Using intelligent/random library screening to design focused libraries forthe optimization of homogeneous catalysts: Ullmann ether formation

A 96-member "pyridine" library consisting of both rationally chosen and "ra ndom" members was used to screen Ullmann ether forming reactions. The react ion of 2-bromo-4,6-dimethylaniline and other substrates with a variety of a lkoxides was investigated under different conditions with the aid of an aut omated liquid handler. From the results of the 96-member library screening, a structure activity profile was determined which led to the design of sma ller "focused" ligand libraries. The focused libraries produced a higher fr equency of hits compared to the original 96-member library. Some of the mor e effective ligands discovered in this work were found to be generally usef ul for alkoxylation of a variety of substrates, and also functioned in intr amolecular ether forming reactions. This work demonstrates for homogeneous catalysis the analogy to the pharmacological model of drug discovery. By us ing a large library to screen for a lead compound followed by screening the diversity space closest to the lead, a larger fraction of increased perfor mance ligands was discovered.