Hydrazine hydrate (1:1) → 3-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-1H-indol-5-amine

HRID 552968Notes

Reaction equation

HRID 552968 reaction equation
[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.O.NN>CO.[Ni]>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1

Participants

5

Reactant 2

HCID 24654Hydrazine hydrate (1:1)HCID 153897603-(1,2,3,4,5,8-Hexahydroindolizin-7-yl)-5-nitro-1H-indole

Product 1

HCID 537825203-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-1H-indol-5-amineYield 81.2%

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 887MethanolSolvent

Procedure

A solution of compound 141 (0.12 g, 0.423 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g), hydrazine hydrate (0.13 mL, 4.235 mmol) at room temperature. The resulting mixture was refluxed for 2 min, in pre-heated oil bath. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2 20 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 95:5) to obtain 3-(1,2,3,5,8,8a-Hexahydroindolizin-7-yl)-1H-indol-5-amine, (0.087 g, 81%) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.33-1.48 (m, 1H), 1.67-1.79 (m, 2H), 1.94-2.13 (m, 2H), 2.16-2.26 (m, 2H), 2.58-2.65 (m, 1H), 2.85 (d, 1H, J=15.6 Hz), 3.08-3.17 (m, 1H), 3.59 (dd, 1H, J=4.5, 15.7 Hz), 4.49 (s, 2H), 6.01 (d, 1H, J=4.5 Hz), 6.48 (dd, 1H, J=1.8, 9.1 Hz), 7.01 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS (m/z, %) 254 (MH+, 62), 185 (100). A solution of the amine (0.053 g, 0.209 mmol) in dry ethanol (3 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.12 g, 0.418 mmol) at room temperature and the solution was stirred for 24 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 5:95) to obtain compound 142 (0.06 g, 79%) as a solid. mp 122-124° C.; 1H NMR (DMSO-d6) δ 1.38-1.46 (m, 1H), 1.70-1.78 (m, 2H), 1.93-2.12 (m, 2H), 2.20-2.28 (m, 2H), 2.62-2.72 (m, 1H), 2.83 (d, 1H, J=15.9 Hz), 3.07-3.13 (m, 1H), 3.59 (dd, 1H, J=4.5, 16.0 Hz), 6.07 (d, 1H, J=3.9 Hz), 6.22 (brs, 2H), 6.66 (d, 1H, J=8.1 Hz), 7.09 (dd, 1H, J=3.9, 4.9 Hz), 7.22 (s, 1H), 7.30-7.32 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.92 (s, 1H); ESI-MS (m/z, %) 363 (MH+, 20), 294 (100), 182 (15), ESI-HRMS calculated for C21H23N4S (MH+), calculated: 363.1655; observed: 363.1637.

Workup

  1. temperatureThe resulting mixture was refluxed for 2 min, in pre-heated oil bath
  2. customwas brought to room temperature
  3. filtrationfiltered through celite bed
  4. washwashed with methanol (2 20 mL)
  5. customThe combined methanol layer was evaporated
  6. customcrude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 95:5)

Sources & evidence

ORD record
ord-9e1df307d4204336b38bc24cdfab9a04
Source dataset
uspto-grants-2011_05
Patent number
US07951940B2

Reaction notes

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