Regioselective Thiolation of 2,4-Dihalopyrimidines

Keywords

pyrimidines - regioselectivity - palladium catalysis - thiol

Significance

Substituted pyrimidines are common scaffolds in nature, pharmaceuticals, agrochemicals, and organic materials. 2,4-Dichloropyrimidines offer an inexpensive and abundant starting point towards substituted pyrimidines. Moreover, most reliably undergo C4-selective S_NAr and cross-coupling reactions. However, there are many instances where selective C2-functionalization is desired. The use of removable bulky C5-substituents, like TMS, can bias a reaction towards C2-selectivity; however, this strategy introduces additional synthetic transformations. A catalyst-controlled regioselective C2-functionalization would represent a significant advancement in the synthesis of 2,4-disubstituted pyrimidines. In this report, the Neufeldt group describes a palladium-catalyzed thiolation of 2,4-dihalopyrimidines with remarkable C2-selectivity.

Comment

Traditionally, strong nucleophiles, like thiols, undergo uncatalyzed S_NAr reactions with 2,4-dichloropyrimidines at C4. Inspired by recent evidence that bulky NHC ligands can invert conventional site-selectivity in Pd-catalyzed cross coupling, the authors evaluated several different related catalysts before identifying one that gave good yield and excellent selectivity for the C2-coupled product. Many other substrates were disclosed with a range of yield and selectivity. Good functional group tolerance was demonstrated, including an aryl bromide despite the Pd-catalysis conditions. There are some steric and electronic limitations to C2-selectivity. Mechanistic investigations remain ongoing as both BDEs and LUMO coefficients suggests C4-functionalization should be favorable. This indicates a nontraditional mechanism for C–Cl cleavage may be operable.