4-Bromotoluene → AGN 193109 Ethyl Ester

HRID 495906Notes

Reaction equation

HRID 495906 reaction equation
[C:1]([Li:5])([CH3:4])([CH3:3])[CH3:2].Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][C:15]1(C)CC=C(OS(C(F)(F)F)(=O)=O)[C:21]2[CH:20]=[C:19]([C:33]#[C:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=3)[CH:18]=[CH:17][C:16]1=2>C1COCC1.[NH4+].[Cl-].[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Li:5][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:2][C:1]1([CH3:4])[CH2:14][CH:15]=[C:16]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:17]2[CH:18]=[C:19]([C:33]#[C:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:44][CH:45]=3)[CH:20]=[CH:21][C:3]1=2

Participants

9

Reactant 3

HCID 78054-BromotolueneHCID 120176384-[2-[5,6-Dihydro-5,5-dimethyl-8-[[(trifluoromethyl)sulfonyl]oxy]-2-naphthalenyl]ethynyl]benzoic acid ethyl ester2×HCID 178418306HCID 178418306, compound

Product 2

HCID 11796412AGN 193109 Ethyl EsterHCID 178506695HCID 178506695, compound

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent3×HCID 25517Ammonium ChlorideSolvent

Procedure

A solution of 4-lithiotoluene was prepared by the addition of 189.9 mg (1.74 ml, 2.96 mmol) of t-butyl lithium (1.7M solution in hexanes) to a cold solution (−78° C.) of 253.6 mg (1.482 mmol) of 4-bromotoluene in 2.0 ml of THF. After stirring for 30 minutes a solution of 269.4 mg (1.977 mmol) of zinc chloride in 3.0 ml of THF was added. The resulting solution was warmed to room temperature, stirred for 30 minutes, and added via cannula to a solution of 472.9 mg (0.988 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) and 50 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0) in 4.0 ml of THF. The resulting solution was heated at 50° C. for 45 minutes, cooled to room temperature and diluted with sat. aqueous NH4Cl. The mixture was extracted with EtOAc (40 ml) and the combined organic layers were washed with water and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to a yellow oil. Purification by column chromatography (silica, 5% EtOAc-hexanes) yielded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 1.35 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.36 (2H, d, J=4.7 Hz), 2.42 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.99 (1H, t, J=4.7 Hz), 7.25 (5H, m), 7.35 (2H, m), 7.52 (2H, d, J=8.5 Hz), 7.98 (2H, d, J=8.5 Hz).

Workup

  1. additionwas added
  2. temperatureThe resulting solution was heated at 50° C. for 45 minutes
  3. temperaturecooled to room temperature
  4. extractionThe mixture was extracted with EtOAc (40 ml)
  5. washthe combined organic layers were washed with water and brine
  6. dry with materialThe organic phase was dried over Na2SO4
  7. concentrationconcentrated in vacuo to a yellow oil
  8. customPurification by column chromatography (silica, 5% EtOAc-hexanes)

Sources & evidence

ORD record
ord-ffa58d08d421497f8658f0a2d2c3586a
Source dataset
uspto-grants-2005_09
Patent number
US06942980B1

Reaction notes

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