Potassium Carbonate → 6-chloro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-1H-indole-3-carbaldehyde

HRID 338225

Reaction equation

HRID 338225 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][O:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][C:43]=1[Cl: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>[Cl:44][C:43]1[CH:42]=[C:41]2[C:37]([C:38]([CH:45]=[O:46])=[CH:39][NH:40]2)=[CH:36][C:35]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][O:31][CH2:30]2)=[CH:25][CH:24]=1

Participants

10

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 583823793-(4-Bromophenyl)oxetan-3-olHCID 866985665-bromo-6-chloro-1H-indole-3-carbaldehyde

Product 1

HCID 866985766-chloro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-1H-indole-3-carbaldehydeYield 35.5%

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]dioxaborinanyl] (149.0 mg, 0.44 mmol), oven dried potassium acetate (173.0 mg, 1.75 mmol) and 3-(4-bromo-phenyl)-oxetan-3-ol (100.0 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was degassed with N2 for 5 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.0 mg, 0.044 mmol) and subjected to microwave irradiation at 110° C. for 1 hour. The cooled reaction mixture was filtered through celite and concentrated in vacuo to give a black oil. To the dark oil was added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (112.0 mg, 0.43 mmol), 2N aqueous potassium carbonate (0.4 mL, 0.80 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) (25.0 mg, 0.034 mmol), and heated in a pressure tube to 110° C. for 2 hours. The cooled reaction mixture was purified by flash chromatography (33-100% EtOAc/heptanes) to give a solid. The solid was triturated in MeOH and filtered to afford the title compound (50 mg, 35%) as a yellow solid. MS (ES+) 328.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.92 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.66 (d, J=9.4 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 6.36 (s, 1H), 4.80-4.76 (m, 2H), 4.75-4.71 (m, 2H).

Workup

  1. customwas degassed with N2 for 5 minutes
  2. customirradiation at 110° C. for 1 hour
  3. customThe cooled reaction mixture
  4. filtrationwas filtered through celite and
  5. concentrationconcentrated in vacuo
  6. customto give a black oil
  7. customThe reaction mixture was degassed with N2 for 10 minutes
  8. customThe cooled reaction mixture
  9. customwas purified by flash chromatography (33-100% EtOAc/heptanes)
  10. customto give a solid
  11. customThe solid was triturated in MeOH
  12. filtrationfiltered

Sources & evidence

ORD record
ord-8152ea7e50ec43aea5cafab497fadaef
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Linked notes

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