Synthesis of Trifluoromethylated Analogues of 4,5‐Dihydroorotic Acid

Abstract

4‐(Trifluoromethyl)pyrimidin‐2(1H)‐ones react with trimethylsilyl cyanide in the presence of a tertiary amine catalyst to give Michael‐like 1,4‐conjugate hydrocyanation adducts exclusively at the 3,6‐positions. The resulting 2‐oxo‐6‐(trifluoromethyl)‐1,2,3,4‐tetrahydropyrimidine‐4‐carbonitriles have been used to synthesize new trifluoromethylated 4,5‐dihydroorotic acid analogues and their esters in racemic as well as enantiopure forms by a chiral auxiliary approach. The orthogonal intramolecular C–F···C=O interaction between the fluorine atom of the CF3 group and the carbon atom of the ester group observed in the crystal state may stabilize the sterically unfavourable conformation of the methyl 2‐oxo‐6‐(trifluoromethyl)hexahydropyrimidine‐4‐carboxylate molecule with axially oriented substituents.

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

“…These compounds are unique heterocyclic conjugated trifluoromethylketimines with two competing electrophilic centers which can enable either Michael- or Mannich-type nucleophilic additions. As found in our previous studies, organocatalytic addition of acetone [ 37 ], nitromethane [ 38 ] and trimethylsilyl cyanide [ 39 ] in most cases can be performed regioselectively after optimization of the reaction conditions (temperature, solvent, time and catalyst nature). In general, under kinetic reaction control, the Michael-type 1,4-adducts are the predominant products while under thermodynamic control, the regioisomeric Mannich-type 1,2-adducts are more likely to be formed.…”

“…In general, under kinetic reaction control, the Michael-type 1,4-adducts are the predominant products while under thermodynamic control, the regioisomeric Mannich-type 1,2-adducts are more likely to be formed. These observations allowed us to develop selective methods for the synthesis of functionalized partially saturated 4-trifluoromethyl-substituted pyrimidin-2(1 H )-ones, in particular, 4,5-dihydroorotic acid analogues 3 [ 39 ]. Here we report the preparation of acid 3 homologues (with a methylene linker between the carboxylic group and the pyrimidine ring) and their isomers resulting from two alternative regioselective pathways for the decarboxylative nucleophilic addition of malonic acid and its mono(thio)esters.…”

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

“…[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.…”

“…[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.…”

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].…”