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We report a Pd-catalyzed ring-opening/arylation/cyclization reaction sequence between 2-aminothiazoles and aryl (pseudo)halides that provides modular access to isocytosine analogues. The scope of the reaction is broad with respect to both coupling partners and a robustness test demonstrated the functional group tolerance of the methodology. Visual kinetic analysis revealed that the product may inhibit catalyst turnover for some substrates.

A screening method for the rapid identification of catalytic conditions for Pd-catalyzed C-N cross-coupling reactions is reported. The strategy evaluates mixtures of precatalysts, ligands, and bases to identify productive conditions that are subsequently optimized through two deconvolution steps, which uncover the active catalyst and identify the optimal solvent and base for the catalytic system. The efficacy of this approach was demonstrated through application to a previously reported reaction, whereby both the literature conditions and additional solutions were retrieved. The same approach to Ni-catalyzed C-N cross-coupling was investigated in parallel but was found to be less successful due to limited activity of the evaluated reagent combinations. Finally, the utility of this method was showcased by identifying effective conditions for the Pd-catalyzed cross-coupling of complex molecules, which not only revealed nonobvious solutions for the processes under evaluation but also resulted in the discovery of new chemical 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.

1,1,4,7,10,10-Hexamethyltriethylenetetramine (HMTTA) emerged from a limited parallel screening of selected polyamines as the most appropriate additive for an especially problematic Koenigs-Knorr glucuronidation. This initial finding rapidly evolved into a reliable and high-yielding procedure through the use of two sets of experimental designs. The detailed effect of the stoichiometry of reagents and the amount of amine additive on reaction yield was elucidated. The complexity of the response surface for product yield, described by a third-order polynomial equation, together with ancillary kinetic experiments evidenced the multiple role of HMTTA in the present glucuronidation process.