Chan-Evans-Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones.

The Chan-Evans-Lam reaction of 1-unsubstituted 4-fluoroalkylpyrimidin-2(1Н)-ones with arylboronic acids is reported as a facile synthetic route to hitherto unavailable N1-(het)aryl and N1-alkenyl derivatives of the corresponding pyrimidines. An efficient C-N bond-forming process is also observed by using boronic acid pinacol esters as coupling partners in the presence of Cu(II) acetate and boric acid. The 4-fluoroalkyl group on the pyrimidine ring significantly assists in the formation of the target N1-substituted products, in contrast to the 4-methyl and 4-unsubstituted substrates which do not undergo N1-arylation under similar reaction conditions.

Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones.

Background: Due to the high reactivity towards various C-nucleophiles, trifluoromethylketimines are known to be useful reagents for the synthesis of α-trifluoromethylated amine derivatives. However, decarboxylative reactions with malonic acid and its mono(thio)esters have been poorly investigated so far despite the potential to become a convenient route to ß-trifluoromethyl-ß-amino acid derivatives and to their partially saturated heterocyclic analogues. Results: In this paper we show that 4-trifluoromethylpyrimidin-2(1H)-ones, unique heterocyclic ketimines, react with malonic acid under organic base catalysis to regioselectively provide either Michael- or Mannich-type decarboxylative addition products depending on solvent polarity. Malonic mono(thio)esters give exclusively Michael-type products. The two regioisomeric products can be converted into saturated (2-oxohexahydropyrimidin-4-yl)acetic acid derivatives by mild hydrogenation of the endocyclic C=C double bond in the presence of Pd/C as catalyst. The cis-stereoisomers selectively formed upon reduction of the Michael-type products were structurally determined by X-ray diffraction. As a result of this study, a number of novel acetic acid derivatives containing trifluoromethylated, partially or fully saturated 2-oxopyrimidine cores were prepared and characterized as promising building blocks. Conclusions: Regio- and stereoselective protocols have been developed for the synthesis of novel isomeric 4(6)-trifluoromethylated 1,2,3,4-tetrahydro- and perhydro-(2-oxopyrimidin-4-yl)acetic acid derivatives.