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Toluene → methyl 6-chloro-5-[4-(1-hydroxy-cyclobutyl)-3-methoxy-phenyl]-1H-indole-3-carboxylate

HRID 1054712
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Reaction equation

HRID 1054712 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:29]=[CH:28][C:27]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)=[CH:26][C:25]=1OC.[C:37](=O)([O-])[O-:38].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=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].ClCCl.C(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:25]=[CH:26][C:27]([C:30]2([OH:34])[CH2:31][CH2:32][CH2:33]2)=[C:28]([O:38][CH3:37])[CH:29]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 1140TolueneHCID 11430Potassium CarbonateHCID 86698665methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylateHCID 866987131-(4-Bromo-3-methoxyphenyl)cyclobutanol

Product 1

HCID 86698712methyl 6-chloro-5-[4-(1-hydroxy-cyclobutyl)-3-methoxy-phenyl]-1H-indole-3-carboxylateYield 32%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of methyl 6-Chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1H-indole-3-carboxylate (50 mg, 0.16 mmol), 1-(4-Bromo-3-methoxy-phenyl)cyclobutanol (52 mg, 0.2 mmol), 2 M aqueous potassium carbonate (0.31 mL, 0.63 mmol), toluene (3 mL), and ethanol (1 mL) was sparged with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (6 mg, 0.007 mmol). The reaction mixture was heated to 100° C. and stirred. After 2 hours the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil, which was purified by flash chromatography (12 g silica, 0-35% ethyl acetate/heptane, 24 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless solid (19 mg, 32% yield). MS (ES−) 341.2 (M−H)−; 1H NMR (500 MHz, CD3OD) δ 8.03 (d, J=1.95 Hz, 2 H), 7.60 (s, 1 H), 7.38 (d, J=7.56 Hz, 1 H), 7.06 (d, J=1.46 Hz, 1 H), 7.01 (dd, J=7.68, 1.59 Hz, 1 H), 3.89 (d, J=7.32 Hz, 6 H), 2.65-2.75 (m, 2 H), 2.34-2.44 (m, 2 H), 2.08-2.19 (m, 1 H), 1.70-1.80 (m, 1 H).

Workup

  1. customwas sparged with nitrogen for 10 minutes
  2. temperatureAfter 2 hours the reaction was cooled to room temperature
  3. washwashed with water and saturated brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto afford a yellow oil, which
  8. customwas purified by flash chromatography (12 g silica, 0-35% ethyl acetate/heptane, 24 column volumes)
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-80cbf1efd5b54b45a73f9c5238658e9c
Source dataset
uspto-grants-2016_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09394285B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes