Reaction Steps
A solution of 5-nitroindole (38) (3.0 g, 18.501 mmol) in dry methanol (50 mL) was treated with KOH (5.6 g) at room temperature. After stirring for 10 min., 1,4-cyclohexanedione monoethylene ketal (7.22 g, 46.253 mmol) was added and the resulting solution was refluxed for 36 h. The reaction was brought to room temperature and solvent was evaporated. Crude was diluted with water (50 mL), precipitated solid was filtered off and washed with water (2 10 mL). The precipitate was dried under vacuum to obtain compound 78 (4.7 g, 85%) as a solid. For spectral data, please see Example 23. 4-(5-Nitro-1H-indol-3-yl)cyclohex-3-enone (79): A solution of compound 78 (4.7 g, 15.650 mmol) in acetone (50 mL) was treated with 10% aq. HCl (50 mL) at room temperature and stirred for over night (14 h). Acetone was evaporated and crude was basified using 10% aq. NH4OH solution (100 mL). The precipitate was filtered off, washed with 10% NH4OH solution (2 10 mL) and water (2 10 mL). The product was dried under vacuum to obtain compound 79 (4.0 g, quantitative) as a solid. For spectral data, please see Example 23. N,N-Dimethyl-4-(5-nitro-1H-indol-3-yl)cyclohex-3-enamine (112): A solution of compound 79 (1.0 g, 3.902 mmol) in dry 1,2-dichloroethane (10 mL) was treated with N, N-dimethyl amine hydrochloride (0.31 g, 3.902 mmol), AcOH (0.22 mL, 3.902 mmol), NaBH(OAc)3 (1.24 g, 5.853 mmol) at room temperature and the resulting mixture was stirred for overnight (14 h). The reaction was diluted with 1 N NaOH (30 mL) and product was extracted into ethyl acetate (2 50 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 112 (0.73 g, 66%) as a brown solid. mp 234-236° C.; 1H NMR (DMSO-d6) δ 1.43-1.57 (m, 1H), 1.98-2.06 (m, 1H), 2.12-2.23 (m, 7H), 2.39-2.62 (m, 4H), 6.15 (t, 1H, J=1.5 Hz), 7.54 (d, 1H, J=9.0 Hz), 7.62 (s, 1H), 8.00 (dd, 1H, J=2.1, 9.0 Hz), 8.67 (d, 1H, J=2.1 Hz), 11.82 (s, 1H); ESI-MS m/z %): 286 (MH+, 100). 3-(4-(Dimethylamino)cyclohex-1-enyl)-1H-indol-5-amine (113): A solution of compound 112 (0.21 g, 0.735 mmol) in dry methanol (5 mL) was treated with Ra—Ni (0.05 g) followed by hydrazine hydrate (0.22 mL, 7.359 mmol) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 5 min. The reaction brought to room temperature, filtered through celite bed and washed with methanol (2 10 mL). The solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 113 (0.185 g, quantitative) as a foam. mp 63-65° C.; 1H NMR (DMSO-d6) δ 1.40-1.52 (m, 1H), 1.97-2.02 (m, 1H), 2.08-2.57 (m, 11H), 4.47 (s, 2H), 5.99 (brs, 1H), 6.47 (dd, 1H, J=1.8, 8.4 Hz), 6.99 (d, 1H, J=0.9 Hz), 7.04 (d, 1H, J=8.7 Hz), 7.13 (d, 1H, J=2.4 Hz), 10.55 (s, 1H); ESI-MS m/z (%): 256 (MH+, 100), 211 (41). N-(3-(4-(dimethylamino)cyclohex-1-enyl)-1H-indol-5-yl)thiophene-2-carboximidamide (114): A solution of compound 113 (0.18 g, 0.704 mmol) in dry ethanol (10 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.4 g, 1.409 mmol) at room temperature and stirred for 24 h. Solvent was evaporated and crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 114 (0.24 g, 90%) as a solid. mp 113-115° C.; 1H NMR (DMSO-d6) δ 1.42-1.53 (m, 1H), 1.97-2.02 (m, 1H), 2.08-2.22 (m, 8H), 2.31-2.60 (m, 3H), 6.03 (s, 1H), 6.21 (brs, 2H), 6.65 (dd, 1H, J=1.2, 8.4 Hz), 7.09 (t, 1H, J=4.2 Hz), 7.20 (s, 1H), 7.28-7.31 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.88 (s, 1H); ESI-MS m/z (%): 365 (MH+, 39), 320 (38), 183 (76), 160 (100); ESI-HRMS calculated for C21H25N4S (MH+), Calculated: 365.1813; Observed: 365.1794.
