Hydroquinone → 9-methyl-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

HRID 2176137Notes

Reaction equation

HRID 2176137 reaction equation
[Na].[CH3:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH:12]4[CH2:18][CH2:17][N:15]([CH2:16][C:6]=3[C:5]=2[CH:4]=1)[CH2:14][CH2:13]4.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.C1(C=CC(O)=CC=1)O>CS(C)=O>[CH3:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:7]3[CH:12]4[CH2:13][CH2:14][N:15]([CH2:16][C:6]=3[C:5]=2[CH:4]=1)[CH2:17][CH2:18]4

Participants

6

Reactant 4

HCID 785HydroquinoneHCID 5360545SodiumHCID 574168485-Ethenyl-2-(trifluoromethyl)pyridineHCID 67544841HCID 67544841, compound

Product 1

HCID 453806669-methyl-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent2×

Conditions

Temperature
115 °C

Procedure

Sodium dispersion in paraffin (30%, 46 mg, 0.60 mmol; Aldrich) was combined with 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (100 mg, 0.442 mmol; Example 2B) in a 20 mL vial with stir bar and septum cap. Dimethyl sulfoxide (2.5 mL) was added, and the vial was evacuated and purged with nitrogen (10 cycles). The mixture was stirred at room temperature for 10 minutes, and a solution of the product of Example 143A (115 mg, 0.663 mmol) and hydroquinone (12 mg, 0.110 mmol) in dimethyl sulfoxide (0.5 mL) was added. The vial was evacuated and purged with nitrogen (5 cycles) and the mixture was stirred with heating at 115° C. for 39 hours. The dark brown mixture was cooled to room temperature, applied directly to a column of silica gel and eluted with chloroform, followed by CHCl3—CH3OH-14.8 M aqueous NH4OH (90:10:1). The product-containing fractions were combined and concentrated under vacuum, and the residue was purified by HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-90% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ 1.46-1.64 (m, 2H), 1.79-1.98 (m, 2H), 2.38 (s, 3H), 2.84-3.01 (m, 3H), 3.05-3.22 (m, 4H), 4.16 (s, 2H), 4.42 (t, J=6.27 Hz, 2H), 6.89 (dd, J=8.48, 1.02 Hz, 1H), 7.09 (d, J=7.80 Hz, 1H), 7.10 (d, J=0.68 Hz, 1H), 7.54 (dd, J=8.10, 1.70 Hz, 1H), 7.59 (d, J=8.10 Hz, 1H), 8.12 ppm (s, 1H); MS (ESI) m/z 400 (MH)+.

Workup

  1. customseptum cap
  2. customthe vial was evacuated
  3. custompurged with nitrogen (10 cycles)
  4. stirringThe mixture was stirred at room temperature for 10 minutes
  5. customThe vial was evacuated
  6. custompurged with nitrogen (5 cycles)
  7. stirringthe mixture was stirred
  8. temperatureThe dark brown mixture was cooled to room temperature
  9. washeluted with chloroform
  10. concentrationconcentrated under vacuum
  11. customthe residue was purified by HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-90% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes]

Sources & evidence

ORD record
ord-eaf9018a155446039fb294dea3b614bd
Source dataset
uspto-grants-2015_06
Patent number
US09063126B2

Reaction notes

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