Control of Regio‐ and Enantioselectivity in the Asymmetric Organocatalytic Addition of Acetone to 4‐(Trifluoromethyl)pyrimidin‐2(1H)‐ones

Abstract

The reactions of variously substituted 4‐(trifluoromethyl)pyrimidin‐2(1H)‐ones with acetone in the presence of L‐proline or chiral secondary amine organocatalysts were studied. As demonstrated, 4‐(trifluoromethyl)pyrimidin‐2(1H)‐ones unsubstituted at the 6‐position of the heterocyclic ring react with acetone at the endocyclic C=N or C=C bond depending on whether thermodynamic or kinetic control is operative in the addition reaction and also depending on the catalyst used. Racemic kinetically preferred regioisomers, 6‐(2‐oxopropyl)‐4‐(trifluoromethyl)‐3,4‐dihydropyrimidin‐2(1H)‐ones, were found to undergo intermolecular organocatalytic rearrangement into enantioenriched thermodynamically stable products, 4‐(2‐oxopropyl)‐4‐(trifluoromethyl)‐3,4‐dihydropyrimidin‐2(1H)‐ones, with enantiomeric ratios up to 83:17.

Synthesis of Trifluoromethylated Analogues of 4,5‐Dihydroorotic Acid

“…We found that a catalytic amount of organic base (triethylamine) was necessary for the reaction to take place. The formation of the 3,6-adduct was initially confirmed by 19 F and 13 C NMR spectroscopy. The isolated yield after filtration and washing with hexane was 72 % (Table 1, entry 1).…”

“…After as little as 3-5 min of stirring the reaction mixture at room temperature, the sparingly soluble starting pyrimidone (i.e., 1a) had completely dissolved, and this was followed by the rapid precipitation of 3-methyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-carbonitrile (4a) as a white bulky solid. [19] The use of acetone cyanohydrin and HCN instead of TMSCN in toluene did not result in any noticeable formation of 4a (Table 1, entries 3 and 4). We also found that a toluene/hexane mixture (2:1) gave a higher yield (93 %) of 4a (Table 1, entry 2).…”

“…19 F NMR analysis of the reaction mixture always indicated the presence of the starting material (up to 20 %), along with regioisomeric product 6 having a chemical shift of δ = -81.90 ppm (in toluene). 19 F NMR analysis of the reaction mixture always indicated the presence of the starting material (up to 20 %), along with regioisomeric product 6 having a chemical shift of δ = -81.90 ppm (in toluene).…”

“…[15] Compounds of this type have found widespread application as starting materials in the synthesis of new fluorinated cyclic amine derivatives [15c,16] and 3,4-dihydroquinazolin-2-ones (including asymmetric versions). [19] We demonstrated that compounds 1 reversibly react with acetone at the endocyclic C=N or C=C bond, depending on the catalyst used, and also on whether thermodynamic or kinetic control is operative (Scheme 1). [18] They have been much less studied until now, despite their synthetic availability [15d-15f] and the fact that they are original fluorinated derivatives of pyrimidin-2-one, a key heterocyclic component of nucleic acids.…”

“…, copies of 1 H and 13 C spectra of all new compounds, 19 F NMR spectra with quinine additive as a chiral solvating agent, detailed X-ray structure analysis of 4g, 7h, 8 and 10a.…”