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

HRID 1849772Notes

Reaction equation

HRID 1849772 reaction equation
Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([C:28]#[N:29])[CH:25]3[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:27][CH:19]2[CH2:20]4)[CH2:24]3)=[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:30]1(B(O)O)[CH2:32][CH2:31]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.CC(O)=O.CC(O)=O.[Pd].O>[C:28]([C:18]1([CH2:17][O:16][C:3]2[C:2]([CH:30]3[CH2:32][CH2:31]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)[CH:25]2[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2)#[N:29]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703653Tert-butyl 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoate

Product 1

HCID 86703654Tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoateYield 89.2%

Reagents, catalysts & solvents 3

HCID 4144353Palladium (II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

To a solution of tert-butyl 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoate (1.12 g, 2.66 mmol) in toluene (40 mL) was added water (5 mL), cyclopropylboronic acid (1.32 g, 15.40 mmol), tribasic potassium phosphate (1.69 g, 7.94 mmol), tricyclohexylphosphine tetrafluoroborate (0.658 g, 2.13 mmol) and palladium(II) acetate trimer (0.25 g, 1.09 mmol) while degassing with argon. The reaction mixture was heated to reflux under an argon atmosphere for 16 hours, cooled to ambient temperature. The mixture was filtered through a pad of diatomaceous earth that was washed with ethyl acetate (100 mL). The filtrate was diluted with ethyl acetate (100 mL), washed with a 3:1 mixture of saturated aqueous ammonium chloride and water (150 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound as a yellow foamy solid (1.01 g, 89%): 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J=8.3 Hz, 1H), 6.51 (d, J=12.2 Hz, 1H), 4.26 (s, 2H), 2.36-2.27 (m, 4H), 2.08-2.00 (m, 2H), 1.91-1.87 (m, 5H), 1.78-1.73 (m, 4H), 1.56 (s, 9H), 0.94-0.87 (m, 2H), 0.64-0.59 (m, 2H); MS (ES−) m/z 426.1 (M+1).

Workup

  1. customwhile degassing with argon
  2. temperatureThe reaction mixture was heated
  3. temperatureto reflux under an argon atmosphere for 16 hours
  4. filtrationThe mixture was filtered through a pad of diatomaceous earth that
  5. washwas washed with ethyl acetate (100 mL)
  6. additionThe filtrate was diluted with ethyl acetate (100 mL)
  7. washwashed with a 3:1 mixture of saturated aqueous ammonium chloride and water (150 mL), brine (200 mL)
  8. dry with materialdried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo to dryness
  11. customThe residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-0add85cd8b46453e88aed560a2483bf3
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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