Synthesis of 2-Aryl-2,3,3,3-tetrafluoropropanoic Acids, Tetrafluorinated Fenoprofen and Ketoprofen by Electrochemical Carboxylation of Pentafluoroethylarenes

Abstract

Synthesis of 2,3,3,3-tetrafluoro-2-(3-phenoxyphenyl)­-propanoic acid and 2-(3-benzoylphenyl)-2,3,3,3-tetrafluoropropanoic acid (tetrafluorinated fenoprofen and ketoprofen) was achieved by electrochemical carboxylation of pentafluoroethyl­arenes.

carboxylic acids - fluorine-containing compounds - magnesium anode - electrochemical carboxylation - NSAIDs

References

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The yield of tetrafluorinated ibuprofen and loxoprofen by EC of the corresponding tetrafluoroethylarenes were 31% and 32%, respectively, as determined by ^¹9F NMR spectroscopy.

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The low yields in the synthesis of tetrafluorinated ibuprofen and loxoprofen are due to the elimination of a fluoride ion from the intermediate A producing the corresponding trifluorostyrenes, [¹0] [¹7] whose electrochemical reduction followed by the fixation of CO₂ would likely lead to several carboxylic acids as by-products [9a,f] resulting in low yields of the expected products.

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We independently prepared α,β,β-trifluoro-4-isobutyl­-styrene and confirmed its formation in the EC of 4-(penta­-fluoroethyl)isobutylbenzene by ^¹9F NMR spectra of the crude products. We also tried the EC of α,β,β-trifluoro-4-isobutylstyrene under the same conditions as the EC of 4-(pentafluoroethyl)isobutylbenzene and found that ^¹9F NMR spectra of the crude products closely resembled that of the EC of 4-(pentafluoroethyl)isobutylbenzene. These results indicated that similar products would be produced in both reactions and α,β,β-trifluoro-4-isobutylstyrene would be produced in the EC of 4-(pentafluoroethyl)isobutylbenzene. Because both reactions were complicated and several products were produced, isolation and identification of the products could not be carried out.