Diazomethane → Ethyl 2-(3,5-difluoro-4-hydroxyphenyl)cyclopropanecarboxylate

HRID 445800Notes

Reaction equation

HRID 445800 reaction equation
CN(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+].[N+](=[CH2:15])=[N-].[F:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[C:21]([F:24])[C:22]=1[OH:23]>CCOCC.O.C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:25]2[CH2:15][CH:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[C:21]([F:24])[C:22]=1[OH:23]

Participants

9

Reactant 4

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 59419842Ethyl 2-(3,5-difluoro-4-hydroxyphenyl)cyclopropanecarboxylate

Reagents, catalysts & solvents 4

HCID 176Acetic AcidCatalystHCID 167845palladium(II) acetateCatalyst2×HCID 962WaterSolventHCID 3283Diethyl EtherSolvent2×

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 potassium hydroxide (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 in vacuo, the residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes) to afford the desired product (12) as a white solid. 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 in vacuo
  5. customthe residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-45403e174eac4c0fbea9d3af3d3b7fdc
Source dataset
uspto-grants-2013_07
Patent number
US08476308B2

Reaction notes

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