Synthesis of highly substituted 5-(trifluoromethyl)ketoimidazoles using a mixed-solid/solution phase motif

Using a combination of solid phase synthesis for the preparation of N-subst ituted-N-acylglycines 7 followed by solution-phase ring transformation of t rifluoromethylacyl munchnone intermediate 8, a library of 200 trisubstitute d-5-trifluoromethylketo (TFMK) imidazoles 9 was prepared. In a sublibrary, bromoacetate resin 4 was treated with 5 amines in parallel to give N-substi tuted glycines 5 followed by acylation with 12 acid chlorides to provide, u pon cleavage from the resin, 60 individual N-substituted-N-acylglycines 7. The glycines 7 were converted to munchnones 8 by treatment with trifluoroac etic anhydride followed by reaction with benzamidine to give trisubstituted -5-TFMK-imidazoles 9. The structural content of the library was analyzed us ing PlateView of the LCMS results, and individual members were isolated by automated preparative LCMS. (C) 2000 John Wiley & Sons, Inc.