60 (C-3a′′, C-4′′, C-5′′, C-6′′), 134.71 (5a-C=N), 144.63 (C-7a′′), 157.75 (2-C=O), 171.73 (8-C=O), 176.25 (2′′-C=O). HRMS (ESI): Calculated for C22H27N7O3S [M + H]+: 470.1960, Found: 470.1969.
(3aR*,4′S*,7R*,9aR*)-1,1′,1″,3-Tetramethyl-2-thioxo-1,2,3,3a,4,9a-hexahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2″,8-dione (7c). Yield 101 mg (42%); Rf = 0.66; white solid; mp: 224–226 °C. IR (KBr): ν 3398 (NH), 3112, 3056 (ArH), 2969, 2930, 2838, 2785 (Alk), 1711, 1698, 1636, 1609 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 2.50 (s, 3H, 1′-NCH3), 2.81 (s, 3H, NCH3), 3.10–3.15 (m, 4H, CH2, NCH3), 3.22 (s, 3H, NCH3), 3.38–3.47 (m, 2H, CH2), 3.68 (d, J = 10.7 Hz, 1H, CH2), 4.98 (d, J = 6.7 Hz, 1H, 3a-H), 5.82 (d, J = 6.9 Hz, 1H, 9a-H), 7.03–7.08 (m, 2H, 5′′-H, 7′′-H), 7.17 (d, J = 7.7 Hz, 1H, 4′′-H), 7.37 (t, J = 7.7 Hz, 1H, 6′′-H), 7.66 (s, 1H, 4-NH). 13C NMR (150 MHz, DMSO-d6): δ 27.29 (1′′-NCH3), 32.17, 36.39 (1,3-NCH3), 43.21 (1′-NCH3), 61.54, 62.53, 64.38, 64.78, 68.95, 69.58 (C-2′, C-3′, C-3′′, C-3a, C-9a), 110.22 (C-7′′), 124.00, 124.34, 125.04, 130.92 (C-3a′′, C-4′′, C-5′′, C=6′′), 137.15 (5a-C=N), 145.86 (C-7a′′), 172.81 (8-C=O), 177.41 (2′′-C=O), 184.61 (2-C=S). HRMS (ESI): Calculated for C20H23N7O2S2 [M + H]+:458.1421, Found: 458.1427.
(3aR*,4′S*,7R*,9aR*)-1,3-Diethyl-1′,1″-dimethyl-2-thioxo-1,2,3,3a,4,9a-hexahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2″,8-dione (7d). Yield 107 mg (44%); Rf = 0.67; white solid; mp: 148–150 °C. IR (KBr): ν 3311 (NH), 3056 (ArH), 2971, 2935, 2867, 2849, 2796 (Alk), 1709, 1648, 1612 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 0.97 (t, J = 6.6 Hz, 3H, CH3), 1.19 (t, J = 6.9 Hz, 3H, CH3), 2.50 (s, 3H, 1′-NCH3), 3.09–3.15 (m, 4H, 1′′-NCH3, CH2), 3.19–3.29 (m, 1H, CH2), 3.37–3.61 (m, 4H, CH2, NCH2), 3.67 (d, J = 10.5 Hz, 1H, CH2), 3.97–4.04 (m, 1H, NCH2), 5.01 (d, J = 6.9 Hz, 1H, 3a-H), 5.85 (d, J = 6.9 Hz, 1H, 9a-H), 7.04–7.08 (m, 2H, 5′′-H, 7′′-H), 7.17 (d, J = 7.5 Hz, 1H, 4′′-H), 7.37 (t, J = 7.5 Hz, 1H, 6′′-H), 7.64 (d, J = 1.9 Hz, 1H, 4-NH). 13C NMR (75 MHz, DMSO-d6): δ 11.49, 13.08 (2CH3), 26.06 (1′′-NCH3), 37.80, 41.24, 41.97 (1,3-NCH2, 1′-NCH3), 60.30, 61.25, 63.21, 65.57, 66.34 (C-2′, C-3′, C-3′′, C-3a, C-5′, C-9a), 108.97 (C-7′′), 122.81, 123.08, 123.83, 129.67 (C-3a′′, C-4′′, C-5′′, C-6′′), 135.47 (5a-C=N), 144.63 (C-7a′′), 171.35 (8-C=O), 176.18 (2′′-C=O), 181.83 (2-C=S). HRMS (ESI): Calculated for C22H27N7O2S2 [M + H]+: 486.1737, Found: 486.1740.
(3aR*,4′S*,7R*,9aS*)-1′-Cyclohexyl-1,1″,3-trimethyl-1,3a,4,9a-tetrahydro-8H-dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indoline]-2,2″,8(3H)-trione (7e). Yield 84 mg (33%); Rf = 0.73; white solid; mp: 155–156 °C. IR (KBr): ν 3371 (NH), 2933, 2852 (Alk), 1729, 1699, 1639, 1612 (C=O, C=N) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 1.19–1.27 (m, 5H, Cy), 1.50–1.54 (m, 1H, Cy), 1.67–1.71 (m, 2H, Cy), 1.79–1.83 (m, 2H, Cy), 2.52 (s, 3H, NCH3), 2.59–2.63 (m, 1H, Cy), 2.92 (s, 3H, NCH3), 3.16 (s, 3H, 1′′-NCH3), 3.20 (d, J = 10.5 Hz, 1H, CH2), 3.45–3.52 (m, 2H, CH2), 3.69 (d, J = 10.5 Hz, 1H, CH2), 3.68 (d, J = 10.3 Hz, 1H, CH2), 4.61 (d, J = 6.4 Hz, 1H, 3a-H), 5.55 (d, J = 6.4 Hz, 1H, 9a-H), 7.03–7.08 (m, 2H, 5′′-H, 7′′-H), 7.19 (d, J = 7.5 Hz, 1H, 4′′-H), 7.37 (t, J = 7.6 Hz, 1H, 6′′-H), 7.46 (s, 1H, 4-NH). 13C NMR (75 MHz, DMSO-d6): δ 23.90, 23.99, 25.65, 26.04, 27.57, 30.88, 31.24, 31.34 (3NCH3, Cy), 56.92, 59.26, 59.56, 60.26, 62.28, 65.13, 66.24 (C-2′, C-3′, C-3′′, C-5′, C-3a, C-9a, Cy), 108.91 (C-7′′), 122.68, 123.60, 123.97, 129.59 (C-3a′′, C-4′′, C-5′′, C-6′′), 135.15 (5a-C=N), 144.67 (C-7a′′), 158.76 (2-C=O), 171.81 (8-C=O), 176.13 (2′′-C=O). HRMS (ESI): Calculated for C25H31N7O3S [M + H]+: 510.2282, Found: 510.2284.