Hydrochloric Acid → 3,5-Bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester

HRID 1281438Notes

Reaction equation

HRID 1281438 reaction equation
C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15](I)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(Cl)Cl.Cl>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].O1CCOCC1>[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)[CH:12]=1)[CH3:8].[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 27343883-(Trifluoromethyl)phenylboronic acidHCID 113389853-Bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester

Product 2

HCID 540981933,5-Bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl esterYield 36%HCID 541225173-Bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl esterYield 33%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Procedure

To stirred solution of K2CO3 (2 M in H2O) (1.9 mL, 3.6 mmol) at rt was added dioxane (14.3 mL), 3-bromo-4-(2-hydroxyethoxy)-5-iodo-benzoic acid ethyl ester (0.503 g, 1.21 mmol) and 3-trifluoromethyl-phenyl boronic acid (0.299 g, 1.57 mmol). The reaction mixture was purged with N2 for a few minutes and then [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (0.030 g, 0.036 mmol) was added. The reaction was stirred at rt for 1.5 h and then heated at reflux for 2 h. After cooling to rt, it was poured into a 0.1 N HCl solution and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After concentration in vacuo, the residue was first purified by flash chromatography (25% EtOAc:hexane) and then HPLC [60% CH2Cl2 (6% MTBE):40% hexane to afford 3,5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester (0.215 g, 36%) as a white solid 1H NMR (CDCl3) δ 8.09 (s, 2H); 7.94 (m, 2H); 7.86-7.80 (m, 2H); 7.71-7.58 (m, 4H); 4.42 (q, 2H) 3.63 (m, 4H); 1.42 (t, 3H) and 3-Bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester (0.173 g, 33%) as a white solid 1H NMR (CDCl3) δ 8.29 (d, 1H); 8.00 (d, 1H); 7.86 (m, 1H); 7.80-7.55 (m, 3H); 4.40 (q, 2H); 3.74-3.60 (m, 4H); 1.92 (t, 1H); 1.40 (t, 3H).

Workup

  1. customThe reaction mixture was purged with N2 for a few minutes
  2. temperatureheated
  3. temperatureat reflux for 2 h
  4. temperatureAfter cooling to rt
  5. extractionextracted with EtOAc
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over MgSO4
  8. concentrationAfter concentration in vacuo
  9. customthe residue was first purified by flash chromatography (25% EtOAc:hexane)

Sources & evidence

ORD record
ord-1ec38b18f9c64306a1bb8d59c4f2975f
Source dataset
uspto-grants-2002_09
Patent number
US06451827B2

Reaction notes

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