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

Beilstein J. Org. Chem. 2017, 13, 2617-2625

DOI: 10.3762/bjoc.13.259

Melnykov S. V.; Pataman A. S.; Dmytriv Y. V.; Shishkina S. V.; Vovk M. V.; Sukach V. A.

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 β-trifluoromethyl-β-amino acid derivatives and to their partially saturated heterocyclic analogues.

Results: In this paper we show that 4-trifluoromethylpyrimidin-2(1 H)-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.


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