A Validated “Pool and Split” Approach to Screening and Optimization of Copper-Catalyzed C–N Cross-Coupling Reactions

A general method for the quick identification
of effective catalytic
systems for copper-catalyzed C–N cross-couplings is described.
This is based on evaluating mixtures of copper sources, ancillary
ligands, and bases in different solvents followed by two deconvolution
procedures, which aim at identifying the most proper reagent combination
in only three distinct steps. Despite being a high-throughput approach
in nature, the proposed method utilizes only frugal technological
platforms such as 24-well microplates while offering a screening efficiencythe
number of executed experiments vs the total number
of possible experimentshigher than 95%. To facilitate visualization
and mining of the high-throughput experimentation (HTE) data, Visual
Basic scripts have been developed, which allow streamlining the extraction
of raw HPLC data into TIBCO Spotfire for the graphical display in
the form of pie charts. The unique capabilities of this “pool
and split” approach have been demonstrated by applying it to
literature known cross-coupling reactions. In every case, the described
experimental setup was validated by retrieving the original literature
conditions in addition to exposing several additional solutions with
a minimum number of parallel experiments. Finally, examples are provided
for the successful application of this HTE screening workflow to internal
projects.