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

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.

Hydroaminoalkyl Functionalization of Pyrimidin‐2(1H)‐ones by Visible Light Organophotocatalysis: A Radical Approach to Biginelli‐Type Dihydropyrimidines

“…In order to further broaden our reaction scope, we also investigated the photocatalytic aminoalkylation of various substituted pyrimidin-2(1H)-one substrates (Scheme 5). [27,56,57] Using the most reactive trifluoroborate 1 a, the reaction was shown to have good substituent tolerance at the N-1 position of the starting pyrimidines 2 b-t (substituent R 1 ): N-benzyl, allyl, phenyl, vinyl, styryl, and benzoylmethyl; all of these compounds provided the corresponding products 3 i-l, n, o in uniformly good 61-73% isolated yields (except for the N-unsubstituted product 3 m in a moderate 37% yield). Interestingly, the trans-styryl substrate 2 n gave rise to a mixture of cis and trans isomers of 3 n (isolated as individual pure compounds).…”

“…[16][17][18][19][20][21][22] This method offers interesting molecular diversity by varying the nature of the stabilized carbanions (i. e., alkynide, enolate, nitronate, or cyanide). [23][24][25][26][27][28] In this case, however, regioselectivity is difficult to control due to various factors (i. e. substrate, reagent, reaction con-ditions) and the reversible nature of nucleophilic addition. [25][26][27][28] Notably, the 1,4-conjugate addition route often proves advantageous for the direct preparation of 3(N)-substituted 3,4-dihydropyrimidones in which the second nitrogen in the 1 N position is unoccupied.…”

“…A second approach (Scheme 1b) is based on the addition of C‐nucleophile onto the C=C−C=N endocyclic system of the pyrimidin‐2(1 H )‐one scaffold, either at the C4‐position (direct addition to the C=N bond) or at the C6‐position (1,4‐conjugate addition) [16–22] . This method offers interesting molecular diversity by varying the nature of the stabilized carbanions (i. e., alkynide, enolate, nitronate, or cyanide) [23–28] . In this case, however, regioselectivity is difficult to control due to various factors (i. e. substrate, reagent, reaction conditions) and the reversible nature of nucleophilic addition [25–28] .…”

Substituted Malonic Acid Half Oxyesters (SMAHOs): Green Nucleophiles for Organic Synthesis

“…The reaction between monophenyl malonic acid and coumarin‐3‐carboxylic acid using N ‐methylmorpholine as a catalyst led to the desired product in a 98 % yield after a double decarboxylation. Another relevant example was reported during a study of the addition of malonic acid derivatives to 4‐trifluoromethylpyrimidin‐2(1H)‐ones [110] . The use of a stoichiometric amount of triethylamine led to the decarboxylated 1,6‐addition product but the reaction requires a large excess of MAHO.…”

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

“…Our interest in the development of N-arylation methods resonated with recent studies focused on the addition of various C-nucleophilic reagents to 4-trifluoromethylpyrimidin-2(1H)ones I, heterocyclic analogues of activated ketimines (Figure 1), thus offering potential applications in the design of new heterocyclic chemotypes [21][22][23][24][25]. Compounds I are precursors of trifluoromethyl-substituted dihydropyrimidine derivatives which appear as original and potent scaffolds in medicinal chemistry, given the great importance of fluorinated groups in drug discovery [26][27][28][29].…”