Sodium Carbonate → (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid 2,2-dimethylpropyl ester

HRID 1595988Notes

Reaction equation

HRID 1595988 reaction equation
[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1B(O)O)=[O:6].[CH2:22]([C@@H:29]1[C@@H:38]([OH:39])[C:37]2[C:32](=[CH:33][C:34](Br)=[CH:35][CH:36]=2)[O:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][O:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[C:34]1[CH:33]=[C:32]2[C:37]([C@H:38]([OH:39])[C@@H:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][O:31]2)=[CH:36][CH:35]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 11278601(3S,4R)-3-benzyl-7-bromo-chroman-4-olHCID 154622682-(Neopentyloxycarbonyl)-5-(trifluoromethyl)phenylboronic acid

Product 1

HCID 10918078(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid 2,2-dimethylpropyl esterYield 84%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 1140TolueneSolvent

Procedure

A bi-phasic solution of 2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid (1.72 g, 5.66 mmol), (3S, 4R)-3-benzyl-7-bromo-chroman-4-ol(1.80 g, 5.63 mmol), sodium carbonate (1.82 g, 17.2 mmol), and tretrakis(triphenyl-phosphine)palladium(0) (12 mg, 0.19 mol%) in toluene (15 mL) and water (9 mL) was stirred at refluxfor 100 minutes. The reaction mixture was cooled to room temperature, poured into water (40 mL) and extracted with diisopropylether (75 mL). The organic extracts were washed with brine (50 mL), treated with Darco® G-60, dried over magnesium sulfate, filtered through Celite®, and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate/hexanes20/80) to provide (3S, 4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid 2,2-dimethylpropyl ester as a white foam (2.35 g, 84% yield): Rf: 0.32 (ethyl acetate/hexanes25/75); IR 3407 (br), 2961, 1721, 1336, 1292, 1252, 1172, 1134, 1110, 1022, 848, 749 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.19-7.37 (m, 6H), 6.88-6.93 (m, 2H), 4.53 (t, J=4.4 Hz, 1H), 4.22 (dd, J=11.2,2.5 Hz, 1H), 3.99 (dd, J=11.2, 3.3 Hz, 1H), 3.78 (s, 2H), 2.73 (dd, J=13.8, 6.3 Hz, 1H), 2.54 (dd, J=13.6, 9.4 Hz, 1H), 2.20-2.80 (m, 1H), 1.81 (d, J=5.2 Hz, 1H), 0.74 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 26.64, 30.96, 34.62, 41.53, 64.76, 67.42, 75.33, 116.77, 121.07, 122.97, 124.13, 126.44, 127.50, 127.54, 128.45, 128.60, 128.92, 129.11, 130.25, 130.31, 139.08, 141.69, 142.03, 154.44, 168.14.

Workup

  1. extractionextracted with diisopropylether (75 mL)
  2. washThe organic extracts were washed with brine (50 mL)
  3. additiontreated with Darco® G-60
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered through Celite®
  6. concentrationconcentrated
  7. customThe crude product was purified by chromatography on silica gel (ethyl acetate/hexanes20/80)

Sources & evidence

ORD record
ord-7bcb7e48fc8f475782f06764af1716de
Source dataset
uspto-grants-2001_09
Patent number
US06288242B1

Reaction notes

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