Synthesis of Naproxen and Ibuprofen by C-H Bond Formation

Among the many stereoselective routes currently employed to prepare enantiomerically pure NS AID a-arylalkanoic acids [63], a pre-eminent position is held by the enantioselective catalytic hydrogenation of a-arylsubstituted acrylic acids. 

By this route, Monsanto researchers were able to obtain both (S)-naproxen 22 and (S)-ibu-profen 57 by exploiting the Ru/BINAP-catalyzed hydrogenation originally developed by Noyori and his group. In the synthesis of both drugs the required acrylic acid was obtained by the relevant procedure outlined in Fig. 20. 

Starting from the readily available parent arenes, ketones 54a,b were prepared by standard Friedel-Crafts chemistry. Environment-friendly electrochemical carboxylation of these gave a-hydroxy acids 55a,b, from which acrylic acids 56a,b were easily obtained. Their reduction, catalyzed by the modified Noyori complex Ru(acac)2/BINAP, afforded in high yields the (. -enantiomers of acids 22 and 57 having 98% and 96% e.e., respectively. Improvements of both processes have been reported [64,65], 

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