Kinetic comparison of trifluoroacetic acid cleavage reactions of resin-bound carbamates, ureas, secondary amides, and sulfonamides from benzyl-, benzhydryl-, and indole-based linkers

The kinetics of cleavage reactions of 16 resin-bound carbamates, ureas, sec ondary amides, and sulfonamides from four different acid labile linkers inc luding benzyl, benzhydryl, and indole linkers has been investigated. The op timized cleavage conditions are generally milder than those commonly used a nd reported (e.g,, 0.5% TFA as opposed to 5%). Among various linkers studie d in this work, the indole linker has been found to be the most acid labile followed by the Rink linker. The rate of cleavage of compounds linked to t he resin via various functional groups can be summarized as follows: sulfon amide > carbamate similar to urea > amide. This study shows that cleavages of 16 compounds from four different acid labile linkers have been optimized to much milder conditions in terms of TFA concentration and the reaction t ime. It also demonstrates that single bead FTIR is an effective tool for op timizing cleavage conditions.