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

HRID 1876359Notes

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

Conditions

Temperature: 2.5 °C

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 stifling 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

additionwas added
customto quench any excess reagent
customAfter removal of solvent
customthe residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes)

Sources & evidence

ORD record: ord-1e0fcaf23a7e469abdc5de8052a9ddf8
Source dataset: uspto-grants-2012_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08309600B2

Reaction notes

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