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

Sergii V Melnykov,Volodymyr A Sukach,Svitlana V Shishkina,Andrii S Pataman,Mykhailo V Vovk,Yurii V Dmytriv

doi:10.3762/bjoc.13.259

Sergii V Melnykov, Volodymyr A Sukach + Show 4 more

Open Access

https://doi.org/10.3762/bjoc.13.259

Copy DOI

Abstract

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(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.

Highlights

Organofluorine compounds play an essential role in the development of new materials for solar cells [1,2,3], radiotracers for PET imaging [4], agrochemicals [5,6], sensitive chemical probes for 19F nuclear magnetic resonance investigation of biological experiments [7,8], and are most widely used in the modern drug discovery and development area [9,10]
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
It should be noted that the presence of a strong electron-withdrawing trifluoromethyl group is responsible for the sufficient reactivity of the electrophilic ketimine function with various carbon nucleophiles in these reactions

Summary

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. 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

Introduction

Results and Discussion

Conclusion