Toluene → Methyl 6-chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylate

HRID 338381Notes

Reaction equation

HRID 338381 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][NH:22]2)=[CH:18][C:17]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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].C1COCC1.O.C(O)C>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][NH:22]2)=[CH:18][C:17]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[C:4]([O:13][CH3:14])[CH:3]=1

Participants

9

Reactant 4

HCID 1140TolueneHCID 11430Potassium CarbonateHCID 86698665methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylateHCID 866987222-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol2×

Product 1

HCID 86698724Methyl 6-chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylateYield 56%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
115 °C

Procedure

A mixture of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (crude product from Step 4, containing 40% of the desired material, 75 mg, 0.12 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (45 mg, 0.14 mmol), PdCl2(dppf) (11 mg, 0.013 mmol), potassium carbonate (80 mg, 0.58 mmol), toluene (0.6 mL), ethanol (0.3 mL), water (0.3 mL), and THF (0.3 mL) was stirred at 115° C. for 2.5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (4 mL) of ethyl acetate. The extract was loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane gave the title compound (25 mg, 56% yield). MS (ES−) 386.2 (M−H)−. Retention time: 3.38 min. Column: Phenomenex Gemini-NX, 4.6 mm×50 mm, C18, 3 μm, 110A; Column Temperature 60° C. Mobile Phase A: 0.1% formic acid in water (v/v); Mobile Phase B: 0.1% formic acid in acetonitrile (v/v) Gradient Profile: Flow-1.5 mL/min. Initial conditions: A-95%, B-5%; Linear Ramp to A-0%, B-100% over 0.0-4.10 min; hold at A-0%, B-100% from 4.10-4.50 min; return to initial conditions 4.60-5.0 min.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. extractionextracted with ethyl acetate (4 mL) of ethyl acetate
  3. washChromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane

Sources & evidence

ORD record
ord-131eb00d5cb14089b89f4207890faca5
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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