Tris(1,1-dimethylethyl)phosphine → 9-fluoro-6-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

HRID 2176149Notes

Reaction equation

HRID 2176149 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.C([Li])CCC.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br/[CH:37]=[CH:38]/[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[N:43][CH:44]=1>C1(C)C=CC=CC=1.COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:37]=[CH:38]/[C:39]3[CH:44]=[N:43][C:42]([CH3:45])=[CH:41][CH:40]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4

Participants

8

Reactant 4

HCID 83681Tris(1,1-dimethylethyl)phosphineHCID 675437619-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleHCID 86640696(E)-5-(2-bromovinyl)-2-methylpyridineHCID 178418339Butyllithium

Product 1

HCID 453804829-fluoro-6-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

Reagents, catalysts & solvents 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 1140TolueneSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
70 °C

Procedure

A solution of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (100 mg, 0.434 mmol; Example 161) in a mixture of toluene (4 mL) and 1,2-dimethoxyethane (1 mL) was degassed with nitrogen. n-Butyllithium (2 M in cyclohexane; 217 mL, 0.434 mmol; Aldrich) was added at room temperature and the mixture stirred for 30 minutes. Bis(dibenzylidene-acetone)palladium (19.98 mg, 0.035 mmol; Aldrich), tri-tert-butylphosphine (1 M in toluene; 0.069 mL, 0.069 mmol; Aldrich) and (E)-5-(2-bromovinyl)-2-methylpyridine (86 mg, 0.434 mmol; Example 23C) were added. The reaction mixture was heated at 70° C. for 18 hours. After cooling, the mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, Isco SF15-24, using a of chloroform/methanol/concentrated NH4OH, 90/9/1) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ 2.20 (m, 4H), 2.55 (s, 3H), 3.23 (m, 4H), 3.52 (m, 1H), 4.39 (s, 2H), 6.82 (d, J=14.5 Hz, 1H), 6.97 (td, J=2.5, 9.0 Hz, 1H), 7.10 (dd, J=2.5, 9.0 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.64 (dd, J=4.0, 9.0 Hz, 1H), 7.72 (d, J=14.5 Hz, 1H), 7.99 (dd, J=2.3, 8.0 Hz, 1H), 8.55 (d, J=2.1 Hz, 1H); MS (ESI) m/z 348 (M+H)+.

Workup

  1. customwas degassed with nitrogen
  2. temperatureAfter cooling
  3. filtrationthe mixture was filtered through a pad of diatomaceous earth
  4. concentrationconcentrated in vacuo
  5. customthe residue was purified by flash chromatography (silica gel, Isco SF15-24

Sources & evidence

ORD record
ord-8aec53668a514243bd3193446b6cc74f
Source dataset
uspto-grants-2015_06
Patent number
US09063126B2

Reaction notes

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