5-Nitroindole → 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole

HRID 2223793Notes

Reaction equation

HRID 2223793 reaction equation
[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>C(O)C>[CH3:18][N:19]1[CH2:20][CH:21]=[C:22]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:23][CH2:24]1

Participants

5

Reactant 3

HCID 225235-NitroindoleHCID 31268PyrrolidineHCID 740491-Methyl-4-piperidone

Product 1

HCID 113343733-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indoleYield 75%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (5 mL) was treated with pyrrolidine (0.77 mL, 9.250 mmol), N-methyl-4-piperidone (0.75 mL, 6.167 mmol) at room temperature. The resulting solution was refluxed for 2 days. The reaction was brought to room temperature, the solid was filtered off, washed with ethanol (2×5 mL) and dried to obtain compound (39) (0.591 g, 75%). Solid decomposed at 215° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 2.50-2.59 (m, 4H), 3.06-3.08 (m, 2H), 6.17 (br s, 1H), 7.55 (d, 1H, J=9.0 Hz), 7.66 (s, 1H), 8.01 (dd, 1H, J=2.1, 9.0 Hz), 8.68 (d, 1H, J=2.1 Hz), 11.86 (brs, 1H). N-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-thiophene-2-carboxamidine (40) and N-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]-thiophene-2-carboxamidine (41): A solution of compound 39 (0.4 g, 1.554 mmol) in dry methanol (5 mL) was treated with Ra—Ni (0.1 g), followed by hydrazine hydrate (0.48 mL, 15.546 mmol) at room temperature and the resulting solution was stirred at 65° C. for 3 h. The reaction was brought to room temperature, solid was filtered off though celite bed and washed with methanol: CH2Cl2 (1:1, 2×10 mL). The combined organic layer was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain the free amine (0.35 g, quantitative) as a foam. A solution of the amine (0.18 g, 0.791 mmol) in dry ethanol (10 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.45 g, 1.583 mmol) at room temperature and the mixture was stirred for 24 h. The solvent was evaporated and product was precipitated with ether (100 mL). The solid was dissolved into sat. NaHCO3 sol.:CH2Cl2 (50 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95 to 1:9) to obtain compound 40 (0.165 g, 62%) and 41 (0.02 g, 8%). Compound 40: Solid, mp 203-205° C.; 1H NMR (DMSO-d6) δ 2.26 (s, 3H), 2.50-2.56 (m, 4H), 3.00-3.02 (m, 2H), 6.04 (s, 1H), 6.23 (brs, 1H), 6.66 (dd, 1H, J=1.2, 8.8 Hz), 7.09 (dd, 1H, J=3.9, 5.1 Hz), 7.21 (s, 1H), 7.31 (dd, 2H, J=2.4, 5.4 Hz), 7.59 (d, 1H, J=4.2 Hz), 7.71 (d, 1H, J=3.6 Hz), 10.93 (s, 1H); ESI-MS m/z (%): 337 (M+, 100); Compound 41: Solid, mp 148-150° C.; 1H NMR (DMSO-d6) δ 1.62-1.79 (m, 2H), 1.90-1.94 (m, 2H), 2.04-2.12 (m, 2H), 2.23 (s, 3H), 2.63-2.72 (m, 1H), 2.86-2.89 (m, 2H), 6.28 (brs, 1H), 6.63 (dd, 1H, J=1.8, 8.7 Hz), 6.98 (s, 1H), 7.02 (d, 1H, J=2.1 Hz), 7.09 (dd, 1H, J=3.9, 5.1 Hz), 7.27 (d, 1H, J=8.4 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.6 Hz), 10.60 (s, 1H); ESI-MS m/z (%): 339 (M+, 100).

Workup

  1. temperatureThe resulting solution was refluxed for 2 days
  2. customwas brought to room temperature
  3. filtrationthe solid was filtered off
  4. washwashed with ethanol (2×5 mL)
  5. customdried

Sources & evidence

ORD record
ord-b298b3f2034a44cf8510dfa940c258da
Source dataset
uspto-grants-2008_05
Patent number
US07375219B2

Reaction notes

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