Water → methyl 6-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate

HRID 338323Notes

Reaction equation

HRID 338323 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:39]=[CH:38][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:39]=[CH:38][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[CH:26][CH:25]=1

Participants

9

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 23047294-[3-(4-Bromophenoxy)propyl]morpholineHCID 86698665methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate

Product 1

HCID 86698670methyl 6-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylateYield 40%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (45 mg, 0.14 mmol), 4-[3-(4-bromophenoxy)-propyl]-morpholine (42 mg, 0.14 mmol) prepared using the procedure in Le Sann, C.; Huddleston, J.; Mann, J. Tetrahedron, 2007, 63, 12903-12911, and 2M potassium carbonate solution (0.28 mL, 0.56 mmol) in toluene (0.9 mL) and ethanol (0.3 mL) was degassed with nitrogen for 5 minutes then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.0 mg, 0.007 mmol). The reaction vessel was sealed and heated at 110° C. for 2.5 h. The cooled reaction mixture was poured into water and ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using flash column chromatography eluting with heptanes/ethyl acetate (4:1 to 0:1) and ethyl acetate/methanol (9:1) to give the title compound (24 mg, 40%). MS (ES+) 429.2 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.37 (br. s., 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.33 (d, J=8.59 Hz, 2H), 6.97 (d, J=8.78 Hz, 2H), 4.11 (t, J=5.95 Hz, 2H), 3.84 (s, 3H), 3.79 (t, J=4.69 Hz, 4H), 2.89-2.97 (m, 2H), 2.86 (m, 4H), 2.11 (dt, J=15.42, 5.86 Hz, 2H).

Workup

  1. customprepared
  2. customThe reaction vessel was sealed
  3. customThe cooled reaction mixture
  4. customThe layers were separated
  5. extractionthe aqueous layer was back-extracted twice with ethyl acetate
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified
  10. washeluting with heptanes/ethyl acetate (4:1 to 0:1) and ethyl acetate/methanol (9:1)

Sources & evidence

ORD record
ord-6af513259f8b48be808e831a51e8cfc2
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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