C2-Selective Palladium-Catalyzed C–S Cross-Coupling of 2,4-Dihalopyrimidines

Under most conditions, 2,4-dihalopyrimidines undergo
substitution
reactions at C4. Here we report that Pd(II) precatalysts supported
by bulky N-heterocyclic carbene ligands uniquely
effect C2-selective cross-coupling of 2,4-dichloropyrimidine with
thiols. The regioselectivity of this reaction stands in stark contrast
to ∼1500 previously reported Pd-catalyzed cross-couplings that
favor C4 in the absence of other substituents on the pyrimidine ring.
Selectivity in the catalytic system reported herein is extremely sensitive
to the structure of the Pd(II) precatalyst, largely due to competing
C4-selective nucleophilic aromatic substitution. C2-selectivity is
high with most 1° thiols and thiophenols, and a range of substituted
dichloropyrimidines can be used. The atypical selectivity of this
transformation may facilitate diversity-oriented synthesis, as demonstrated
for derivatives of an antiviral agent. Under these conditions, C2Cl
cleavage may not take place through a typical oxidative addition pathway.