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‐substituted‐N‐acylglycines 7 followed by solution‐phase ring transformation of trifluoromethylacyl munchnone intermediate 8, a library of 200 trisubstituted‐5‐trifluoromethylketo (TFMK) imidazoles 9 was prepared. In a sublibrary, bromoacetate resin 4 was treated with 5 amines in parallel to give N‐substituted glycines 5 followed by acylation with 12 acid chlorides to provide, upon cleavage from the resin, 60 individual N‐substituted‐N‐acylglycines 7. The glycines 7 were converted to munchnones 8 by treatment with trifluoroacetic anhydride followed by reaction with benzamidine to give trisubstituted‐5‐TFMK‐imidazoles 9. The structural content of the library was analyzed using PlateView of the LCMS results, and individual members were isolated by automated preparative LCMS. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 71:28–37, 2000.