Potassium Phosphate, Tribasic → Tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

HRID 1849739Notes

Reaction equation

HRID 1849739 reaction equation
[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]3[C:25](Cl)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]3[C:25]([CH:28]4[CH2:30][CH2:29]4)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703617Tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate

Product 1

HCID 86703618Tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-cyclopropyl-2-fluorobenzoateYield 259.1%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
150 °C

Procedure

To a mixture of tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate (1.20 g, 3.00 mmol) in toluene (18 mL) was added cyclopropylboronic acid (1.55 g, 18.00 mmol), potassium phosphate tribasic (1.91 g, 9.00 mmol), tricyclohexyl- phosphine tetrafluoroborate (0.884 g, 2.40 mmol), palladium acetate (0.269 g, 1.20 mmol) and water (2 mL). The reaction mixture was thoroughly degassed by passing argon through it and then heated in a microwave at 150° C. for 30 minutes. The reaction was performed 4 times as described. After cooling to ambient temperature, the reaction mixtures were combined, diluted with ethyl acetate (200 mL) and filtered over anhydrous sodium sulfate. After removing all volatiles under reduced pressure, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a yellowish oil (3.16 g, 16%): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=8.4 Hz, 1H), 6.48 (d, J=12.7 Hz, 1H), 3.95-3.92 (m, 4H), 3.80 (d, J=6.1 Hz, 2H), 2.04-1.70 (m, 10H), 1.54 (s, 9H), 0.91-0.82 (m, 2H), 0.64-0.57 (m, 2H).

Workup

  1. customThe reaction mixture was thoroughly degassed
  2. temperatureAfter cooling to ambient temperature
  3. customthe reaction mixtures
  4. filtrationfiltered over anhydrous sodium sulfate
  5. customAfter removing all volatiles under reduced pressure
  6. customthe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-6e4a47ef2b014429a016647758e186b3
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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