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

HRID 475006Notes

Reaction equation

HRID 475006 reaction equation
[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 220499004-(4-Fluorobenzyloxy)-1h-pyridin-2-oneHCID 66874851tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

Product 1

HCID 70805234tert-butyl 8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylateYield 54%

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-(4-fluorobenzyloxy)pyridin-2(1H)-one (95 mg, 0.43 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (180 mg, 0.47 mmol), 8-hydroxyquinoline (13 mg, 0.086 mmol) and Cs2CO3 (154 mg, 0.47 mmol) in DMSO (10 mL) was degassed under reduced pressure for 40 min. CuI (98 mg, 0.52 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 2×5 min. The reaction mixture was then heated at 135° C. under nitrogen overnight. The reaction 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 5 min. Celite was added, and the suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was dissolved in DCM and stirred with charcoal for 10 min. The suspension was filtered, concentrated and purified to afford the title compound (0.12 g, 54%) as a mixture of rotamers: 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J=8.5 Hz, 0.4H), 7.53 (d, J=8.0 Hz, 0.6H), 7.41 (dd, J=8.0, 6.0 Hz, 2H), 7.33-7.26 (m, 2H), 7.10 (t, J=8.5 Hz 2H), 7.00 (d, J=8.0 Hz, 1H), 6.07 (s, 1H), 6.02 (d, J=5.5 Hz, 1H), 5.01 (s, 2H), 4.71 (s, 0.7H), 4.63 (s, 1.3H), 3.76 (br s, 1.3H), 3.68 (br s, 0.7H), 3.65 (s, 3H), 2.97 (br s, 2H), 2.05-2.03 (m, 2H), 1.44 (s, 3.1H), 1.37 (s, 5.9H).

Workup

  1. customwas degassed under reduced pressure for 40 min
  2. customthe reaction mixture was degassed under reduced pressure for 2×5 min
  3. temperatureThe reaction suspension was cooled
  4. addition9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added
  5. additionCelite was added
  6. stirringthe suspension was stirred for 5 min
  7. filtrationThe suspension was filtered through Celite
  8. washthe filtrate was washed with brine
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated under reduced pressure
  11. dissolutionThe resulting residue was dissolved in DCM
  12. stirringstirred with charcoal for 10 min
  13. filtrationThe suspension was filtered
  14. concentrationconcentrated
  15. custompurified

Sources & evidence

ORD record
ord-42290e11e0b44716a91a744bd85b739e
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

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