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

HRID 474893

Reaction equation

HRID 474893 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]1=2

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 576255234-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-oneHCID 58093439tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

Product 1

HCID 66873733tert-Butyl 6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylateYield 36.7%

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-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (178 mg, 0.740 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (255 mg, 0.673 mmol), CuI (154 mg, 0.808 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol) and Cs2CO3 (241 mg, 0.740 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135° C. for 36 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH was added and the resulting suspension was stirred at 25° C. for 20 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (133 mg, 33%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.00 (br s, 1H), 8.07 (br d, J=8.3 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.60-7.52 (m, 2H), 7.32 (s, 1H), 7.28-7.20 (overlapping with solvent peak, 1H), 7.11-7.02 (m, 2H), 3.84-3.60 (m, 7H), 3.12-2.95 (m, 4H), 1.49 (s, 9H).

Workup

  1. customwas degassed under reduced pressure for 45 min
  2. temperatureThe suspension was cooled
  3. addition9:0.9:0.1 CH2Cl2/MeOH/NH4OH was added
  4. stirringthe resulting suspension was stirred at 25° C. for 20 min
  5. washthe filtrate was washed with brine
  6. dry with materialThe resulting solution was dried over Na2SO4
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-fffd03993a4a4559a7f315ca925f6975
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Linked notes

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