Diethyl Ether → Ethyl 2-(2-(3,5-difluoro-4-hydroxyphenyl)cyclopropyl)acetate

HRID 445802Notes

Reaction equation

HRID 445802 reaction equation
CN(N=O)C(N[N+]([O-])=O)=N.[OH-:11].[K+].[N+](=C)=[N-].[F:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27](OCC)=O)[CH:20]=[C:21]([F:24])[C:22]=1[OH:23].[CH3:32][CH2:33][O:34][CH2:35][CH3:36]>O.C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:21]1[CH:20]=[C:19]([CH:25]2[CH2:26][CH:27]2[CH2:32][C:33]([O:34][CH2:35][CH3:36])=[O:11])[CH:18]=[C:17]([F:16])[C:22]=1[OH:23]

Participants

9

Reactant 5

HCID 3283Diethyl Ether2×HCID 9550Diazomethane3×HCID 14797Potassium HydroxideHCID 59419838ethyl (2E)-3-(3,5-difluoro-4-hydroxyphenyl)prop-2-enoateHCID 135436526N-Methyl-N'-nitro-N-nitrosoguanidine

Product 1

HCID 58566498Ethyl 2-(2-(3,5-difluoro-4-hydroxyphenyl)cyclopropyl)acetate

Reagents, catalysts & solvents 3

HCID 176Acetic AcidCatalystHCID 167845palladium(II) acetateCatalyst2×HCID 962WaterSolvent

Procedure

To a mixture of N-methyl-N′-nitro-N-nitrosoguanidine (TCI-America catalogue #M0527, 10 g on a dry weight basis, 0.068 mol) in ether (150 mL) at 0° C. was added a cold solution of KOH (12.60 g) in water (21 mL). After stirring for 2 minutes, a portion of the yellow ethereal solution of the resulting diazomethane was added to a solution of ethyl 3-(3,5-difluoro-4-hydroxyphenyl)acrylate (10) (2.28 g, 0.010 mol) in ether (100 mL) at 0° C. A portion of palladium (II) acetate (0.372 g, 1.66 mmol) was added followed by an additional portion of diazomethane solution. This process was continued until all the diazomethane solution and palladium (II) acetate was added. The resulting dark mixture was stirred at 0-5° C. for 4 hours and acetic acid (6 drops) was added to quench any excess reagent. After removal of solvent, the residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes) to afford 2.04 g of the desired product as a white solid (12). 1H NMR (400 MHz, CDCl3) δ: 6.67 (d, J=8.4 Hz, 2H), 5.05 (br, 1H), 4.20 (q, J=7.1 Hz, 2H), 2.45-2.40 (m, 1H), 1.87-1.74 (m, 1H), 1.39-1.14 (m, 5H).

Workup

  1. additionwas added
  2. stirringThe resulting dark mixture was stirred at 0-5° C. for 4 hours
  3. customto quench any excess reagent
  4. customAfter removal of solvent
  5. customthe residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-305b3aba1d5e4793a878650860c0d6e0
Source dataset
uspto-grants-2013_07
Patent number
US08476308B2

Reaction notes

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