Potassium Phosphate, Tribasic → Tert-butyl 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoate

HRID 1849828Notes

Reaction equation

HRID 1849828 reaction equation
Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([C:24]#[N:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:26]1(B(O)O)[CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd]>[C:24]([C:18]1([CH2:17][O:16][C:3]2[C:2]([CH:26]3[CH2:28][CH2:27]3)=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([F:15])[CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)#[N:25]

Participants

10

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703716Tert-butyl 5-chloro-4-((1-cyanocyclohexyl)methoxy)-2-fluorobenzoate

Product 1

HCID 86703715Tert-butyl 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoateYield 86.4%

Reagents, catalysts & solvents 5

HCID 23938PalladiumCatalystHCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

To an argon-degassed solution of tert-butyl 5-chloro-4-((1-cyano-cyclohexyl)methoxy)-2-fluorobenzoate (0.571 g, 1.55 mmol) in toluene (8 mL) and water (1 mL) was added cyclopropylboronic acid (0.66 g, 7.71 mmol), tribasic potassium phosphate (1.02 g, 4.80 mmol), tricyclohexylphosphine tetrafluoroborate (0.28 g, 0.92 mmol), and palladium acetate trimer (0.11 g, 0.47 mmol Pd). The mixture was heated at 150° C. in a microwave reactor for 0.5 hour, then diluted with ethyl acetate (150 mL), washed with a 3:1 mixture of saturated aqueous ammonium chloride and water (2×150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of ethyl acetate in hexanes from 0-10% to afford the title compound as a yellow syrup (0.50 g, 86%): 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J=8.3 Hz, 1H), 6.46 (d, J=12.2 Hz, 1H), 3.93 (s, 2H), 2.18-2.13 (m, 2H), 2.07-1.98 (m, 1H), 1.82-1.63 (m, 5H), 1.55 (s, 9H), 1.48-1.39 (m, 2H), 1.29-1.21 (m, 1H), 0.94-0.88 (m, 2H), 0.65-0.60 (m, 2H); MS (ES+) m/z 374.0 (M+1).

Workup

  1. washwashed with a 3:1 mixture of saturated aqueous ammonium chloride and water (2×150 mL)
  2. dry with materialdried over anhydrous magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo to dryness
  5. customThe residue was purified by column chromatography with a gradient of ethyl acetate in hexanes from 0-10%

Sources & evidence

ORD record
ord-d5c248637a96473e991af9e8e99fe900
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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