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

HRID 474892

Reaction equation

HRID 474892 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=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[N:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=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 579502624-(6-(Trifluoromethyl)pyridazin-3-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 66873862tert-Butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1 (2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylateYield 31.3%

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-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (106 mg, 0.438 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (183 mg, 0.482 mmol), CuI (100 mg, 0.526 mmol), 8-hydroxyquinoline (13 mg, 0.09 mmol) and Cs2CO3 (157 mg, 0.482 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added and the resulting suspension was stirred at 25° C. for 30 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 (74 mg, 30%) as a viscous oil: 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=8.7 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.65 (d, J=6.9 Hz, 1H), 7.62-7.53 (m, 1H), 7.33 (br s, 1H), 7.30-7.21 (overlapping with solvent peak, 2H), 7.08 (d, J=8.1 Hz, 1H), 3.71-3.62 (m, 7H), 3.11-2.98 (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 (10 mL) was added
  4. stirringthe resulting suspension was stirred at 25° C. for 30 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-dc14e45cce6d4c1893900be22c19f517
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Linked notes

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