5-Iodo-2-methylthio-6-methyl(trifluoromethyl)pyrimidin-4(3 <i>H</i> )-ones vs Their 4-Methoxylated Derivatives in Suzuki-Miyaura Cross-Coupling Reaction for the Synthesis of Bioactive 5-Arylpyrimidines

The reactivities were compared for 5-iodo-2-methylthio-6-methyl(trifluoromethyl)pyrimidin-4(3<i>H</i>)-ones and their 4-methoxylated derivatives in the Suzuki-Miyaura cross-coupling reactions. The iodopyrimidinones were shown to be poorly involved in these reactions, since the target 5-arylpyrimidinones (5 examples) were obtained in low yield (<35%). For the first time, it has been established that the presence of the acidic NH proton of the lactam fragment is the reason for the low reactivity of pyrimidin-4-ones; with the involvement of this fragment, the formation of salts and palladium complexes occurs, leading to the removal of substrates and the Pd catalyst from the catalytic cycle. In contrast, 5-iodo-4-methoxy-2-methylthio-6-methyl(trifluoromethyl)pyrimidines readily undergo cross-coupling to form 5-arylpyrimidines (11 examples). The best yields were achieved by using the Pd₂(dba)₃/XPhos catalytic system. Demethylation with 33 wt % HBr allowed 5-arylpyrimidin-4-ones to be obtained in overall yield higher than those with direct cross-coupling. Using biological testing, it was shown that introducing an aryl substituent at the C5 position of the pyrimidines promotes antimicrobial and antitumor activity.