Potassium Phosphate, Tribasic → Tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

HRID 1849783Notes

Reaction equation

HRID 1849783 reaction equation
[C:1]12([CH2:8][O:9][C:10]3[C:22](Cl)=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([F:24])[CH:11]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]12([CH2:8][O:9][C:10]3[C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([F:24])[CH:11]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703665Tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate

Product 1

HCID 86703666Tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoateYield 75%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

In a sealed tube containing tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate (1.30 g, 3.70 mmol), cyclopropylboronic acid (0.47 g, 5.50 mmol), tricyclohexylphosphine tetrafluoroborate (0.27 g, 0.74 mmol) and palladium acetate (0.08 g, 0.37 mmol) and potassium phosphate (3.13 g, 14.8 mmol) in toluene (20 mL) and water (2.0 mL) was bubbled with a nitrogen atmosphere for 10 minutes. The reaction mixture was heated to 140° C. for 6 hours and cooled to ambient temperature. The solvent was concentrated in vacuo to dryness. The crude residue was purified column chromatography (10% gradient ethyl acetate in hexanes) afforded the title compound as a colorless solid (1.00 g, 75%): 1H NMR (300 MHz, CDCl3) 7.37 (d, J=8.5 Hz, 1H), 6.42 (d, J=12.8 Hz, 1H), 3.61 (d, J=9.1 Hz, 1H), 3.78 (d, J=9.1 Hz, 1H), 1.96-1.52 (m, 7H), 1.55 (s, 9H), 0.92-0.82 (m, 4H), 0.67-0.61 (m, 4H), 0.38-0.33 (m, 1H).

Workup

  1. customwas bubbled with a nitrogen atmosphere for 10 minutes
  2. temperaturecooled to ambient temperature
  3. concentrationThe solvent was concentrated in vacuo to dryness
  4. customThe crude residue was purified column chromatography (10% gradient ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-41906bff08654de1af0bb5341bf14897
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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