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

HRID 475009Notes

Reaction equation

HRID 475009 reaction equation
[Cl: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>[Cl: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 574978644-[(4-Chlorophenyl)methoxy]pyridin-2(1H)-oneHCID 66874851tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

Product 1

HCID 70805149tert-butyl 8-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylateYield 49.3%

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-(4-chlorobenzyloxy)pyridin-2(1H)-one (84 mg, 0.38 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (160 mg, 0.42 mmol), 8-hydroxyquinoline (11 mg, 0.076 mmol) and Cs2CO3 (137 mg, 0.42 mmol) in DMSO (10 mL) was degassed under reduced pressure for 40 min. CuI (87.0 mg, 0.42 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 10 min. The reaction mixture was heated at 135° C. under nitrogen 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 5 min. Celite was added, and the resulting 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 by prep-TLC (CH2Cl2/MeOH 95:5) to afford the title compound (0.10 g, 49%) as a light yellow solid and as a mixture of rotamers: 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J=7.0 Hz, 0.3H), 7.53 (d, J=8.0 Hz, 0.7H), 7.39 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.35-7.27 (m, 2H), 6.99 (d, J=8.5 Hz, 1H), 6.05 (s, 1H), 6.03 (dd, J=7.5, 2.0 Hz, 1H), 5.02 (s, 2H), 4.71 (s, 0.7H), 4.63 (s, 1.3H), 3.76-3.65 (m, 2H), 3.65 (s, 3H), 2.99-2.97 (m, 2H), 2.05-2.00 (m, 2H), 1.44 (s, 3.3H), 1.37 (s, 5.7H).

Workup

  1. customwas degassed under reduced pressure for 40 min
  2. customthe reaction mixture was degassed under reduced pressure for 10 min
  3. temperatureThe suspension was cooled
  4. addition9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added
  5. additionCelite was added
  6. stirringthe resulting 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 by prep-TLC (CH2Cl2/MeOH 95:5)

Sources & evidence

ORD record
ord-db9a596fda3e44d3a25739c6b2108ae5
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

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