Use of a Droplet Platform To Optimize Pd-Catalyzed C–N Coupling Reactions Promoted by Organic Bases

Recent
advances in Pd-catalyzed carbon–nitrogen cross-coupling
have enabled the use of soluble organic bases instead of insoluble
or strong inorganic bases that are traditionally employed. The single-phase
nature of these reaction conditions facilitates their implementation
in continuous flow systems, high-throughput optimization platforms,
and large-scale applications. In this work, we utilized an automated
microfluidic optimization platform to determine optimal reaction conditions
for the couplings of an aryl triflate with four types of commonly
employed amine nucleophiles: anilines, amides, primary aliphatic amines,
and secondary aliphatic amines. By analyzing trends in catalyst reactivity
across different reaction temperatures, base strengths, and base concentrations,
we have developed a set of general recommendations for Pd-catalyzed
cross-coupling reactions involving organic bases. The optimization
algorithm determined that the catalyst supported by the dialkyltriarylmonophosphine
ligand AlPhos was the most active in the coupling of each amine nucleophile.
Furthermore, our automated optimization revealed that the phosphazene
base BTTP can be used to facilitate the coupling of secondary alkylamines
and aryl triflates.