Potassium Carbonate → 4,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carbaldehyde

HRID 1054574Notes

Reaction equation

HRID 1054574 reaction equation
CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:35]1[C:36]([F:47])=[C:37]2[C:41](=[CH:42][C:43]=1[F:44])[NH:40][CH:39]=[C:38]2[CH:45]=[O:46].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].CCO.C1(C)C=CC=CC=1>[F:47][C:36]1[C:35]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3([OH:33])[CH2:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[C:43]([F:44])[CH:42]=[C:41]2[C:37]=1[C:38]([CH:45]=[O:46])=[CH:39][NH:40]2

Participants

10

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 120954191-(4-Bromophenyl)cyclobutanolHCID 866985785-Bromo-4,6-difluoro-1H-indole-3-carbaldehyde

Product 1

HCID 866985794,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carbaldehydeYield 66.5%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 702EthanolSolventHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (188.0 mg, 0.55 mmol), oven dried potassium acetate (230.0 mg, 2.34 mmol), and 1-(4-bromophenyl)cyclobutanol (114.0 mg, 0.50 mmol) in 1,4-dioxane (2 mL) was degassed with N2 for 15 min, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.0 mg, 0.027 mmol). The reaction mixture was subjected to microwave irradiation at 110° C. for 1 hour. The cooled reaction mixture was filtered through celite, rinsed with EtOAc and concentrated to dryness. To the resulting dark solid ((45.0 mg, 0.17 mmol) was added 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (45.0 mg, 0.17 mmol), 2 N aqueous potassium carbonate (0.20 mL, 0.40 mmol), toluene (1.5 mL) and EtOH (0.5 mL). The reaction mixture was degassed with N2 for 10 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.0 mg, 0.019 mmol), and heated in a sealed pressure tube at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography (0-67% EtOAc/heptanes) to give the title compound (37 mg, 65%) as a white solid. MS (ES+) 328.0 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 10.04 (d, J=2.68 Hz, 1 H), 8.15 (s, 1 H), 7.64 (d, J=8.05 Hz, 2 H), 7.48 (d, J=8.05 Hz, 2 H), 7.21 (d, J=9.51 Hz, 1 H), 2.57-2.66 (m, 2 H), 2.39-2.46 (m, 2 H), 2.03-2.12 (m, 1 H), 1.73-1.83 (m, 1 H).

Workup

  1. customwas degassed with N2 for 15 min
  2. customirradiation at 110° C. for 1 hour
  3. customThe cooled reaction mixture
  4. filtrationwas filtered through celite
  5. washrinsed with EtOAc
  6. concentrationconcentrated to dryness
  7. customThe reaction mixture was degassed with N2 for 10 minutes
  8. temperatureThe reaction mixture was cooled to room temperature
  9. custompurified by flash chromatography (0-67% EtOAc/heptanes)

Sources & evidence

ORD record
ord-1f851abb00684c958da9bba46a587d7f
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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