Palladium Catalyst-Controlled Regiodivergent C–H Arylation of Thiazoles

We report Pd-catalyzed direct C–H arylation of
thiazole,
where the regioselective outcome is controlled by the appropriate
selection of a base and a ligand. Employing Pd/PPh3/NaOtBu in the reaction with a broad range of
aryl halides affords access to C2-arylated thiazoles with high yields.
Conversely, a catalytic system comprising a Pd catalyst, Bphen (bathophenanthroline),
and K3PO4 provides various C5-arylated thiazoles.
These catalytic conditions enable sequential arylation at positions
C5, C2, and C4 of thiazole, providing a streamlined approach to the
synthesis of 2,4,5-triarylated thiazole scaffolds. Our computational
models for C–H bond cleavage exhibit subtle differences from
the well-established carbonate-assisted nCMD mechanism. We found that
the interplay of stabilizing and destabilizing interactions between
the Pd catalyst and the reacting partners, namely, thiazole and the
aryl group, in the critical transition states directs the reaction
toward C2 arylation. Furthermore, our study reveals that the C2 and
C5 arylation of thiazole may proceed through different pathways involving
either monometallic or bimetallic complexes. The pathway involving
the bimetallic complex, which is inaccessible for C2 arylation, represents
the lowest-energy route for the C5 arylation of thiazole.