8-Hydroxyquinoline → tert-butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate

HRID 475012Notes

Reaction equation

HRID 475012 reaction equation
[CH2:1]([C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:26][N:23]1[C:24]2[CH:25]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:10][C:11]3=[O:15])[CH:18]=[CH:19][C:20]=2[C:21]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][CH2:27][C:22]1=2

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 66874851tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylateHCID 178517723HCID 178517723, compound

Product 1

HCID 66873854tert-butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylateYield 25%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
135 °C

Procedure

A suspension of 4-phenethylpyrimidin-2(1H)-one (55 mg, 0.28 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (0.13 g, 0.34 mmol), 8-hydroxyquinoline (10 mg, 0.07 mmol) and Cs2CO3 (0.12 g, 0.36 mmol) in DMSO (4.5 mL) was degassed under reduced pressure for 15 min. CuI (65.0 mg, 0.34 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 5 min. The suspension was heated at 135° C. in a microwave for 150 min. The mixture was then cooled and diluted with ethyl acetate. The resulting mixture was washed sequentially with an aqueous solution of LiCl (5%) and ammonium hydroxide (1%) (2×) and brine. The organic extract was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was dissolved in DCM, treated with charcoal for 20 min and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (DCM to DCM/MeOH 95:5) to give the title compound (34.0 mg, 25%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.67-7.53 (m, 2H), 7.33-7.20 (m, 6H), 7.05-6.98 (m, 1H), 6.22 (d, J=6.5 Hz, 1H), 4.71-4.62 (m, 2H), 3.76-3.68 (m, 2H), 3.66 (s, 3H), 3.15-3.12 (m, 2H), 3.02-2.96 (m, 4H), 2.08-2.02 (m, 2H), 1.49-1.27 (m, 9H).

Workup

  1. customwas degassed under reduced pressure for 15 min
  2. customthe reaction mixture was degassed under reduced pressure for 5 min
  3. temperatureThe mixture was then cooled
  4. additiondiluted with ethyl acetate
  5. washThe resulting mixture was washed sequentially with an aqueous solution of LiCl (5%) and ammonium hydroxide (1%) (2×) and brine
  6. extractionThe organic extract
  7. customwas separated
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. dissolutionThe crude material was dissolved in DCM
  11. additiontreated with charcoal for 20 min
  12. filtrationfiltered through a pad of celite
  13. concentrationThe filtrate was concentrated under reduced pressure
  14. customthe residue was purified by flash column chromatography (DCM to DCM/MeOH 95:5)

Sources & evidence

ORD record
ord-64784daa9eb845c094b58009a272a128
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

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